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PMC7985240_01 | Male | 31 | A 31-year-old male patient presented to the emergency department (ED) with a 6-week history of left-sided lateral neck pain, accompanied by a minor localized swelling. He denied throat aches, dyspnea, fever, weight loss, or other constitutional symptoms.
Three weeks after the appearance of the neck pain, the patient contracted a mild coronavirus disease 2019 (COVID-19), manifesting with anosmia and ageusia. The latter symptoms improved within several days, but the neck pain persisted throughout the whole period. The patient's past medical history was otherwise unremarkable.
On physical examination, prominent tenderness was noted over the left common carotid (LCC) artery, with subtle swelling. Upper extremity pulses were symmetrical. While blood counts, serum creatinine, and erythrocyte sedimentation rate were within normal limits (WNLs), C-reactive protein (CRP) was mildly elevated (Table 1). Doppler ultrasound (US) displayed evident LCC wall thickening, without luminal stenosis (Figure 1(a)). Head and neck computed tomography angiography (CTA) scan, however, showed no vasculitic lesions (Figure 1(b)). In light of the laboratory and CTA results, the patient was discharged, with the diagnosis of vasculitis being erroneously deferred.
A repeat US performed two days later, per the radiologist's insistence, confirmed significant LCC wall thickening, thus, the patient was again referred to the ED for further evaluation. This time, he was hospitalized, and a head and neck magnetic resonance imaging (MRI) scan was completed, showing prominent LCC wall thickening, compatible with vasculitis (Figure 1(c)). Antinuclear antibodies (ANAs), anti-neutrophil cytoplasmic antibodies (ANCAs), and immunoglobulin levels, including immunoglobulin G4 (IgG4), were all unremarkable (Table 1). Serologies for syphilis and human immunodeficiency virus (HIV) were negative. In light of these findings, positron emission tomography (PET)-CT was carried out. While no active vasculitis was observed, hypermetabolic mediastinal and hilar lymphadenopathy was seen (Figure 1(d)). As such, bronchoscopy with endobronchial US transbronchial needle aspiration (EBUS-TBNA) was performed, and mediastinal lymph nodes (LNs) were biopsied. Pathology results demonstrated noncaseating granulomas (Figure 2), with negative acid fast and silver stains. Immunohistochemical staining for IgG4 was also negative. Further evaluations, including electrocardiography, transthoracic echocardiography, ophthalmologic check-up, pulmonary function tests, urinalysis, and urinary calcium levels, were all unremarkable. Angiotensin-converting enzyme (ACE) levels in blood were elevated, however. The typical radiologic and pathological features led to the diagnosis of sarcoidosis.
Prednisone, 40 mg, was started, leading to immediate resolution of carotidynia. Repeat neck US, within 6 weeks of therapy, revealed improvement of the sonographic findings (Figure 3). Likewise, a chest CT scan, performed within 4 months, showed diminution of the known hilar and mediastinal lymphadenopathy. | null | Not supported with pagination yet | null |
PMC8348862_01 | Female | 30 | A 30-year-old, human immunodeficiency (HIV) negative woman with no past medical history presented to the obstetrics clinic in 2014 for an antenatal evaluation. At this time, she was found to have a positive tuberculin skin test and was referred to the tuberculosis clinic for possible treatment. Further workup included a chest radiograph showing right upper and lower zone nodular lung disease necessitating sputum collection for microbial isolation and evaluation (Fig. 1). Induced sputum cultures returned positive for MAC. Given her pregnancy, treatment for latent tuberculosis was deferred and she was subsequently referred to her primary care for follow-up with the instruction that pulmonary follow-up would be necessary post-partum for continued follow up of her MAC infection.
Her postnatal follow-up was erratic and over subsequent years, she received multiple courses of macrolides for sinus infections, broad spectrum antibiotic treatment for "pneumonia" and at times guideline-based therapy (GBT) for MAC with Rifampin, Ethambutol and Clarithromycin through various clinics and specialists. She remained culture positive for MAC during these clinical encounters and confirmed that she was not adherent to her treatment regimen during this time.
In December 2019, she was hospitalized with fever and cough productive of copious purulent sputum. She appeared malnourished and dyspneic. Vital signs revealed tachycardia, BP 91/45 mm Hg, RR 32/min with 94% oxygen saturation at rest. Lung exam demonstrated decreased breath sounds with transmitted bronchial breathing on the right side. Chest X-ray and CT Scan showed destruction of right lung parenchyma, volume loss, right sided air-fluid level and BPF. A large cavity was also seen in the left lung (Fig. 2A,B,2C).
Pleural fluid analysis revealed WBC count at 1.05 x 106/microliters with 100% lymphocytes and LDH at 1 x 105 U/L, glucose 37 mg/dl and protein 2.8 g/dl. Multiple sputum and pleural fluid cultures showed growth of Pseudomonas aeruginosa, macrolide resistance MAC with varying minimal inhibitory concentrations (MIC) to Amikacin. Serologic tests for expanded ANA were negative and Immunoglobulins were within normal range. A1-AT levels were normal. Repeat HIV testing and CFTR screen was negative.
The patient completed a six-week course of parenteral anti-pseudomonas antibiotics and subsequently continued on parenteral Amikacin along with Rifampin, Ethambutol, Clofazimine and Linezolid as long term treatment for macrolide resistant MAC. Chest tube drainage was also concurrently initiated.
CT surgery was planned for long-term surgical drainage with Eloesser flap, but this had to be deferred initially due to patient's poor clinical condition at that time and later due to her reluctance to have this procedure. Meantime, chest tube drainage was continued at home with regular interventional radiology review. On-going multi-drug antibiotic treatment regimen was subsequently supplemented with Amikacin liposomal inhaled solution (ALIS). | alis, amikacin liposomal inhaled solution, bpf, broncho-pleural fistula, broncho pleural fistula, gbt, guideline-based therapy, mac-ld, mycobacterium avium complex-lung disease, mac-pleural disease, mic, minimum inhibitory concentration, macrolide resistance mac, mycobacterium avium complex-lung disease, ntm, non-tuberculous mycobacteria, ob, obstetrics, tb, tuberculosis | Not supported with pagination yet | null |
PMC6125761_01 | Female | 45 | The patient was a 45-year-old woman, divorced, without known pathological antecedents and without any usual medication. She consumed about 24-48 g of alcohol per day, for several years and without any recent increase. She denied previous or current use of tobacco or recreational drugs and had never been subjected to blood transfusions. Her current sexual partner had active HCV and HIV infection, both without ongoing treatment.
The patient presented to the emergency department with an acute epigastric pain and food vomiting. She denied other changes in gastrointestinal transit, bilirubinuria or light colored stools, pruritus, fever, anorexia, and asthenia. There was no history consistent with consumption of any other hepatotoxic agent. Upon physical examination she had jaundice of the skin and mucous membranes and hepatomegaly with regular borders on the abdominal palpation. The rest of the physical examination was normal.
Analytically the patient presented mild anemia (hemoglobin 11.5 g/dL, macrocytic and normochromic), platelets 135000/uL, without changes in the leukocyte series; hyperbilirubinemia at the expense of direct bilirubin (total bilirubin (TB) 7.46 mg/dL - 7 times above the upper limit of normal - and direct bilirubin (DB) 6.81 mg/dL); elevation of hepatic cytolysis enzymes (aspartate aminotransferase (AST) 862 U/L - 32 times above the upper limit of normal - and glutamate-pyruvate transaminase (ALT) 317 U/L - 9 times above the upper limit of normal); normal albumin (3.3 g/dL); INR of 1.00; antibodies for HIV-1 positive; anti-HBc and HBs negative; anti-HCV negative; anti-HAV IgM negative and IgG positive. Abdominal ultrasound (Fig. 1) showed hepatomegaly (17.5 cm in diameter at the mid-clavicular line), with the parenchyma being globally homogenous and with increased echogenicity, with no other changes of relief. She was hospitalized for acute hepatitis of unknown cause.
During the first 4 days of hospitalization the patient presented progressive aggravation of hepatic cytolysis (AST 4042 U / L and ALT 1050 U / L, always maintaining a AST approximately 3 times greater than ALT) and, until the 13th day of hospitalization, worsening of hepatic cholestasis parameters (maximum values of TB 19.13 mg / dL and DB 17.6 mg / dL). Transient changes in liver function were observed between the 4th and 9th day of hospitalization, with hypoalbuminemia most abnormal value - 2.6 g / dL) and changes in coagulation parameters (most abnormal value of INR - 1.69). The patient remained asymptomatic throughout the hospitalization and objectively only presented worsening jaundice of the skin and mucous membranes. Of the remaining analytical study carried out during hospitalization: CD4 + T lymphocytes 388 cells / mL and HIV RNA polymerase chain reaction (PCR) 54,652 copies / mL. On the 10th day of hospitalization, for diagnostic clarification, a percutaneous liver biopsy was performed and blood was collected for HCV PCR evaluation, in spite of anti-HCV negative. Due to the clinical and analytical improvement (AST 103 U / L, ALT 52 U / L, TB 11.78 mg / dL, DB 11.16 mg / dL, albumin 3.8 g / dL and INR 0.92), patient was discharged on the 17th day of hospitalization.
At the re-evaluation internal medicine appointment, about one week after discharge, the HCV RNA PCR collected during hospitalization was already available and was> 10,000,000 IU/mL. The hepatic biopsy revealed irregular expansion of portal spaces by moderate inflammatory lymphocytic infiltrate with formation of lymphoid aggregates and rare associated neutrophils, with no evidence of plasma cells; proliferated bile ducts, but apparently not involved by the inflammatory process; slight portal fibrosis, with thin septa surrounding individual hepatocytes; interface necrosis of moderate intensity; intralobular necro-inflammatory foci of mild to moderate intensity; balloonized hepatocytes with reticulation and numerous Mallory-denk hyaline bodies and intense mixed steatosis with xanthelasmic hepatocytes; cholestasis in sinusoidal and portals Kupffer cells, minimal in hepatocytes; no epithelioid granulomas were identified; and absence of signs of malignancy. These findings were compatible with active toxic / alcoholic steatohepatitis. New serum samples for anti-HCV was obtained and demonstrated seroconversion to positive. In view of the presented, the diagnosis of acute HCV hepatitis with risk factor of heterosexual transmission was established. The virus genotype, subsequently determined, was the 3a, the same as that of his sexual partner. The patient started antiretroviral therapy for HIV infection and presented spontaneous clearance of HCV, with undetectable HCV RNA PCR about 11 weeks after discharge from hospital. | acute infection, hepatitis c, heterosexual transmission | Not supported with pagination yet | null |
PMC4913996_01 | Female | 32 | Our case report describes a 32-year-old woman diagnosed with lymphangioleiomyomatosis who was placed on an organ transplant waiting list in February 2014, due to rapidly progressing respiratory insufficiency. Her history was significant for multiple lymphangioleiomyomas in the retroperitonium along with repeated spontaneous pneumothoraces that required drainage. Transesophageal echocardiography (TEE) was performed during preoperative assessment and the patient was found to have a low ejection fraction. In March 2014, the patient was intubated and ventilated due to respiratory failure. She went on to develop bronchopneumonia caused by multiresistant Pseudomonas aeruginosa, followed by sepsis and disseminated intravascular coagulopathy with severe bleeding from the nose, hypopharynx, and lower respiratory tract. At this point, mechanical ventilation was no longer sufficient to sustain oxygenation and venovenous ECMO (VV-ECMO) was commenced, as a bridge to urgent lung transplantation (Figure 1). Six days later a donor was found and sequential bilateral lung transplant with a clamshell incision was performed with the support of the arteriovenous ECMO (AV-ECMO). The cannulae from the VV-ECMO were left in place and an arterial cannula was inserted centrally into the ascending aorta. Cannulation of the vena jugularis interna dextra was terminated. Due to anatomic disproportion, the donor lungs were partially resected at the right middle lobe and lingula.
Perioperative TEE showed severely hypokinetic right and left ventricles along with a large thrombus in the left atrium near the pulmonary veins (Figure 2). The procedure was complicated by diffuse bleeding due to coagulopathy present in the septic state, which resulted in a 10 L blood loss. Postoperatively, the AV-ECMO was left in place due to the poor myocardial function; therefore, the sternotomy was not closed to allow the arterial cannula to remain in the aorta. During admission to the intensive care unit, severe pulmonary edema was noted with the continuous leakage of edematous fluid from the endotracheal tube. Tidal volumes were 30-40 mL with a peak pressure of 30 cm H2O and a positive end-expiratory pressure of 10 cm H2O. Cardiovascular support with high-dose norepinephrine (>1 microg/kg/min) was in place. Arterial blood gas results showed good oxygenation due to the support of AV-ECMO. Immunosuppression therapy was commenced with tacrolimus, mycophenolate mofetil, and corticosteroids.
Anticoagulation with heparin was initiated with a target of activated coagulation time (ACT) 150-200 seconds. Six hours later, a TEE was performed and thrombi were noted in both the left and right atria. Due to the high risk of embolism, we were faced with making a crucial decision: to start thrombolysis, which is generally contraindicated in immediate postoperative period, or not. We evaluated that the risk of massive embolism was superior to the risk of bleeding when the sternotomy was not closed. The primary thrombolysis was undertaken with 25 mg alteplase given over 2 hours into the pulmonary artery as the rescue procedure declared in medical documentation. The left atrial thrombus was quickly reduced, after which a second identical dose of alteplase was given. Pulmonary edema began to resolve after the completion of thrombolysis. A further TEE showed no thrombi in the left ventricle or pulmonary veins, although small thrombi remained in the right and left atria. The following day a full dose of thrombolytic agent was given - 50 mg alteplase over 2 hours intravenously - after which no further thrombi could be detected on TEE (Figure 3). Lung function continued to improve along with radiological findings within 1 week following the thrombolysis (Figure 4).
In the following days, the patient developed acute kidney injury for which she was placed on continuous renal replacement therapy. Gradually, her heart and lung function improved and on postoperative day 8, ECMO support was stopped. The sternotomy was closed after resolution of the P. aeruginosa infection. Weaning and rehabilitation were complicated by poor muscle strength. Due to worsening lung function, a transbronchial biopsy was performed which confirmed tissue rejection A 1-2 (histologic grading of lung allograft rejection- the Classification of Pulmonary Allograft Rejection: Lung Rejection Study Group) and was successfully treated with pulses of steroids. The following days were significant for the loss of consciousness that was thought to be caused by posterior reversible encephalopathy syndrome. An electroencephalograph showed an epileptic status, and antiepileptic medications were prescribed. Three months postoperatively, stenosis of the right main bronchus was diagnosed bronchoscopically, and a biodegradable stent ELLA (ELLA-CS s.r.o. Milady Horakove, Hradec Kralove, Czech Republic) was implanted. Another setback of pulmogenic sepsis and multiorgan failure, with a need for continuous renal replacement therapy occurred. Six months postoperatively, the patient was extubated and began to actively rehabilitate. Seven months postoperatively, the patient was discharged to home. Currently, she enjoys a good quality of life without any signs of stenosis of the upper respiratory tract and with stationary spirometric values (last forced expiratory volume in 1 second [FEV1] 38%) (Figure 5). | double-lung transplantation, extracorporeal membrane oxygenation, general anesthesia, lymphangioleiomyomatosis, thrombolysis | Not supported with pagination yet | null |
PMC10424439_01 | Male | 20 | A 20-year-old, non-Hispanic Black, cis-gender male with a history of iron deficiency anemia presented with several weeks of intermittent headache and mild fever. While the fever resolved, the headache became constant, and over the following month, he developed a worsened peripheral vision with mild photophobia, left upper extremity weakness, expressive aphasia, and difficulty in walking due to the loss of balance. Since the age of 15, he had experienced recurrent, painful oral and scrotal ulcers that would last for several days at a time. He was sexually active but had not been tested for sexually transmitted infections.
Vital signs were unremarkable. On physical examination, he had left lower facial droop, weakness of his left wrist and fingers, and hyperreflexia of the left lower extremity. A scrotal ulcer was present. On ophthalmologic exam, he had decreased vision in the left homonymous inferior quadrantanopia, bilateral posterior uveitis, chorioretinal scarring, and a single white retinal lesion suspicious for infectious or metastatic disease. On admission, he was found to have CD4 lymphocytopenia (163,000 cells/mcL).
Computerized tomography (CT) of the brain was obtained which showed a heterogenous region with surrounding vasogenic edema centered in the right thalamus and gangliocapsular region (involving the entire right basal ganglia, including the putamen, globus pallidus, and caudate, as well as the posterior aspects of the internal and external capsule). There was a 3-mm leftward midline shift; a mass effect on the Foramen of Monro, right lateral ventricle, and third ventricle; and dilation of the bilateral lateral ventricles. The CT scan also demonstrated a partial effacement of the basal cisterns.
Given the concern for an infectious or neoplastic process or central venous infarct sequelae, contrast-enhanced magnetic resonance imaging (MRI) of the brain was obtained. On MRI, abnormalities were also found involving the right midbrain, with further extension into the pons with mixed regions of T1 isointense and hypointense dense regions and with predominantly T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense lesions. Additionally, there were multiple ring-enhancing lesions in the right thalamic region (with the largest measurement of 9 mm) and midbrain (with the largest measurement of 7 mm), with a surrounding T2 hyperintense region attributable to edema (Figure 1). At this point, additional differential diagnoses were considered, including neurocysticercosis, autoimmune encephalitis, vasculitis, and multiple sclerosis among others.
CT angiography (CTA) of the head and neck with and without contrast showed no large branch arterial occlusion, high-grade stenosis, arteriovenous malformation, or aneurysm.
Due to concerns for autoimmune etiologies, edema, and mass effects, the patient was started on dexamethasone, while the workup was ongoing. Given concerns for an infectious process (brain mass suspicious for brain abscess, in a sexually active person with CD4 lymphopenia), he was also started on broad-spectrum antibiotics.
Right-sided stereotactic needle biopsy with stealth navigation was performed, and a representative brain tissue sample showed only polymorphonuclear cells on the frozen specimen; therefore, no further neurosurgical intervention was performed. The brain tissue sample histopathology showed parenchymal and perivascular mixed inflammation and reactive gliosis with no evidence of malignancy or inflammation. Infectious studies of the brain tissue biopsy, including cultures (bacterial, fungal, and mycobacterial) and stains (Grocott's methenamine silver, periodic acid:Schiff, and gram stains), were all negative. Most parenchymal and vascular lymphocytes stained positive for CD3, with a subset of these positive for CD8 as well. Immunohistochemistry of the brain tissue also revealed rare CD20+ perivascular cells, numerous CD68+ histiocytes (some of which are microglia), and a Ki67 nuclear proliferation index of 2-3% (Figure 2).
Given the concern for malignancy, a CT scan of the chest, abdomen, and pelvis was completed, but the results were completely unremarkable for any disease process. Other infectious workups included blood cultures and fungal (histoplasmosis and cryptococcus), parasitic (toxoplasmosis and echinococcosis), bacterial (syphilis and tuberculosis), and viral (human immunodeficiency virus, cytomegalovirus, herpes simplex virus, hepatitis B, and hepatitis C) studies, which were all negative.
Further studies revealed that he had mildly elevated antinucleotide antibody titers (1:40:speckled), an erythrocyte sedimentation rate (ESR) of 69 mm/hr (normal range, 0-10), and C-reactive protein (CRP) of 1.3 mg/dl (normal range: <1). He had an elevated total serum protein of 8.3 gm/dL (normal range, 6.3-8.2), a normal serum albumin of 4 gm/dL, an elevated serum globulin of 4.3 gm/dl (normal range, 2-3.5), elevated immunoglobulin (Ig) G of 1830 mg/dl (normal range, 700-1600), and IgA of 534 mg/dl (normal range: 70-400). IgM was within normal limits.
An MRI of the brain after 5 days of high-dose methylprednisolone (1 g daily) and antibiotics showed an improvement in ring-enhancing lesions of the right thalamus, midbrain, and pons with a less mass effect. His neurological symptoms also improved significantly after several days of treatment. Given the negative infectious workup, antibiotics were discontinued after day 7 of admission. Neuro-Behcet's syndrome was diagnosed, given the patient's history, workup, clinical, and radiographic improvement after steroids and absence of alternate diagnostic etiologies. The pathergy test was negative. Genetic testing for HLA-B51 was collected but not resulted. The patient responded well to high-dose steroids and continued on an oral prednisone taper and azathioprine therapy after discharge. A 2-year follow-up brain MRI later showed no new or enhancing lesions (Figure 3) although the patient continued to have minimal residual deficits in mobility and vision. | brain stem, genital ulcer, immunoglobulin, neuro-behçet's, uveitis | Not supported with pagination yet | null |
PMC7534398_01 | Male | 4 | A 4-year-old boy was admitted with fever for more than 30 days, low back pain, peripheral and abdominal adenomegaly, hepatomegaly and splenomegaly. The abdominal ultrasound showed disseminated nodules in the liver and spleen. The chest X-ray showed a lytic lesion in the 11th right costal arch and a slight upper left pulmonary infiltrate. Tuberculin skin test (TST) with PPD Rt-23 was > 10 mm. He was not vaccinated with BCG. Anti-HIV serology was negative.
A cervical lymph node biopsy showed nonspecific inflammatory findings and granulomatous hepatitis was found in liver biopsy. Computed tomography (CT) and magnetic resonance imaging showed osteolytic lesions with partial destruction of C6 and C7 vertebral bodies and a paravertebral abscess.
Afterwards, he presented limited cervical movement, without neurological symptoms. A neck brace was prescribed and treatment for TB with rifampicin, isoniazid and pyrazinamide (RHZ) was started. During his hospitalization, it was found out that the patient had previously remained in a ward in contact with a patient undergoing TB treatment, about six months prior to the onset of his symptoms.
Sixty days after starting treatment, the patient no longer had fever and and hepatic and splenic granulomas were calcified. There was a progressive improvement in bone lesions, but a painless nodular lesion appeared in the skullcap, without neurological symptoms. A new cranial CT scan showed multiple lytic lesions on the external board of the left frontal region (Figure 1), left parietal and right occiput, with soft tissues edema, without subgaleal fat involvement. Another lesion with an extradural soft tissue component was identified in the right frontal region and reached both, the inner and the outer bone layers measuring 1 cm in diameter. Excisional biopsy of the frontal lesion showed AFB-positive granulomas (Figure 2). Mycobacterial cultures were negative in all analyzed materials. The patient underwent immunological investigation and the only alteration found was the lack of response to IL-12 and also to IFN-g in an in vitro functional assay with mycobacteria and BCG vaccine. | null | Not supported with pagination yet | null |
PMC7534398_02 | Male | 9 | A 9-year-old boy had an increase in abdominal volume associated with nonspecific abdominal pain and fever for 2 months, evolving without improvement of symptoms, so he was admitted for investigation presenting a swelling in the left foot. After 3 weeks the patient presented a painless swelling of frontal region, without other signs of inflammation or cervical lymph node enlargement. Painful swelling also appeared in the left ankle. There was no epidemiological history of TB. TST with PPD Rt23 was 11 mm and the HIV-test was negative. Chest X-ray was normal; chest CT revealed the presence of 1.1 cm lymph nodes in the pre-tracheal region, 0.8-1.1 cm near the right anterior costophrenic sinus and other smaller lymph nodes in anterior mediastinum and infracarinal region. In addition, there was a small right pleural effusion without lesions in pulmonary parenchyma. Ultrasonography and abdominal CT performed one week before revealed the presence of a moderate ascite, enlarged liver (regular contour and homogeneous density), small lymph nodes along the right common iliac vessels and 1.9 x 1.2 cm nodular image next to the left diaphragmatic dome (probably a lymph node). The cranial CT showed a frontal lytic lesion in the midline measuring 2 cm and a thickness of 0.7 cm; the internal bone layer was intact and there was a rupture of the external plate extending beyond the extra-cranial layer (Figure 3). The extracranial segment had a soft tissue density of 1.6 x 0.7 cm, with normal cerebral parenchyma, ventricular system and cisterns. The skull biopsy showed a chronic inflammatory process with granuloma and multinucleated giant cells; Ziehl Neelsen, Groccot and PAS staining did not show microorganisms. A left ankle synovium biopsy was also performed. The Xpert MTB/RIF test on synovium material for Micobacterium tuberculosis complex was positive. The patient underwent an immunological investigation but it was not possible to show an altered functional assay for the IFN-g/IL12 axis, with no response to either cytokine. | null | Not supported with pagination yet | null |
PMC6791222_01 | Female | 62 | A 62-year-old female patient with the acute type of ATL received five sessions of mLSG-15 therapy combined with mogamulizumab. A dose-intensified chemotherapy called mLSG-15 therapy is commonly used as an initial treatment for aggressive ATL and consists of VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone), AMP (doxorubicin, ranimustine, and prednisone), and VECP (vindesine, etoposide, carboplatin, and prednisone). She achieved a complete response (CR) from ATL. Three months later, she was referred to our hospital for allogeneic hematopoietic stem cell transplantation (alloHSCT). On admission, she had persistent fever accompanied by repetitive skin rash and arthralgia. The skin rash exhibited patches of 2-3 cm in diameter and sometimes harbored a subcutaneous mass with pain. Interestingly, these skin and joint symptoms always recovered spontaneously in a few days before recurring in different parts of the body. Peripheral blood (PB) examination showed WBC 4.9 x 109/L (neutrophils 32.5%, lymphocytes 15.0%, monocytes 48.5%, myeloblasts 0.0%, abnormal lymphocytes 0.5%, and monocytoid cells 3.5%), Hb 9.6 g/dL, and platelets 87 x 109/L. The absolute monocyte count in PB was 2.4 x 109/L. Monocytosis had been persistently observed, although ATL cells had hardly been detected in PB by either morphological or immunophenotypic analysis. Lactate dehydrogenase increased slightly (LDH: 247 IU/L, normal range 105-211 IU/L). C-reactive protein was highly elevated (CRP: 20.46 mg/dL). The proviral load (PVL) of HTLV-1 was only 0.45%. A systemic computed tomography scan indicated no hepatosplenomegaly or lymphadenopathy or other signs associated with malignant diseases, infectious diseases, or inflammatory diseases. Bone marrow (BM) examination revealed a slight hypocellularity with a predominance of differentiated monocytes (58% of nuclear cell count) without an increase of blast cells (2%) (Figure 1(a)). Screening analysis for the representative 11 leukemic chimera genes including BCR-ABL1 by polymerase chain reaction was negative. Flow cytometric analysis revealed that the monocytes increased in the BM were positive for CD45, CD33, CD4, CD14, and HLA-DR but negative for CD2, CD13, and CD56. Fluorescence in situ hybridization (FISH) analysis showed split mixed lineage leukemia (MLL) gene signals in 78% of the interphase cells (Figure 1(b)) but no rearrangement signals with regard to two genes: platelet-derived growth factor receptor alpha and beta. Karyotyping analysis using the G-band method detected the t(11;22)(q23;q13) translocation as a solo cytogenetic abnormality (Figure 1(c)). This chromosomal aberration was not observed at the onset of ATL. Human T-cell leukemia virus type 1 (HTLV-1) provirus DNA analysis (via inverse polymerase chain reaction) of CD14-sorted monocytes revealed no monoclonal integration (Figure 1(d)).
Therefore, the patient was diagnosed with therapy-related myeloid neoplasm (t-MN), which phenotypically resembled chronic myelomonocytic leukemia (CMML)-1. The latent period between the initial therapy and the onset of t-MN was 10 months. On the contrary, ATL was confirmed as CR, in accordance with the response criteria for ATL. Our case did not have clinical evidence of ATL disease such as increase of ATL cells in PB and BM, swollen lymph nodes, hepatosplenomegaly, and skin involvement of ATL cells. Additionally, the results from PVL and inverse PCR analysis were also consistent with the conclusion that her ATL had remained in CR (Figure 1(d)). She underwent alloHSCT but died of viral complications of encephalomyelitis at 4 months after transplantation (7 months after diagnosis of t-MN).
In order to identify the partner gene of MLL gene rearrangement in this case, we performed RNA sequencing analysis. Total RNA was extracted from the patient's BM sample using a QIAGEN RNeasy Mini Kit (QUIAGEN, Venlo, Netherlands). cDNA libraries for next-generation sequencing were constructed from 24 ng of total RNA using a Truseq RNA Access Library Prep Kit (Illumina, San Diego, CA, USA). Each paired-end indexed library was sequenced to a length of 75 nucleotides per mate (2 x 75 bp) on a Nextseq instrument (Illumina). Sequence reads were processed by our in-house Genomon-RNA pipeline (available at http://genomon.readthedocs.org/ja/latest/, http://genomon.hgc.jp/rna/). Fusion transcripts were detected by Genomon-fusion. The Integrative Genomics Viewer (IGV) version 2.3.57 (https://software.broadinstitute.org/software/igv/download) was used to visualize the fusion-sequence. For validation of the fusion transcripts, reverse transcription polymerase chain reaction (RT-PCR) and Sanger sequencing were performed. Total RNA was extracted from the patient's BM sample using a PAXgene blood RNA kit (QIAGEN) and QIAqube. The RNA was reverse transcribed into cDNA by using SuperScript IV VILO Master Mix (Thermo Fisher Scientific, Massachusetts, USA). DNA was amplified and sequenced using Platinum Taq HF (Thermo Fisher Scientific) and the following primers: primer F 5'-GTGTGGGAGATGGGAGGCT-3' from MLL exon 10 and primer R 5'-CCTCCATCTTCACTTCCTGGG-3' from EP300 exon 15.
Next, to explore the molecular mechanisms of leukemogenesis in this case, we performed a targeted deep sequencing analysis. Flow cytometric sorting of the CD14-positive monocytes and CD4-positive T-cells (control 1) from the patient's peripheral blood was performed using a FACS Aria II (BD Biosciences, San Jose, CA). Oral epithelial cells (control 2) were collected via buccal swab from the patient. Targeted sequencing was performed using 20 ng of DNA via the TruSight Myeloid Panel on the MiSeq platform (Illumina), which included the analysis of the following 54 genes related to myeloid malignancies: ABL1, ASXL1, ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CBLC, CDKN2A, CEBPA, CSF3R, CUX1, DNMT3A, ETV6/TEL, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KRAS, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, and ZRSR2. T cells and oral epithelial cells served as a germline control in this case. Bioinformatic analysis was performed using standard procedures.
Cytogenetic and FISH analyses revealed that MLL on chromosome 11q23 was involved in gene rearrangement as the result of chromosomal translocation t(11;22)(q23;q13). RNA sequencing analysis followed by RT-PCR validation was performed to identify the partner gene of MLL rearrangement. RNA sequencing analysis detected a chimeric gene, MLL-EP300, formed by the in-frame fusion of MLL exon 10 to EP300 exon 15. The fusion gene was also confirmed by RT-PCR and Sanger sequencing (Figure 2).
To seek the molecular details underlying leukemogenesis in this case, mutation screening analysis with a targeted deep sequencing method was performed. The panel was focused on myelodysplastic syndrome- (MDS-) and acute myeloid leukemia- (AML-) related genes. Among these 54 genes, SRSF2, TET2 and ASXL1 are frequently mutated in CMML patients. However, any additional somatic mutations were not detected in our case (data not shown).
This study was approved by the Institutional Review Board of the Institute of Medical Science, the University of Tokyo, and informed consent was obtained from the patient in accordance with the Declaration of Helsinki. | null | Not supported with pagination yet | null |
PMC4861786_01 | Male | 7 | A 7-year-old boy was admitted to the emergency room with reduced consciousness, incoherent speech, hallucinations, and prolonged fever. He had complaints of nausea, vomiting, and diarrhea for 10 days, and he received oral antibiotics for pharyngitis. The physical examination revealed exudative pharyngitis and neck stiffness. Laboratory analysis results were as follows: hemoglobin: 12.5 g/dL, white blood cell count: 11.3 x 109/L, erythrocyte sedimentation rate: 78 mm/h, and C-reactive protein: 4 g/dL (0-5). Liver transaminases were within normal ranges. Lumbar puncture was performed. Cerebrospinal fluid (CSF) opening pressure was 100 mm/H2O. Direct microscopic examination showed 80 erythrocyte/mm3 and 20 leukocytes/mm3. The CSF protein level was 59 mg/dL and CSF glucose level was 50 g/dL (simultaneous serum glucose level: 130 g/dL). In the initial evaluation, CSF polymerase chain reaction (PCR) analysis for herpes-simplex virus types 1 and 2 and enteroviruses was negative. Vancomycin, ceftriaxone, and acyclovir therapies were initiated empirically, based on the preliminary diagnosis of meningoencephalitis. Magnetic resonance imaging (MRI) showed contrast enhancement in the posterior side of the bilateral insular cortex, right hypothalamus, and inferior left frontal cortex consistent with encephalitis (Figures 1(a) and 1(b)). His level of consciousness worsened, and his Glasgow coma score decreased from 15 to 12 within the first six hours of his admission. He was unresponsive to verbal commands and had resting tremors, rigidity, and hypertonia localized to his right arm. The electroencephalography (EEG) showed no abnormalities. On the third day of admission, a lumbar puncture was reperformed to examine other rare viral causes of encephalitis, autoimmune disorders, and subacute sclerosing panencephalitis, since no clinical improvement was achieved. Real-time quantitative polymerase chain reaction (PCR) of the blood was positive for EBV under the 1500 copies/mL. Real-time quantitative PCR of the CSF was positive for EBV at the level of 1600 copies/mL. Cytomegalovirus, herpes-simplex virus types 1 and 2, parechovirus, echovirus, and Mycobacterium tuberculosis PCR analyses produced negative results in CSF. Meanwhile, serum EBV serology was suggestive for primary infection, whereas EBV antiviral capsid antigen (VCA) IgM was positive and EBV anti-VCA Ig G was negative. Serologic testing for West Nile encephalitis, Japanese virus encephalitis, Lyme borreliosis, and measles were all negative in CSF. Vancomycin and ceftriaxone were discontinued, while acyclovir therapy was continued. On the fifth day of admission, his level of consciousness improved. Acyclovir therapy was administered for 14 days. He was investigated for immunodeficiency; however, no significant immunodeficiency was found. His symptoms fully recovered and he was discharged without any sequelae.
In the second month of his follow-up, cranial MRI findings showed improvement with markedly decreased contrast enhancements localized to the insular cortex and frontal lobe and the disappearance of hypothalamic lesions (Figure 2). His physical examination findings were normal and he had no complaints. | null | Not supported with pagination yet | null |
PMC6713098_01 | Male | 54 | On 9 October 2017, a 54-year-old Chinese man with poorly controlled type 2 diabetes sought medical care at Henan Provincial People's Hospital. He had been living in Laos as a tunnel worker for ten years and visited the hospital seeking treatment for intermittent fever and abdominal pain, which lasted for approximately two months. At Laos, he was diagnosed as dengue and treated for two months at a local hospital. He also underwent treatment at other hospitals in Henan province but with poor therapeutic results. His body temperature fluctuated between 38.3 C and 38.9 C, mainly in the afternoon. Upon admission to our hospital's infection department for managing his irregular fever and left upper abdominal pain, preliminary examination indicated that the highest temperature was 38.9 C. His abdomen was soft with tenderness in the upper-left portion and knocking pain around the spleen area. Additionally, laboratory tests showed that the patient had signs of a bacterial infection and uncontrolled diabetes (Figure 1(A)). Abdominal computed tomography (CT) revealed an enlarged spleen with multiple low-density shadows suggesting a spleen abscess. These symptoms, in combination with the case that the patient had a history of diabetes and was from a melioidosis epidemic area, strongly hint a probability of melioidosis. To examine this suspicion, 8 bottles of blood samples were consecutively collected from different sites of the patient with an interval of 1 day. While the first test was negative, samples from two bottles showed positive in the second test for B. pseudomallei. Therefore, the antimicrobial imipenem was administered. However, the pain in the left upper abdomen increased further and another CT scan of the abdomen was performed, which showed that the patient had splenic vein emboli and a possible infarct; the spleen was irregular in shape and less dense (Figure 1(B)). The interventional and vascular surgery departments recommended to perform a continuing anti-infection treatment and conduct an exploratory laparotomy when necessary. After 25 days of treatment with intravenous imipenem, fever, abdominal pain, and other uncomfortable symptoms disappeared. The patient became stabilized with a negative blood test results. The patient was also requested to orally take doxycycline and sulfonamides for another 6 months. Subsequent regular follow-up showed that the patient remained healthy for 1 year after completing the melioidosis therapy. This study was approved by the Research Ethics Committee of Henan Provincial People's Hospital. Informed consent of this patient was not required.
The two bottles of admitted blood cultures grew Gram-negative rods after 30 h of incubation. Short bacilli with an intense staining at both ends and a light staining in the middle were visualized in the gram-stained direct smear blood culture (Figure 1(C)). The isolate grew on blood, MacConkey, and chocolate agar when subcultured based on Gram staining, the isolate was found to be the same kind of bacteria as in the original culture. The strain was later identified as B. pseudomallei by conventional phenotype methods, using COMPACT VITEK2 identification system (BioMerieux Ltd., France). Furthermore, the PCR results using specific primers (LPW13372: 5'-CAA GAA CGGTTT ATG CG-3' and LPW13373: 5'-GAA GTG ATC CAT CAA ATGTC-3') and 16S rRNA amplification (Fd1:5'CCGAACGTCGACAACAGAGTTTGATCCTGGCTCAG-3'and rp2: 5'-CCCGGGATCCAAGCTT ACGGCTACCTTGTTACGACTT-3') for sequence analysis confirmed that the isolate was B. pseudomallei (Figure 1(D-H)). Whole-genome sequencing conducted by Shanghai Novel Bioinformatics Company, China, further verified the isolate as B. pseudomallei. The drug susceptibility test showed that the isolate was susceptible to imipenem, amoxicillin/clavulanic acid, trimethoprim/sulfamethoxazole, and ceftazidime, but resistant to aminoglycosides and cephalosporins.
To type the identified isloate, multilocus sequence typing (MLST) was conducted and it was turned out that this isolate can be grouped as sequence type 46 (ST46) (https://pubmlst.org/) (Figure 1(D)), which is consistent with those isolates that originated from Laos. To further define the relatedness of ST46 isolates, whole-genome sequencing was performed. To this end, genomic DNA was extracted using the LAIFENG DNeasy cell and bacteria kit (LAIFENG, Shanghai, China) according to the manufacturer's instructions. The sample was sequenced at Novel Bioinformatics Co., Ltd (Shanghai, China) using HiSeq 2000 (Illumina, San Diego, CA, USA). Denovo assembly was performed with SPANDx version 3.10 using the B. Pseudomallei strain K96243 from the NCBI database (http://bpseudomallei.mlst.net/) as the reference genome. The current known whole-genome sequences of all other B. Pseudomallei strains were downloaded from the National Centre for Biotechnology Information (NCBI) website (https://www.ncbi.nlm.nih.gov/genome/) and were used to construct a phylogenetic tree. Whole-genome identification of single-nucleotide polymorphisms (SNPs) was performed by MUMmer Version 3.9.4 alpha, followed by a phylogenetic construction using RAxML v8.2.9 with the GTR+ nucleotide substitution model, respectively. The results confirmed that the isolate was most closely related to that of ST48 from Thailand (Figure 1(I)).
Clinical diagnosis of melioidosis in non-endemic areas is extremely challenging because the signs of this disease are non-specific and similar to those of other common diseases, such as pneumonia and dengue. Laboratory diagnosis is also challenging. In the present case, B. pseudomallei grew readily in culture. However, the Phoenix 100 Identification System (BD Company, USA) or matrix-assisted lasers desorption/ionization time of flight mass spectrometry (Bruker Co. Ltd., Germany) could not identify the species definitively. To make these methods potentially useful for identifying B. pseudomallei, the database needs to be optimized by adding reference spectra for this organism and close relatives (e.g. B. thailandensis). B. pseudomallei differ from other Burkholderia spp. in its pathogenicity and epidemiology. Unfortunately, it can be easily misidentified as B. Thailandensis and B. cepacia complex based on phenotypic tests.
Epidemiological data from different countries support the hypothesis that inhalation and injection is the most possible predominant transmission route of B. Pseudomallei under severe weather events (e.g. storms and typhoons). A study from Taiwan reported an air sampling technique that uses a filtration real-time quantitative PCR method to quantify ambient B. pseudomallei DNA; high positive rates were found during typhoons. Presumably, the subject of our study was infected through air or soil in Laos, where B. pseudomallei is endemic . To date, no other case of melioidosis has been reported from Henan province.
In summary, B. pseudomallei infection should be suspected in patients with chronic fever who have travelled to endemic areas, particularly to Southeast Asian tropical countries. The significance of this case report is that doctors in non-endemic areas may easily misdiagnose melioidosis as tuberculosis, pneumonia or sepsis, which thus significantly delay the treatment or even lead to a death. Specific symptoms of this disease are multiple abscesses, especially in the lungs, liver and spleen together with a long-term fever. Therefore, if a patient is from endemic areas and have a long-term fever together with single or multiple sites of abscesses in the body combined with immunodeficiency baseline disease, the first suspicion should be this disease, which demands a confirmation by several times of blood culture test. A key treatment is to against the pathogen according to the drug sensitivity test and general treatment guidelines by use of correct antibiotics. A subsequent consolidation treatment must last for at least a half year until a complete absorption of the abscess before ending the treatment in order to avoid an incomplete treatment, which will result in a relapse of this disease. Doctors in non-endemic areas must be very sensitive of this disease because the mis-diagnosis derived mortality rate is 40-60%. Moreover, because of the risk of transmission to laboratory workers and potentials using B. pseudomallei for bioterrorism, clinical laboratories should perform only limited tests on the suspected isolates before referring them to a professional biosafety laboratory for more definitive verification. | melioidosis, emerging infectious disease, multilocus sequence type, whole-genome sequence | Not supported with pagination yet | null |
PMC8343840_01 | Female | 14 | A 14-year-old girl presented to the tertiary referral Children's Hospital orthopedic outpatient clinic due to dull pain and periodic wound drainage on the lateral side of her right thigh. Her mother noted two previous surgeries on that area performed at a county hospital. The first one, eight years ago, was performed due to right thigh swelling and fluctuance. These symptoms were initially suspected to be caused by pyomyositis of the vastus lateralis. A small longitudinal incision on the lateral side of the thigh was done and a purulent cyst was evacuated. Samples were sent for microbiological, cytological, and pathological examination. The laboratory reports were not evaluated properly by the treating surgeon, and the girl was discharged from the hospital with recommendations for oral antibiotics to treat pyomyositis. A month after the operation, purulent wound drainage appeared. The child was continued to treated with oral antibiotics and underwent frequent dressing changes, until complete wound closure was achieved. However, 10 months later, swelling, pain and purulent drainage reappeared at the place of the initial incision. The patient underwent repeated surgical incision and evacuation of what was considered to be a recurrent subfascial abscess. After surgery, the patient was instructed to continue with antibiotics and to dressing changes while waiting for wound closure. Unfortunately, her wound was not completely closed. For the next seven years, she suffered from monthly purulent drainage accompanied by moderate swelling and dull thigh pain that was most intense a few days before the appearance of drainage. During that period, there were no complaints about fever or malaise.
Physical examination and initial considerations
Seven years after the second surgery, physical examination performed at our institution showed a chronic wound on the lateral right thigh with mild drainage and local erythema. Palpation was slightly painful; however, there was full, painless range of motion of the hip and knee. A swab was taken for microbiological examination and an initial laboratory work-up was done. Microbiology results became positive for Pseudomonas stutzeri, while the laboratory findings were within the normal range. Initial radiographs of the femur were deemed normal. A thigh ultrasound scan revealed a sharply bordered hypoechoic collection between muscles and subcutaneous fat tissue that measured 3X1 cm in size, which was considered to be an abscess. Oral ciprofloxacin 1,000 mg was prescribed for 10 days; however, there was no change in her exam. Therefore, due to clinical presentation and according to previous diagnostic work-up findings, recurrent abscess was suspected. The patient was scheduled for surgical excision followed by continuous intravenous antibiotic therapy. However, while waiting for surgery, she developed intense pain in the right hip.
Radiological findings
Hip radiographs revealed a lytic lesion within the greater trochanter with partial reactive sclerosis (Figure 1). Unfortunately, due to the initial symptoms, as well as the site of the previous surgeries and ultrasound findings, surgery was performed without additional imaging studies.
Surgical technique
Surgery started with scar tissue excision around the previous wound. However, due to the intraoperative finding of a cutaneous fistula, the skin incision was extended to track the fistula proximally. The fistula was marked with a probe, and a detailed exposure showed a subfascial fistula connected to the enlarged trochanteric bursa (Figure 2a). While operating on the trochanteric bursa, it partially ruptured and whitish liquid tissue, resembling pus was observed. At this point, TB was suspected and the material was taken for acid fast laboratory diagnostics. The fistula and trochanteric bursa were excised completely and sent to pathology (Figure 2b).
Postoperative findings
Postoperative intravenous antibiotic therapy was administered for 10 days with 2 g of ceftazidime. The direct microscopic smear examination from the specimen was negative for acid-fast bacilli. The pathology report described tissue changes characteristic for fistula, without specifying the underlying disease. The wound healed uneventfully. There was no longer any local tenderness and the patient was discharged home with recommendations to continue with antibiotic therapy.
Prior to first postoperative visit, the microbiology culture returned positive for Mycobacterium tuberculosis (M. tuberculosis). The experienced pathologist who reviewed the recent histological findings was notified. The specimen was re-reviewed and corrected identified M. tuberculosis and amended the report to possible TB infection (Figure 3). While discussing these results with the patient's mother, it was found that a close relative that lived with them was TB positive at the time of the index surgery eight years ago. The genotyping results of both M. tuberculosis strains were identical, confirming the likelihood of transmission. In the retrospective analysis of the initial cytology report from eight years ago, it was clearly reported as granulomatous inflammation with necrosis. Therefore, we concluded that the initial presentation with swelling and fluctuance on the right thigh was as a result of TTB. Hip and thigh magnetic resonance imaging (MRI) performed soon after surgery did not show any signs of TB.
Pulmonology work-up and oral TB therapy
Due to these findings, a complete pulmonology work-up was indicated. On pulmonary examination, the patient was immunocompetent, afebrile, had non-labored breathing, with normal breath sounds on lung auscultation. Bacille Calmette-Guerin (BCG) vaccination after birth was confirmed by her visible BCG scar. There was no history of previous pulmonary TB, and her chest radiograph showed no signs of pathologic lesions. Culture of sputum samples were negative for M. tuberculosis. Oral TB treatment with four drugs was initiated (isoniazid 300 mg daily; rifampicin 450 mg daily; pyrazinamide 1 g daily; ethambutol 600 mg daily) for two months and continued with two drugs (isoniazid 300 mg daily; rifampicin 450 mg daily) for 10 months.
The patient completed one year of TB therapy and was followed closely by a pulmonologist and orthopedic surgeon. Twenty months after surgery, she complained about snapping and pain of the right hip, which was successfully managed with physical therapy. At the most recent four-year follow-up, there was no evidence of local recurrence, and the patient returned to all normal activities of daily living.
An informed consent was obtained from the parents of the patient. | null | Not supported with pagination yet | null |
PMC4239443_01 | Female | 50 | A 50 year old lady presented with the history of a lump in the left breast for one year duration. The lump was painless and slowly increasing in size. There was no family history of breast cancer or any history of taking oral contraceptives or estrogen therapy. There was no history of nipple discharge. Physical examination was unremarkable. The rest of the systemic examination revealed no abnormality. Local examination of the left breast showed 6.0x3.0 cm large, hard, irregular, non- tender mobile lump involving mainly the lower outer quadrant. There was puckering of the overlying skin with retracted nipple. Two lymph nodes were palpated in her left axilla and both were slightly tender. Contralateral breast and axilla were normal. The patient was referred for fine needle aspiration cytology (FNAC) with the clinical diagnosis of carcinoma of the left breast with axillary lymph nodes involvement. FNAC from the breast mass showed clusters, acinar pattern and dissociative population of pleomorphic cells having large nuclei with irregular nuclear membrane, anisonucleosis, prominent nucleoli and moderate amount of cytoplasm. FNAC from the clinically significant axillary lymph nodes showed the presence of similar sheets and groups of malignant tumor cells against clear lymphoid background. Diagnosis offered on cytology was ductal carcinoma of the left breast with metastasis to the left axillary lymph nodes. The preoperative workup consisted of a complete haemogram, ESR, chest X- ray and ultrasound examination of the abdomen. Complete haemogram showed mild microcytic hypochromic anemia while other investigations were within normal limits. The patient subsequently underwent modified radical mastectomy of the left breast with axillary lymph nodes clearance and the specimen was sent for histopathology examination.
The mastectomy specimen measured 16x15x4 cm and the axillary tail was 8.0 cm in length. The overlying skin showed puckering whereas nipple was retracted. On slicing, the specimen revealed an irregular yellowish gray mass measuring 3.5x2.5x1.5cm in size. It was firm in consistency with infiltrating margins. On sectioning there was a gritty sensation. The axillary tail revealed 14 lymph nodes ranging from 0.5cm to 1.0cm in diameter, and all were sampled.
Representative samples were fixed in 10% neutral buffered formalin, dehydrated and embedded in paraffin. Sections were stained in haematoxylin and eosin. Microscopic examination of the tumor showed sheets, clusters and duct- like arrangement of tumor cells of having large vesicular nucleus containing prominent nucleoli embedded within dense collagenous stroma. Of the fourteen lymph nodes, thirteen showed tuberculous lymphadenitis in the form of numerous well formed caseating granulomas composed of epithelioid cells, Langhans' giant cells surrounded by lymphocytes, two of the lymph nodes showed coexistent carcinomatous deposits along with well defined caseating granulomas and reactive hyperplasia in one. Ziehl Neelsen stain for acid- fast bacilli was positive (Figure 1, Figure 2) Sections from resected margins, deep resection plane and nipple and areola did not show any evidence of infiltration by tumor. The surrounding breast was normal. The final diagnosis offered on histopathology was infiltrating ductal carcinoma, grade II (Nottingham modification of Scarff Bloom Richardson System) of the left breast with metastasis in left axillary lymph nodes harbouring tuberculous lymphadenitis.
Since preoperatively tuberculosis was not suspected, Mantoux test, culture, serology or polymerase chain reaction were not performed. On the basis of histopathological report, the patient was put on anti- tuberculous therapy along with adjuvant chemotherapy with cyclophosphamide, methotrexate and 5- fluorouracil (CMF) and responded well to treatment. | ductal carcinoma, breast, lymph node, tuberculous | Not supported with pagination yet | null |
PMC3747996_01 | Female | 31 | A 31-year-old woman with a previous history of 2 cesarean sections received dilatation and curettage under the diagnosis of missed abortion at 7 weeks of gestation. Although retrospective evaluation of the ultrasonographic image indicated the presence of a gestational sac in the previous cesarean section scar (Fig. 1A, arrow), such a diagnosis was not made at that time. Seven weeks later, she was transferred to our hospital due to hypovolemic shock status with massive vaginal hemorrhage. Prominent vascular flow was noted around the retained gestational products (Fig. 1B). On iodine-enhanced computerized tomographic image, active extravasation of contrast agent (Fig. 1C, arrow) originating from the left uterine artery (Fig. 1C, arrowhead) was identified. On emergent pelvic angiography, the occurrence of major bleeding was confirmed from the left uterine artery. After intra-arterial infusion of dactinomycin (Cosmegen, Merck & Co, Inc, Whitehouse Station, NJ, USA), arterial embolization was performed with Tornado platinum coils (Cook, Bloomington, IN, USA) for left uterine arterial occlusion (Fig. 1D, arrow) and with gelatin sponge particles (Gelpart, Nippon Kayaku, Tokyo, Japan) for right uterine arterial occlusion. With successful hemostasis, further conservative management was chosen and systemic intramuscular administration of MTX (50 mg/m2/day) was additionally performed 3 times. Subsequently, gestational products resolved without any further hemorrhagic complications, and first menstruation resumed 97 days after TACE.
The patient reported a missed period after 4 cycles of resumed menstruation and was diagnosed as having intrauterine pregnancy. At 8 weeks of gestation, normal fetal growth was identified (Fig. 2A). The lower segment of the placenta was attached to the cesarean section scar (Fig. 2A, arrow). Intermittent bleeding occurred from 16 weeks of gestation and was conservatively managed. To achieve more accurate diagnosis of the site of placental attachment, magnetic resonance imaging (MRI) was performed at 19 weeks of gestation. Attachment of the lower part of the placenta to the previous cesarean section scar was confirmed (Fig. 2B, arrow). After 21 weeks of gestation, uterine bleeding spontaneously ceased, and the pregnancy course was uneventful.
Elective cesarean section was scheduled at 37 weeks and 2 days of gestation. However, at 36 weeks and 5 days of pregnancy, the patient was transferred due to sudden massive bleeding. Since peritoneal fluid pooling was not evident on ultrasonography, uterine rupture was less likely. Regular fetal heartbeat was audible. Her hemoglobin value was 9.6 g/dL. Coagulation disorders were not identified. Emergency cesarean section was initiated under endotracheal general anesthesia. At laparotomy, the uterine scar from the previous cesarean section showed slight decompression, but scar dehiscence or rupture was not evident (Fig. 2C, arrow). When anterior transverse hysterotomy at 2 cm above previous cesarean section scar was performed, abruptio placentae was diagnosed with expulsion of substantial blood and clots. Since the placenta occupied the anterior wall of the uterus, manual removal of the placenta was initially performed, and then a healthy 2486 g girl was delivered. After confirming the absence of placental retention, the hysterotomy incision was closed with 2-layered sutures. Intraoperative blood loss was 1800 mL. The mother was admitted to the intensive care unit for cardiopulmonary management. Her hemoglobin value was 6.6 g/dL on postoperative day 1. Since her vital signs were well maintained, red blood cell transfusion was not performed. The postoperative course was uneventful. | abruptio placentae, cesarean scar pregnancy, methotrexate, transcatheter arterial chemoembolization | Not supported with pagination yet | null |
PMC7277026_01 | Male | 61 | A 61-year-old male, nonsmoker, with a past medical history of ulcerative colitis, dyslipidemia, and exercise-induced asthma, presented to the clinic for evaluation of multiple-year history of chronic cough productive of white sputum with associated occasional dyspnea on exertion, nonresponsive to inhalers. Family history pertinent for a father with lung cancer at age 70. The patient had no identifiable acute or chronic toxigenic exposure. Vital signs, including SpO2, were within normal limits, and physical examination was unremarkable. Spirometry performed six months prior demonstrated normal FVC, FEV1, FEV1/FVC ratio, and DLCO. Posteroanterior and lateral chest X-ray demonstrated a thin band-like opacity overlying the cardiac contour suggesting atelectasis of the right middle lobe (Figure 1).
Noncontrast CT of the chest showed an endobronchial soft tissue mass at the origin of the right middle lobe bronchus with postobstructive right middle lobe collapse (Figures 2-4).
A flexible bronchoscopy was performed, showing an exophytic, sessile polypoid lesion attached to the medial wall of the right middle lobe origin causing a significant luminal occlusion (Figure 5).
Endobronchial biopsies were taken, with pathology reporting lipoid fragments of the respiratory mucosa and submucosal adipose tissue with mild inflammation and reactive changes. The patient underwent a second flexible bronchoscopy with snaring forceps for a second biopsy; complete removal of the lesion was performed with pathology reporting endobronchial myxoid spindle cell lipoma (Figure 6).
Postbronchoscopy chest X-ray demonstrated complete resolution of the right middle lobe collapse. On follow-up, the patient reported complete resolution of his chronic productive cough as well as the dyspnea negating need for further pulmonary function tests. | null | Not supported with pagination yet | null |
PMC4629595_01 | Unknown | 10 | A 10-year-old mixed medium size breed dog was presented with a 4 months of gradually enlarging swelling in the left zygomatic area of the head. Clinical examination revealed a facial deformation, due to the localization of the mass and mild dyspnea. Neurological examination didn't reveal any specific dysfunctions. The skin over the mass was tense and no ulcerations were observed. Radiographic examination of the head was performed and revealed the presence of a homogeneous radiodense bony swelling attached to the skull and involved a large area, from the left zygomatic arch to the left nasal cavity (Fig. 1).
The pathognomonic findings of a lytic geographic lesion with expansion and chondroid matrix seen on radiographic were diagnostic for a tumor. Prior to surgery, 3-view thoracic radiographs were performed to assess whether metastatic disease was present but the results were within normal limits. Initial diagnostic tests included a complete blood cell count, serum biochemical profile, prothrombin time (PT) and partially thromboplastin time (PTT).
All results were within reference limits similar to the values on urinalysis on voided urine. The dog was sedated by 5 microgm/Kg bodyweight (BW) of Medetomidine (Domitor 0,2 ml EV) and 0,1 mg/Kg BW of Butorphanol (Dolorex 0,4 ml EV) premedication. The induction was achieved using propofol at 4 mg/Kg BW (17 ml EV) followed by isoflurane for maintenance. The surgery was performed using a lateral access, on the left side of dog's face. After a careful isolation of anatomic structures and the exposure of the tumor, the mass was removed. Grossly the mass consisted of multiple, variably sized, grayish-white to yellow nodules which occasionally contained whitish, hard areas on cut surface interpreted to be mineral.
The resected mass was fixed in 10% neutral buffered 10% formalin and submitted to the Dipartimento di Scienze Biopatologiche e Igiene delle Produzioni Animali e Alimentari, Universita degli Studi di Perugia, Italy.
Histologically, the tumor was characterized by the presence of multiple lobules of irregularly shaped and sized islands and nests containing well differentiated osteoid and cartilage separated by diffuse anastomosed fibrovascular septa (Fig. 2).
In some areas there were broad poorly differentiated areas of mesenchymal tissue which blended into the lobules and islands of cartilagineous, osseous or osteocartilagineous tissue. Within the islands there were also diffuse areas of ossification and mineralization. The mitotic index of neoplastic cells was always low grade in all the examined samples. According to the characteristics and histological appearance of the tumor a diagnosis of MTB was made.
A radiation therapy was declined by the owner and after 3 months a recurrence was not observed and the dog did not present clinical signs. | dog, multilobular tumor of bone, zygomatic bone | Not supported with pagination yet | null |
PMC7395468_01 | Male | 35 | A 35-year-old male presented with progressive headache, paraesthesia, and blurred vision. The MRI showed diffuse meningeal enhancement with thickening, along with areas of brain edema [Figure 1a-c]. Despite this mild meningeal inflammatory syndrome, cultures were negative. Although there was an initial perceived response to steroids, the patient had a relapse. A dural biopsy revealed epithelioid-giant cell granulomas with caseous necrosis, and TB- PCR of tissue was positive [Figure 1d]. In addition, the anaerobic culture (requiring about 4 weeks) eventually grew Actinomyces species. The patient had a good response to oral ciprofloxacin and antituberculous medication. The conclusion was that dural biopsy, histology, and cultures are imperative in pachymeningitis for establishing the diagnosis and guiding treatment.
The authors certify that they have obtained all appropriate patient consent. | actinomycosis, hypertrophic cranial pachymeningitis, intracranial infection, pachymeningitis, tuberculosis | Not supported with pagination yet | null |
PMC8357509_02 | Male | 54 | This patient is a 54-year-old homeless man with a history of schizophrenia who presented to the emergency department in November 2020 after being found down with a penetrating injury to the left anterior chest. On arrival, his GCS was 3, and he was being ventilated via bag valve mask by EMS. He was promptly intubated for airway protection. His vital signs were stable. On further exposure, he had an approximately 3 cm stab wound to his left anterior chest, medial to the nipple line, at approximately the level of the 7th rib. Otherwise, he was noted to have ecchymosis of the occiput and superficial lacerations to his right flank. Also concerning was a fixed and dilated left pupil. A pan CT scan revealed a left subdural hematoma with bilateral frontal hemorrhagic contusions and 5 mm of midline shift. Additionally, he was found to have a moderate left-sided pneumothorax and associated left anterior 7th rib fracture for which he underwent chest tube placement with resolution of his pneumothorax (Figure 2). A cerebral oxygenation monitor and drainage device was placed by neurosurgery revealing an elevated opening pressure of 31 mmHg. At this time, there was also concern for possible diaphragmatic injury given the location of his stab wound and imaging findings; however, in the setting of his elevated intracranial pressures, he was deemed unsafe for the OR and admitted to the neuro ICU for further monitoring.
On hospital day 0, his routine workup included a negative COVID-19 nucleic amplification assay. His intracranial pressure was controlled using mannitol and hypertonic saline bullets while he was started on levetiracetam for seizure prophylaxis. Repeat CT imaging the following day showed stability in his intracranial bleeds and a decrease in midline shift. His mental status improved, and he self-extubated on hospital day 3. After his intracranial pressures normalized his drains were removed, and on hospital day 6, he underwent diagnostic laparoscopy to rule out diaphragmatic injury given the location of his initial stab wound. Prior to this procedure, he had a repeat COVID nucleic amplification assay as per institutional policy, which again resulted negative.
Following this intervention, his condition continued to improve. His diet was advanced as tolerated and he was otherwise normalized, although he continued to have issues with agitation and altered mental status secondary to his traumatic brain injury and underlying schizophrenia. Psychiatry was consulted for titration of his medications, and plans were made for discharge to a TBI rehab; however, his discharge was complicated by his homelessness status and frequent behavioral outbursts, occasionally requiring chemical sedation. Beginning on hospital day 13, he was given a one-to-one bedside nursing assistant and was occasionally placed in a SOMA Safe Enclosure bed.
In anticipation of discharge, repeat COVID nucleic amplification assay was done in compliance with rehabilitation center policies. Tests sent on hospital days 49 and 50 both resulted negative; however, an additional test sent on hospital day 55 resulted positive. As before, the patient was given an isolated room and placed on contact, droplet, and airborne precautions. Later that evening, the patient became febrile to 103 F but refused additional fever workup. A second COVID nucleic amplification assay was repeated the following day, which confirmed his COVID-positive status. He was treated with a 10-day course of dexamethasone as per infectious disease recommendations, and his fevers resolved. Repeat COVID testing on hospital day 66 remained positive, and he had his first negative test on hospital day 72. Shortly thereafter, he was accepted to a facility for ongoing rehabilitation. | null | Not supported with pagination yet | null |
PMC7080341_01 | Unknown | 18 | Between July 1, 2017, and May 1, 2018, we evaluated patients admitted to the center with a presumed diagnosis of STEMI. One criterion for inclusion in the study was age >=18 years old. Another inclusion criterion was the diagnosis of STEMI accompanied by the following criteria was required: chest pain or equivalent symptoms of more than 20 minutes duration within the last 24 hours before admission and, electrocardiographic changes consistent with new or presumed new ST-segment elevations or left bundle branch block, according to third universal definition of myocardial infarction defined by the European Society of Cardiology/ACCF/AHA/World Heart Federation Task Force for the Universal Definition of Myocardial Infarction. STEMI must be primary diagnosed by the emergency medical doctors. Data collection and validation of the diagnosis was then supervised by a physician who was responsible for the quality control of the project.
Patients were excluded from the study if they developed STEMI after admission in the hospital, or developed STEMI after percutaneous coronary angioplasty or coronary bypass surgery and/or hospitalized in another hospital more than 24 hours before coming to Imam Ali hospital, or who did not sign the consent form to participate in the study.
Using case report forms, data were collected by a nurse and a research assistant working in the Kermanshah Cardiovascular Research Center (KCRC), who were trained in uniform protocols for patient entry and data gathering. Case report form was developed by the EORP. All completed case report forms were verified and checked for errors by the quality control physician before submission for final analysis, and then forwarded online to the EORP website. We used patients' national identification numbers to avoid duplicate admissions to the registry. The collected data included demographic characteristics (e.g. age), clinical histories (e.g. previous myocardial infarction), admission process (e.g. presenting symptoms), biochemical and electrocardiographic findings (e.g. blood sugar), treatment procedures (e.g. percutaneous coronary intervention, PCI), in-hospital outcomes (e.g. vital status). Standardized definitions of all variables (e.g. clinical diagnoses) were used. Likewise, mortality data (in-hospital) were obtained for all included cases.
Baseline data including demographic characteristics were compared between men and women. Data were described using mean +- standard deviation (SD) if they were normally distributed; otherwise, frequencies and percentages were reported. Differences between subgroups were assessed using independent t tests for continuous and normally distributed variables and chi-square (or Fisher exact tests) for other variables. We compared the in-hospital mortality rates among women and men and assessed the independent role of sex in patients' mortality using multivariable logistic regression models. Odds ratios (ORs) and 95% confidence Intervals (CIs) were calculated. The body mass index (BMI) >=25, HTN, DM, current smoking, hypercholesterolemia, congestive heart failure (CHF), Killip class (at first presentation) >= II, symptom-to-balloon (STB) time> 360 minutes and door-to-balloon (DTB) time > 90 minutes (18) used as covariates, while the dependent variable was in-hospital mortality. A test was considered statistically significant if the probability value (P value) was less than 0.05. The Statistical Package for Social Science (SPSS) software, version 23 (IBM Corp., Armonk, NY USA) was used for analyzing data.
STB time was defined as the time between the onset of symptoms to first balloon inflation or first device delivery in the culprit vessel.
DTB time was defined as the time between patient's arrival at the PCI hospital and the first balloon inflation or first device delivery in the culprit vessel. | cohort, mortality, myocardial infarction, registry, sex | Not supported with pagination yet | null |
PMC2901615_01 | Male | 63 | A 63-year-old man was diagnosed of chronic lymphoproliferative syndrome in 2006, classified as chronic lymphocytic leukaemia (CLL) of B cells and treated with chlorambucil for 9 months; fludarabine for 4 months; cyclophosphamide, vincristine, prednisone, and rituximab (CVP-R) for 3 months; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for 6 months. In November 2007, he consulted for a 1-year history of recurrent, painful nodules with inflammatory signs on his limbs and trunk (Figure 1(a)). This skin eruption had appeared since onset of the CLL and cutaneous lesions sometimes worsened after chemotherapy cycles. Individual lesions showed a typical course of one-week duration and spontaneous resolution without scar formation. There were not constitutional symptoms or mucosal lesions.
The histopathologic study of a cutaneous specimen showed an inflammatory infiltrate predominantly composed by eosinophils that involved both the fat lobules and the septa (Figure 1(b)). No changes in dermis or epidermis were observed. The results of laboratory studies were normal except for an eosinophilic count of 0.69 x 109/L (8.6%). The remaining laboratory findings (elevated beta 2 microglobulin level and polymorphous lymphocytes in peripheral blood smears) were consistent with his haematological condition. Other possible causes of eosinophilic tissue infiltration were ruled out, and he was diagnosed of eosinophilic panniculitis related to his hematologic disease. Skin nodules disappeared after a short course of systemic steroids, and chemotherapy was changed to CHOP.
During successive outbreaks the lesions changed their morphology to urticarial, prurigo-like lesions resembling insect bites. Examination of skin revealed a widespread eruption consisting of erythematous papules, some with central crust and excoriations (Figure 2(a)). He denied history of arthropod assaults. A skin biopsy specimen showed a dense eosinophilic interstitial infiltrate that affected dermis (Figure 2(b)) with occasional "flame figures" (Figure 2(c)), and no changes in subcutaneous tissue were observed. The patient was diagnosed of insect bite-like reaction related to CLL. Skin lesions had a good response to topical and systemic steroid treatment, and recurrences were reduced with dapsone (150 mg daily). Cutaneous eruptions fully resolved when leukaemia was controlled.
This case was classified as an eosinophilic dermatosis associated with lymphoproliferative disease that began as eosinophilic panniculitis and later evolved into lesions characteristic of insect bite-like reaction. | null | Not supported with pagination yet | null |
PMC9198317_01 | Male | 71 | A 71-year-old man was referred to a gastroenterological clinic due to macrocytic anemia (hemoglobin 9.9 g/dl, mean corpuscular volume 107 fL) and hyperbilirubinemia (4.4 mg/dL). Haptoglobin was absent (<0.08 g/L) and lactate dehydrogenase was normal (187 U/L). Serum folate levels had previously been low, and the patient was taking iron supplements and folic acid. An ultrasound of the abdomen showed gallstones and splenomegaly. Morphological evaluation of bone marrow biopsy and aspirate showed single-lineage dysplasia (SLD) of >10% of the erythroid precursors, which was found compatible with MDS-SLD if alternative diagnoses such as hemolysis could be excluded. Cytogenetics was not performed.
The patient was referred to a hematological clinic where a CT scan of the chest, neck and abdomen showed a slightly enlarged spleen (13.9 x 6.5 cm). Direct anti globulin test and a flow cytometric direct anti globulin test were both negative and cold agglutinins were not present. Genetic testing for Gilbert's syndrome and pyruvate kinase deficiency as well as flowcytometric testing for paroxysmal nocturnal hemoglobinuria were also negative. Osmotic gradient ektacytometry was initially negative for hereditary spherocytosis (Fig. 1A) and the small pathological erythrocyte population on the EMA-binding test was initially discarded by the laboratory as an artefact (Fig. 1B). A myeloid neoplasm NGS performed on DNA from peripheral blood cells revealed an MDS associated U2AF1 mutation (NM_006758.2: c.470A>G) with an allele burden of 24%. Careful examination of the peripheral blood smear (Fig. 2) revealed numerous spherocytes. This prompted a hemolysis NGS panel which demonstrated a SPTB mutation (NM_001024858.2: c.398T>G), associated with hereditary spherocytosis. The allele burden was 31% at the time of diagnosis and increased to 42% three years later. The SPTB mutation was not found in germline DNA obtained from cultivated fibroblasts. Repeated EMA-binding tests exposed two different erythrocyte populations, whereof one indicated spherocytosis (Fig. 1B). The EMA binding was not reduced for the normal fraction of erythrocytes whereas the pathological population consistently had a decrease of >15% compared to normal controls. The patient was thus diagnosed with acquired spherocytosis, whereas the MDS associated U2AF1 could likely be attributed to clonal hematopoiesis without effect on the patient's hemolytic anemia.
The patient received three units of blood in the setting of surgery and one unit due to chronic fatigue. The patient underwent splenectomy due to persistent anemia with hemoglobin levels around 8.0-9.7 g/dL, need of blood transfusions, and a declining performance status. This resulted in reduced hemolysis with normalization of hemoglobin levels around 13.1 g/dL and bilirubin levels around 2.3 mg/dL (Fig. 1C). Follow-up 2 months after splenectomy showed persistent, close to normalized hemoglobin, and the patient reported substantially improved quality of life. | acquired hemolysis, hemolysis, mds, spherocytosis, splenectomy | Not supported with pagination yet | null |
PMC4010028_01 | Male | 35 | A 35-year-old male patient was admitted to our medical intensive care unit (ICU) because of multiple organ failure.
The patient was born in Somalia and migrated to Austria six years ago. In his past history there were tuberculosis detectable about 15 years ago, which was treated successfully, and unspecific heart problems. Because of insomnia and depression, a tricyclic antidepressant (amitriptyline) and diazepam were prescribed. In addition, every day the patient chewed khat leaves. According to his next of kin, khat intake increased considerably during the past few days before hospital admission. In this context, they reported that the patient was sleeping nearly until noon. However, on the day of hospital admission it was difficult to rouse the patient even in the early afternoon. Hence, an emergency physician was called to the patient, who found him neurologically disturbed with the risk of aspiration. Thus, the patient was sedated, intubated, and transferred to the emergency department (ED) of our hospital thereafter. A CT scan of the brain was performed to exclude any underlying structural cause within the brain for the present unconsciousness. At the ED an electrocardiogram showed arterial fibrillation with a heart rate of 143 bpm. Conversion into sinus tachycardia was achieved spontaneously within six hours subsequently. Hemodynamics was stable during that time period. However, gas exchange was considerably compromised. After the performance of bronchoscopy, which showed no foreign bodies or massive secretions but reddened mucosa indicating aspiration of gastric acid, the patients was transferred to our medical ICU. Further clinical and laboratory data at ED admission as well as at ICU admission are presented in Table 1.
At ICU admission SOFA score was found to be 8, and SAPS II score was 46. Hemodynamic condition was stable without catecholamine support. Moreover, during ICU stay the patient developed arterial hypertension, which was treated accordingly. The patient remained intubated and under analgosedation (combined propofol and remifentanil administration) administered continuously. Pulmonary function remained significantly compromised due to present aspiration pneumonia, which proceeded into ARDS over the next few days. Therefore, transient prone positioning of the patient was performed. However, gas exchange improved under antibiotic therapy that the patient could be extubated after two weeks of mechanical ventilation.
After the cessation of the mechanical ventilation the patient showed massive agitation indicating present delirium, which could be improved by the administration of clonidine as well as lorazepam and trazodone. Finally, the patient was discharged from the ICU after 22 days and discharged from the hospital in good condition another 14 days thereafter. | null | Not supported with pagination yet | null |
PMC8592304_01 | Female | 0 | A 3-month-old girl was referred for jaundice, hepatomegaly, acholic stools, and dark urine. At blood testing, conjugated hyperbilirubinemia, thrombocytosis, and raised liver enzymes were found, and triangular cord sign was observed at liver ultrasound. Cholangiography confirmed BA, and KPE was performed at the age of 94 days. At surgical exploration, the liver was fully mobilized and appeared enlarged and greenish-brown in color with increased consistency and macronodular surface. Hepatic histological evaluation revealed severe fibrosis (METAVIR F3-F4). During the following 4 months, the girl was in good clinical conditions, and bile flow was completely restored within 1 month after KPE with total bilirubin serum levels falling under 1 mg/dl. Unfortunately, she developed refractory ascites requiring chronic diuretic treatment with furosemide (1 mg/kg/day) and spironolactone (3 mg/kg/day). At the age of 7 months, the patient experienced a sudden respiratory distress. On admission, she was apyretic with subcostal and jugular retractions. Thoracic auscultation revealed decreased airflow in the right basal region, with oxygen saturation at room air 94%. Laboratory data showed normal liver function tests (albumin 3.2 g/dl; prothrombin time international normalized ratio 1.2) with normal values of aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase; conjugated serum bilirubin was 0.6 mg/dl. Blood count was normal (platelet count 230,000/mul), and C-reactive protein was negative. Echocardiogram revealed normal left ventricular wall motion and contractility. Chest X-ray and computed tomography (CT) scan showed pleural effusion with an almost complete opacification of the right hemithorax (Figure 1). Rapid deterioration of pulmonary function led to an emergency intubation, and thoracentesis drained about 250 ml of transudate (proteins = 1.3 g/dl, 1 leukocytes/mm3, sterile).
Subsequently, in combination with diuretic therapy, non-invasive ventilation (NIV) with full-face mask to high-flow nasal cannula oxygen (HNFC) was started. Infections (including tuberculosis) and inflammatory, renal, and neoplastic diseases were also excluded. Esophagogastroduodenoscopy showed absence of esophageal varices. After discharge, pleural effusion recurred three times despite aggressive diuretic therapy; in one circumstance, imaging revealed only minimal ascitic effusion. In the following months, serial ultrasound evaluations confirmed persistent perihepatic and perisplenic ascites with fluid between intestinal loops and showed signs of PHT with hepatofugal venous flow.
At 10 months of age, despite a low pediatric end-stage liver disease (PELD) score (equal to 3), the infant was listed for LT due to repeated episodes of respiratory distress, the need for multiple thoracentesis, and frequent hospitalizations. At the age of 11 months, the patient underwent deceased donor split LT. During surgery, no vascular, diaphragm, or azygous vein changes were identified. Intraoperatively, PHT was advanced, and the native liver appeared enlarged and with a multinodular cirrhotic aspect. Histological evaluation showed signs of biliary cirrhosis due to BA. In the following 12 months after transplantation, the infant showed good liver function and no further HH relapse. | ascites, biliary atresia, liver cirrhosis, liver transplant, portal hypertension | Not supported with pagination yet | null |
PMC8639695_01 | Female | 70 | In July 2020, a 70-year-old woman presented with progressive dyspnea and was admitted to a local hospital. The patient had no medical history. Blood tests and electrocardiography showed no abnormalities. Transthoracic echocardiography (TTE) showed massive pericardial effusion. Chest enhanced computed tomography (CT) revealed pericardial effusion with no signs of tumors or tuberculosis. The local hospital performed 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), which showed intense FDG uptake in the pericardium (maximum standardized uptake value: 9.6), the area surrounding the left atrium, and mediastinum (Figure 1). The corresponding CT images demonstrated a mass in the pericardium (1.7 x 1.2 cm) combined with pericardial effusion and scattered soft tissue masses in the area surrounding the left atrium and mediastinum. No distant tumor sites or infiltration were detected. A pericardial window was performed via thoracoscopy, and a limited pericardiectomy was carried out. A pericardial biopsy was performed, and a pathological diagnosis of mesothelial cell hyperplasia was made at the local hospital. The patient was discharged without a definitive diagnosis and was prescribed a diuretic to alleviate her symptoms at home.
After 3 months, the patient was referred to our hospital because of worsening shortness of breath and increasing volume of the pericardial effusion. On physical examination, her respiration rate was 25 breaths/min, her pulse rate was 90 beats/min, and her blood pressure was 105/70 mmHg. Reduced breath sounds were heard in both lungs. TTE revealed a homogeneous isoechoic pericardial mass (75 x 30 mm) with massive pericardial effusion (Figure 2A). Neither ventricle was enlarged, and the left ventricular ejection fraction was estimated at 70%. The cardiac valves were morphologically and functionally normal. Contrast-enhanced ultrasonography (CEUS) was then performed with ultrasound contrast agent Sono Vue (Bracco, Italy) intravenous injection. Compared with the adjacent myocardium, the mass was hyper-enhanced (Figure 2B). Further cardiac MRI (CMRI) (Figure 3) showed a pericardial mass attached to the wall of the left atrium with invasion to the pericardium and vessels. The tumor showed irregular enhancement after gadolinium injection. The pericardial biopsy showed that the cells were positive for mesothelial cell markers (calretinin and D2-40) by immunohistochemistry (IHC), and CDKN2A (p16) deletion was detected by fluorescence in situ hybridization (FISH) (Figure 4). Finally, the patient was diagnosed with epithelioid mesothelioma of the pericardium. Given the invasion of adjacent tissues and metastasis, the cancer was deemed inoperable. The patient's dyspnea was alleviated by diuretics and drainage of the pleural effusion. Chemotherapy was not administered because the patient could not tolerate the side effects. She died nearly 2 months after the diagnosis. | case report, computed tomography, contrast-enhanced ultrasonography, echocardiography, magnetic resonance imaging, primary pericardial mesothelioma | Not supported with pagination yet | null |
PMC5948813_01 | Female | 27 | A 27-year-old Malay woman presented at our hematology clinic with a fever and sore throat. She had a history of hereditary thrombocytopenia that affected her father and 3 brothers. Preliminary clinical investigation at diagnosis revealed abnormal levels of hematological markers - the patient had a white blood cell count of 1.97 x 109 /L (normal: 3.4-9.6 x 109 /L), hemoglobin levels of 7.0 g/dL (normal: 10.9-15.1 g/dL) and platelet count of 20 x 109 /L (normal: 132-372 x 109/L). On morphological analysis, her bone marrow was moderately cellular, with dysplastic changes as well as increased numbers of myeloblasts and monoblasts/promonocytes, indicative of AML with myelodysplastic changes (Fig. 1a). Initial molecular testing by conventional Sanger sequencing revealed the same novel RUNX1 mutation in the patient, her father and 3 brothers (Fig. 2). A buccal analysis also confirmed that the RUNX1 mutation identified in this FPD/AML patient is germline in nature.
The patient received standard induction chemotherapy that consisted of high-dose anthracycline and cytarabine in a 3 + 7 regimen and subsequently attained complete morphological remission. Post-induction evaluation of her bone marrow revealed a regenerating bone marrow in morphological remission with myelodysplastic changes (Fig. 1b), as well as 0.3% residual disease, measured using Flow Cytometry. Thereafter, she was given consolidation chemotherapy with cytarabine. As no matched sibling donor or matched unrelated donor was available, she received a haploidentical stem cell transplant (haplo-SCT) from her mother, who is RUNX1-mutation negative. While she engrafted on Day 15 of her transplant, her admission was complicated by Klebsiella bacteraemia, acute Graft-versus-Host Disease (GvHD) of her liver and Cytomegalovirus reactivation. Post-haplo-SCT, she was given Tacrolimus, Mycophenolate Mofetil and Methotrexate as GvHD prophylaxis. A post-transplant bone marrow aspirate after count recovery showed a normocellular reactive marrow (Fig. 1c) and 0% residual disease on Flow Cytometry.
With informed consent obtained from the patient, a comprehensive genomic mutational analysis on a targeted next-generation sequencing (NGS) platform was conducted using either peripheral blood (PB) or bone marrow (BM) samples collected at three different stages - at diagnosis (pre-treatment), post-treatment (after induction and consolidation chemotherapy) and post-haplo-SCT. These time points coincided with the bone marrow examinations done for the patient, as mentioned above. In brief, 568 amplicons ('tiles') covering 54 genes that were previously implicated in myeloid neoplasms were assessed for the presence of genomic variants. At each stage, the patient's genomic DNA was extracted and processed using the TruSeq Custom Amplicon (TSCA) assay for the TruSight Myeloid Sequencing Panel, according to a previously described methodology. The 54 genes evaluated in this targeted gene panel were as follows: ABL1, ASXL1, ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CBLC, CDKN2A, CEBPA, CSF3R, CUX1, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, MPL, MYD88, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1 and ZRSR2. After sequence alignment against the reference GRCh37/hg19 human genome assembly, BAM and VCF files were produced by the TruSeq Amplicon software (V.1.1.0.0). Genome annotation was done on the VCF files using the Illumina VariantStudio (V.2.2). Only variants that met the following criteria were selected: non-synonymous mutation, variant not present in dbSNP, read-depth > 100x, variant-allele frequency (VAF) > 5% and acceptable sequence quality. The comprehensive list of mutations, including the hitherto unreported germline RUNX1 mutation, identified in the pre-treatment, post-treatment and post-haplo-SCT blood samples can be found in (Table 2; Fig. 3). A total of 8 mutations were detected in the pre-treatment sample when she had AML, 5 mutations remained on her post-chemotherapy analysis where there was residual myelodysplasia, and no mutations were present after haplo-SCT. At the time of writing, she is currently 14 months post-transplant, with no evidence of disease relapse, with 100% Donor chimerism. | acute myeloid leukaemia, familial platelet disorder, runx1, stem cell transplant | Not supported with pagination yet | null |
PMC3806712_01 | Male | 50 | A 50-year-old male visited our hospital in October 1996 because of abnormalities detected in a medical checkup. Urinary protein and occult hematuria had been documented in medical checkups over the previous few years, with marked proteinuria of up to 3.8 g/day being a prominent feature of his clinical presentation. Renal biopsy performed in December 1996 revealed segmental sclerosis in 1 of 7 glomeruli and deposition of immunoreactive substances into glomeruli, including IgM and complement. Therefore, a diagnosis of FSGS was made on the basis of the results of a renal biopsy. Also, chest computed tomography (CT) delineated interstitial changes accompanied by cystic lesions in the lung and pleural thickening (fig. 1a), along with chest X-ray abnormalities that had been noted in a past medical checkup. He had worked as a demolition worker and smoked approximately 30 cigarettes a day since he was 18 years old. Work- and smoking-related lung conditions were therefore the most likely causes of the pulmonary lesions. An annual chest CT showed little change over several years, in contrast to progression of the renal disorder. Pleural thickening strongly suggested concomitant TB based on epidemiological reports showing a strong association of TB with pneumoconiosis, although mycobacterium species were not detected by sputum culture tests that were repeatedly performed over a couple of years.
Cyclosporine A (CsA) was administered at doses of 50-100 mg per day under therapeutic drug monitoring (the trough level was usually around 50 ng/ml) in lieu of steroid therapy to reduce the risk of excessive immunosuppression, but the serum creatinine (Cr) level showed a rapid elevation in 2000, at approximately 3 years after biopsy (fig. 2a). He had presented with persistent microscopic hematuria, which is inconsistent with the clinical presentation of FSGS, since the first visit. By contrast, a temporary decrease in proteinuria (down to 1.3 g/day) was observed afterward, unlike with treatment-resistant FSGS. Rapidly progressive glomerulonephritis was suspected despite the biopsy findings, and circulating ANCA was measured (this test has been clinically available since 1998 in Japan). Elevation of the MPO-ANCA titer (168 EU) was found, along with an altered clinical presentation. However, potent immunosuppressive therapies such as glucocorticoids were still withheld due to the possibility of an underlying infection (TB). Apheresis was alternatively conducted in an effort to avoid decreased immune competence, but initiation of HD was required in September 2001 because of end-stage renal disease (ESRD). Thrice-weekly HD was performed uneventfully for several years, and there were also no changes in pulmonary signs. An annual CT checkup had shown little change (fig. 1b), and elevation of serum KL-6 had not been documented. In contrast, circulating MPO-ANCA had ranged from 10.5 to 32.5 U/ml, even in the dialysis period, indicating possible AAV (fig. 2b). However, steroid therapy was postponed due to the unconfirmed diagnosis, presumed TB, and lack of problematic clinical events.
Abruptly, the patient developed gross hemoptysis accompanied by severe cough at night in bed and was transported to our facility by ambulance in October 2010. Chest CT showed infiltrative shadows in the bilateral lung fields (fig. 1c). Under a presumptive diagnosis of alveolar hemorrhage associated with AAV, steroid therapy comprising 3-day intravenous infusion of 500 mg methylprednisolone followed by daily oral administration of 20 mg prednisolone (PSL) was launched. A preventive dose of 100 mg isoniazid per day was also prescribed. As expected, the hemorrhagic shadows almost disappeared as early as 2 days after hospitalization (fig. 1d), and the serum MPO-ANCA titer subsequently fell to normal (fig. 2b). The patient was discharged after 17 days and has had no recurrence of hemoptysis. At present, PSL has slowly been tapered to a daily dose of 5 mg, but there has been little change over time in the serum MPO-ANCA level and follow-up CT. | anca-related nephritis and vasculitis, focal and segmental glomerulosclerosis, pulmonary hemorrhage, tuberculosis | Time course of pulmonary lesions in our patient. b; Chest CT from September 2001 shows little change. |
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PMC3806712_01 | Male | 50 | A 50-year-old male visited our hospital in October 1996 because of abnormalities detected in a medical checkup. Urinary protein and occult hematuria had been documented in medical checkups over the previous few years, with marked proteinuria of up to 3.8 g/day being a prominent feature of his clinical presentation. Renal biopsy performed in December 1996 revealed segmental sclerosis in 1 of 7 glomeruli and deposition of immunoreactive substances into glomeruli, including IgM and complement. Therefore, a diagnosis of FSGS was made on the basis of the results of a renal biopsy. Also, chest computed tomography (CT) delineated interstitial changes accompanied by cystic lesions in the lung and pleural thickening (fig. 1a), along with chest X-ray abnormalities that had been noted in a past medical checkup. He had worked as a demolition worker and smoked approximately 30 cigarettes a day since he was 18 years old. Work- and smoking-related lung conditions were therefore the most likely causes of the pulmonary lesions. An annual chest CT showed little change over several years, in contrast to progression of the renal disorder. Pleural thickening strongly suggested concomitant TB based on epidemiological reports showing a strong association of TB with pneumoconiosis, although mycobacterium species were not detected by sputum culture tests that were repeatedly performed over a couple of years.
Cyclosporine A (CsA) was administered at doses of 50-100 mg per day under therapeutic drug monitoring (the trough level was usually around 50 ng/ml) in lieu of steroid therapy to reduce the risk of excessive immunosuppression, but the serum creatinine (Cr) level showed a rapid elevation in 2000, at approximately 3 years after biopsy (fig. 2a). He had presented with persistent microscopic hematuria, which is inconsistent with the clinical presentation of FSGS, since the first visit. By contrast, a temporary decrease in proteinuria (down to 1.3 g/day) was observed afterward, unlike with treatment-resistant FSGS. Rapidly progressive glomerulonephritis was suspected despite the biopsy findings, and circulating ANCA was measured (this test has been clinically available since 1998 in Japan). Elevation of the MPO-ANCA titer (168 EU) was found, along with an altered clinical presentation. However, potent immunosuppressive therapies such as glucocorticoids were still withheld due to the possibility of an underlying infection (TB). Apheresis was alternatively conducted in an effort to avoid decreased immune competence, but initiation of HD was required in September 2001 because of end-stage renal disease (ESRD). Thrice-weekly HD was performed uneventfully for several years, and there were also no changes in pulmonary signs. An annual CT checkup had shown little change (fig. 1b), and elevation of serum KL-6 had not been documented. In contrast, circulating MPO-ANCA had ranged from 10.5 to 32.5 U/ml, even in the dialysis period, indicating possible AAV (fig. 2b). However, steroid therapy was postponed due to the unconfirmed diagnosis, presumed TB, and lack of problematic clinical events.
Abruptly, the patient developed gross hemoptysis accompanied by severe cough at night in bed and was transported to our facility by ambulance in October 2010. Chest CT showed infiltrative shadows in the bilateral lung fields (fig. 1c). Under a presumptive diagnosis of alveolar hemorrhage associated with AAV, steroid therapy comprising 3-day intravenous infusion of 500 mg methylprednisolone followed by daily oral administration of 20 mg prednisolone (PSL) was launched. A preventive dose of 100 mg isoniazid per day was also prescribed. As expected, the hemorrhagic shadows almost disappeared as early as 2 days after hospitalization (fig. 1d), and the serum MPO-ANCA titer subsequently fell to normal (fig. 2b). The patient was discharged after 17 days and has had no recurrence of hemoptysis. At present, PSL has slowly been tapered to a daily dose of 5 mg, but there has been little change over time in the serum MPO-ANCA level and follow-up CT. | anca-related nephritis and vasculitis, focal and segmental glomerulosclerosis, pulmonary hemorrhage, tuberculosis | Time course of pulmonary lesions in our patient. c; Chest CT from October 2010 shows infiltrative shadows (arrows) in bilateral inferior lobes, simultaneously with hemoptysis. |
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PMC3806712_01 | Male | 50 | A 50-year-old male visited our hospital in October 1996 because of abnormalities detected in a medical checkup. Urinary protein and occult hematuria had been documented in medical checkups over the previous few years, with marked proteinuria of up to 3.8 g/day being a prominent feature of his clinical presentation. Renal biopsy performed in December 1996 revealed segmental sclerosis in 1 of 7 glomeruli and deposition of immunoreactive substances into glomeruli, including IgM and complement. Therefore, a diagnosis of FSGS was made on the basis of the results of a renal biopsy. Also, chest computed tomography (CT) delineated interstitial changes accompanied by cystic lesions in the lung and pleural thickening (fig. 1a), along with chest X-ray abnormalities that had been noted in a past medical checkup. He had worked as a demolition worker and smoked approximately 30 cigarettes a day since he was 18 years old. Work- and smoking-related lung conditions were therefore the most likely causes of the pulmonary lesions. An annual chest CT showed little change over several years, in contrast to progression of the renal disorder. Pleural thickening strongly suggested concomitant TB based on epidemiological reports showing a strong association of TB with pneumoconiosis, although mycobacterium species were not detected by sputum culture tests that were repeatedly performed over a couple of years.
Cyclosporine A (CsA) was administered at doses of 50-100 mg per day under therapeutic drug monitoring (the trough level was usually around 50 ng/ml) in lieu of steroid therapy to reduce the risk of excessive immunosuppression, but the serum creatinine (Cr) level showed a rapid elevation in 2000, at approximately 3 years after biopsy (fig. 2a). He had presented with persistent microscopic hematuria, which is inconsistent with the clinical presentation of FSGS, since the first visit. By contrast, a temporary decrease in proteinuria (down to 1.3 g/day) was observed afterward, unlike with treatment-resistant FSGS. Rapidly progressive glomerulonephritis was suspected despite the biopsy findings, and circulating ANCA was measured (this test has been clinically available since 1998 in Japan). Elevation of the MPO-ANCA titer (168 EU) was found, along with an altered clinical presentation. However, potent immunosuppressive therapies such as glucocorticoids were still withheld due to the possibility of an underlying infection (TB). Apheresis was alternatively conducted in an effort to avoid decreased immune competence, but initiation of HD was required in September 2001 because of end-stage renal disease (ESRD). Thrice-weekly HD was performed uneventfully for several years, and there were also no changes in pulmonary signs. An annual CT checkup had shown little change (fig. 1b), and elevation of serum KL-6 had not been documented. In contrast, circulating MPO-ANCA had ranged from 10.5 to 32.5 U/ml, even in the dialysis period, indicating possible AAV (fig. 2b). However, steroid therapy was postponed due to the unconfirmed diagnosis, presumed TB, and lack of problematic clinical events.
Abruptly, the patient developed gross hemoptysis accompanied by severe cough at night in bed and was transported to our facility by ambulance in October 2010. Chest CT showed infiltrative shadows in the bilateral lung fields (fig. 1c). Under a presumptive diagnosis of alveolar hemorrhage associated with AAV, steroid therapy comprising 3-day intravenous infusion of 500 mg methylprednisolone followed by daily oral administration of 20 mg prednisolone (PSL) was launched. A preventive dose of 100 mg isoniazid per day was also prescribed. As expected, the hemorrhagic shadows almost disappeared as early as 2 days after hospitalization (fig. 1d), and the serum MPO-ANCA titer subsequently fell to normal (fig. 2b). The patient was discharged after 17 days and has had no recurrence of hemoptysis. At present, PSL has slowly been tapered to a daily dose of 5 mg, but there has been little change over time in the serum MPO-ANCA level and follow-up CT. | anca-related nephritis and vasculitis, focal and segmental glomerulosclerosis, pulmonary hemorrhage, tuberculosis | Time course of pulmonary lesions in our patient. d; Chest CT 2 days later in October 2010 shows disappearance of the hemorrhagic shadows shortly after initiation of steroid therapy. |
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PMC4435386_01 | Female | 14 | A 14-year-old female presented with a 2-month history of intermittent abdominal pain, nausea, bloating, and diarrhea. She was diagnosed with CD, with a positive celiac serology (tissue transglutaminase [tTG] IgA 100 U/mL) and Marsh 3b duodenal histology (Figure 1). GFD resulted in mild symptomatic improvement and a drop in the tTG IgA to 11 U/mL. However, abdominal pain and poor weight gain persisted through 10 months of a strict GFD at home. Endomysial antibody titers were negative. Genetic testing was positive for HLA-DQ2 and negative for HLA-DQ8.
Our nutritionist performed a detailed dietary assessment, which did not reveal any gluten exposure. Under close supervision of our nutritionist, the patient tried a modified diet excluding all grains and processed foods for 3 months with no improvement. Subsequently, a diet of only elemental nutritional supplements was attempted for 4 weeks, followed by complete bowel rest with total parenteral nutrition (TPN) for 4 weeks, each with no improvement.
Repeat upper endoscopy and colonoscopy was completely normal. Tests were negative for giardiasis, tropical sprue, post-infectious enteritis, inflammatory bowel disease (including negative p-ANCA, anti-Saccharomyces cerevisiae antibodies, anti-OmpC, and anti-CBir serology), small intestinal bacterial overgrowth, lactase deficiency, HIV, common variable immunodeficiency, eosinophilic gastroenteritis, autoimmune enteropathy, and Mycobacterium tuberculosis. Video capsule endoscopy showed jejunal scalloping (Figure 2). Jejunal biopsies obtained via push enteroscopy showed active CD, Marsh 3a lesions with villous blunting and increased intraepithelial lymphocytes (50 IELs/100 enterocytes). After 20 months of GFD and persistent villous atrophy, the patient was diagnosed with RCD.
Immunostaining of the IELs showed normal CD3 and CD8-positive lymphocytes, and T-cell rearrangement (TCR) analysis showed polyclonal T-cell bands, consistent with the diagnosis of type I RCD. The patient was offered prednisone, budesonide, and azathioprine, but the patient and her family did not want corticosteroids due to the patient's high BMI (>97th percentile), severe acne, a prior diagnosis of polycystic ovarian syndrome, and a family history of hypertension. The patient was started on 5 mg/kg infliximab, and symptoms and serology improved over 8 months of treatment with normalization of mucosa on jejunal biopsy. The patient continues to be on a GFD while receiving 5 mg/kg infliximab every 8 weeks, and remains asymptomatic. | null | Not supported with pagination yet | null |
PMC4283356_01 | Male | 26 | We describe a case of a 26-year-old Hispanic male, who presented (Day 1) to his primary care physician (PCP) office after he noticed progressively worsening yellowish discoloration of his eyes and skin for 10 days' duration. In addition, he had noticed dark urine for 2-3 weeks and pale colored stools for 5-7 days. He complained of nausea, generalized fatigue, and malaise but did not have any abdominal pain, fever, chills, diarrhea, or any skin rash. He was noted to have diffuse jaundice, hepatomegaly, and mild epigastric tenderness on examination. The laboratory evaluation revealed abnormalities in liver panel, with total bilirubin (TBili) of 12.2 mg/dL, alkaline phosphatase (AlkP) 272 IU/dL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) of 2112 and 1055 IU/dL, respectively (Table 1). The complete blood count (CBC) and coagulation panel (INR) were normal at that time. He was admitted to our hospital where he underwent initial workup for painless jaundice. Upon initial evaluation by hepatology service, he informed us that he was originally from Puerto Rico and was living in the US for 17 years. He denied any history of significant illness as a child or any known history of liver disease in any family member. He denied any episodes of mental confusion and excessive sleepiness, as well as hematemesis, hematochezia, melena, or poor appetite. He also denied pruritus at any time and lower extremity edema or increased abdominal girth. He denied any recent sick contacts, animal exposure, or travel outside the US. He denied any history of incarceration, tattoos, or blood transfusions. He denied any history of tobacco use, illicit drug usage such as marijuana, cocaine, and heroin, or abuse of amphetamines. He reported drinking alcohol only on occasions and his last drink was approximately 7 months prior to this admission. However, he did report that he had been using over-the-counter anabolic steroids and a supplement from a vitamin store as a muscle-building high performance protein supplement (the ingredients are indicated in Table 3) on a daily basis for approximately 6 months. On examination, he appeared comfortable with diffuse jaundice and somewhat tender hepatomegaly. No clinical stigmata of advanced liver disease were identified on examination. The baseline serologic workup is shown in Table 2 which ruled out any infectious, autoimmune, or metabolic causes of his liver disease. The radiological workup with ultrasound, and a Magnetic Resonance Cholangiopancreatography did not reveal any biliary obstruction. He was suspected to have probable DILI with significant hyperbilirubinemia based on the negative etiologic workup. For further confirmation, he underwent a liver biopsy (Day 5) which revealed quite an impressive inflammatory process involving both portal areas and the lobules displaying also a pattern of sinusoidal lymphocytosis (Figure 1). The hepatocytic injury was identified and was more prominent in centrilobular (zone 3) location. Trichrome stain revealed only mild portal and periportal fibrosis and some perisinusoidal fibrosis especially in centrilobular location where the majority of the hepatocytic damage was identified along with mild collapse of the reticulin framework and likely was the result of hepatocytic dropout. Within the lobules, there was prominent "spotty necrosis," highlighted with the PAS positive, diastase resistant stain, revealing macrophages loaded with phagocytic debris. Iron stores were not increased and immunostain for adenovirus, cytomegalovirus (CMV), herpes virus, and hepatitis B surface antigen were also negative on the histologic tissue. Iron stain was negative and copper stain showed no increased copper deposition in the hepatocytes. Based on the above findings, he was started on a short course of oral prednisone and ursodiol (Day 8) as the treatment for severe AH with cholestasis. His laboratory tests showed gradual improvement in hepatitis and subsequently he was discharged to be followed up as outpatient. He was seen in the clinic for monitoring (Day 35) and reported over all symptomatic improvement and he had started back his job as a residential painter. His follow-up monitoring laboratory testing 6 weeks later showed continued improvement in AH (Figure 2) while he stayed on low dose ursodiol.
On his next set of monitoring laboratory testing (Day 142), new onset severe pancytopenia (Table 1) was identified which prompted urgent hospital admission for evaluation and management of his pancytopenia. All viral etiologies of acute pancytopenia were ruled out by serologic analysis. He did not have any family history of AA. Extensive hematological workup was performed and all other causes of primary SAA were ruled (negative anti-CD55 and anti-CD59 antibodies, negative urinary collections for lead and arsenic, and negative flow cytometry). Peripheral blood smear analysis revealed severe neutropenia and normocytic anemia with frequent target cells, consistent with clinical history of liver disease along with severe thrombocytopenia. He underwent a bone marrow biopsy and flow cytometry analysis which showed severe hypocellular bone marrow (less than 5%) with dyserythropoiesis (Figure 1). The cytogenetic study showed normal karyotype. Immunostain with CD3 and PAX5 stains showed no involvement of lymphoma. CD34, TdT, and CD117 stains confirmed no significant increase of blasts. D31 and Factor-VIII stains show virtual absence of megakaryocytes. In view of the patient's age, gender, and his presentation with initial AH, the diagnosis of HAAA was made. The patient did not have any full siblings and in view of the absence of matched HLA siblings, the decision was made to immediately initiate IST. He initially received thymoglobulin (ATG) along with methylprednisolone treatment for a total of 5 days. He received prophylactic antimicrobials, in addition to filgrastim daily and platelet transfusions as needed to support his peripheral cell count. He responded to the induction therapy with the improvement in cell counts and significant reduction in his liver enzymes. Later, he was kept on cyclosporine (Cys) and prednisone was tapered off. This resulted in stable cell counts and partial recovery of bone marrow (Day 160). IST was continued as cyclosporine monotherapy and further improvement in cell counts was seen (Figure 2). He continues on cyclosporine with complete recovery of HAAA (Table 1) after 3 years of initial presentation. | null | Not supported with pagination yet | null |
PMC8179094_01 | Unknown | 12 | From these meetings, the leadership team developed connections with each other, generated value and excitement for the project, and collaboratively established the project goals, which included: (a) develop a training program that will build staff's competencies to apply sport-based trauma-sensitive practices at their clubs, (b) have staff implement these practices as the BBL program across 13 clubs (reaching 20-25 members [9-12 years old]/club, per season [3 seasons a year]), (c) use a train-the-trainer model to build BGC Canada's capacity to maintain and sustain BBL, and (d) evaluate program components to inform BBL adaptations. In line with each goal were the intended outcomes: (a) staff implement BBL effectively at their clubs; (b) BBL members experience improvements in basic psychological needs support, resilience-related life skills, and well-being; (c) a master trainer team is formed to train future BBL staff beyond grant duration; and (d) program materials are developed with guidelines for effective BBL implementation.
The leadership team established to communicate regularly on BBL program development over monthly phone/video calls. Roles of team members were also established. Here, BGC Canada administrators were responsible for coordinating, communicating, and checking-in with clubs on an ongoing basis, which included relaying expectations and arranging for staff involvement in BBL trainings. The consultants were responsible for designing and delivering the sport-based trauma-sensitive practice training to staff and holding ongoing phone/video calls with lead staff at each club to answer design questions and offer feedback. BGC Canada managers were responsible for participating in trainings and managing their own club's design and delivery of BBL.
The researchers were responsible for developing evaluation tools, training staff on how to use the tools, assisting clubs with collecting data during on-site visits, analyzing and communicating these data, and soliciting staff feedback regarding the feasibility of evaluation activities in practice. The program was to be carried out over 4 subsequent years, including 2 years of piloting across three clubs with ongoing adaptation. Evaluation findings from pilot and adaptation stages would inform the expansion to 10 clubs in the final 2 years. Use of a train-the-trainer model would help build and maintain project sustainability beyond grant duration.
The pilot stage involved implementing the BBL training with three BGC Canada clubs, who then went on to design and deliver their first seasons of BBL:with the leadership team's close monitoring, evaluation, and ongoing support, as per their established roles in the planning stage. In alignment with the KTAC phase assess barriers and facilitators to knowledge use, this BBL stage focused on exploring the successes and challenges that arose in the pilot. Given that multiple KTAC phases can be an undergone concurrently, three sub-phases were also carried out: select, tailor, and implement an intervention, monitor knowledge use, and evaluate outcomes. A multi-faceted, sport-based, trauma-sensitive practice training intervention was designed for staff to learn how to develop BBL programs at their home clubs. Twelve staff participants (three managers, three supervisors, six coaches) across three clubs, were gathered to attend an initial 3-day intensive workshop.
The workshop was primarily facilitated by the consultants, with the support and participation of the researchers and BGC Canada administrators. The topics broadly covered: (a) psychoeducation of the prevalence and impact of trauma on the child, (b) factors that contribute to trauma healing in sport, (c) strategies to intervene with members in times of dysregulation, (d) strategies for coaching and re-designing sport to facilitate resilience-building, (e) strategies to facilitate members' skill development. The topics were further adapted in subsequent iterations of the training workshop during the BBL's adaptation stage (see Table 1 for list of workshop modules). The facilitators used delivery strategies such as brief lectures, story sharing, paired and group discussions, active games and sports, coaching practice, role play activities, and workbook activities. Staff received a guidebook as a resource to use post-workshop as they returned to their home clubs to implement BBL. Staff gathered again at 4- and 12-months into programming to attend refresher workshops (2-days each). An online social learning space was established via Slack, where the leadership team and participating clubs shared experiences, resources, strategies, media, and questions with one another throughout the project, in effort to ease access to communications, resources, and learning opportunities.
During program implementation, each club aimed to recruit 20-25 members (ages 9 to 12) per season. The goal was for each club to run three seasons a year, with each season building on the relationships and skill development of the previous season. Members were welcome to participate in multiple seasons. Clubs could choose season length (6-10 weeks), the sport (e.g., basketball, soccer, ball hockey), and session frequency (all clubs chose 1/week). All clubs were responsible for structuring sessions around a universal BBL workout structure, comprised of seven intentional components (see Table 2 for complete details): (a) arrival, (b) warm-up, (c) skill play, (d) transition time, (e) cool down, (f) team time, and (g) departure. This structure offered a predictable schedule of activities, in which members could experience safety, skill-building opportunities, and practice regulating themselves in competitive, real stakes environments (Bergholz et al.,).
Staff were trained on several techniques to proactively facilitate members' regulation (e.g., practicing deep breathing to help calm emotions, allowing unlimited timeouts to rest when feeling overwhelmed, and structuring a space [The Zone] to enter, self-regulate, and return to main activities when ready). Staff also adopted a 4-step framework to connect with members in times of dysregulation: (a) stabilize:support member in a triggered state to re-regulate and arrive to a place where they can have a conversation, (b) explore:facilitate a judgment-free inquiry about what the member is experiencing, (c) plan:co-construct strategies to resolve what happened and to regulate better in the future, and (d) return:co-construct strategies to transition back to the activities on the member's own will.
The program also focused on teaching three BBL skills tied to resilience-building (see Table 2): (a) come to play (e.g., preparation, self-awareness), (b) build my team (e.g., empathy, seeking support), and (c) play on (e.g., effort, recovery). Strategies to facilitate these BBL skills included defining skills out loud, having a 'skill of the week', posters with skills and definitions, encouraging and praising skill use, and reflecting on skills during team time (Bean et al.,). These skills were constructed based on evidence of what works in trauma-sensitive sport programming (Edgework Consulting,), understandings of life skill development through sport (Holt et al.,), and BGC Canada core values (BGC Canada,). See Supplement 1 for strategies on facilitating BBL skills within the BBL Workout Structure.
In evaluating the program, three questions were proposed: (a) how did staff perceive their training experiences and what value was generated from these experiences? (b) what were the successes and challenges that staff met in implementing their training into practice? and (c) what was the impact of programs on members? A mixed-methods approach was used to address these questions. To explore staff's training experiences, knowledge surveys and interviews were conducted pre- and post-training, and field notes, pictures, and audio-recordings were taken during training. To monitor successes and challenges, staff completed structured logbooks after each BBL session, participated in multiple focus groups and interviews, and shared conversations on Slack. To examine program impact, members completed surveys on well-being (Tennant et al.,), resilience-related skills (Windle et al.,), and basic needs support (Bean, Rocchi, et al.,; Bean, Sewell, et al.,). Members also took part in interviews and arts-based activities, and staff completed report cards of members' participation (Shaikh et al.).
Evaluation results related to staff's training experiences revealed that many desired outcomes were reached, including high satisfaction and usefulness of the training workshop for staff, building staff's BBL-related knowledge and skills, and staff's use of trauma-sensitive practices in the BBL and into their everyday lives (Shaikh et al.,; Shaikh, Bergholz, et al.,). Several facilitators to knowledge use were identified: (a) staff's existing experiences with trauma-exposed members in BGC Canada helped ease adoption of sport-based trauma-sensitive practice, (b) staff found the training workshops highly engaging, useful, applicable, and valuable; (c) staff perceived that training content aligned with what they experienced in practice, (d) ongoing meetings with consultants facilitated continuous learning for staff, and (e) the pilot allowed room for trial and error, which eased staff's apprehensions in applying a novel program and practice (Shaikh et al.,; Shaikh, Bergholz, et al.,; Shaikh, Forneris, et al.,).
Despite these facilitators, clubs reported several challenges (i.e., Shaikh, Bergholz, et al.,) that were consistent with research in community programs (Forneris et al.,; Larson et al.,). A major difficulty was in recruiting and retaining children (e.g., scheduling difficulties, building value for the BBL, competition with other programs, referral-recruitment versus open-to-all recruitment. Inconsistent attendance made it difficult for staff to maintain an engaging experience where members can foster positive peer connections. Staff also found it challenging to balance the demands of a structured program with the myriad of children's behavioral issues (e.g., outbursts, disengagement, aggression), given that BGC Canada staff:and members:are most familiar with unstructured, free play opportunities. As well, clubs encountered staff turnover:an inevitable reality of youth-serving organizations where many staff are part-time or in transition phases of their careers:which led to loss of capacity, especially when staff were BBL trained.
Consistent relationships are primary protective factor in supporting trauma healing (NCTSN,). A benefit of having BBL managers and supervisors attend training was their capacity to step in when staff were absent. This strategy worked well given that the BBL members were also BGC Canada members who attended other programs within the club. Thus, members interacted with supervisors and managers on a regular basis beyond BBL:contributing to consistency in mentorship. Evaluation results related to program impact revealed improvements in outcomes, albeit non-significant; here, perceived well-being trended upward from pre-post season, and members who attended > 80% sessions reported higher basic psychological needs support (Shaikh & Forneris,). Qualitative data analysis revealed that the members reported feeling accepted, having improved friendships, and developing sport and life skills (Shaikh & Forneris,). These positive learning experiences suggested some initial effectiveness of the BBL. Overall, these evaluation findings informed BBL adaptations in the next stage.
Concurrently with the pilot stage, the adaptation stage was informed by the combination of ongoing leadership team meetings, consultations and check-ins with each club, and evaluation results. The KTAC phase of adapt knowledge to the local context was re-visited, using insights of barriers and facilitators to knowledge use to inform ongoing BBL project development; adapting BBL processes at the organizational-level and club-level. These adaptations were communicated through email, bi-monthly meetings, Slack, and refresher training workshops. The major adaptations included: (a) tailoring the training intervention, (b) supporting staff's motivations and accounting for staff turnover, (c) enhancing recruitment strategies, and (d) transition of training responsibilities to master trainers.
The leadership team worked together to develop 12 BGC Canada-adapted modules, covering how to build staff's awareness and value for sport-based trauma-sensitive practice, and how to structure and design a BBL program (see Table 1). These modules were the foundational structure for the training workshop and the development of BBL resources (i.e., the coach guidebook, operating manual, training manual). To address the challenges that staff encountered in intervening with dysregulated members, more focus was added to strategies for managing groups and helping members return to a stabilized state.
At the organizational level, the leadership team established bi-monthly check-ins with all pilot clubs together. This strategy offered additional mentorship and oversight to the staff, building morale, shared understanding, and value for BBL (Ika & Donnelly,), and enabled staff to share experiences and learn from each other. At the club level, managers were encouraged to: (a) choose trainee candidates that were full-time staff and planned to invest in the club long-term; (b) supervise at least half of staff's BBL sessions and provide them feedback to help monitor, support, and enhance the quality of their BBLs; and (c) have other staff sit in on BBL sessions to observe, participate, learn, and eventually transition into BBL when faced with staff turnover.
At the organizational level, customizable promotional materials were created (i.e., posters, infographics) with BBL branding for clubs to use in their marketing. To enhance recruitment, all clubs were encouraged to remove limits to BBL membership and invite all children to participate regardless of pre-identified risk status. This strategy helped maximize reach and inclusiveness to unscreened trauma-exposed children.
To promote the self-sustaining capacity of the BBL, a train-the-trainer model was used to train BGC Canada managers and other key staff to become BBL master trainers (Shaikh, Bean, et al.,). To carry this out, an intensive training workshop was facilitated by the leadership team, in which BGC Canada managers learned and delivered the 12 BGC Canada-adapted BBL training modules to their peers and received feedback to improve their delivery. Following the workshop, these newly trained master trainers returned to their home clubs to plan the delivery of BBL training workshops to their staff. These workshops were also observed by leadership team members, who provided feedback. The master trainers were then expected to be help train newly onboarded staff in the expanded rollout.
The expansion involved rolling out, monitoring, and evaluating the adapted training intervention and BBL programs in ten additional clubs across Canada. Three KTAC phases of select, tailor, and implementing interventions, monitor knowledge use, and evaluate outcomes were undergone (again). Here, the master trainers carried out the training intervention as an intensive, in-person workshop to 20 staff, covering the 12 BGC Canada-adapted training modules. The leadership team supported master trainers in communicating expectations, coordinating travel and logistics for clubs, and modifying evaluation tools. The newly trained staff went on to deliver programs at their home clubs, while continuing to receive support from master trainers (e.g., bi-monthly calls), and the leadership team (e.g., via Slack, email, and on-site visits). The same evaluation questions were used to monitor BBL training and program implementation, using a slightly modified mixed-methods approach. For instance, items on knowledge assessments and logbooks were matched to the adapted training modules, and the length and wording of member's surveys were simplified.
Each club ran one season (~ 6-10 weeks); the second season was cut short due to the COVID-19 pandemic. Currently, evaluation is still ongoing, as clubs offer either in-person, physically distanced program delivery, or virtual delivery. However, initial outcomes of the BBL expansion have indicated that: (a) the training intervention was successful in improving knowledge and attitudes of participating staff in sport-based trauma-sensitive practice; (b) the training intervention was perceived as enjoyable and useful for staff; (c) in most clubs, recruitment of members successfully reached 20-25 + members; however, at least two clubs were well under this mark; (d) having trained staff is essential for running high-quality BBL programs; yet, with staff turnover, clubs without trained staff resorted to traditional practices of youth engagement in sport, resulting in loss of trauma-sensitive practice. Thus, there is a need for incorporating alternative sustainability practices within BGC Canada to maintain BBL quality during and beyond grant duration.
The sustainability stage involves initiatives put in place to continue BBL beyond grant- end, in alignment with the sustain outcomes phase of KTAC. The first goal in this plan was to maintain and expand the BBL (as a sport-based trauma-sensitive practice program) to more clubs across Canada. A second, broader goal was to build staff's capacities in trauma-sensitive practices across BGC Canada clubs and programs, beyond sport. This second goal was constructed based on advocacy from BBL staff of the value of trauma-sensitive practices and their applicability in club work outside the BBL, as well as interest from additional clubhouses in building their club's trauma-sensitive capacity. Several processes will contribute to reaching these two goals: (a) using a train-the-trainer model, (b) developing context-specific resources, (c) expanding to reach Canadian newcomers, (d) transitioning to a virtual platform in COVID-19.
Using a train-the-trainer model helped build the organization's ownership of the program, promoting internal sustainability (Shaikh, Bean, et al.,; Whitley et al.,). Here, BBL managers who delivered BBL in the pilot were offered training to develop into master trainers and went on to facilitate BBL training for staff within and beyond their clubs. Clubs with access to master trainers were then able to host sport-based trauma-sensitive practice as a core part of their club's training. Master trainers also train staff at a national level, whether through facilitating training workshops or consultations with newly onboarded BBL clubs.
Developing context-specific knowledge products was important for communicating knowledge in clear and user-friendly ways, which can facilitate continued use of knowledge in practice (Holt et al.,). Materials were created that can be shared and used universally across the clubs, including the coach guidebook, training manual, promotional materials, and evaluation activities. As well, evaluation findings were shared throughout the project through user-friendly media (i.e., presentations, reports, infographics, and posters). Blogging was used as an effective means of disseminating knowledge beyond academic audiences (Stoneham & Kite,); here, the leadership team published a blog on strategies for integrating trauma-sensitive practices into play (Shaikh et al.. The authors also shared their experiences on integrating evaluation activities within community organizations along with effectives strategies for sport stakeholders to build evaluation capacity (Shaikh et al.).
Given the importance of funding in maintaining relationships and capacity building (Coppola & McHugh,), various means of extending BBL funding have been explored. BGC Canada secured funding to extend BBL across five additional clubs to target Canadian newcomer populations. Direct support for newcomers is needed as they may face unique traumatic exposure; refugees from conflict regions can face loss, grief, family separation, mental health disorders, and migratory stressors (Ley & Mario,). In this expansion, an advisory group was created with BBL managers to share and co-construct strategies for meeting newcomer needs and integrating equity, diversity, and inclusion principles in BBL design, recruitment, and practice. Development of BBL for newcomers is currently underway. This extension has taken on a unique look post-pandemic, where clubs have had to shift their BBL programs to virtual and physically distanced settings.
To effectively meet BBL staff's needs in the pandemic, staff perspectives were sought through virtual meetings and a needs assessment survey. Staff largely requested more training in trauma-sensitive practices, support to shift BBL virtually, and strategies to facilitate small group, in-person activities. Thus, the leadership team delivered virtual training for staff during Summer 2020, which covered refreshers of BBL content and strategies to facilitate virtual BBL. All clubs then transitioned to a modified BBL in Fall 2020 (i.e., physically-distanced in-person or virtually). Monitoring and evaluation are currently ongoing, to gain insights of successes and challenges of facilitating BBL in a COVID world.
The abrupt shift, the need for trauma-sensitive practices across clubs in Canada, and the success in adapting the BBL based on changing conditions, made it ideal for the leadership team to pursue further options for project scale-out (Ika & Donnelly,). Thus, funding was secured to develop virtual trauma-sensitive training for scale-out to BGC Canada's 775 clubs nationally. Here, the KTAC will be re-cycled as a second iteration. The problem identified was the need for integrating trauma-sensitive practices across all BGC Canada clubs; the selected knowledge was the BGC Canada-adapted trauma-sensitive practice modules and program materials; this knowledge will be adapted from in-person to virtual via BGC Canada's virtual e-learning platform; and this training will be implemented to ten BGC Canada clubs, reaching ~ 150 staff.
The strength of the BBL partnership has led to many successes and effective responses to challenges in the BBL development process. Three lessons are shared that were most pertinent to advancing KT processes in BGC Canada. These lessons may be considered by sport, community, and recreation groups when integrating trauma-sensitive practices for effective project development: (a) meaningful change starts with small steps, (b) maintain ongoing two-way communication with stakeholders, and (c) integrate-with rather than add-on to existing activities.
The leadership team avoided using an all-at-once approach in both the training and implementation to ease integration and prevent overburdening staff (Bromley et al.,). Instead, a developmental approach was taken, involving short, intensive training workshops and ongoing consultations over a long period of time. This approach enabled more time for staff skill-building (i.e., BBL design and delivery) and learning through trial and error (an oft-preferred source of learning in sport; Walker et al.,). The ongoing consultations helped monitor skill development and generate insights on high impact behaviors:staff skills used to generate effective results. High impact behaviors are not necessarily known from the outset:their effectiveness will depend on the staff's characteristics, the demands of the context, and the member's needs (Larson et al.,). Thus, it was worth investing time in the design and pilot process to determine these high impact behaviors and prioritize them in project development. For instance, a high impact behavior in BBL was integrating BBL skills (e.g., naming and defining skills, using skills in informal conversations, integrating a "skill of the week").
When staff integrated BBL skills, members were more likely to understand and internalize the skills. While effectiveness of explicit life skill teaching is supported in youth sport research (Bean et al.,), the developmental approach used in BBL was necessary to explore what these behaviors looked like, under what conditions do they manifest, and how effective they were (Holt et al.,). Then, these skills were emphasized in further training and communications (e.g., sharing strategies), and in evaluation (e.g., logbooks included a space for staff to describe how they embedded BBL skills).
It was beneficial to engage BGC Canada stakeholders (i.e., program managers, club staff) from the outset, and communicate using easy channels of access (i.e., regular phone/video meetings, consultations with specific clubs, emails, and Slack). This ongoing communication aligned with the project's CBPR approach and was conducive to relationship building between the leadership team, stakeholders, and their peers (Coppola & McHugh,). Such relationship building can contribute to synergies between groups and build stakeholders' value for the project and its future (Schinke et al.,). Stakeholder input (e.g., feedback) and insights (e.g., club-specific successes and challenges) were also gathered in-depth through ongoing evaluation activities (e.g., interviews, focus groups, logbooks). These findings were valuable in actively supporting adaptations to existing programs, as opposed to exclusively at the end of the grant period (Brush et al.,). As well, open communication helped identify which clubs needed extra support and intervene with them (e.g., if clubs faced challenges in recruitment, planning activities for a wide age-range of members or integrating evaluation within a fixed time schedule).
Given the multi-faceted nature of staff's work within a community program context (Newman et al.,), it was important to work within the existing capacities of clubs and staff, rather than starting from scratch. For example, several clubs found it challenging to create an entirely new BBL (e.g., recruitment of members and staff, scheduling) and found that adapting an existing sport program to BBL was more feasible. Moreover, evaluation activities were developed and adapted through trial and error of what works. This process revealed that the act of doing evaluation was beneficial for participants.
With staff, logbooks were used to report session-by-session experiences, which brought insights into program fidelity; the logbooks also mutually benefitted staff in reflecting on the program session together:by discussing successes and challenges and setting goals for the next session. With members, quantitative pre-post surveys were used:which members found unengaging. Thus, evaluation was shifted to more creative, engaging, and participatory activities (e.g., drawing, storytelling) that could be integrated within existing programming (Shaikh et al.). These activities enabled participants to share their experiences:which mutually benefitted the program and members in applying BBL skills (e.g., applying come to play by being willing to share, applying build my team when giving praise to another member; Jacquez et al.,). | child, community-engaged, evaluation, knowledge translation, scale-out | Not supported with pagination yet | null |
PMC5297488_01 | Male | 40 | A 40-year-old male was admitted to our hospital with a 3-month history of recurrent respiratory infections and persistent pitting pedal edema. His past history revealed 3 to 5 episodes of recurrent respiratory tract infections and diarrhoea each year since last 20 years. He had been successfully treated for sputum positive pulmonary tuberculosis 8 years back for which he was prescribed isoniazid (300 mg/day), rifampicin (600 mg/day), ethambutol (1.5 g/day) and pyrazinamide (2 g/day) for 3 months, followed by isoniazid and rifampicin for 6 more months. Sputum smear examination for acid fast bacillus (AFB) was negative at 3 and 9 months of treatment. Physical examination revealed a malnourished afebrile male with blood pressure 100/60 mm Hg; and a heart rate of 96/min with pitting pedal edema in both lower limbs. Laboratory studies disclosed; hemoglobin level of 12 g/dl, white blood cells (WBC); 17270/mul, platelets; 641000/mul, erythrocyte sedimentation rate (ESR); 110 mm/h, C-reactive protein (CRP); 32 mg/dl (normal 0-5), total protein; 2.4 g/dl; and serum albumin of 1.4 g/dl. Liver function tests were normal. Urinalysis revealed 3+ proteinuria. Twenty four-hour urine protein was 3.4 g/day. Serum immunoglobulins were as follows: IgG; 1.28 g/l (normal 7-16), IgM ; <0.4 g/l (normal 0.4-2.3); IgA ; <0.6 g/l (normal 0.7-4). CD4/CD8 ratio and CD3 level was normal. C3 and C4 complement levels were normal. The abdominal and pelvic ultrasonography (USG) revealed that the liver was normal in size with a homogenous parenchyma. The spleen was also of normal size, and the parenchymal echotexture was homogenous. Both kidneys were enlarged (right kidney; 120 mm and left kidney; 130 mm) with normal corticomedullary differentiation. Chest x-ray and Electrocardiography (ECG) were normal. Cultures of blood and urine were negative. Serologies for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) were negative. Thoracic computed tomography (CT) scan revealed fibrotic scars with bronchiectatic changes in both upper lobes of lungs, suggestive of old healed tuberculosis. Since the patient had recurrent infections, hypogammaglobulinemia, nephrotic level proteinuria, and enlarged kidneys in the renal USG we conducted a renal biopsy. Biopsy revealed, AA positive secondary renal amyloidosis. Glomeruli showed variable widening of mesangial regions with deposition of periodic schiff stain (PAS) pale positive pink matrix showing apple green birefringence on Congo-red staining under polarizer. Immunohistochemistry was AA stain positive (Figure 1). Immunofluorescence microscopy revealed no staining with anti-human IgG, IgM, IgA, C3, C1q, kappa and lambda light chains antisera. Patient was treated symptomatically for respiratory tract infection and was discharged with low dose angiotensin receptor blocker. | immunodeficiency, proteinuria, secondary amyloidosis, tuberculosis | Not supported with pagination yet | null |
PMC8286186_01 | Female | 60 | A 60-year-old woman underwent 80 mg BCG (Tokyo strain) intravesical instillation therapy for high-grade pTa bladder cancer. She presented with fever (>48 hours), knee joint pain, and conjunctival hyperemia after receiving four infusions. She was administered 10 mg/day of prednisolone (as per 0.2 mg/kg body weight), an NSAID (loxoprofen sodium hydrate, 180 mg/day), and antituberculosis drugs (isoniazid (INH), 300 mg/day; rifampicin (REP), 450 mg/day; and ethambutol (EB), 750 mg/day) because she was diagnosed with BCG-induced Reiter syndrome. She was administered steroid pulse therapy (methylprednisolone, 1000 mg/day) for three days because high white blood cell (WBC) and C-reactive protein (CRP) levels and fever persisted. After the third day of administration, fever, joint pain, and inflammation improved quickly. Subsequently, the dose of prednisolone was gradually reduced to a maintenance dose of 30 mg (as per 0.6 mg/kg body weight), and the symptoms did not recur. | null | Not supported with pagination yet | null |
PMC8286186_05 | Male | 73 | A 73-year-old man underwent 80 mg BCG intravesical instillation therapy for high-grade pT1 bladder cancer. In addition, after receiving six infusions, he underwent BCG maintenance therapy every three months for three weeks, which was administered after using a urethral bougie to dilate his urethral stricture. On the same day, he was referred to our hospital because of fever and impaired consciousness. Upon examination, fever and decreased blood pressure were noted and the infected area was unclear; however, computed tomography (CT) revealed an increase in the perirenal fat concentration. BCG sepsis was diagnosed based on these findings and the patient's medical history of BCG administration after receiving the urethral bougie. The progress of treatment after hospitalization is shown in Figure 1. He was administered antituberculosis drugs (INH, 300 mg/day; RFP, 450 mg/day; and EB, 750 mg/day), an empirical nonspecific antibiotic, and an antidisseminated intravascular coagulation drug (thrombomodulin alfa) for BCG sepsis and disseminated intravascular coagulation after various tuberculosis tests were performed. Steroids were not administered because of the possibility of M. bovis infection. Ventilator management was performed for airway obstruction caused by oral bleeding, and dialysis management was required because of acute renal failure. Steroid pulse therapy was started because the fever persisted. CT on day 12 revealed findings suggestive of interstitial pneumonia. A diagnosis of interstitial pneumonia due to BCG was established based on the patient's presentations as follows: fever, decreased oxygenation, and no history of imaging findings of interstitial pneumonia. Steroid pulse therapy was administered (methylprednisolone, 1000 mg/day) for three days, and prednisolone was administered at a maintenance dose of 80 mg/day (as per 1 mg/kg body weight). The fever and inflammatory response reduced, and dialysis was no longer required. Additional steroid pulse therapy (methylprednisolone, 1000 mg/day for three days) was administered on day 19, and mechanical ventilation was discontinued on day 20. The dose of prednisolone was gradually reduced from 80 mg, and the symptoms did not recur. He was discharged on day 51. EB was stopped on day 64, and INH and REP were stopped on day 322; the symptoms have not recurred since then. | null | Not supported with pagination yet | null |
PMC10294263_01 | Male | 73 | A 73-year-old male patient, with no relevant medical history, had recently been diagnosed with stage IV urothelial cancer. The patient's diagnosis was discussed with a multidisciplinary tumor board, and enfortumab vedotin (1.25 mg/kg body weight on day one and eight of a three-weekly regimen) together with pembrolizumab (200 mg, every 3 weeks) was initiated. After three cycles, the patient developed a checkpoint inhibitor-related pneumonitis. Steroid therapy was initiated, i.e., prednisolone 1 mg/kg body weight/day. The pneumonitis resolved and treatment was rechallenged by only the admission of enfortumab vedotin during the last three cycles.
Following six cycles, the patient was hospitalized due to acute abdominal pain, nausea, vomiting, and diarrhea. An abdominal computed tomography (CT) scan was performed and revealed a diffuse edematous wall thickening of the level of the ileal loops (maximum 1 m in length) and of the rectosigmoid (shown in Fig. 1). Repetitive cultures were positive for Campylobacter-induced enterocolitis. Subsequently, cytomegalovirus (CMV)-induced colitis was also suspected due to fever spikes and high CMV viremia. Nevertheless, no CMV inclusions were noticed on histology of the colon and ileum. Treatment with azithromycin, 500 mg/day, and ganciclovir, 5 mg/kg body weight/12 h, was initiated.
Despite adequate treatment of these infectious complications, the patient deteriorated with persistent high-output diarrhea. Radiological reassessment showed unchanged edematous wall thickening at the level of the preterminal ileal loops. Extensive gastro-intestinal checkup was executed with infectious workup (multiplex PCR panel, CMV PCR), laboratory evaluation (TBC, HIV testing among other), fecal pancreatic elastase, total IgA and tissue transglutaminase IgA, repeat ileocolonoscopy, enteroscopy and esophagogastroduodenoscopy with multiple biopsies. Interestingly, the ileocolonoscopy and enteroscopy showed no mucosal changes in the ileum. Histopathology findings at the level of the colon were normal, while the ileal biopsies showed an enteritis, characterized by a marked inflammatory cellular infiltrate in the lamina propria consisting of neutrophils, lymphocytes, and plasma cells. During this period, blood tests showed a normal renal function, thyroid function, and liver tests.
At this point, grade 3 ICI enteritis (in casu ileitis) was identified, according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). The patient was treated with high-dose corticosteroids without any clinical and radiographic improvement. The following 6 months, he received multiple high doses of infliximab (10 mg/kg body weight), methotrexate, mycophenolate mofetil, and vedolizumab. Different opportunistic infections, such as catheter-related infections and sepsis secondary to bacterial translocation, were treated with antibiotics. A combination of enteral and parenteral nutrition was initiated because of cachexia. Eventually, surgical resection was considered due to persistent signs of obstruction. A presurgery CT enterography still showed extensive ileitis involving multiple segments but also suspected fibrotic strictures with significant prestenotic dilatations (shown in Fig. 2). These fibrotic areas were characterized by abnormally thickened loops with minimal enhancement, no adjacent mesenteric inflammation and demonstrated upstream small bowel dilatation.
During the laparotomy, an 80-cm pathological thickened and inflammatory-appearing ileum segment was resected and an entero-enterostomy was constructed. There were no immediate or late complications following surgery. Histopathology findings of the resected ileum showed a chronic, extensive, ulcerative, and active ileitis with transmural lymphocytic infiltration. Following surgery, the patient was included in a rehabilitation program where he made a full recovery and regained a normal level of exercise capacity.
The CARE Checklist has been completed by the authors for this case report, attached as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000530832). | abdominal surgery, case report, immune checkpoint inhibitor enterocolitis, immunotherapy, toxicity | Not supported with pagination yet | null |
PMC6205060_01 | Female | 26 | We report a case of breast tuberculosis that was treated in the Breast Unit of our hospital. A 26 year-old Eritrean female with a personal history of HIV infection and familiar history of breast cancer (her sister had died at the age of 34) came to our Emergency Department showing generalized limphoadenopathy and weakness in addition to a huge right breast mass. The patient was subjected to a CT scan of neck, abdomen and chest, that revealed a big mass in the right breast of about 10 x 7 cm, bilateral latercervical colliquated lymph nodes, the biggest being 27 x 20 mm, many right ascellary and retropectoal lymph nodes, and paraaortic, celiac and paracavale lymph nodes, but no nodes in the chest and no pleural effusion. For this reason she was hospitalized in Medicine Department with a suspicious diagnosis of lymfoma. During the stay, she underwent a mammography (Fig. 1) which showed a generalized increased radioopacity spread throughout the right breast.
Ultrasound scan was apparently useful for characterising the ill-defined breast mass and excluding the presence of solid masses. But the findings of a hypoechoic lesion with heterogeneous internal echoes and irregular borders were not specific ones. The Color Doppler showed increased circumferential vascularization in avascular centered lesions which might be interpreted as a sign of continuity of the infective process. For this reason it was diagnosed a breast abscess.
While being treated with antinflammatory drugs and a aspecific antibiotica therapy, the patient came up to our Breast Surgery Unit Department because she had not had any improvement of symptoms.
Our examination revealed a tender mass measuring 12 x 10 cm that involved all right breast. Her skin was not erythematous and local temperature was normal. She was painless. The mass was soft in consistency, floating and mobile on the chest wall and there were no signs of inflammation. It meant the possible presence of a "cold abscess" or a big cystis. Moreover, there was a clinically palpable right axillary lymphadenopathy.
The total leukocyte count and erythrocyte sedimentation rate were low; the other blood tests were normal except for the electrophoretic protidogram where we found a high level of gamma globuline.
Fine needle aspiration (FNA) showed a milky and greenish shaded fluid. On needle aspiration, some thick pus came out and it was drained out of about 200 ml. The pus was sent for bacteriological, citological and coltural test, the results of which were negative for aerobic, anaerobic bacteria and fungi.
The patient had a latercervical lymph node core biopsy that exluded lymphoma. The evaluation of the specimen revealed only inflammatory cells, including neutrophils, lymphocytes, and abundant macrophages, granulomas with central caseaous necrosis and epitheloid histiocytes. But by means of nucleic acid probes and PCR, it was possibile to identify the Mycobacterium tuberculosis. The laterocervical limph node was due to a scrofulous swelling.
The patient was put on anti-tubercular drugs treatment (rifampicin 600 mg, isoniazid 300 mg, pyrazinamide 1500 mg and ethambutol 1000 mg per day) for 2 months which continued with the addition of rifampicin and isoniazid therapy for 4 additional months. In the follow-up period of 6 months, the patient recovered very well and was advised to continue the treatment.
At the end of the antituberculous treatment period, the patient appeared to be clinically and radiologically without any evidence of residual disease. | case reports, extra-pulmonary localization, fine nipple aspiration, granulomatous mastitis, scrofola, tuberculosis | Not supported with pagination yet | null |
PMC9547605_01 | Male | 62 | The case involved a 62-year-old male farmer with a history of alcoholic liver disease. He was admitted to the hospital on March 2, 2022, and the chief complaint was "fever and cough with difficult breathing for 4 d". Four days before admission, the patient had a fever with no obvious cause, a maximum temperature of 41.0C, chills, poor appetite, fatigue, headache and generalised muscle aches, intermittent disordered speech, cough, expectoration, and gradually worsening dyspnoea, for which he visited a local hospital. Chest computed tomography (CT) suggested infection and partial consolidation of the right lung. The patient was diagnosed to have "severe pneumonia" and administered the antibiotics piperacillin sulbactam, meropenem, and levofloxacin, and antiviral agent oseltamivir; however, a recurrent persistent fever and worsening dyspnoea were observed. The patient was admitted to the RICU of Huizhou Central People's Hospital for further treatment.
Physical examination presented the following findings: body temperature: 39.2C, pulse: 93 beats/min, respiratory rate: 35 breaths/min, blood pressure: 113/76 mmHg, pulse oximetry: 90% (5 L/min oxygen by face mask). The patient was conscious and lethargic and had no yellowing of the skin, mucosa, or sclera and no enlargement of superficial lymph nodes. He was tachypnoeic with coarse breath sounds in both lungs, and wet rales could be heard in the bilateral lower lungs. The heart rate was 93 beats/min and regular; no pathological murmurs were heard in any of the valve auscultation areas and no other significant abnormalities were observed.
Laboratory examination presented the following findings: negative for novel coronavirus RNA and influenza A and B virus antigens; blood gas analysis (FiO2: 41%): pH: 7.445, PO2: 49.0 mmHg, PCO2: 25.4 mmHg, HCO3: 18.7 mmol/L, base excess: -4 mmol/L, oxygen saturation index: 119.5. Complete blood count was as follows: white blood cell (WBC): 3.7 x 109/L, neutrophil percentage: 86.1%, lymphocyte count: 0.24 x 109/L, haemoglobin: 105 g/L, platelets: 69 x 109/L; high-sensitivity C-reactive protein (hs-CRP): 320.25 mg/L, procalcitonin (PCT): 47.86 ng/mL. The liver function test results were as follows: alanine aminotransferase (ALT): 116 U/L, aspartate aminotransferase (AST): 696 U/L, total bilirubin: 32.3 micromol/L, albumin: 23.5 g/L. The kidney function test results were as follows: urea: 11.8 mmol/L, serum creatinine: 119 mumol/L, lactate: 1.22 mmol/L, plasma ammonia: 42.3 mumol/L, blood potassium: 3.53 mmol/L, blood sodium: 130 mmol/L. Coagulation function: fibrinogen: 9.95 g/L, D-dimer: 12,500 ng/mL; creatine kinase (CK): 8454 U/L, lactate dehydrogenase (LDH): 785 U/L. Brain natriuretic peptide precursor: 1470 pg/mL and high-sensitivity troponin T: 35.73 ng/L. Chest CT at the time of admission (Figure 1A-C) showed multiple patchy exudative opacities in the right lung and a large consolidated shadow in the right lower lung. Six hours after admission, the patient's condition worsened, obvious respiratory distress was observed, and the oxygen saturation index dropped to 95 mmHg. A diagnosis of severe community-acquired pneumonia (SCAP) with acute respiratory distress syndrome (ARDS) was considered, and the patient was administered tracheal intubation with invasive mechanical ventilation, methylprednisolone (40 mg) as an anti-inflammatory and liver protective drug, and an antibiotic regimen of meropenem injection (1.0 g q. 8 h), moxifloxacin injection (0.4 g q.d.), and oseltamivir capsules (75 mg q. 12 h). The patient had a severe infection with rapidly progressing pulmonary lesions, the efficacy of conventional antibiotics was poor, and the causative pathogen was not obvious. After obtaining written consent from his family members, 10 mL of bronchoalveolar fluid (BALF) collected via fibreoptic bronchoscopy was sent to the Daan Gene sequencing platform (Daan Gene Co., Ltd. of Sun Yat-sen University) for metagenomic next-generation sequencing (mNGS). During this period, the Widal test, Weil-Felix test, tuberculosis antibodies, anti-neutrophil cytoplasmic antibodies, and IgM antibodies for respiratory pathogens (Legionella pneumophila, Chlamydia pneumoniae, Mycoplasma pneumoniae, Q fever Rickettsia, adenovirus, respiratory syncytial virus, influenza A virus, influenza B virus, and parainfluenza virus) were all negative. The bacterial and fungal cultures of blood, phlegm, and BALF were negative. After the initial antibiotic treatment, the patient's condition did not improve; he still had a persistent fever and showed limited improvement in oxygenation, decreased platelets, and progressive increase in liver enzymes and blood creatinine. On March 4 (day 3), laboratory re-examination showed the following: platelets: 52 x 109/L, ALT: 559 U/L, AST: 1548 U/L, and serum creatinine: 341 micromol/L. On the same day, the DNA mNGS results indicated the presence of C. psittaci, with a sequence number of 14940, coverage of 97%, and relative abundance of 74.2%. Follow-up based on the patient's medical history indicated that he raised chickens, ducks, and other fowl at home. Taking together, the patient's clinical presentation and mNGS results led to a diagnosis of severe C. psittaci pneumonia. The patient had severe hepatic and renal insufficiency, and treatment with respiratory quinolones, macrolides, and antibiotics, such as doxycycline and minocycline, was not appropriate. After consultation with the hospital clinical pharmacist, the antibiotic regimen was adjusted to omadacycline injection (first dose: 100 mg IV q. 12 h, followed by: 100 mg IV q.d.). After 72 h of treatment, the patient's temperature gradually decreased to a normal level (Figure 2), and a complete blood count re-examination on March 7 (day 6) showed the following: WBC: 6.3 x 109/L, neutrophil percentage: 85.1%, lymphocyte count: 0.64 x 109/L, haemoglobin: 85 g/L, platelets: 116 x 109/L, hs-CRP: 127.14 mg/L, PCT: 5.53 ng, ALT: 228 U/L, AST: 430 U/L, serum creatinine: 202 micromol/L. The patient's condition gradually improved; inflammation indices decreased significantly; and liver enzymes, creatinine, CK, and LDH gradually returned to normal levels (Figures 3-7). On March 14 (day 13), the patient was successfully extubated and high-flow oxygen therapy was continued. Chest CT re-examination indicated significant resorption of the right lung lesion (Figure 1D-F). The patient's condition was considered stable and his gastrointestinal function improved. On March 16 (day 15), the omadacycline injection was changed to an oral preparation (300 mg p.o. q.d.), and the patient was administered low-flow oxygen therapy and transferred to the general ward. On March 23 (day 22), chest CT re-examination indicated further resorption of the right lung lesion (Figure 1G-I), and the patient was discharged the following day. The final diagnosis was psittacosis, severe community-acquired pneumonia, ARDS, multiple organ system failure (type I respiratory failure, liver failure, and renal failure), rhabdomyolysis, and alcoholic liver disease. Outpatient follow-up at 1 month after discharge indicated no significant abnormalities in inflammation indices (hs-CRP and PCT) and liver and kidney functions, and chest CT indicated that the lung lesions were largely resorbed, leaving only a small number of fibrous linear opacities (Figure 1J-L). | chlamydia psittaci, metagenomic next-generation sequencing, multiple organ failure, omadacycline, pneumonia | Not supported with pagination yet | null |
PMC3272788_01 | Unknown | 13 | Linear scleroderma en coup de sabre (LCsc) is a rare subset of LS. The typical presentation affects frontoparietal region, and the mean age of onset is around 13 years old. In this paper, clinical presentation of LScs and its neurological involvement are described.
Skin pathogenesis seems to be similar between LScs, LS, and systemic sclerosis, although not fully understood. Clinical and pathological data support the hypothesis that vasculature is the primary target in LS. Early skin biopsies revealed damaged endothelial cells preceding the development of fibrosis by months to years. Increased vascular permeability is associated with mononuclear cell infiltration, leading to perivascular inflammatory cell infiltrates, vascular intimal thickening, and vessel narrowing. Gradually, the vessels lose their elasticity; media and adventitia become fibrotic and more prone to small-artery occlusion. The latter is further exacerbated by thrombotic events driven by platelets activation, resulting in fibrosis and end-organ damage.
The inciting event for microvascular damage remains unknown. Preceding trauma has been observed as initial event in pediatric population. Previous infection, particularly due to Borrelia burgdorferi, has been implicated in Europe and Japan, but not confirmed in the United States. Genetics participation in pathogenesis appears to be relatively weak, since only a 4.7% concordance between twins has been observed and family studies revealed only 1.6% frequency among first-degree relatives. However, several groups have identified polymorphisms in potential candidate genes involved in immune regulation, such as BANK1, C8orfl3-BLK, IL-23R, IRF5, STAT4, TBX21, and TNFSF4, which may underlie the pathogenesis of systemic sclerosis. Intriguingly, many of these polymorphisms are shared with other rheumatic diseases, such as systemic lupus erythematosus.
More than 1800 genes are differentially expressed in scleroderma skin compared to healthy controls; however analysis of visually unaffected skin reveals a similar gene expression as diseased skin. Altered gene expression is mapped to fibroblasts, endothelial, epithelial, smooth muscle, T, and B cells. Recently, Gardner et al. have found significant gene-expression signature in systemic sclerosis patients, which has been mapped to TGF-beta and WNT signaling pathways, the production of extracellular matrix proteins and CCN family proteins.
Pathogenesis of CNS involvement in LScs is due to perivascular infiltrate and vasculitis; however biopsy is not routinely done and histological findings are available only for patients with severe neurological findings. Gliosis, suggesting chronic inflammatory process, leptomeningeal band-like sclerosis, and thickened blood vessels' walls, as well as intraparenchymal calcification, have also been described in the few available studies.
To sum up, available data suggests a complex pathogenesis of scleroderma, in which blood vessels, the immune system, and extracellular matrix are affected and may contribute to the development of the disease.
Ivory-colored, sclerotic lesions, with violaceous borders, characterize LS. Number and distribution of lesions vary, as well as their extent. These characteristics and tissue involvement (dermis, subcutaneous tissue, fascia, and muscle) determine the localized scleroderma classification (Table 1).
LScs presents in a band-like fashion on the frontoparietal scalp and forehead. Alopecia is common and many times is the patient's main concern. Skin lesions may extend to the nose, cheek, chin, and neck and usually have an active stage lasting 2-5 years. Muscle, cartilage, and bone lesions incur in facial atrophy: in this scenario, Parry-Romberg syndrome (PRS) must be considered a differential diagnosis. Up to 28% of patients having LScs manifests PRS features, such as a unilateral slowly progressive atrophy of the face. PRS commonly affects dermatomes of trigeminal nerve. Skin, soft tissue muscles, and underlying bone structures are involved. Skin hyperpigmentation and discoloration and hairless patches can be present. Many authors postulate that LScs and PRS are clinical variants of the same disease. Arguments for PRS inclusion on the spectrum of LS disorders are compelling. LScs and PRS coexist in 20-37% of the patients with LScs diagnosis, and both conditions have similar age of onset and disease course. Furthermore, dermatologic findings in PRS are sometimes indistinguishable from those of LS. However, some authors still consider them as different entities, since PRS does not always have skin thickening and the hemifacial atrophy occurring in PRS is usually more prominent (Table 2).
The diagnosis is clinical and based on characteristic cutaneous and soft tissue findings. Currently no diagnostic laboratory tests exist. Nonetheless, 37-50% of the patients may present a positive ANA test (homogenous or speckled patterns), as well as anti-single-stranded-DNA antibodies. Antinucleosome antibodies, soluble interleukine-2 receptor, and, recently, antiagalactosyl immunoglobulin G antibodies have been reported in LS. In some patients, autoantibody may be present even before the disease manifestation and patients with Scl-70, anticentromere, Ro/La, or U1RNP antibodies should be followed closely, as systemic disease might ensue.
LScs has been associated with a variety of neurologic abnormalities and typically is preceded by the development of cutaneous disease by months to years. Nervous system involvement is usually not correlated to skin activity and may present years after the disease initial symptomatology. In 16% of cases, neurologic symptoms predate the cutaneous manifestations.
Neurological symptoms and signs in LScs are protean and include epilepsy, headache, focal neurologic deficits, and movement disorders, as well as neuropsychiatric symptom and intellectual deterioration.
Epilepsy is a frequently reported manifestation in LScs. An analysis of 54 patients with LScs or PRS has revealed a prevalence of 73% of seizures, 33% of them refractory to antiepileptic medications. Complex partial seizures have been reported most frequently, followed by tonic-clonic, absence seizures, as well as status epilepticus. Electroencephalography analyses show abnormalities in the majority of patients. Some authors advocate that brain lesions of LS are more epileptogenic than those of other autoimmune disorders.
Focal neurologic deficits and movement disorders secondary to brain lesions have also been described, but seem to be relatively uncommon. In an analysis of 54 patients, focal neurological deficits were described in 11% of patients at presentation and in 35% of patients overall. While facial palsy and extraocular movement disorder may be due to cutaneous involvement, trigeminal neuralgia and masticatory spasms are considered primary neurologic involvement.
Around 35% of LScs patients refer headache, which is usually associated with other neurologic complaints. Few studies have investigated headache subtype, but migraines and mimics of hemiplegic migraine seem to be more prevalent.
Neuropsychiatric symptoms have been described in 15% of patients, including behavioral changes and progressive intellectual deterioration with or without seizures.
Computed tomography (CT) and magnetic resonance (MRI) studies have shown central nervous system abnormalities in LScs patients. Neurologic findings are more frequently ispilateral to the skin lesions, but contralateral involvement has been described. Neurologic symptoms should not be used as a predictor for MRI abnormalities because neurologic lesions have been discovered in asymptomatic patients. Moreover, symptomatic patients were sometimes proven to have normal radiologic exams.
Outer diploe thinning, cerebral atrophy, white matter lesions, focal subcortical calcifications, and meningocortical alterations have been described. Intraparenchymal calcifications involving basal ganglia, thalami, and dentate nuclei are the most common brain lesion in LScs patients. Characteristically, the calcifications are ipsilateral, but contralateral involvement may occur.
MRI usually exhibits T2 hyperintensities, mostly in subcortical white matter, but also in corpus callosum, deep grey nuclei, and brain stem.
Cerebral atrophy is generally subtle, characterized by blurring of the gray-white interface, cortical thickening, and abnormal gyral pattern. Atrophy is usually focal but widespread lesions involving an entire cerebral hemisphere have been described. Hippocampal atrophy is unusual, but has been reported. Infratentorial lesions and cerebellar hemiatrophy have been observed in patients presenting more severe neurological symptoms.
Cerebral angiograms and magnetic resonance angiograms studies showed vascular involvement suggestive of vasculitis. Reports of cerebral aneurysms and other vascular malformations, as brain cavernomas, exist and could represent late sequelae of vasculitic process. | null | Not supported with pagination yet | null |
PMC5586922_01 | Male | 58 | A 58-year-old man presented to the outpatient department of our hospital with recurrent fever (38-41.2 C) and weight loss (up to 16 kg) for over 2 months and was admitted for pyrexia of unknown origin (PUO). At the time of admission, the physical examination revealed a conscious man with the following characteristics: temperature 39.6 C, pulse rate 102 beats/min, blood pressure 100/75 mm Hg and respiratory rate 22 breaths/min. There was no jaundice or lymphadenopathy. Abdominal examination revealed no tenderness or ascites and no hepatosplenomegaly or any other palpable mass in his abdomen. Laboratory analyses revealed the following data: haemoglobin 11.0 g/dl, white blood cells 7,600/mm3 (70% neutrophils), blood platelets 207,000/mm3, blood urea 3.7 mmol/l and creatinine 56 mumol/l. Liver enzymes showed a total bilirubin level of 17 mg/l with a direct component of 10 mg/l. Alanine aminotransferase and aspartate aminotransferase levels were 30 and 36 U/l, respectively (the normal range for alanine aminotransferase is 5-40 U/l and that for aspartate aminotransferase is 8-40 U/l), and alkaline phosphatase levels were 702 and 561 U/l (the normal range for gamma-glutamyl transpeptidase is 11-50 U/l and that for alkaline phosphatase is 40-150 U/l). The C-reactive protein level was 56.8 mg/l (normal range 0.0-8.0 mg/l) and the erythrocyte sedimentation rate was 29 mm/h (normal range 0-15 mm/h for males). The levels of tumour markers, such as alpha-fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19-9, were within the normal limits. The patient was non-reactive in HIV serology. A chest CT scan showed no lesion suggestive of TB but revealed mild bilateral hydrothorax and hydropericardium. US of the abdomen revealed a hepatic portal lymph node of 1.7 by 1.2 cm and gallbladder wall oedema. All other abdominal viscera appeared normal with no free fluid. An echocardiogram revealed moderate hydropericardium about 15 mm before the myocardium of the anterior free wall of the right ventricle. A contrast-enhanced CT scan of the abdomen revealed calcifications in the posterior segment of the right liver and lymph node enlargement in the hepatic portal, intraperitoneal and retroperitoneal regions (fig. 1a). Lymphoma, lymphatic TB and autoimmune tissue disease were initially suspected but the hydrothorax and hydropericardium were too small to obtain a sample, and the location of the intraperitoneal and retroperitoneal lymph nodes made them difficult to biopsy. Hence, the patient was referred for a whole-body PET/CT scan to find the lesion site for biopsy. The patient was injected with 350 MBq 18F-fluorodeoxyglucose (FDG) and after 120 min he underwent a head-to-toe scan in a dedicated PET/CT scanner (Biograph, Germany) and a standard uptake value was calculated. Abnormal diffuse hypermetabolic activity in the liver was observed, especially in the junction of the left and right liver, with maximum FDG standard uptake values of 8.81 and 12.47 at the delayed scan (180 min after the injection) (fig. 1), and a nodular hypermetabolic lesion was found in segments V and VI. The standard uptake values of lymph nodes in the mesentery and retroperitoneal space were 7.17 and 9.11, respectively, at the delayed scan. Primary liver lymphoma and hepatocarcinoma were suspected. In order to establish a diagnosis, an ultrasound-guided percutaneous liver biopsy was performed in segments V and VI, and 2 strips of liver tissue were extracted from the liver.
Histological examination of the biopsy showed a TB follicle with central caseous necrosis surrounded by lymphocytes, multinucleate giant cells and epithelioid macrophages, revealing several acid-fast bacteria (fig. 2). To further confirm the diagnosis, a T-SPOT TB test was performed and it was highly positive for ESAT-6 (>20) and CFP-10 (>20). The diagnosis of hepatic TB was confirmed.
Four drugs for anti-tubercular therapy (rifampicin, isoniazid, ethambutol and pyrazinamide) with methylprednisolone 16 mg/day were started. At the 4-week follow-up the patient was asymptomatic and his body temperature had returned to normal. At the 3-month follow-up the patient had no hydrothorax or hydropericardium on chest CT and no enlargement of lymph nodes on abdominal US. | null | Not supported with pagination yet | null |
PMC3566897_02 | Unknown | 12 | All probands with OPA1 mutations had clinical symptoms and signs of DOA (Table 4). The disease occurred insidiously in most probands, with reduced visual acuity noticed at about 12 years old (12+-9.5 years; ranging between 2 and 35 years). The mean age for the probands' first visit to the eye clinic was about 15 years (15+-8.8 years; ranging from 4 to 35 years). Interestingly, two probands (le1574 and le1601) experienced significant visual deterioration after taking antituberculosis medicine. Additional segregation analysis of the mutations was performed in two sporadic cases, i.e., le1432 and le2062, through contact tracing of the OPA1-positive probands (Figure 2). The two patients had no siblings, but their parents were available for further analysis. All four parents were farmers and were visually asymptomatic by self-report. However, the father of le1432 and the mother of le2062 harbored an OPA1 mutation. Ophthalmic examination of the two "healthy carriers" demonstrated mild phenotype of optic atrophy: mild reduced visual acuity, attenuated retinal vessels, temporal disc pallor, and thinning RNFL on the OCT scan (Table 4). | null | Not supported with pagination yet | null |
PMC5634589_01 | Male | 39 | A 39-year-old male with a past medical history of alcohol abuse of several years' duration presented to the Emergency Department with chief complaint of headache. At the time of presentation he denied any chest pain, weakness, or other neurologic symptoms. Basic labs including complete blood count and basic metabolic panel were performed in the ED, which showed severe hyponatremia with a sodium of 116 mmol/L (normal 135-145 mmol/L) and serum osmolality of 235 mmol/L (normal 275-285 mmol/L). Further questioning of a family member revealed the patient was also experiencing mild confusion in the past few days. Physical exam showed the patient was oriented to person and place, while showing signs of chronic malnutrition. The rest of his serum chemistries, including complete blood count, were normal on presentation with the exception of hypochloremia (81 mmol/L). CT of the head on admission was obtained due to the patient's altered mental status, and it showed no edema or signs of infarct at the time. His chest X-ray performed in the ED showed nonspecific increased reticular markings. Kernig's and Brudzinski's signs were negative on physical exam. The patient had no pain or stiffness of the neck on admission. His vitals were otherwise stable, with normal temperature, O2 saturation, and respiratory rate on presentation. Alcohol level was negative in the ED, although he was kept on alcohol withdrawal protocol for the duration of his hospital stay due to the history of alcohol abuse and likelihood for withdrawal. The patient was admitted to a medical floor for hyponatremia and alcohol withdrawal workup. He did not receive any antibiotics in the ED as there was no indication of an infection at the time.
On the first day of admission, the patient was difficult to arouse in the morning after he spiked a fever of 101.5 F (38.6 C) overnight. Infectious Disease was consulted due to concern for meningitis due to altered mental status and fever. ID recommended starting the patient on Vancomycin, Zosyn, and Acyclovir, which the patient continued for the duration of his two-week hospital stay. A lumbar puncture was also performed the same day. The patient was transferred to the ICU due to concerns over airway protection due to rapidly worsening mental status. At this time a nine-panel drug screen was ordered which was negative. Lactic acid, procalcitonin, and blood cultures were all taken and were within normal limits. Nephrology was consulted for the hyponatremia, thought to be secondary to beer potomania and possible SIADH. In the ICU, the patient had a central line placed and he was started on 3% normal saline. Measurement of urine sodium was 191 mmol/L and urine osmolality was 626 mOsm/kg, although these labs were likely drawn after the administration of the hypertonic saline.
Initial results of the spinal tap showed a traumatic tap with 49 red blood cells/mm3, 8 white blood cells/mm3, glucose of 20 mg/dL, and protein of 188 mg/dL. Due to the low white blood cell count, ID felt meningitis was thought to be low on the differential. Acid fast culture was sent but would not return for several weeks from the health department. PCR for Mycobacterium tuberculosis was not available. A teleneurology consult was obtained due to the lack of an in-hospital neurology service, and they recommended treating the hyponatremia as a cause of the patient's encephalopathy. Due to the low white blood cell count in the cerebrospinal fluid, sterile blood cultures, and explanation of hyponatremia for the patient's altered mental status, antibiotics were discontinued on day #3 but eventually restarted as the patient's condition declined. He had a total of two weeks' course of antibiotics.
Over the next two days the patient's mental status continued to wax and wane, as did his low grade fevers. Additional infection workup was ordered, including RPR, GC/chlamydia, hepatitis, and HIV, all of which were negative. Repeat chest X-ray showed worsening of the reticulonodular opacities previously visualized on the chest X-ray performed in the ED. A cardiac ECHO was ordered which was limited due to the patient developing tachycardia but showed normal EF and no signs of vegetations or valvular dysfunction. A repeat CT of the head was ordered as the patient's mental status continued to decline (Figure 1). CT of the head showed new onset hydrocephalus, leading to a consult being placed with neurosurgery. Due to the new findings on CT scan an MRI was ordered, which showed subtle increased T2/flair signal interdigitating between the gyri, concerning for leptomeningitis (Figure 2). Neurosurgery placed an external ventricular drain catheter to drain the cerebrospinal fluid and relieve the hydrocephalus. There was no elevated intracranial pressure. The neurosurgeon did raise concern for meningitis based on the abnormal results of the original cerebrospinal fluid studies and the MRI; however treatment for TB was not started due to the negative cerebrospinal fluid samples.
Daily cerebrospinal fluid counts were sent to the lab from the ventriculostomy fluid collected. These repeat cerebrospinal fluid samples showed elevated white blood cell count, elevated red blood cell count, and low glucose with elevated protein. In total, three acid fast cultures were sent to the lab for analysis but their results would not come out for some time from the Health Dept. Patient was continued on Vancomycin, Acyclovir, and Cefepime. Culture results did not return until almost one month later.
Eight days into the patient's hospital stay and seven days into his ICU stay the patient experienced a cardiac arrest, likely due to increased pulmonary secretions and respiratory failure. He received ACLS with several rounds of epinephrine and suctioning and he eventually achieved return of spontaneous circulation. He was intubated for airway protection. A CT scan of the chest was ordered due to the persistently abnormal chest X-rays. CT of the chest showed diffuse airspace disease with associated reticular nodular opacities and apparent tree in bud configuration with small cavitary pulmonary nodule noted at the superolateral left lung apex (Figure 3). Bronchoalveolar lavage was performed by pulmonology to rule out infectious causes. Cultures were negative for fungus and grew out only normal respiratory flora. Either an acid fast culture was not sent from the bronchoalveolar washings or its results never came out at the Health Dept. Decision was made to transfer the patient to a local tertiary care hospital and the patient was accepted. However, no beds were available and the patient remained in critical condition in the ICU. A repeat MRI was performed which showed infarct of the left internal capsule and left putamen, as well as an acute small infarct in the right side of the pons. Neurosurgery continued to be concerned with infection including the possibility of TB. The ventricular drain shunt was discontinued as the intracranial pressure remained normal and the daily cerebrospinal fluid collection was stopped.
The patient began to experience worsening brain stem function during daily physical exams. QuantiFERON test was ordered and came back positive. This test was ordered due to the concern for extrapulmonary or meningeal TB from the prior chest CT which had showed a cavitary lesion. The patient was briefly started on four-drug RIPE therapy for only one day; however this was stopped as none of the acid fast cultures had yet returned positive. A cerebral perfusion test was ordered and was consistent with brain death. Family was contacted and present when the patient was extubated. He expired shortly after extubation. | null | Not supported with pagination yet | null |
PMC10029757_01 | Male | 27 | A previously healthy 27-year-old man presented with skin ulceration and exudation in January 2022. He received antibiotics. Three months later, fever, generalized body swelling, and fatigue were experienced by the patient. The laboratory data revealed abnormal liver functions, with an alanine aminotransferase (ALT) level of 92 units/L (normal: 7-40 units/L), aspartate aminotransferase (AST) level of 181.3 units/L (normal: 13-35 units/L), and total bilirubin (TBil) level of 73 micromol/L (normal: 0-23 micromol/L). The laboratory data also revealed thrombocytopenia with a platelet (PLT) count of 24 x 109/L ( Figure 1A ). The level of haemoglobin (HGB) was 74 g/L. His ferritin level was 13504 ng/ml (normal: 23.9-336.2 ng/ml), and triglyceride (TG) level was 3.61 mmol/L (normal: 0-1.7 mmol/L) ( Figure 1C, D ). He had severe hypoalbuminemia (20 g/L). Epstein-Barr virus (EBV)-DNA in blood plasma was 3.46 x 103 copies/ml (normal: < 400 copies/ml). The level of soluble CD25 (sCD25) was 12062 pg/ml (normal: <= 6000 pg/ml) ( Figure 1C ). The patient tested negative for human immunodeficiency virus (HIV). He denied a personal and family history of haematological pathologies, specifically HLH.
The patient's symptoms worsened, as evidenced by deteriorated coagulopathy with a prothrombin time (PT) of 25.5 s (normal: 10.4-12.7 s) and an active thromboplastin time (APTT) of 102 s (normal: 22.3-32.5 s) ( Figure 1B ). The fibrinogen level was only 0.41 g/L (normal: 1.8-3.5 g/L) ( Figure 1D ). Bone marrow aspiration and biopsy demonstrated inflammatory changes and an increase in the number of macrophages and histiocytes with intense haemophagocytosis. Therefore, the patient fulfilled 7 of 8 diagnostic criteria for HLH ( Table 1 ). NK-cell activity was not analysed due to the lack of availability in Shanghai during the pandemic.
The patient experienced extreme fatigue, severe oedema, persistent high fever, and large skin ulcerations with exudation. He became expressionless and unresponsive. We decided to start with RUX 15 mg twice daily plus dexamethasone (DXM) 10 mg/m2/day per HLH-94 dosing, not only because of his poor performance status (PS) and progressive deterioration of liver function but also because of the short supply of blood products, including red blood cells and platelets, at specific periods in Shanghai. Fourteen days later, DXM was reduced to 5 mg/m2/day. Broad-spectrum antibiotics, fibrinogen, prothrombin complex, and immunoglobulin were also given. The patient had no fever on Day 3 (Day 0 corresponds to RUX initiation). Eighty percent of skin ulcers were healed on Day 7. Oedema and fatigue symptoms were significantly relieved. The TBil level dropped to 58 micromol/L. After two weeks of therapy, the PLT count recovered to 136 x 109/L ( Figure 1A ). The fibrinogen level, PT, and APTT improved ( Figure 1B, D ). The sCD25 level decreased to 7238 pg/ml ( Figure 1C ). The patient achieved a partial response (PR) according to the response criterion described in previous studies. He underwent two skin biopsies and a cervical lymph node biopsy by a core needle, but all were negative for lymphoma. The histopathology of the excised right inguinal lymph node indicated an NK/T-cell lymphoma on Day 22. The pegaspargase + Gemox regimen was started on Day 23. He developed a fever again on Day 28. The levels of C-reactive protein (CRP, 97 mg/L) and ferritin (10532 ng/ml) were all elevated ( Figure 1A, C ). The values of PLT (31 x 109/L) and fibrinogen (0.80 g/L) were reduced again ( Figure 1A, D ). The pulmonary computed tomography (CT) scan suggested pneumonia. The result of alveolar lavage fluid culture was Pseudomonas aeruginosa. Although broad-spectrum antibiotics were administered according to the drug susceptibility, the patient died on Day 33 with incomplete induction chemotherapy. | dexamethasone, first-line, haemophagocytic lymphohistiocytosis, ruxolitinib, therapy | Not supported with pagination yet | null |
PMC10029757_02 | Female | 33 | A 33-year-old female with a history of encephalomyelitis treated with high-dose methylprednisolone in 2018 presented with neutropenia and mild anaemia in November 2021. A month later, she developed a high fever, fatigue, headache, and pancytopenia with an absolute neutrophil count (ANC) of 0.3 x 109/L, HGB of 93 g/L, and PLT of 37 x 109/L ( Figure 1E, H ). The CRP level was 131 mg/L (normal: 0-8 mg/L) ( Figure 1E ). She was admitted to our hospital. Bone marrow aspiration and biopsy demonstrated haemophagocytosis. Flow cytometric (FC) analysis of bone marrow showed no clonal abnormalities, and chromosome karyotype analysis was normal. The laboratory data revealed abnormal liver function with an ALT of 70 units/L, AST of 182 units/L, and TBil of 24 micromol/L. Coagulation detection showed a decreased level of fibrinogen (0.25 g/L) and prolonged APTT (75.4 s) ( Figure 1F, H ). Her ferritin level was 12459 microg/L and the TG level (7.04 mmol/L) was four times higher than normal ( Figure 1G ). EBV-DNA in blood plasma was 896.68 copies/ml (normal: <400 copies/ml). EBV nuclear antigen IgG (EBNA-IgG) and EBV capsid antigen IgG (EBCA-IgG) antibody titers were 235 U/ml (normal: < 5 U/ml) and 218 U/ml (normal: < 20 U/ml), respectively. Abdominal CT showed splenomegaly. The patient denied that she had repeatedly developed HLH and denied a family history of HLH. According to her clinical manifestations and laboratory parameters, she was diagnosed with HLH ( Table 1 ).
Magnetic resonance imaging (MRI) showed multiple inflammatory demyelinating lesions in the bilateral paraventricular area, bilateral radiation crown area, and bilateral frontoparietal temporal cortex. Cerebrospinal fluid pressure was high, protein content was normal, and no tumour cell infiltrations were found. The recurrence of encephalomyelitis was considered. No clear malignant, autoimmune, or infectious triggers for HLH were identified. EBV infection was suspected as a potential trigger for her HLH. The level of sCD25 and NK-cell activity were unavailable during this time in Shanghai.
The patient was given 90 mg DXM a day for 3 days. At the same time, RUX 10 mg was administered orally twice a day. The DXM dose was reduced by half every three days, finally reaching a reduced dose of 10 mg. After that, the dose was adjusted every two weeks to 1.5 mg according to the patient's laboratory examination results. Then, DXM was replaced with 8 mg methylprednisolone for maintenance treatment. Her fever was controlled on Day 2. The PLT and ANC counts had normalized on Day 7 ( Figure 1E, H ). The ferritin, fibrinogen, and TG level improved on Day 14 ( Figure 1G, H ). She achieved PR according to the response criterion on Day 14.
Treatment with RUX and a low dose of methylprednisolone were continuous. Plasma EBV-DNA load was 423 copies/ml on Day 265. EBNA-IgG and EBCA-IgG antibody titers were 185 U/ml and > 750 U/ml on Day 273, respectively. Two antibodies were still positive with high avidity. The onset of primary HLH in adults may lead clinicians to ignore or even misdiagnose the disease. To further clarify the aetiology of HLH in Case 2, the next-generation sequencing (NGS) of HLH-related genes was performed on Day 275. A mutation of the PRF1 gene, c.1349C > T (p. T450M) was reported. Two mutations of the lysosomal trafficking regulator (LYST) were also detected: c.1183C > T (p. R395C) and c.2183G > T (p. S938I). All of them were heterozygous missense mutations. The NGS results are shown in Table 2 . Unlike PRF1 mutations, which are known pathogenic variants responsible for FHL, the clinical significance of the two LYST gene variants is unclear. FC analysis revealed the decreased expression of PRF1 in NK cells ( Figure 2A ). NK cells stimulation test showed severe dysregulation of immune response ( Figure 2B ) on Day 352. The final diagnosis of the patient was FHL type 2 from homozygous c.1349C > T (p. T450M) missense variants in the PRF1 gene. The patient's parents were reluctant to test HLH-related genes for financial stress, so it was impossible to determine the location of these variants. She remained well without neurological symptoms at the monthly follow-up. The brain MRI on Day 329 showed stable disease without any new lesions. The ferritin level, liver function, coagulation, and hematologic parameters were normal at the last follow-up on Day 353 ( Figure 1E, F, G, H ). The patient is currently enjoying excellent PS. | dexamethasone, first-line, haemophagocytic lymphohistiocytosis, ruxolitinib, therapy | Not supported with pagination yet | null |
PMC9951122_01 | Male | 72 | We present a case of a 72-year-old male with essential hypertension and benign prostatic hyperplasia who presented to the emergency department on January 2018 with an intense right temporal headache with retroocular irradiation, which was pulsatile and associated with scalp hyperesthesia. The patient also reported fatigue, anorexia low-grade fever, night sweats, and non-quantified weight loss over the last two months. He denied any visual symptoms, such as ocular pain or loss of visual acuity. The physical exam revealed a tortuous and indurated right superficial temporal artery that was tender to palpation. An ophthalmology consultation was requested, and anterior ischemic optic neuropathy and other ophthalmological conditions were excluded. The cranial computed tomography (CT) performed in the emergency department was normal, and analytic evaluation showed an elevated ESR of 82 mm/h (normal range < 20 mm/h) as well as an elevated CRP of 20 mg/dL (normal range < 0.5 mg/dL). Furthermore, he also had an inflammatory anemia with a hemoglobin of 11.7 g/L (normal range: 13-17 g/L).
The diagnosis of temporal arteritis was suspected, and the patient was started on prednisolone (1 mg/kg). A biopsy of the right temporal artery was performed on the first week after the initiation of corticotherapy and was negative for GCA. Nevertheless, after the initiation of corticosteroids, there was a remission of symptoms accompanied by a normalization of inflammatory markers with an ESR of 18 mm/h and CRP of 0.4 mg/dL. After two months of 1 mg/kg prednisolone, slow steroid tapering was started. However, at the dose of 20 mg of prednisolone, there was a reappearance of constitutional symptoms, namely fatigue, anorexia weight loss, and night sweats with a new increase of ESR to 80 mm/h. Besides the constitutional symptoms, there were no other organ-specific symptoms, such as headache, visual loss, arthralgias, or others. The corticosteroid dose was increased to the initial dosage (1 mg/kg), but there was no improvement in the symptoms this time.
At this point, due to its persistence, other causes for the constitutional symptoms were excluded. The patient underwent a full-body CT scan, which was negative for neoplastic causes, as well as endoscopic exams, which were also normal. Given the high prevalence of tuberculosis in Portugal, the patient also underwent bronchoscopy and sputum examination, which were negative for this agent (negative direct examination with Ziehl-Neelsen stain and negative polymerase chain reaction for Mycobacterium tuberculosis). The patient was negative for the human immunodeficiency virus, and the venereal disease research laboratory (VDRL) test was also negative. The serologies for Rickettsia, Borrelia, and Brucella were also negative.
Therefore, given the maintenance of constitutional symptoms that caused functional limitation to the patient, a PET scan was performed, which showed a grade 2 aortitis extending from the aortic arch to the emergency of the renal arteries (Figure 1). The transthoracic echocardiogram revealed an ascending aortic dilation of 44 mm (normal range: 17-33 mm) (Figure 2). Furthermore, the antinuclear antibodies were positive with a titer of 1/160, and the rheumatoid factor was negative. The anti-neutrophil cytoplasmic autoantibodies (p-ANCA) to bactericidal/permeability-increasing (BPI) protein were 1.6 UI/ml (positive cut-off value of 1.1 UI/ml). However, there were no manifestations specific to ANCA vasculitis, such as pulmonary-renal syndrome, skin vasculitis, chronic destructive airway disease, pulmonary nodules, or mononeuritis multiplex. The fact that the initial clinical presentation was very suggestive of GCA with temporal involvement which later progressed to aortic involvement, and also as the patient never had any signs or symptoms of ANCA vasculitis, led to the diagnosis of giant cell aortitis. Given the lack of clinical response to corticotherapy, tocilizumab was initiated (162 mg subcutaneous weekly), with a resolution of constitutional symptoms as well as normalization in inflammatory markers. A second PET scan was performed nine months after therapy with an improvement of inflammation in the previously affected areas with grade 1 aortitis (Figure 1). | constitutional syndrome, giant cell aortitis, giant cell arteritis, large-artery vasculitis, tocilizumab | Not supported with pagination yet | null |
PMC4325702_01 | Female | 67 | A 67-year-old woman, receiving oral steroid therapy for SLE, presented to her physician because of fever (>38 C) and arthralgia. Her steroid dosage was increased with suspicion of SLE exacerbation. Subsequently, she developed redness, swelling, and blistering on the right thumb, and then was referred to our hospital. Clinical examination revealed erythematous swelling on the right thumb with erosion and maceration (Fig. 1A). We diagnosed it as bacterial cellulitis and treated her with antibiotics and antiviral agents, but her symptoms did not improve. Therefore, we performed skin biopsy of the right thumb. Histopathologic examination revealed caseous necrosis surrounded by histiocytes and a positive result was obtained for acid-fast bacilli by Ziehl-Neelsen staining (Fig. 1B-D). In addition, polymerase chain reaction (PCR) assay of the biopsy specimen identified tubercle group bacilli. Based on these results, we made a diagnosis of TB cellulitis and started to treat the patient with isoniazid, ethambutol, rifampicin, and pyrazinamide. Her symptoms completely resolved after the treatment. | cellulitis, cutaneous tuberculosis | Not supported with pagination yet | null |
PMC9470883_01 | Female | 87 | A typical case is described in detail here. The patient was an 87-year-old woman admitted to the hospital with a sudden onset of epigastric pain for 8 h. On admission, her vital signs were stable. On examination, she was found to have mid-upper abdominal pressure and suspicious rebound pain, and the rest of her abdomen was free from peritoneal Irritation signs. Laboratory investigations revealed the following: WBC 5.8*109/L, NP 73.2%, PLT 87*109/L; AMY 1,450U/L, TB 34.90 micromol/L, CB 19.00 micromol/L, ALT 492U/L, and AST 515U/L. The CECT scan suggested (Figure 2A) suspected duodenal diverticulum perforation. Given the patient's stable vital signs and the absence of significant peritoneal irritation, but with advanced age and hepatic insufficiency, there was no better surgical access on the CT scan. We decided to treat the patient with nonoperative management for one week (anti-infective, fasting, gastrointestinal decompression, and maintaining acid-base balance). The patient's blood count and liver and kidney function were dynamically reviewed during conservative treatment. During this period, the patient's white blood cells gradually increased, and she developed intermittent fever with a maximum temperature of 38.5 C. One week later, a repeat CECT revealed a significant increase in fluid accumulation around the lateral descending duodenum, posterior ascending colon, and perirenal fat sac (Figure 2B). Gastrointestinal imaging showed that the diverticulum was located at the beginning of the horizontal segment of the duodenum, and contrast leakage was seen, leading to a definite diagnosis of retroperitoneal perforation of the duodenal diverticulum (Figure 2D). We then performed percutaneous retroperitoneal drainage through a small incision in the right lumbar region under basis anesthesia and local anesthesia with ultrasound localization (Figure 3). The patient's temperature and inflammatory indicators (white blood cell count, C-reactive protein, etc.) gradually returned to normal levels after the operation. A review of CT scans on postoperative day 7 showed a significant reduction in retroperitoneal fluid (Figure 2C), and the patient was discharged 9 days after surgery.
Only one patient developed a postoperative complication of incisional infection after surgery. The remaining patient had no long-term complications during the postoperative period and postdischarge follow-up (median follow-up of 12 months). The median length of stay was 12 days (range: 3-21 days). One patient considered himself to be recovering well on the third postoperative day and strongly requested to be discharged. There were no long-term complications during the follow-up period (median follow-up of 12 months). The case characteristics, treatment modalities, and prognosis of the 10 patients are placed in Table 1. | duodenum, duodenum diverticulum, perforation, stepped treatment, surgery | Not supported with pagination yet | null |
PMC7566206_01 | Female | 1 | One year and seven months old female child presented with a complaint of intermittent dry cough of 3 weeks' duration associated with high grade intermittent fever and loss of appetite. She has no contact history with known pulmonary tuberculosis patients. For her above complaints, she was taken to a nearby health center where she was given antibiotics (amoxicillin syrup) for 7 days but showed no improvement. Subsequently, she was referred to our hospital, but her parents preferred to take her home. Two weeks later she presented to our institute with worsening of cough and shortness of breath. On presentation her vital signs were deranged and oxygen saturation was 70% with atmospheric air. She was in respiratory distress with grunting, intercostal and subcostal retraction. She also had absent air entry on her left posterior lower two-third of the lung field. She was also cachexic with evidence of severe acute malnutrition. Otherwise, she has no history of drug allergy, self or family history of relevant medical or surgical illness.
Her basic laboratory examinations revealed leukocytosis of 26,500 with left shift. Sputum gene x-pert for tuberculosis was negative and chest x-ray showed homogenous opacity on the left side.
With these findings, the surgeon tapped her left chest which revealed frank pus. With an impression of post pneumonic empyema thoracis, chest tube was inserted at the left triangle of safety using a feeding (nasogastric) tube due to lack of the proper thoracic tube. Upon chest drain insertion, about 100 ml frank pus was drained and her respiratory distress improved. Pleural fluid analysis revealed an increased white cell count of 16,000 with neutrophil of 77.7%. Post procedure, she was transferred to an intensive care unit and put on oxygen support as well as wide spectrum antibiotics (ceftriaxone and metronidazole). On the 2nd post procedure day after chest tube insertion, she developed a worsening of shortness of breath. Together with this, she became tachycardic (120-140 beats/minute) with muffled and distant heart sounds. For these new findings, a control chest x-ray was taken (Fig. 1) and it showed pneumopericardium with a classical "halo sign". In addition to the pneumopericardium, there was also left side pneumothorax, and a misplaced chest tube. Otherwise, the cardiac functions were reserved upon echocardiographic evaluation.
With the diagnosis of iatrogenic simple pneumopericardium with pneumothorax, the surgical team decided to manipulate the chest drain and observe her closely with conservative management. She was put on facemask oxygen, intravenous (IV) antibiotics, nutritional treatment, and analgesics. In subsequent days following the procedure, the pneumopericardium decreased and the chest drain output reduced remarkably (Fig. 2, Fig. 3). The left side chest tube was removed on the 10th day after insertion.
Subsequently, the patient showed a remarkable improvement and was discharged from the hospital in a stable condition. | case report, chest drain, iatrogenic, pneumopericardium | Not supported with pagination yet | null |
PMC5511790_01 | Male | 15 | A previously healthy 15-year-old Hispanic male born at full term presented to our emergency department complaining of blurry vision in his right eye with dark spots for 3 days. He denied eye pain or photopsias. He endorsed a history of an approximate 100-pound weight loss over the previous 6 months, fevers, fatigue, epigastric pain, and frequent nonbloody vomiting. He reported an intermittent erythematous macular rash on his arms, legs, and belly but sparing his palms and soles. He was born in the United States and had no recent travel history.
His vision was 20/30-2 in the right eye and 20/20 in the left eye. Intraocular pressure and anterior segment examination were within normal limits. No neovascularization of the iris, anterior chamber cell, or vitreous cell was noted. Dilated fundus examination showed mild blurring of the optic disk margins, scattered intraretinal hemorrhages, some of which were Roth spots, and mild tortuosity of the retinal vessels in the right eye. These findings appeared consistent with a CRVO in the right eye. The left eye appeared normal.
The following day, he reported sudden worsening vision in the right eye. Visual acuity declined to 20/200 in the right eye, and fundus examination showed worsening of the baseline retinal findings (Figure 1). Fluorescein angiography confirmed the diagnosis of a nonischemic CRVO (Figure 2). Optical coherence tomography showed lack of cystoid macular edema (Figure 3).
The patient was admitted to the pediatrics service, which conducted a thorough evaluation for his ocular and systemic symptoms. Extensive diagnostic testing was performed, and consultations were obtained from the infectious disease, hematology/oncology, cardiology, neurology, and rheumatology services.
Blood cultures and serology studies excluded an infectious etiology, including syphilis, tuberculosis, HIV, toxoplasmosis, Bartonella disease, and Lyme's disease. An echocardiogram revealed no cardiac vegetations or a patent foramen ovale but showed left ventricular dilation, trivial aortic insufficiency, and mild mitral regurgitation, which cardiology attributed to a panvalvitis/pancarditis because of his underlying inflammatory process.
Laboratory results were consistent with a normocytic anemia, thrombocytopenia, and hyperbilirubinemia. He had an elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), prothrombin time (PT), partial thromboplastin time (PTT), and immunoglobulin levels, whereas levels of Factor VII and IX were low. Factor V Leiden was negative. Triglyceride and homocysteine levels were normal. Serological markers of systemic lupus erythematosus, sarcoidosis, Wegener's granulomatosis, and polyarteritis nodosa were negative.
A peripheral blood smear showed reactive inflammatory cells without evidence of malignancy. A bone marrow biopsy showed hypocellular bone marrow and was not consistent with an oncologic process. Lupus anticoagulant and anticardiolipin IgG and IgM antibodies returned markedly positive.
A magnetic resonance imaging of the brain and orbits and a magnetic resonance venography study did not show vascular occlusions or other abnormalities. Neurologic testing showed no deficits other than his vision loss. A computed tomography of the chest was suggestive of small infarcts of the lower lung lobes. Computed tomography of the abdomen showed innumerable ill-defined small hypoenhancing lesions in the liver. A positron emission tomography scan revealed hypodense regions in the liver that likely represent regions of vasculitis with thrombosis.
Treatment recommendations from the rheumatology service included IVIG infusion and 3 days of intravenous Solumedrol followed by maintenance on oral prednisone. He was also placed on systemic anticoagulation.
On hospital Day 8, the patient reported diminished vision in his right eye. Visual acuity declined to bare light perception in the right eye. Examination showed worsening of the CRVO and the development of an ophthalmic artery occlusion (Figure 4). An optical coherence tomography scan showed diffuse macular edema and retinal thickening (Figure 5). He was medically stabilized and discharged home on anticoagulation and immunosuppressive therapy with outpatient ophthalmology follow-up. No acute ophthalmic intervention was indicated, as he had no evidence of neovascularization, and intravitreal bevacizumab was deferred given his underlying medical issues.
The patient, however, was subsequently lost to follow-up and returned approximately 8 months later complaining of pain in the right eye. He was found to have neovascular glaucoma and underwent prompt panretinal photocoagulation and an intravitreal bevacizumab injection. Despite repeated efforts to reach his family, he was lost to follow-up thereafter. Review of his medical record showed that he was admitted to the pediatrics service about 1 month later for chest pain. Cardiology deemed his symptoms to be due to myocarditis. Evaluation by the rheumatology service during this hospitalization showed persistently elevated levels of lupus anticoagulant and anticardiolipin IgG and IgM antibodies and positive beta 2-glycoprotein antibodies. Reinvestigation by the pediatrics and rheumatology service for an underlying etiology was unrevealing. This led to a diagnosis of primary APS by rheumatology. No ophthalmology consultation from pediatrics was made during this hospitalization. | null | Not supported with pagination yet | null |
PMC6323446_01 | Female | 37 | A 37-year-old pregnant women in her 7th week of gestation presents with NVP. This was not her first pregnancy; she has three healthy children. Her previous pregnancies were a nightmare as a result of NVP. She is reluctant to take prescription medications for her NVP and prefers some "natural" remedy. Her friends told her that ginger (Zingiber officinale Roscoe) might help subside her symptoms. Recently, she caught flu and now she coughs and has nasal congestion. Her medical history shows that she has type II diabetes mellitus and a mild hypertension. She is on antihypertensive medications, oral hypoglycemic agents, insulin, a statin, and a low dose aspirin. Although she tried to breastfeed her three children, in every time her milk was not enough to totally depend on and feeding was supplemented with formula. The woman is overweight and often suffers joints pain. Her previous attempts to lose weight were futile as she could not control her appetite. Although she was not screened for ulcer, she often suffers heartburns and dyspepsia, especially with certain foods. She works as an accountant and often complained having difficulty falling asleep. She always wanted to seek a medical advice for this problem but did not have the opportunity to see a physician for this problem.
Although this case might lead to multiple professional and ethical questions, the question suggested was "should this woman use ginger?" This question was posed in neutral and concrete manner and it does not contain any professional or ethical arguments.
The potential alternative decisions in this case are identified without any final decisions made. These potential alternative decisions could be as follows: (1) this woman is recommended to use ginger without any further discussions, (2) this woman is recommended to use ginger after verifying that she is well-informed and understands the risks of using ginger in her case, (3) making a shared decision between this woman and the healthcare provider to use ginger when considering the risks are negligible, or (4) making a shared decision to avoid using ginger in her case.
Obviously, there were differences in priorities for each alternative decision that need to be considered and which were not immediately clear to make a decision at this stage.
Professional as well as ethical decisions should be substantiated with relevant information. Therefore, all relevant information regarding the potential benefits and risks of using ginger in this case should be understood thoroughly before making any decision. In a previous study, a Delphi technique was followed among gynecologists, other physicians who frequently see pregnant women with NVP, and pregnant women to achieve consensus on the potential benefits and risks of using ginger for NVP that should be addressed in a clinical consultation. The potential benefits and harms were obtained from interviews with gynecologists, physicians, and women as well as from the literature.
It was important to take into consideration that the efficacy and safety of ginger in managing NVP are still indecisive considering a number of conflicting reports. Previous studies showed that ginger decreased aggregation of platelets, increased acid production in the stomach, and had the potential to interact with many medications. A previous study demonstrated that ginger contains gingerols that have the ability to inhibit arachidonic acid-induced human platelet serotonin release and aggregation in a potency comparable to that of aspirin. The compound 8-paradol, which is one of the constituents of ginger, has a relatively potent inhibitory action on the cyclooxygenase (COX-1) and has antiplatelet aggregation activity. Bleeding, especially in the first trimester could be severely detrimental to pregnant women and their fetuses and in many cases was shown to lead to miscarriage. Although ginger is often labeled as "generally regarded as safe" in the US, in Germany and Finland, some health regulatory agencies have advised against using ginger in pregnancy.
Some studies alluded to a link between ginger and increased risk of spontaneous abortion and fetal developmental abnormalities. These suggestions are contradictory to what Portnoi et al. showed in Canada, that the use of ginger in the first trimester did not increase the risk of spontaneous and therapeutic abortions in 187 women exposed to ginger compared to 187 women who were not exposed to ginger, and those shown in a larger study conducted in Norway; however, in conservative views, these results should be considered with caution and patients as well as healthcare providers might take into consideration an inconclusive link between using ginger and risk on the fetus and continuity of the pregnancy. Ginger was also shown to reduce blood pressure and blood sugar levels. However, the effects of ginger on blood sugar are expected at higher doses than those recommended for NVP and might take months to appear. A previous study showed that ginger extracts blocked voltage-dependent calcium channels and lowered blood pressure in animal models. These findings in laboratory animals were contradictory to those shown in a randomized clinical trial in which ginger, among other herbal preparations, did not bring about significant changes to blood pressure of patients with type II diabetes mellitus. Therefore, it is not clear if the use of ginger might potentiate the effects of insulin and antihypertensive medications and might necessitate adjustment of the doses.
Ginger was also shown to be associated with cardiac arrhythmias, sweating, thirst, dehydration, duodenal ulcer, diarrhea, mild headache, fever, mild skin itching, belching, and heartburns. On the other hand, ginger might help alleviate cough, flu, joints pain, and dyspepsia. Ginger might also induce somnolence, help reduce hypercholesterolemia, increase milk production, improve skin, help controlling appetite, and promote weight loss.
The stakeholders in this case were the woman herself and her caring healthcare provider. This healthcare provider could be a physician, pharmacist, herbalist, or another healthcare providers. For this study, a panel of 10 participants was composed. The panelists were 2 physicians, 3 pharmacists, 3 herbalists, and 2 pregnant women. The panelists were provided with the case as well as the potential benefits, side effects, and risks of using ginger in this case. Perspectives of the panelists on the potential benefits, side effects, and risks when appraising benefits and avoiding side effects and risks were obtained.
To investigate how strong these arguments are in this case, the AHP was used. In AHP, panelists use pairwise comparisons to weigh alternatives and facilitate decision making. In this study, the goal was to determine relative weights of benefits to appraise therapeutic effects and avoid side effects and risks on the continuity of pregnancy and the integrity of the developing fetus. The panelists were provided with summaries containing information on safety and efficacy of ginger in NVP. Data relevant to the safety and efficacy of ginger were summarized from Natural Medicines Comprehensive Database, Cochrane Database of Systematic Reviews, and summary of relevant systematic reviews and research papers. The panelists were provided with full text copies of the papers whenever they requested them. The panelists were requested to make pairwise comparisons on a scale of 9-points. The higher the numerical value given to an item (benefit, side effect, or risk), the higher the relative weight of the item compared to the other item being compared with. The panelists were requested to consider the probability of each benefit, side effect, or risk relevant to the case presented while making the pairwise comparisons. The comparisons were conducted in 4 stages. In the first stage, the panelists were requested to rate the weights of the potential benefits. In this stage, 12 potential benefits were compared in pairwise. These benefits were alleviating NVP, alleviating cough, alleviating flu, increasing milk production, decreasing appetite, decreasing cholesterol levels, reducing blood pressure, reducing blood sugar levels, alleviating dyspepsia, improving sleep, improving skin health, and reducing joint pain. In the second stage, the panelists were requested to rate 15 potential side effects in pairwise. These side effects were risk of bleeding, cardiac arrhythmia, irritable bowel syndrome, duodenal ulcer, heartburns, hypotension, hypoglycemia, skin itching, dehydration, belching, thirst, sweating, fever, headache, and diarrhea. In the third stage, the panelists rated 3 potential risks on the continuity of the pregnancy and the integrity of the developing fetus in pairwise. These risks were risk of spontaneous abortion, risk of impairment of fetal development, and risk of fetal hypoglycemia. In the last stage, potential benefits, side effects, and risks were compared in pairwise comparisons. Individual ratings from each panelist were used to compute the comparison matrices in Excel spreadsheets. Relative weight scores as well as their consistency ratios were calculated using the mathematical formulas originally developed by Saaty.
Treatment prioritization analysis was performed on the grounds of analyzing benefits of ginger for this case, potential side effects, and risks to the fetus and pregnancy. Analyzing ratings on the benefits of ginger in this case showed that alleviating symptoms of NVP had the highest weight scores (30.7% +- 16.6%) and the one-way ANOVA with Bonferroni post hoc multiple comparisons showed that this weight score was significantly higher than other weight scores (p-value < 0.001). Therefore, alleviating symptoms of NVP was ranked 1st. Multiple comparisons showed statistically significant difference in weight scores of alleviating symptoms of dyspepsia compared to all other benefits (p-value < 0.001) except for alleviate cough (p-value = 1.000) and flu (p-value = 0.890). Scores for alleviating symptoms of cough and flu were not significantly different (p-value > 0.05), while they were statistically different from reducing joint pain (p-value < 0.05) and improving skin health (p-value < 0.01). Detailed weight scores of the potential benefits are shown in Figure 1. Multiple comparisons are presented in Supplementary Table S1.
Analyzing ratings of the side effects showed that the risk of bleeding was given significantly higher weight score (p-value < 0.001) than others (24.7% +- 13.5%) and was ranked 1st. Scores of cardiac arrhythmia and dehydration were not statistically significant (p-value > 0.05). Scores of heartburns (14.8% +- 6.6%) were significantly higher than all other potential side effects (p-value < 0.01) except duodenal ulcer (p-value = 0.145) and irritable bowel syndrome (p-value = 1.000). Detailed weight scores of the potential unwanted side effects are shown in Figure 2. Multiple comparisons are presented in Supplementary Table S1.
Weight scores for risk of spontaneous abortion (45.8% +- 3.8%) and risk of impairment of fetal development (41.6% +- 3.6%) were significantly higher (p-value < 0.001) than those of fetal hypoglycemia. Detailed weight scores of the potential risks to the fetus and pregnancy are shown in Figure 3. Multiple comparisons are presented in Supplementary Table S1.
When benefits were compared against the side effects and risks to the fetus and pregnancy, the former had significantly higher (p-value < 0.001) weight score (72.3% +- 5.2%). Details of the weight scores are shown in Figure 4. Multiple comparisons are presented in Supplementary Table S1.
From the above results, clearly, we can see that ginger can be recommended for this woman as its potential benefits outweighed its potential side effects and risks to the fetus and pregnancy. In this case, the healthcare provider and the patient herself should take a shared decision to use ginger in her case. The woman should also be informed of the potential side effects and risks of using ginger. In this case, the use of Utrecht method and the AHP provided a framework for ethical as well as professional deliberation to decision making. The use of such methods promotes openness and transparency in decision making based on the perspectives of different stakeholders. Using these methods might help find common grounds between deliberators. It is important to take into consideration that no method of ethical and professional reflection can guarantee the best outcomes. Rather, the quality of outcomes depends on the quality of the ethical as well as professional deliberations themselves and the AHP depends on the perspectives of the stakeholders taken into consideration. Future studies are needed to evaluate the utility of this combined method to facilitate deliberations and decision making in CAM use. Using such methods might help promote transparency in making decisions in patient-centered care in daily CAM practice. | null | Not supported with pagination yet | null |
PMC9035965_01 | Female | 41 | Our patient is a 41-year-old woman with a history of chronic pancreatitis for 21 years due to EtOH abuse, dyspepsia, chronic hepatitis C, and hypertension. Her chronic pancreatitis and dyspepsia were managed with pancrelipase and famotidine. Of note, the patient had a 30-pack-year smoking history and denied current alcohol use. Upon arrival at the emergency department, our patient reported a 3-day history of dyspnea on exertion and orthopnea. She endorsed nonradiating right-sided chest pain and denied hemoptysis, productive cough, chest trauma, or vomiting. The patient presented with tachycardia to 100 s and tachypnea to 30 s and with a pulse oximetry reading of 95%. The patient was trialed on BiPAP for improvement of acute hypoxic respiratory failure and ultimately required placement of a high-flow nasal cannula. She was then weaned to room air within less than 24 h after admission.
The physical exam was remarkable for diffuse crackles in lung fields bilaterally, decreased breath sounds at the lung bases bilaterally, and tachycardia. Abdominal exam was benign. Chest X-ray demonstrated large left pleural effusion and moderate to large right pleural effusion, with predominantly perihilar alveolar opacities (Fig. 1). Therapeutic thoracentesis on the left side revealed 1.550 L of markedly bloody, serosanguinous pleural fluid with the following values: amylase 630 U/L, lipase 805 U/L, LDH 681 U/L, adenosine deaminase 29.3 U/L, cholesterol 58 mg/dL, glucose 114 mg/dL, protein 5.0 g/dL, and triglycerides 25 mg/dL. ANA screen was negative. Cytology demonstrated histiocytes and benign mesothelial cells, with no malignant cells identified.
A chest CT was done after the left thoracentesis that demonstrated the expansion of the moderate to large right pleural effusion and new development of left hydropneumothorax, along with a large posteroinferior mediastinal fluid/mass that could represent pleural and pericardial or pancreatic fluid (Fig. 2). CT of the abdomen was notable for enlargement of the pancreatic duct and a stable pancreatic pseudocyst. Given the positive adenosine deaminase in the pleural fluid, a QuantiFERON Gold was ordered and returned positive. Active TB was subsequently ruled out with negative AFB culture and MTB PCR. A pigtail catheter was placed on the left side for definitive management of hydropneumothorax with a collapsed lung. Subsequent chest X-ray demonstrated slightly worsened hydropneumothorax, concerning for a persistent trapped lung with ex vacuo findings (Fig. 3). A subsequent chest CT demonstrated large left-sided pneumothorax ex vacuo with small persistent right-sided pleural effusion. Thoracic surgery was consulted, and a left lung video-assisted thoracoscopic surgery decortication for the treatment of the trapped lung was performed. Several pleural biopsies were taken to evaluate for malignancy, TB, or fungal etiology, which revealed an abscess with fibrosis and pleura with inflammation and focal mesothelial hyperplasia. Due to recurrent expansion of right-sided exudative loculated effusion, a right chest tube was placed and a few days later, a left chest tube was placed for reaccumulating intrapleural fluid.
Gastroenterology was consulted for ERCP with endoscopic ultrasound to further evaluate for a pancreatic source of elevated amylase in the pleural fluid. Endoscopic ultrasound was negative for masses, lymphadenopathy, or other signs of malignancy. ERCP demonstrated a dilated pancreatic duct and leakage at the tail or upstream body, likely representing a fistula to the pleura. Sphincterotomy was performed, and a plastic stent was placed to promote flow of pancreatic secretions internally, thus decreasing flow through the fistula and facilitating closure of the fistula. Bilateral pleural effusions subsequently improved and did not reaccumulate, and the chest tubes were removed. | pancreaticopleural fistula, pleural effusion, trapped lung | Not supported with pagination yet | null |
PMC9168401_01 | Female | 35 | A 35-year-old female patient presented with painful gross hematuria associated with clots and burning micturition for a duration of 1 month. She also reported urgency, incontinence, and nocturia. She had a history of lower segment cesarean section done 8 months previously. There was no history of fever or other associated comorbidity. The general examination was unremarkable. Figure 1 shows the cytological features of three consecutive urine samples in Giemsa- and Pap-stained smears.
What is your interpretation?
Tuberculosis of urinary tract
Urothelial changes with treatment effect
Malignancy
Cystitis cystica glandularis.
The correct cytopathological interpretation is (a) Urinary tract tuberculosis.
Three consecutive urine samples showed the presence of epithelioid cell granulomas and multinucleated giant cells along with reactive urothelial cells and inflammatory cells [Figure 1a-c]. Special stain for acid-fast bacilli (AFB) was positive [Figure 1d], thereby confirming the diagnosis of tuberculosis. The reverse transcription polymerase chain reaction and cartridge-based nucleic acid amplification test of the urine sample were also positive. The patient was immediately started on antitubercular therapy, to which she responded well.
Ultrasonography for kidney, ureter, and urinary bladder revealed a mid-pole, well-defined, cortical hyperechoic space-occupying lesion (SOL) measuring 7x8x4 mm suggestive of hemangioma. A focal concretion and right-sided mild-to-moderate hydroureteronephrosis were present. Urinary bladder showed circumferentially thickened wall. Contrast-enhanced computed tomography revealed similar findings [Figure 2a and b].
Q2. What is the most common route of infection in renal tuberculosis?
Ascending spread
Hematogenous
Lymphatic spread
Direct invasion.
Q3. In genitourinary TB, which one of the following is true ?
Sterile pyuria is a consistent finding
AFB in early morning sample is always positive.
Most common site is pelvis
It is the commonest cause of pyelonephritis.
Q4. Golf hole ureter is seen in:-
Ureteric calculus
Ureteral polyp
Tuberculosis of ureter
Retroperitoneal fibrosis.
Q5. Which of the following considered as reliable diagnostic modalities for urinary tract tuberculosis?
ZN staining and cultures isolation for Mtb in urine,
PCR for Mtb,
Imaging studies,
Histopathological evidence for TB
All of the above.
Q2. b; Q3. a; Q4. c; Q5. e
Q2.b Genitourinary tuberculosis (GUTB) is mostly secondary to pulmonary infection. Renal TB is a chronic process that can start many years after the initial lung infection.
Q3. a Sterile pyuria is the rule. Tubercle bacilli can be identified on AFB staining of 24 h urine specimen or the first morning urine sample collected on 3 successive days. AFB staining is positive in about 60% of the cases. The most common site of GUTB is kidney. The most common cause of pyelonephritis is E. coli.
Q4. c Fibrosis due to Mycobacterium tuberculosis (Mtb) usually starts around the ureter and causes pull at the ureter leading to a strictured, dilated, and rigid mouthed ureter called as golf hole ureter.
Q5. e The most common procedures used for diagnosis of urinary tract tuberculosis include: (1) Urine cytology smears examination, (2) Ziehl-Neelsen (ZN) staining and cultures isolation for Mtb in urine, (3) PCR for Mtb, (4) imaging studies, and (4) histopathological evidence for TB. | null | Not supported with pagination yet | null |
PMC9314645_01 | Female | 3 | The patient was a 3-year-old girl. In January 2020, because of pale complexion and petechiae over the entire body, she was admitted to a local hospital. She had a full-term natural birth and normal growth and development. Her father was in good health, and her mother had hepatitis B virus infection. They were not in a consanguineous marriage. The parents denied a family history of similar or other cancers or hereditary diseases. Her white blood cell count was 209x10^9/L. She was diagnosed with acute lymphocytic leukemia by MICM of the bone marrow. Since January 15, 2020, according to the CCLG-ALL 2015 protocol, she was evaluated as having intermediate risk and underwent induction chemotherapy. The reexamination showed remission in the bone marrow morphology and MRD<0.01%. After that, she was given regimens of CAM and HD-MTX+6-MP. On August 7, 2020, morphological evaluation of her bone marrow showed 4.5% lymphoblasts and prolymphocytes; flow cytometry indicated 9.85% abnormal naive T lymphocytes. Thus, she was suspected to have a recurrence of acute lymphocytic leukemia. Peripheral blood smears indicated 4% naive T lymphocytes. BLOCK3 chemotherapy was given. On September 18, 2020, morphological evaluation of bone marrow showed 24.5% lymphoblasts and prolymphocytes, and flow cytometry showed 19.98% abnormal naive T lymphocytes. She was given VDS+DEX and VDIP regimens successively, but with no remission. During this period, no abnormal lymphocytes were found in multiple lumbar punctures + sheath injections of cerebrospinal fluid. On November 10, 2020, the patient was admitted to our hospital for the first time. MICM confirmed the previous diagnosis of acute T-lymphocytic leukemia. Gene mutations identified Notch1 p.S2467Pfs * 12, STAT5A p.T6285, and IL7R p.L243_T244insCP, but HBV DNA>1*10^8 IU/ml suggested associated hepatitis B. She was given entecavir 0.25 mg once per day and an intravenous injection of freeze-dried hepatitis B human immunoglobulin 2500 IU once per day for antiviral treatment. The changes in HBV DNA during treatment are illustrated in Figure 1 . On November 19, 2020, the FLU + idarubicin chemotherapy regimen was given to eliminate lymphocytes; on November 25, 2020, she was transfused with humanized CD7 CAR-T cells from a donor (her father). The donor's physical examination results were normal, and his HBV DNA was measured at 0. On Days 15 and 30 after CD7 CAR-T therapy (2020-12-15 and 2020-12-24), the bone puncture reexamination showed morphological remission, with residue negativity. The treatment process is outlined in Table 1 .
Four days after CAR-T transfusion, a CRS reaction (grade 2 at maximum) occurred, which was relieved after hormone therapy. She had a rash 3 weeks after CAR-T therapy, which was considered aGVHD (skin grade II) and was relieved after intense anti-GVHD treatment. Two weeks after CD7 CAR-T transfusion, the white blood cell count was lower than 0.5x10^9/L. After CAR-T transfusion, she still received anti-hepatitis B virus therapy. The HBV DNA copy number increased after CAR-T transfusion and peaked (3.9*106 IU/ml) on the 14th day. After consultation with a liver disease specialist, since there was the possibility of the activation of the hepatitis B virus, tenofovir disoproxil fumarate tablets were given at a dosage of 75 mg once per day, in addition to entecavir and hepatitis B globulin. After that, her hepatitis B HBV DNA copy number fell to 7.3x10^4 IU/ml before transplantation. The BU/FLU/ATG/Me-CCNU conditioning regimen started on December 26, 2020. The donor of CAR-T was also used for the transplant. She subsequently received HLA 5/10-matched, blood type-mismatched (donor O+, recipient B+) haploidentical stem cell transplantation from her father on January 4, 2021. Graft-versus-host disease (GVHD) prophylaxis was performed with cyclosporine, short-term methotrexate and mycophenolate mofetil. Seven days after transplantation, the child had diarrhea and persistent bloody stools, but no pathogenic bacteria were found in the culture; engraftment syndrome was excluded. Eighteen days after transplantation, the neutrophil count was 0.25x109/L, suggesting that the neutrophil were not engrafting. The patient had gastrointestinal bleeding during the neutropenic period soon after the myeloablative conditioning regimen. The bleeding may have been due to the side effects of the anti-hepatitis B drugs and thrombocytopenia. The bleeding symptoms gradually improved after reducing the doses of tenofovir disoproxil fumarate and entecavir and transfusing platelets. The time of neutrophil engraftment was on days 22 after transplantation. The time of platelets engraftment was on days 91 after transplantation. The plasma CMV DNA and EBV DNA of the patient were all negative after transplantation. Bone marrow puncture and lumbar puncture at 1, 2 and 3 months after transplantation showed that the bone marrow morphology was in remission, with residue negativity, and the chimerism rates of bone marrow blood and peripheral blood showed it was of the complete donor type. After transplantation, PCR detected CD7 CAR-Ts again, and stem cell implantation had no effect on hepatitis B virus replication ( Figure 2 ). Four and a half months after transplantation, abnormal T lymphocytes expressing CD7-CD5+ were detected by flow cytometry, but the patient was still in complete remission with full donor chimerism in both bone marrow and CD3+ cells in peripheral blood. Half a month after reducing immunosuppressive agents, the flow cytometry of bone marrow turned negative ( Figure 3 ). As of August 2021, eight months after transplantation, the patient showed complete remission and was HBV DNA negative.
In this case, the patient reached complete remission after CD7 CAR-T therapy, and then bridging HSCT was performed. HBV DNA increased temporarily after CD7 CAR-T therapy and then gradually decreased. Blood indicators (white blood cells, platelets), biochemical indicators (AST, ALT, DBIL, TBIL), and cytokines (interleukin 6, tumor necrosis factor alpha, interleukin 10, soluble CD25, interferon gamma) were all monitored ( Figure 4 ). White blood cells increased to a maximum of 14.93*109/L 11 days after CD7 CAR-T therapy, dropped to less than 0.5*109/L, and remained in continuous agranulocytosis. Engrafted leukocytes survived 18 days after transplantation ( Figure 4A ). The time of neutrophil engraftment was on days 22 after transplantation. Since the patient had hepatitis B virus replication, liver function was monitored (AST and ALT are illustrated in Figure 4B , TBIL and DBIL in Figure 4C ). There was a transient increase in transaminase and bilirubin after transplantation. At that time, there were no other GVHD clinical manifestations such as rash, diarrhea. It has been improved with strengthening liver protection medicines without addition of anti-GVHD treatment. Therefore, the diagnosis of abnormal liver function was considered to be drug-induced liver damage rather than GVHD. The concentrations of cytokines (interleukin 6, tumor necrosis factor alpha, interleukin 10, soluble CD25, interferon gamma) peaked four days after CD7 CAR-T treatment, consistent with the CRS response, then increased to another peak after HSCT, and fell after that ( Figure 4D ). | allogeneic hematopoietic stem cell transplantation, donor-derived chimeric antigen receptor t cells, hepatitis b virus, relapsed/refractory acute t-lymphocytic leukemia, stem cell transplantation | Not supported with pagination yet | null |
PMC3894917_01 | Male | 52 | A 52-year-old man with medical history marked by obesity (body weight 112 Kg, body mass index 33.7 kg/m2) and acute myocardial infarction (20 years ago), presented to our Institution in June 2013 with fever and dental pain. There was no more tobacco intoxication, nor alcohol consumption. Clinical examination was normal. Blood tests displayed hyperleukocytosis with 74% of circulating blasts, anemia, and thrombocytopenia. Hepatic tests showed moderate cytolysis and cholestasis: L-aspartate aminotransferase (AST) level at 59 IU/l, (N<40), L-alanine aminotransferase (ALT) at 44 IU/l, (N<56), gamma-glutamyltransferase (gammaGT) at 69 IU/l, (N<42), alkaline phosphatase (APL) at 49 IU/l, (N<120), and total bilirubinemia (TBIL) at 35 mumol/l, (N<20). An abdominal ultrasound was performed and revealed mild steatosis and absence of hepatomegaly. Because of fever, a piperacillin/tazobactam treatment (4 g/6 h) was rapidly initiated. Bone marrow aspirate confirmed the diagnosis of ALL with medullary infiltration by 90% of blastic cells immunophenotypically of B cell lineage (CD19+, CD22+, CD10-, CD20-). Molecular and cytogenetic analyses showed initial features of high-risk ALL (Ikaros deletion and t(4;11) with MLL rearrangement).
After a 1-week prephase with steroids, induction chemotherapy was started according to the GRAALL 2005 trial, including daunorubicin 50 mg/m2/day on days 1 to 3 and 30 mg/m2/day on days 15 and 16; vincristine 2 mg total dose on days 1, 8, 15, and 22; cyclophosphamide 750 mg/m2/day on days 1 and 15; and (theoretically) 8 injections of L-aspa 6000 IU/m2/day on days 8, 10, 12, 20, 22, 24, 26, and 28. Neuromeningeal prophylaxis was performed by intra-thecal injections of methotrexate (15 mg), methylprednisolone (40 mg), and cytarabine (40 mg). Granulocyte colony-stimulating factor (G-CSF) was planned from day 18 to the ultimate neutrophil recovery. During neutropenia, Candida albicans was isolated twice from systematic stool examination, without any digestive symptoms. At day 19, the patient presented abdominal tenderness, especially in the right upper quadrant, and hepatomegaly. While recovering neutrophils on day 22, he experienced fever again and an increase of biological inflammatory markers (grey zone, Figure 1). On day 25, after 5 injections of L-aspa (day 10 injection was not performed), hepatic enzyme levels significantly increased, showing cholestasis and to a lesser extend cytolysis (AST level at 168 IU/l, ALT at 148 IU/l, gammaGT at 735 IU/l, APL at 148 IU/l, and TBIL at 128 mumol/l). Another L-aspa injection was done on day 26, but the last one was not prescribed, as hepatic enzymes still increased. At that time, bone marrow aspirate showed achievement of complete remission. A large and systematic diagnosis strategy, including screening for viral infections (HBV, HCV, HAV, HEV, VZV, EBV, HSV, CMV, HIV, PVB19), and autoantibodies (anti nuclear, anti-neutrophil cytoplasmic, anti-mitochondria, anti-actin, anti-endoplasmic reticulum, anti-LKM1, and anti-GP210), was negative. Lipid profile only revealed an isolated hypertriglyceridemia (3.3 g/l). A second abdominal echography, and contrast computed tomography were performed, this time showing homogeneous hepatomegaly (hepatic arrow at 22.2 cm) with signs of major steatosis (Cf Figure 2A), and no sign of biliary obstruction or vascular abnormality. There were no hypodense nodular lesions. Bacterial and mycological blood cultures remained negative. A liver biopsy was performed at J34 (AST level at 179 IU/l, ALT at 266 IU/l, gammaGT at 1425 IU/l, APL at 266 IU/l, and TBIL at 124 mumol/l) by transjugular route. Pathology examination revealed macro- and microvesicular severe steatosis, affecting more than 50% of hepatocytes, with a moderate hepatocyte necrosis, and a mild portal and lobular inflammatory infiltration, including rare neutrophils (Figure 2B). Gomori-Grocott coloration was negative, and bacterial assessment remained sterile. All running treatments were stopped except acetyl salicylic acid because of the cardiac history.
Concomitantly, the patient presented a cough related to an interstitial pneumonia. Pneumocystis jirovecii infection was documented by PCR from bronchoalveolar lavage products. Arterial oxygen pressure was at 58 mmHg (without oxygen therapy). A curative treatment, combining atovaquone with systemic corticosteroids (0.5 mg/kg/day for 10 days), was initiated on day 36 (CRP level at 50 mg/l, AST at 200 IU/l, ALT at 292 IU/l, gammaGT at 1755 IU/l, APL at 260 IU/l, and TBIL at 123 mumol/l), yielding to a rapid decrease of the inflammatory syndrome. Antioxidant therapy with N-acetyl cysteine was concomitantly started. Prothrombin time was maintained at about 60-70% with daily intravenous vitamin K supplementation.
No clinical or biological evidence of hepatic failure was observed. Finally, biological cholestasis and hepatic cytolysis progressively decreased. A control abdominal ultrasound also revealed the regression of hepatomegaly. On day 68, hepatic tests tended to be in normal range (AST level at 43 IU/l, ALT at 79 IU/l, gammaGT at 80 IU/l, APL at 47 IU/l, and TBIL at 19 mumol/l). Consolidation chemotherapy could therefore be administered, but L-aspa was definitively banned. After 3 months, hepatic test results were in normal range, except for gammaGT level at 85 IU/l. Intensification by allogeneic stem cell transplantation is ongoing. | l-asparaginase, acute lymphoblastic leukemia, cholestasis, hepatomegaly, steatosis | Not supported with pagination yet | null |
PMC9874938_01 | Male | 7 | A 7-year-old boy, firstborn of non-consanguineous parents, presented to our institute with recurrent episodes of colitis noted from early infancy. The child underwent colonoscopy five times from different hospitals in the last 6 years and was diagnosed with inflammatory bowel disease. A colonoscopy revealed diffuse erosions, ulcerations, granularity, and loss of vascularity in the rectum, sigmoid colon, and descending colon. In addition, the transverse colon showed discrete erosions. However, ascending colon and terminal ileum were found to be normal. Colonoscopy-guided biopsy showed patchy ulcers with neutrophilic exudate, crypt abscess, and crypt loss. Multiple mucosal granulomas with dense epithelioid cells were noted. He was managed as a case of inflammatory bowel disease with mesalamine and intermittent doses of oral glucocorticoids. He showed clinical response with oral glucocorticoids; however, symptoms recurred once the steroid doses were tapered or stopped. For the same, the child was later initiated on oral mesalamine, which was continued for the last 3 years. He had a past history of Burkholderia cepacia septicaemia at 3 years, pneumonia requiring hospital admission at 5 years, and an episode of cervical lymphadenitis at 6 years. He had received one course of antitubercular therapy (ATT) based on empirical grounds. NBT assay was performed on multiple occasions at different facilities; however, there was a reduction of NBT to formazan on every occasion that was not conclusively suggestive of CGD.
He had an average build and a healthy scar the bacille Calmitte-Guerin (BCG) vaccination site. He had moderate pallor and left anterior lower cervical lymphadenopathy. The rest of the clinical examination was unremarkable. Complete blood count showed anaemia (Hb 7 g/L), neutrophilic leukocytosis (total leucocyte count 14.1 x 109/L; polymorphs 66%, lymphocytes 26%, monocyte 7%, and eosinophil 1%), and thrombocytosis (platelet 498 x 109/L). Erythrocyte sedimentation rate was 70 mm at the first hour. C-reactive protein was 66 mg/L. Fine needle aspiration cytology from the cervical lymph node showed scattered multinucleated giant cells along with few immunoblasts, plasma cells, and histiocytes. Cartridge-based nucleic acid amplification test (CBNAAT) from lymph node aspirate revealed Mycobacterium tuberculosis complex. Endoscopic biopsy from the sigmoid colon revealed features suggestive of inflammatory colitis (Figure 1). | chronic granulomatous disease, colitis, dihydrorhodamine, nitroblue tetrazolium, residual nadph oxidase | Not supported with pagination yet | null |
PMC8423496_01 | Male | 12 | Review and presentation of this case were in accordance with the Institutional Review Board at Nationwide Children's Hospital (Columbus, Ohio). The informed consent form at Nationwide Children's Hospital allows for de-identifiable information related to a patient's anesthetic care to be used for teaching and publication. Written informed consent for anesthetic care and publication was obtained from a parent prior to the procedure. A 12-year-old, 48.3 kg adolescent male with a past medical history of ADHD, generalized anxiety disorder, and behavioral issues, presented for debridement and dressing of partial-thickness burns of the trunk, bilateral extremities, and face (20-29% TBSA) with split thickness skin graft and placement of skin substrate on the face. He had been in the intensive care unit (ICU) receiving mechanical ventilation for 3 weeks prior to the procedure, with burn injury and a hospital course complicated by inhalational injury with respiratory failure, hypoxic encephalopathy, and wound infection. He was premedicated with midazolam (4mg) and transported to the OR, where standard American Society of Anesthesiologists' monitors were placed. Anesthesia was induced with propofol and maintained with sevoflurane, dexmedetomidine, and hydromorphone. Anesthetic care was uneventful until shortly before the end of the procedure when during the change of wound dressing on the face, the pilot balloon for the size 5.5 endotracheal tube in situ was inadvertently cut off (Figure 1). Immediately following this, a hemostat was placed on the remainder of the pilot cuff tubing to secure the remaining air and maintain the pressure in the cuff. Ventilation was also maintained with increased flows to compensate for air leaks. The patient remained stable, and once the dressing was secure, his trachea was re-intubated. This event led to a departmental quality improvement investigation with a literature search and development of an in vitro technique to determine an effective means to re-inflate the cuff of an endotracheal tube in the event that immediate exchange was not feasible. | endotracheal tube, pediatric airway, pilot balloon | Not supported with pagination yet | null |
PMC10187644_01 | Male | 45 | A 45-year-old man visited our hospital on May 12, 2021, due to hemoptysis with a four-month duration. The patient had a history of hypertension, diabetes, lipid metabolism disorders and coronary heart disease. In 2019, he experienced sudden cardiac death and required endotracheal intubation and tracheotomy, but he survived; the patient had a higher limb muscle tone and minor cognitive impairment after taking aspirin for a long time. Four months prior, he experienced recurrent bouts of blood-tinged sputum. Laboratory parameters were within the normal limits. Computed tomography (CT) scans showed consolidation of the outer basal segment of the left lung's lower lobes and a few cord shadows surrounding it. The results of the clinical examination were inconclusive. He was admitted to a local hospital for a trial of antibiotics and hemostasis, and his condition quickly improved.
He subsequently visited our hospital for recurrent hemoptysis and deterioration and ceased taking aspirin. On admission, his physical symptoms were normal. The white blood cell count was 10.4 x109/L, the percentage of neutrophils was 78%, the C-reactive protein level was 15 mg/L, and the procalcitonin level was 0.03 ng/mL. The serology for HIV was negative. Chest CT showed consolidation of the outer basal segment of the left lower lobe, measuring 2.8 x3.0x 3.5 cm (Figure 1A and B). To stop the haemorrhage, bronchial artery embolization was performed, and the patient was treated with intravenous phentolamine, tranexamic acid, and haemagglutin. The tumour markers (CEA, CYFRA21-1, SCC, NSE, proGRP) were normal. Additional tests were performed, including the T-cell spot test for tuberculosis infection, cryptococcal antigen tests, G-tests, galactomannan antigen detection tests, extractable nuclear antigen tests, and anti-neutrophil cytoplasmic antibody tests, which were within the normal limits. Antinuclear antibody positivity was 1:100. For diagnosis, bronchoscopy with R-EBUS, bronchial brushing (BB), a transbronchial biopsy (TBB), and bronchial washing were performed. The specimens were sent to the lab and pathologist as soon as possible; however, the results of the pathological examination only showed inflammation and a small amount of necrosis in the bronchial mucosa, with no indication of malignancy. Moreover, conventional cultures for bacterial, fungal, and tuberculosis infection were all negative. He underwent a second bronchial artery embolization for massive hemoptysis (approximately 400 mL) on June 12, 2021. Persistent hemoptysis led to repeat chest CT, which revealed a reduced consolidation lesion measuring 2.0 cm x 2.6 cm x 3.0 cm, with ground glass density foci and cords surrounding the lesion (Figure 1C and D). We considered that the lesion was complicated with bacterial infection and administered amoxicillin clavulanate potassium orally.
Hemoptysis recurred on June 29. The patient had intermittent bouts of massive hemoptysis (>150 mL) every few hours, and intravenous injection of hemostatic drugs was ineffective. The third bronchial artery embolization showed no bleeding. On July 6, 2021, the patient experienced extensive hemoptysis, which was voluminous, and bright red; the estimated volume of blood was 700 mL. CT showed an increase in the size of consolidation to 2.0 cm x 2.7 cm x 3.1 cm and bilateral ground-glass opacities (Figure 1E and F). Bronchoscopy revealed the presence of old blood clots in the upper and lower left lungs, as well as scattered evidence of recent blood in the trachea. We decided to perform emergency VATS. The left lower lung was resected. The patient did not have hemoptysis after the operation and was given meropenem, which was degraded to ceftriaxone. Histopathology revealed a grey-white area with a range of 1.8x1.5x1.3 cm in the gross lung tissue, bronchiectasis in the lung, disintegration of the tube wall, and acute inflammatory exudate in the lumen. Under a microscope, chrysanthemum shapes in the lumen and dense centres of intertwined, branched hyphae surrounded by radially-arranged eosinophilic long hyphae were observed; Glan staining was positive, and epithelioid cells surrounded the granules, macrophages, lymphocytes, and other inflammatory cells, which were positive for hexamine silver and Periodic Acid-Schiff stain (Figure 2). The final diagnosis was pulmonary actinomycosis. His condition was stabilized with oral amoxicillin following discharge. He has remained in a stable condition for a year while receiving routine follow-up. | actinomycosis, bronchoscopy, hemoptysis | Not supported with pagination yet | null |
PMC7479372_04 | Female | 44 | Another 44-year old woman (I) with involuntary muscle movement in both legs stated:
'I do not like working with different textures; some textures tangle, I so wish they can get proper material that does not tangle, but we were told that there is no money. I cannot proceed with my work the way I would like to because I need to keep on fixing the wool. It is a waste of time and energy, and it is frustrating me'.
Lack of funds continues to be a challenge for people with disabilities and is a barrier to participation. This challenge resulted in participants having to use inappropriate material for their projects, which in return resulted in poorly constructed products. This hindered the growth of their projects. Kaeane and Ross and Schneider also reported that limited funding hindered the ability of projects to grow. Lack of non-human resources specifically funds, were frequently mentioned to be barriers in a study by Hastbacka, Nygard and Nyqvist. This lead to increased demands for cost-effectiveness, as well as demands for eliminating unnecessary and costly obstacles in service provision. It is also evident from the findings that generally, programmes for the empowerment of people with disabilities were underfunded or not funded at all. This finding is supported by White Paper on the Rights of Persons with Disabilities (Republic of South Africa), which indicates that one of the weaknesses in the subsidised supported employment environment that offers income generating activities opportunities to their members is the lack of financial support. Non-payment of stipends is a serious concern because it has a direct influence on the motivation of the participants (Lack of motivation is another barrier addressed in this section). Remuneration plays a role in attracting and retaining individuals (Mabaso & Dlamini) and could be a reason for participants' lack of motivation and dissatisfaction. | barriers, income generating activities, participation, people with disabilities, sheltered workshop | Not supported with pagination yet | null |
PMC4785670_01 | Female | 25 | A 25 year old female was diagnosed of CVID in 2006 (at age of 18) with initial presentation of recurrent episodes of bacterial sinusitis and outbreaks of genital herpes. Laboratory work revealed hypogammaglobulinemia with poor antibody responses to both polysaccharide and protein antigens. She was found to have IL-2-Inducible T-cell kinase (ITK) mutation, which is potentially involved in the pathogenesis of her CVID. She was started on IVIG and has been receiving it every month.
The patient has additional history of type 1 diabetes diagnosed at 18 months of age, for which she has been depending on insulin, as well as immune thrombocytopenia purpura (ITP) diagnosed at age of 11. She had multiple episodes of recurrent thrombocytopenia managed with IVIG and corticosteroids. In 2002, at the age of 14, she was hospitalized with a presentation of fever and pain, and found to have lymphadenopathy, lymphopenia, neutropenia, and thrombocytopenia. An extensive infectious workup was negative. She had bone marrow biopsy, which was unremarkable with the exception of findings consistent with cytopenias. She ultimately underwent a splenectomy and lymph node resection in 2002. Lymph node and spleen pathology revealed noncaseating granuloma. After the splenectomy, her fevers and pain resolved. Her blood counts have remained relatively normal since splenectomy. | brentuximab, cvid, hodgkin lymphoma, rituximab | Not supported with pagination yet | null |
PMC7968529_01 | Male | 37 | A 37-year-old Indonesian man was referred to the emergency department of Dr. Soetomo General Hospital, Indonesia, in June 2019, with complaints of shortness of breath and swollen legs. His occupation was a farmer. Two months earlier, the patient went to the public health center for a prolonged cough (+- five months), which was sometimes accompanied by shortness of breath. In the public health center, acid-fast bacillus (AFB) testing was performed with a negative result. Based on a chest radiograph, the doctor decided to give group 1 anti-tuberculosis drugs through the public health center. The treatment prescribed was fixed-dose combination, four tablets daily taken orally, with the composition of each tablet as follows: Rifampicin 150 mg, Isoniazid 75 mg, Pirazinamide 400 mg, and Ethambutol HCl 75 mg. Thus, in the emergency department, he was referred to the pulmonology department with a diagnosis of pulmonary tuberculosis.
In addition, the patient also had a history of proximal bilateral femoral deep vein thrombosis (DVT) of the left inferior limb proven by ultrasonography examination; the patient had undergone a thrombectomy a month before his referral to the hospital. The complaints of swollen leg were slightly reduced at that time; however, had recurred again, accompanied by swelling on his right limb.
The patient had been diagnosed with uncontrolled diabetes mellitus and heart failure one month before admission. He received subcutaneous injection 8 units of insulin aspart three times a day before meals, captopril 6.25 mg every eight hours orally, spironolactone 25 mg once daily orally, digoxin 0.25 mg once daily orally, codeine 10mg every eight hours orally, and rivaroxaban 15 mg every twelve hours orally.
When admitted to the pulmonary ward, the patient complained of shortness of breath, accompanied by pain and swelling in both legs. His blood pressure was 120/80 mmHg, pulse 128 beats per minute, respiratory rate 26 breaths per minute, and 3 liters per minute oxygen via nasal cannula. Physical examination revealed jugular venous distention, bilateral basal rales, hepatomegaly, and pitting edema in lower extremities.
In laboratory findings, serum electrolytes revealed hypokalemia (K: 3.3 mmol/L; normal range 3.5-5.1 mmol/L), serum protein showed hypoalbuminemia (albumin: 3.1g/dL; normal range 3.4-5.0 g/dL), while other parameters were between normal limits. An electrocardiogram (ECG) showed sinus tachycardia rhythm 125 beats per minute, right-sided frontal axis, horizontal axis clockwise rotation, and slow progression of R waves at V1-V4 ( Figure 1). A chest X-ray showed cardiomegaly, pulmonary congestion, and minimal bilateral pleural effusion ( Figure 2). Echocardiographic examination revealed moderate mitral regurgitation (dilated mitral annulus), dilatation of all cardiac chambers (Left ventricular internal diastolic diameter 5.8 cm), visible thrombus in inferior vena cava to right atrium, decreased left and right ventricular systolic function (EF teich 35%, TAPSE 1.3 cm), and global hypokinetic of the left ventricle with eccentric left ventricular hypertrophy. The scans from a transthoracic echocardiogram (TTE) showing thrombus is shown in Figure 3 and Figure 4.
A chest CT scan ( Figure 5) showed right pulmonary artery embolism at +- 5.9 cm from bifurcation on the anterior side of the intermediate right bronchus; emboli on the left pulmonary artery bifurcation and the left pulmonary artery basal part; multiple right intraatrial hypodense lesions not showing contrast enhancement leading to a visualization of the right intraatrial thrombus; pulmonary infarction in the lateral-posterior segment of the base of the inferior lobe of the right lung, the lateral-posterior segment of the base of the inferior lobe of the left lung, and the anterior segment of the superior lobe of the left lung; and superior vena cava thrombus at VTH level 1-5. Figure 6 shows the protruded thrombus in the right atrium passing through the tricuspid valve. TTE also showed the position of the thrombus moving from the inferior vena ca va towards the right atrium ( Figure 7). The movement of the large protruding thrombus can be seen in the supplementary video files 1-3 - .
In the course of the assessments, no clinical, laboratory, or radiological signs of pulmonary tuberculosis were found. Eventually, the patient was transferred to the cardiology ward with the assessment of dilated cardiomyopathy + acute decompensated heart failure + deep vein thrombosis of the right and left inferior limbs + right atrial thrombus + pulmonary embolism + type II diabetes mellitus. During three days of treatment, the patient received Spironolactone 50 mg, Ramipril 5 mg, and low-dose Bisoprolol started at 1.25 mg each once daily orally, 20 mg of Furosemide by the intravenous injection every eight hours, subcutaneous injection of Enoxaparin 60 mg every twelve hours, and subcutaneous injection 6 units of insulin aspart three times daily before meals. However, in the course of this treatment in the cardiology ward, the patient suddenly complained of shortness of breath accompanied by chest pain and cold sweat. His blood pressure became 60/40 mmHg, pulse 110 beats per minute, and respiratory rate 28-30 breaths per minute, thus showing hemodynamic instability and shock. Therefore, he was reassessed as having high risk acute pulmonary embolism, and the patient was transferred to the cardiovascular care unit (CVCU) for observation and reperfusion therapy.
In the CVCU, we gave the patient hemodynamic support with Norepinephrine starting at 50 nanograms/kg/minute by titration. Reperfusion was carried out by giving a loading dose of 250,000 units of Streptokinase intravenously for 30 minutes, followed by 100,000 units of Streptokinase per hour for 24 hours with continuous intravenous pump. After revascularization, the patient's hemodynamic condition improved until vasopressors/inotropic drugs could be tapered off. TTE also showed the disappearance of the large protruding thrombus (supplementary video files 4-5) , . After the patient's condition was stable, he was transferred to the cardiology ward until the patient was discharged after one week of thrombolytic treatment. In his discharge, rivaroxaban was prescribed at a daily dose of 20 mg as an oral anticoagulant for at least three months. The diabetes mellitus was well-controled with subcutaneous injection 6 units of insulin aspart three times daily before meals.
One week after discharge, the patient made a follow-up visit at the cardiology outpatient clinic. At that time, it was found that the patient's symptoms and exercise tolerance had improved, and his shortness of breath and swollen leg were reduced. The patient's adherence to treatment was good, and there was neither sign of minor nor major bleeding due to anticoagulants' use. Even though the clinical condition has improved, there was no improvement in the ejection fraction. Therefore, anticoagulant therapy and insulin injection were continued, accompanied by therapy for heart failure according to guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). | massive pulmonary embolism, large protruding thrombus, reperfusion, unstable hemodynamic | Not supported with pagination yet | null |
PMC7074614_01 | Female | 2 | A 2-year-old female neutered domestic shorthair cat presented with a 6-month history of an intermittent bilateral forelimb lameness, an intermittent 'bunny-hopping' hindlimb gait, difficulty with use of stairs and jumping and occasional vocalisation suspected to be pain-related. The gait was worse following rest and improved with walking. Eighteen months prior to presentation, there had been a period of right hindlimb lameness followed by a period of left hindlimb lameness that later resolved. The cat had been in the owner's possession since the age of 12 weeks, had not left the UK, had outdoor access and was fed a complete commercial cat food. Meloxicam (0.05 mg/kg PO q24h [Metacam; Boehringer Ingelheim]) had been used intermittently for several months prior to presentation but with limited effect.
On initial presentation to the neurology department, there was a right forelimb lameness at rest, which improved with walking. A mild medial patellar luxation was palpable bilaterally. Neurological examination detected a normal gait with normal postural reactions, normal spinal reflexes, normal cranial nerve testing and no pain on spinal palpation. The cat was discharged with a further course of 0.05 mg/kg meloxicam PO q24h and restricted activity was advised.
On follow-up examination with the orthopaedic department 8 weeks later, the cat was markedly lame on all four limbs but particularly on the forelimbs. There was alternation between toe-walking on the forelimbs with a hunched posture and using the dorsal aspect of the carpi to walk on (Figure 1a,b). The cat would hiss repeatedly when walking and would lie down tentatively, appearing happier and less painful when lying down. When not lying down, the cat preferred to sit back on the hindlimbs and non-weightbear on the forelimbs (Figure 1c; so-called kangaroo stance). A source of pain could not be localised on the forelimbs, but there was a repeatable pain response to palpation around the calcaneus bone and insertion of the Achilles tendon bilaterally. Differential diagnoses included a diffuse neuromuscular disease, an autoimmune disease such as systemic lupus erythematosus or polyarthritis, or an infectious disease such as toxoplasmosis.
Haematology was unremarkable. Serum biochemistry revealed a mild elevation in creatine kinase (237 U/l; reference interval [RI] 50-150 U/l) but was otherwise unremarkable. Serology for feline leukaemia virus and feline immunodeficiency virus (FIV) was negative. Serology for antinuclear antibodies (ANA) and T gondii IgG and IgM were pending.
The cat was sedated with 5 microg/kg dexmedetomidine (Dexdomitor; Zoetis) intravenously (IV) and 0.02 mg/kg buprenorphine (Buprecare; Animalcare) IV with a top-up of propofol (Propoflo Plus; Zoetis) IV to effect. Radiographs of the elbows and antebrachii were unremarkable. Radiographs of the tarsi revealed a small spur of bone projecting distally from the plantar aspect of the flexor surface of the left calcaneus, slight undulation to the plantar surface of the proximal calcaneal tuberosity bilaterally, and mild soft tissue swelling over the point of the calcaneal tuberosity and distal calcaneus and Achilles tendon bilaterally. These changes were considered mild and non-specific. Arthrocentesis of the left stifle, left shoulder, left carpus and left tarsus was unremarkable. A sample of bursal fluid from the right Achilles tendon revealed neutrophilic inflammation with intracytoplasmic inclusions suspected to be lupus cells or Dohle bodies (Figure 2). Sedation was reversed with 50 microg/kg atipamezole (Antisedan; Zoetis) intramuscularly.
The cat was hospitalised prior to further investigations and received 0.02 mg/kg buprenorphine IV q6-8h and 0.05 mg/kg meloxicam PO q24h. There was no improvement with this treatment.
Anaesthesia was induced with propofol IV to effect, following a premedication of 0.2 mg/kg methadone (Methadyne; Jurox) IV and 5 microg/kg dexmedetomidine IV and was maintained with isoflurane (IsoFlo; Zoetis) and oxygen. Cefuroxime 20 mg/kg (Zinacef; GlaxoSmithKline) IV was provided perioperatively. Nerve conduction velocity (NCV) studies of the left tibial motor nerve, left ulnar motor nerve and left tibial sensory nerves were within normal limits. All F wave latencies were within normal limits. Sensory nerve studies were also normal. Electromyography (EMG) of the left flexor carpi ulnaris, left biceps, left supraspinatus, left gastrocnemius, left cranial tibial and left middle gluteal muscles showed increased insertional activity. The left extensor carpi radialis longus, left deltoid and the left triceps muscle showed increased spontaneous activity. The left supraspinatus muscle showed increased insertional activity and slightly increased spontaneous activity. The left palmar interossei, left semimembranosus, left biceps femoris and left quadriceps muscles showed no evidence of electrical instability.
NCV and EMG findings were consistent with a diffuse muscular disease, worse in the proximal thoracic limb and distal pelvic limb muscles. An axonopathy without secondary myelin disturbance was considered less likely. Results from the EMG are summarised in Table 1. A sample of fluid taken from the left Achilles tendon bursa was consistent with findings from the contralateral side: neutrophilic inflammation with intracytoplasmic inclusions suspected to be lupus cells or Dohle bodies. Biopsies were taken from the right infraspinatus, right triceps brachii, right extensor carpi radialis, right cranial tibialis and right gastrocnemius muscles and submitted for histopathology and T gondii PCR. The cat was discharged from hospital with 0.05 mg/kg meloxicam PO q24h while results were pending.
T gondii serology using an immunofluorescent antibody assay returned with a markedly elevated IgG titre of 1:1600 (RI <1:50) and borderline IgM titre of 1:25 (RI <1:25). ANA titre was negative. Clindamycin (Antirobe; Zoetis) was started at 19.2 mg/kg PO q12h and the course of 0.05 mg/kg meloxicam PO q24h continued. Histopathology of each muscle biopsy revealed a diffuse, chronic, moderate myopathy with some myofibre resorption. There was no evidence of T gondii DNA on PCR testing of the right triceps brachii muscle.
An improvement was seen within 3 days of starting the clindamycin. T gondii serology 2 weeks after starting the clindamycin revealed a markedly elevated IgG titre of 1:1600 and a mildly elevated IgM titre of 1:50.
The cat re-presented following a 6-week course of clindamycin. The owners reported an occasional forelimb lameness, but otherwise there had been significant improvement. The cat was more sociable, would play with the other in its home cat and had stopped vocalising. On examination, the cat was walking relatively normally. There was no toe-walking, no walking on the dorsal aspect of the carpi and no sitting back on the hindlimbs. There was mild enlargement of the Achilles tendon bursae, more so on the right, with some resentment on palpation. An ophthalmological examination detected a small chorioretinal scar that could be compatible with a toxoplasmosis lesion; there was no evidence of active lesions and no ophthalmic nerve pathology. The clindamycin was stopped, and meloxicam continued at the same dose for a further 3 weeks. T gondii serology repeated 13 weeks after finishing the clindamycin revealed a positive IgG titre of 1:400 and a normal IgM titre of 1:20.
The cat was presented for a follow-up examination 20 months after the cessation of treatment. The owners reported there was full resolution of clinical signs 3 months from the start of the clindamycin. The cat had not received any medication since that time and there had been no recurrence of clinical signs. On examination, the gait was normal with no signs of lameness (see video 1 in the supplementary material). The cat could jump up and down from a chair and consultation table normally (see video 2 in the supplementary material). There was mild irregularity on palpation of the point of the calcaneus bilaterally, but no swelling of the Achilles tendon bursae and no patellar luxation. The remainder of the physical examination was unremarkable. | toxoplasma, bursitis, myalgia, myositis, protozoan infections, toxoplasmosis | Not supported with pagination yet | null |
PMC7219375_01 | Female | 33 | A 33-year-old female without comorbidity who had symptoms of the cold a week ago referred to treatment clinic for COVID-19 in Imam Reza hospital of Tabriz, Iran. After Polymerase chain reaction (PCR) test through the nasopharyngeal swab and radiologic examination, she was hospitalized. The symptoms worsened and she was intubated on the second day. The patient was also pregnant with a gestational age of 34 weeks. Lopinavir/ritonavir (200mg/50mg) two tablet tow times, Ribavirin 200mg every 6 h, and Oseltamivir 75mg tow times were given for the treatment of COVID-19. The medications used for treatment of pneumonia were Meropenem, Ciprofloxacin, Vancomycin. All doses of drugs were administrated by adjusted dose assuming the patient is anephric. This study have been approved by the Medical Ethics Committees of Tabriz university of medical sciences before patient enrollment and treatment (Approval ID: IR.TBZMED.REC.1398.1314).
The patient did not receive nephrotoxic drugs such as antibiotics before uremia, and when her BUN and Cr increased, the patient's urine became muddy brown and the volume of urine decreased, and we called it Acute kidney injury (AKI). In our urine sedimentation, there were a lot of granular casts along with cellular debris, which was interpreted as ATN. Due to the presence of urinary sedimentation and the presence of granuloma casts in the urine and muddy brown nature of urine, the diagnosis of ATN was more important than urinary toxicity. In spite of using Furosemide, urine output was 600 cc in 24 hours. After hemoperfusion, urine output reached above 2 L in 24 hours and we entered the polyuria phase.However, Vancomycin was eliminated and Linzolid started for the patient because it is not nephrotoxic.
Also, a few supplements were also prescribed after developing ATN including daily Rocaltrol and Nephrovit (as a multivitamin appropriate for patients with renal failure), Folic acid and Calcium carbonate. Vitamin C 250 mg is administrated by gavage. Hemoglobin and white blood cell at admission time were 11 mg/dl and 2400 per microliter, respectively; so that pancytopenia was diagnosed and suspected of having lupus erythematous. Therefore, rheumatology consultation was asked, all of lupus diagnostic criteria were negative but received Intravenous immunoglobulin (IVIG) 5 gr daily for 5 consecutive days after consultation with hematologist.
The patient did not have peripheral schistocyte in the blood, we did not make diagnoses such as microangiopathy (thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: TTP-HUS) and only Collagen vascular disease (CVO) due to anemia and vascular thrombocytopenia was evaluated. The patient's anemia and thrombocytopenia improved after hemoperfusion and the patient had an increase in hemoglobin and platelets. The patient's electrolytes were regularly monitored. As mentioned, due to the lack of schistocyte in the peripheral blood, microangiopathy was ruled out. Lupus tests including C3, CH50, Cu and Anti-dsDNA were negative. Primary LDH was 1360 that decreased to 380 after hemoperfusion. Serum glutamic oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT) were 78 and 46 units per liter of blood serum, respectively.
The patient's PCR test was positive, so a CT scan was taken and showed ground glass opacity (GGO) with consolidation in upper right lobe indicating lung involvement. Preoperative CT is presented when the patient was not intubated yet (Fig. 1). After admission, creatinine levels gradually increased up to 6.8 mg/dl accompanied by respiratory and metabolic acidosis in the arterial blood gas (ABG). The patient's respiratory rate increased to 36 breaths/minute and the patient was intubated. She underwent caesarean section after consultation with a gynecologist. he patient had to undergo dialysis 12 hours before caesarean section. The baby was negative for COVID-19 and was in good health. Due to the low platelet count, the patient entered the operating room with 10 platelet injections. Before surgery Hb was 7.25 mg/dl (Blood Pressure = 100/66 mmHg, prothrombin time (PT) = 16s, partial thromboplastin time (PTT) = 36s, Pco2 = 45 mmHg, Hco3 = 18 mEq/L).
After surgery, hemoglobin had reached 7.8 mg/dl, which inevitably received a unit washed packed cell, and hemoglobin is now 9.5 mg/dl. White blood cell (WBC) increased to 7,400 per microliter. On the sixth day of hospitalization, diuresis was established, and the patient's creatinine declined sharply. The patient's creatinine had reached 3 mg/dl and conservative treatment was launched. The patient is still hospitalized due to COVID-19 and is in the recovery phase with fluid control and does not receive medication for her ATN. The patient is still intubated with a fraction of inspired oxygen (FiO2) of 60% and Positive end-expiratory pressure (PEEP) of eight. SpO2 is 94% but the patient's ATN has been resolved. We started weaning the mechanical ventilation. The patient is conscious with full awareness to time, person and place. The maternal well-being is achieved and her neonate was discharged. Postoperative Chest-x ray is presented (Fig. 2). As shown, pneumonia is clear in the figure that's why the patient is giving Ciprofloxacin, Vancomycin and Meropenem now. | atn, infection, kidney, pregnancy, renal involvement, sars-cov-2 | Not supported with pagination yet | null |
PMC4414853_01 | Female | 40 | A 40-year-old woman, previously healthy, Colombian, was admitted to the Department of Rheumatology at Hospital Militar Central, with a fever of 39 C, generalised arthralgia involving the elbows, wrists, proximal and distal interphalangeal joints, metacarpophalangeal and metatarsophalangeal joints, knees and ankles, and fatigue. She had been in her usual state of good health until 2 weeks before admission and these symptoms starting shortly after the patient had a sore throat for 7 days.
Examination revealed angioneurotic edema detected on soles, palms and tongue (Figure 1a) and widespread red, urticated plaques in a symmetrical distribution affecting the arms, dorsal hands, upper and lower chest and back (Figure 1b). The rest of the examination was unremarkable. These lesions were present for less than 10 h per day and were not more pronounced at night with no associated bruising. She was diagnosed as having infection-associated-urticaria in a peripheral hospital and was treated with antibiotics (ciprofloxacin) and antihistamines (loratadine) without diminishment of her symptoms. Followed 5 days later by fever, the patient presented dyspnea, cough and hypoxemia. A chest x-ray film showed a patchy right lower lobe infiltrate (Figure 2a) and computed tomography showed unilateral consolidation and pleural effusion (Figure 2b).
An early bronchoscopy with bronchoalveolar lavage was indicated revealing hemorrhagic lavage and pathological examination showed hemosiderin-containing macrophages in 80%. Bronchoalveolar lavage specimen was sent for routine bacterial cultures, fungal, viral and Pneumocystis carinii; all of the results were negative. A skin biopsy demonstrated dermal oedema, and a marked perivascular and neutrophilic infiltrate with no evidence of structural vasculitis. These features were consistent with neutrophilic urticaria (Figure 3). Other investigations revealed a normocytic anaemia Hb 11.5 g/dL erythrocyte mean corpuscolar volume 86 fl platelet count 408.000/mm3, a marked white blood cell count (WBC) 67.200 mm3 with 91% neutrophils, 5% lymphocytes, 1% eosinophils, 3% monocytes and markedly elevated acute phase reactants: erythrocyte sedimentation rate 49 mm in the first hour, C-reactive protein 11,43 mg/dl and ferritin 1650 mug/L, alanine aminotransferase was mildly elevated at 74 IU/L, lactate dehydrogenase 1200 IU/L and serum albumin reduced at 3,4 g/L. Antinuclear antibodies (immunofluorescence-Hep-2 cells), rheumatoid factor (nephelometry), antistreptolysin O, cold agglutinins, cryoglobulins and serum electrophoresis were unremarkable. There was no serological evidence for active or recent infection with the following organisms: Toxoplasma gondii, group B streptococci, hepatitis A, B or C, HIV, cytomegalovirus, tuberculosis and syphilis. Blood cultures were negative. Ultrasound investigation of the liver and biliary tract was normal. In the bone marrow aspiration, we found remarkable hyperplasia and granulocytes of each mature state, without an increase of myeloblasts, the neutrophil alkaline phosphatase score was high, Ph chromose was negative. Immunophenotyping showed mature neutrophils expressing surface antigens CD13 and CD15 at a level higher than 95% and negative for CD34 and HLA-DR.
She was diagnosed with AOSD and methylprednisolone (mini-boluses of 125 mg/ day per 3 days) was initiated as prednisone sparing therapy. The patient's pulmonary symptoms improved with the doses of pulsed corticosteroids. After 3 days of pulsed methylprednisolone, therapy was maintained with 0.5 mg/kg of prednisone orally. Treatment with NSAIDs and prednisone controlled the rash, fever, arthritis, angioedema and significantly reduced the serum ferritin levels and all markers of activity disease. Two weeks after the pulse treatment, the chest radiography became normal. Methotrexate was prescribed for long term control of the disease at a dose of 7,5 mg/week. One month later prednisone was slowly decreased to 12,5 mg/day and withdrawn over three months. No activation period was observed during the one-year follow-up period. | adult-onset still’s disease, angioedema, leukemoid reaction, pulmonary hemorrhage, urticaria | Unusual Paraclinical findings of AOSD in lung. A chest radiograph shows a patchy right lobe consolidation in the lower lung zone (a). CT image shows extensive areas of airspace consolidation due to alveolar hemorrhage in right lung. |
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PMC5632488_01 | Male | 79 | A 79-year-old Japanese man with a previous history of tuberculosis, myocardial infarction, cerebral infarction, diabetes mellitus, and hypertension noticed hoarseness in December 2008. He underwent a medical examination at the hospital and whole-body positron emission tomography-computed tomography (PET-CT) was performed, showing a left renal tumor. The patient was transferred to our department.
The left renal tumor was clinically diagnosed as renal cell carcinoma. Left nephrectomy was performed, and the pathologic diagnosis was clear cell carcinoma (pathological T3aN0).
Six months after the operation, follow-up CT revealed local recurrence (14 mm). However, upon evaluation of the patient's age and activities of daily living, we opted for observation every 2 or 3 months using PET-CT. Fourteen months after the nephrectomy, PET-CT revealed metastases to the spleen, right lung, and retroperitoneal lymph nodes (LNs). We initiated molecular targeted therapy with sorafenib (400 mg/day). We did not increase sorafenib dosage owing to adverse reactions including malaise and hand-foot syndrome. However, the treatment was effective, as evidenced by shrinkage of the metastases on PET-CT. He continued the therapy, and the majority of metastases disappeared, except for those at the retroperitoneal LNs. However, 24 months after the sorafenib initiation, new lumbar vertebral body metastases appeared. We subsequently increased the sorafenib dose to 800 mg/day (Figure 1).
We discontinued sorafenib administration 26 months after it was initiated, owing to obvious growth of the metastasis and increased maximum standard uptake value (SUVmax) of the lesions. Next, we initiated therapy with sunitinib at 37.5 mg/day. Sunitinib administration was stopped after 4 months because tumor expansion was evident on PET-CT. The patient was not treated with bisphosphonate agents or anti-RANKL antibodies, as he had tooth pain, and his lumbar pain was mild. Furthermore, irradiation therapy (to target bone metastases) was not administered.
As third line therapy, we started axitinib administration at 10 mg and increased the dose weekly, while monitoring for adverse effects. With axitinib, the tumors were effectively controlled for 16 months.
However, PET-CT revealed new lymph node metastasis near the tracheal bifurcation (Figure 2(a)). We decided to start sorafenib rechallenge therapy at 600 mg/day. He was diagnosed with stable disease 4 months after the initiation of the sorafenib rechallenge. Because there were no severe adverse effects, we increased the sorafenib dose to 800 mg/day.
In the next month (5 months after the sorafenib rechallenge), PET-CT showed dramatic shrinkage of the metastatic lesions, considered a complete response (Figure 2(b)). Ten months later, PET-CT revealed lumbar vertebral body (L3) metastasis. However, this lesion was growing very slowly; therefore, we continued sorafenib administration. This sorafenib rechallenge therapy effectively suppressed the tumor for approximately 30 months, and at the time of this report, the patient was alive for 7 years after the first local recurrence. | null | Not supported with pagination yet | null |
PMC10076110_01 | Male | 38 | A 38-year-old male was involved in a motor-vehicle collision and found with a Glasgow Coma Scale (GCS) of 3/15 outside his vehicle. He was intubated by the emergency medical services (EMS) at the scene before being transferred to the level 1 trauma center. On arrival to the emergency department (ED), the patient was hemodynamically unstable with a left-sided tension pneumothorax and a positive Focused Assessment with Sonography for Trauma (FAST) test. An emergency thoracostomy tube (TT) was inserted, and the patient was taken to the operating room (OR) for emergent laparotomy. Splenectomy was performed for ruptured spleen. The abdomen was closed, and the patient underwent pan-computed tomography (CT) scan.
Further investigation revealed a traumatic brain injury (TBI) with brainstem contusion, traumatic mydriasis of the right pupil, a right ear laceration, mandibular fractures, and fracture of the spinous process of C6 and T6 and T7 vertebral bodies. Fractures of left ribs 1-11 and 6-12 on the right side were associated with a left hemopneumothorax. Of note, no mediastinal abnormalities were noted on admission CT imaging (Figure 1).
Further management included feeding via a 16 French gauge OGT, the position of which had been confirmed by X-ray (Figure 2), and auscultation as per trauma intensive care unit (ICU) protocol. Later, he was started on Jevity (Abbott Nutrition) enteral feeding at 80 ml/hour for 24 hours, providing 1,920 kcal/day in accordance with our ICU protocol. Jevity is a 1 kcal/ml enteral feed with fiber for patients with, or at risk of developing, disease-related malnutrition; it contains a mix of fiber and fructo-oligosaccharides.
A repeat head CT on day 7 revealed a brainstem contusion. A decision was made to insert a percutaneous tracheostomy on the 8th day of admission. Furthermore, 1 liter of transudative pleural effusion was drained via a right-sided 32 French chest drain (inserted using an open technique). The OGT was kept in place during this period. However, the OGT side hole was higher in position (Figure 2).
On day 10, the oral and maxillofacial (OMF) team performed an open reduction and internal fixation (ORIF) of the mandibular para-symphyseal fracture with upper and lower arch bars. During the surgery, the oral endotracheal tube was changed to nasal intubation to facilitate the facial surgery, and the OGT was removed at the same time. Difficultly was encountered by the anesthetist during OGT removal. Video-laryngoscopy revealed whitish solid cheesy material at the upper esophageal orifice, which was manually fragmented and removed using a McGill's forceps. The material was described as "cheesy", calcified feeding substance formed around the tube and taking the shape of the esophagus. An attempt was made to re-introduce a nasogastric feeding tube (NGT) under direct video-laryngoscopic guidance, but resistance was encountered, and the procedure was abandoned.
On the following day, the patient's oxygen saturation readings dropped to 94-96%, accompanied by tachycardia. A new 16 French NGT was inserted smoothly (one attempt), and the left TT was removed.
After 2 days, a CT scan pulmonary angiogram was requested to rule out pulmonary embolism due to persistent tachycardia; this revealed pulmonary embolism in the right main pulmonary artery and left upper lobe. Incidentally, a localized area of heterogeneous air and fluid density was noted along the left upper paraoesophageal region with minimal pneumomediastinum, raising the suspicion of an esophageal injury (Figure 3). The gastroenterology team decided to manage the injury conservatively without endoscopy but with antimicrobial cover, as the patient was hemodynamically stable. No organic gastrointestinal pathology was present. The patient made an uneventful recovery from the esophageal injury, without the development of mediastinitis or further complications. However, his functional recovery from the TBI was poor. | null | Not supported with pagination yet | null |
PMC8553500_01 | Male | 65 | A 65-year-old male was referred to the gastroenterology department with obstructive icterus. His medical history was remarkable for arterial hypertension, gastric ulcer, and chronic gastritis, diverticulosis of the colon and sideropenic anemia. He presented with epigastric abdominal pain, nausea, and heartburn. His physical examination revealed icterus of the skin and conjunctiva. His bilirubin was found to be elevated (107 mumol/l). AST and ALT were 114 IU/l and 217 IU/l, respectively. The WBC count was 10.42 x 103/mm, and segments were 24.7%.
Ultrasound revealed an elongated gallbladder (10.5 cm) filled with sludge and tiny concrements, and the common bile duct was normal in diameter, without visible intraluminal substrate. The liver was slightly enlarged with hyperechogenic parenchyma diffusely. Computed tomography (CT) of the abdomen showed normal liver structure and an enlarged gallbladder without signs of pathological changes in the wall or lumen. MRCP showed choledocholithiasis, no signs of common bile duct dilation, and normal intrahepatic bile ducts (Figure 1).
He underwent ERCP for choledocholithiasis. Access to the major papilla next to a periampullar diverticulum was obtained, and a widened common bile duct was shown with small concrements prepapillary. A sphincterotomy and concrement extraction with a balloon was performed. The procedure passed without complications.
While waking up from the sedation, the patient immediately complained about abdominal pain. The gastroenterologist found the abdomen to be distended and referred the patient to an urgent CT of the abdomen. The WBC was 10.42 x 103/mm. On CT, free air was found around the duodenum in level of the papilla in the retroperitoneum and around the liver equaling pneumoperitoneum and pneumoretroperitoneum (Figure 2). Postprocedural pneumobilia in the gallbladder, cystic duct, common bile duct, and intrahepatic bile ducts was found. Free contrast was found around the gastric fundus (Figure 3), paracolical, and pelvis, and the radiologist suspected duodenal perforation.
The patient was referred urgently to the general surgery department. The patient's abdomen was found to be distended with signs of peritonitis, no audible peristalsis. The patient was rushed to an emergency laparotomy. Intraoperative biliary peritonitis was found. After thorough exploration of the upper abdomen and kocherization of the duodenum and head of the pancreas, no perforation of the duodenum or common bile duct was found. Hence, retroperitoneal perforation as the source of the intraperitoneal biliary collection could be excluded. Only when removing the liver retractor on the anterior side of the III, liver segment ruptured, but otherwise, normally appearing bile duct was found with bile secretion into the peritoneal cavity (Figure 4). The defect was closed with sutures. A choledochotomy was performed, and a T-drainage positioned to facilitate the biliary drainage. Cholecystectomy, lymphadenectomy, and omentectomy were performed too. Since the site of the intrahepatic bile duct rupture was clearly seen, no indication for an intraoperative cholangiography was found; hence, the rupture of the intrahepatic bile duct was not confirmed radiologically during surgery. The procedure ran without complications.
The postoperative recovery was uneventful. A cholangiography was performed which excluded the presence of any aberrant intrahepatic bile ducts (Figure 5). The patient did not develop jaundice postoperatively. The patient was discharged on POD 15. | null | Not supported with pagination yet | null |
PMC5313428_01 | Male | 73 | A 73-year-old-man was admitted by a local physician with dyspnea on exertion that had begun 2 months earlier. He was diagnosed with interstitial pneumonia, thrombocythemia, hepatic cirrhosis, and diabetes. He was referred to a hematologist for the thrombocythemia. He came from Nagasaki, an area in Japan in which HTLV-1 is prevalent. The hematologist diagnosed him as an HTLV-1 carrier with myeloproliferative disorder (essential thrombocythemia). He was then referred to our pulmonary outpatient clinic for interstitial pneumonia. Fine crackles were heard at the base of the bilateral lungs. He had a family history of interstitial pneumonia, as his brother and sister had both died of interstitial pneumonia, but the etiology of those interstitial pneumonia cases was not identified. Chest X-ray showed bilateral ground-grass opacity (GGO) in both of the lower lung fields (Fig. 1). Chest CT showed bronchovascular bundle-dominant reticular shadows and GGO in the bilateral lung field (Fig. 2, 7a). His percutaneous oxygen saturation in room air was 97% with a Modified British Medical Research Council (mMRC) grade two, and the findings on the pulmonary function test and 6-minute walk test (6MWT) were normal (Table 1). There were no positive data for collagen disease (Table 1). Given that the CT findings were inconsistent with the UIP pattern, we performed video-assisted thoracoscopic surgery (VATS) to confirm a diagnosis of interstitial pneumonia. Lung tissue was obtained by VATS from three parts of the lung (right S3, right S6, and right S8) (Fig. 2). The pathological findings of right S3 and right S6 were similar, and the primary lesions were organizing pneumonia like-lesions and usual interstitial pneumonia (UIP) like-lesions. In contrast, the primary lesions of right S8 were fibrotic non-specific interstitial pneumonia (f-NSIP)-like lesions (Fig. 3, 4). Taken together, the lung specimens revealed various interstitial pneumonia patterns, including UIP like-lesions, f-NSIP-like lesions, and organizing pneumonia-like lesions that were diagnosed as unclassifiable interstitial pneumonia.
Since HTLV-1 was not detected in the plasma or lung tissue, the patient was diagnosed with IIP. Given that some of these lesions showed a UIP pattern, the patient was administered pirfenidone at 1,800 mg/day. The CT findings and the dyspnea on exertion subsequently improved (Fig. 7b); however, the KL-6 and SP-D increased slightly (Fig. 6, clinical course). Gastrointestinal symptoms and depression developed as side effects 3 months after the initiation of pirfenidone at 1,800 mg/day. We reduced the pirfenidone dose to 1,200 mg/day and continued its administration. The symptom of dyspnea on exertion, the percutaneous oxygen saturation in room air, and the findings on the pulmonary function did not progress (Table 2); however, the CT findings of bronchovascular bundle-dominant reticular shadows and GGO had deteriorated 6 months after the initiation of the pirfenidone treatment (Fig. 7c).
We performed transbronchial lung biopsy (TBLB) and bronchoalveolar lavage (BAL) to rule out the infiltration of leukemic cells or lymphocytic interstitial pneumonia. TBLB specimens and cytology of the bronchoalveolar lavage fluid (BALF) showed no leukemic cells (Fig. 5). However, in the BALF, the percentage of lymphocyte was elevated (37%) and the findings for the HTLV-1 proviral pX gene were positive (Table 2). These results suggested the exacerbation of HABA-associated interstitial pneumonitis. Previous studies have reported the effectiveness of steroids in the treatment of HABA; however, we were concerned about the deterioration of the existing diabetes. We therefore increased the dose of erythromycin, which had been administered for viscous sputum two months earlier, from 200 mg/day to 400 mg/day. The GGO, KL-6, and SP-D improved after combined therapy with pirfenidone and erythromycin (Figure 6, 7).
This combined therapy with pirfenidone at 1,200 mg/day and erythromycin at 400 mg/day has been continued in this patient for more than 2 years, with no progression of the dyspnea on exertion or abnormalities on chest CT thus far. | null | The chest HRCT findings. (a) Before being treated, basal and bronchovascular bundle-dominant reticular shadows and GGO were shown. |
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PMC5313428_01 | Male | 73 | A 73-year-old-man was admitted by a local physician with dyspnea on exertion that had begun 2 months earlier. He was diagnosed with interstitial pneumonia, thrombocythemia, hepatic cirrhosis, and diabetes. He was referred to a hematologist for the thrombocythemia. He came from Nagasaki, an area in Japan in which HTLV-1 is prevalent. The hematologist diagnosed him as an HTLV-1 carrier with myeloproliferative disorder (essential thrombocythemia). He was then referred to our pulmonary outpatient clinic for interstitial pneumonia. Fine crackles were heard at the base of the bilateral lungs. He had a family history of interstitial pneumonia, as his brother and sister had both died of interstitial pneumonia, but the etiology of those interstitial pneumonia cases was not identified. Chest X-ray showed bilateral ground-grass opacity (GGO) in both of the lower lung fields (Fig. 1). Chest CT showed bronchovascular bundle-dominant reticular shadows and GGO in the bilateral lung field (Fig. 2, 7a). His percutaneous oxygen saturation in room air was 97% with a Modified British Medical Research Council (mMRC) grade two, and the findings on the pulmonary function test and 6-minute walk test (6MWT) were normal (Table 1). There were no positive data for collagen disease (Table 1). Given that the CT findings were inconsistent with the UIP pattern, we performed video-assisted thoracoscopic surgery (VATS) to confirm a diagnosis of interstitial pneumonia. Lung tissue was obtained by VATS from three parts of the lung (right S3, right S6, and right S8) (Fig. 2). The pathological findings of right S3 and right S6 were similar, and the primary lesions were organizing pneumonia like-lesions and usual interstitial pneumonia (UIP) like-lesions. In contrast, the primary lesions of right S8 were fibrotic non-specific interstitial pneumonia (f-NSIP)-like lesions (Fig. 3, 4). Taken together, the lung specimens revealed various interstitial pneumonia patterns, including UIP like-lesions, f-NSIP-like lesions, and organizing pneumonia-like lesions that were diagnosed as unclassifiable interstitial pneumonia.
Since HTLV-1 was not detected in the plasma or lung tissue, the patient was diagnosed with IIP. Given that some of these lesions showed a UIP pattern, the patient was administered pirfenidone at 1,800 mg/day. The CT findings and the dyspnea on exertion subsequently improved (Fig. 7b); however, the KL-6 and SP-D increased slightly (Fig. 6, clinical course). Gastrointestinal symptoms and depression developed as side effects 3 months after the initiation of pirfenidone at 1,800 mg/day. We reduced the pirfenidone dose to 1,200 mg/day and continued its administration. The symptom of dyspnea on exertion, the percutaneous oxygen saturation in room air, and the findings on the pulmonary function did not progress (Table 2); however, the CT findings of bronchovascular bundle-dominant reticular shadows and GGO had deteriorated 6 months after the initiation of the pirfenidone treatment (Fig. 7c).
We performed transbronchial lung biopsy (TBLB) and bronchoalveolar lavage (BAL) to rule out the infiltration of leukemic cells or lymphocytic interstitial pneumonia. TBLB specimens and cytology of the bronchoalveolar lavage fluid (BALF) showed no leukemic cells (Fig. 5). However, in the BALF, the percentage of lymphocyte was elevated (37%) and the findings for the HTLV-1 proviral pX gene were positive (Table 2). These results suggested the exacerbation of HABA-associated interstitial pneumonitis. Previous studies have reported the effectiveness of steroids in the treatment of HABA; however, we were concerned about the deterioration of the existing diabetes. We therefore increased the dose of erythromycin, which had been administered for viscous sputum two months earlier, from 200 mg/day to 400 mg/day. The GGO, KL-6, and SP-D improved after combined therapy with pirfenidone and erythromycin (Figure 6, 7).
This combined therapy with pirfenidone at 1,200 mg/day and erythromycin at 400 mg/day has been continued in this patient for more than 2 years, with no progression of the dyspnea on exertion or abnormalities on chest CT thus far. | null | The chest HRCT findings. (c) Three months after a dose reduction to 1,200 mg/day, the basal and bronchovascular bundle-dominant reticular shadows and GGO had deteriorated. |
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PMC6131554_01 | Male | 76 | A 76-year-old man with severe chronic obstructive pulmonary disease (COPD) presented with a feeling of fatigue, weight loss, and reduced physical activities. He was diagnosed with COPD at the age of 69 years and had retired from work the following year. His smoking history included 40 cigarettes per day between the age of 14 and 69 years; his airflow limitation was classified as severe by the Global initiative for Chronic Obstructive Lung Disease; and a chest computed tomography (CT) scan showed severe emphysema. He had started long-term oxygen therapy at the age of 72 years and is currently inhaling 3 L/min of oxygen. Medical and family histories were otherwise unremarkable. Cardiac ultrasound excluded comorbid congestive heart failure or pulmonary hypertension, and CT pulmonary arteriography also excluded chronic pulmonary thromboembolism. As the patient had a history of acute exacerbations of COPD more than twice a year with extreme respiratory symptoms, he was prescribed a combination of inhaled long-acting antimuscarinic antagonist, long-acting beta2-agonist, corticosteroid, and oral carbocysteine, ambroxol, and theophylline. He reported symptoms of dyspnea on exertion, depression and anxiety, and a decrease in physical activity. He also experienced anorexia with a weight loss of more than 5 kg in a year, and no other possible causes of weight loss, such as tuberculosis and malignant tumor, were observed. Therefore, in addition to respiratory pharmacotherapy, we prescribed an antianxiety drug and provided nutritional supplement therapy, patient education, and pulmonary rehabilitation. However, the patient's mental and physical symptoms did not improve after 4 months. Furthermore, he exhibited deterioration in activities of daily living as well as physical and mental weakness; hospital visits were difficult and therefore, he considered home care. Persistent weight loss, poor endurance and energy, and low physical activity levels led to the diagnosis of physical frailty according to Fried's criteria. This vulnerability was supported by assessments using the Kihon Checklist (KCL), the COPD Assessment Test (CAT), and the Hospital Anxiety and Depression Scale (HADS), all of which revealed high scores indicating inferior status. The KCL is a tool designed by a study group from the Japanese Ministry of Health, Labor and Welfare and comprises 25 items divided into seven categories: physical strength, nutritional status, oral function, socialization, memory, mood, and lifestyle. The KCL scores range from 0 (no frailty) to 25 (severe frailty); a previous study classified the patients' frailty status as non-frail (0-3), prefrail (4-7), and frail (8-25). The CAT is a reliable tool that comprises eight items that assess the various COPD symptoms and is widely used in clinical practice. The CAT scores range from 0 to 40, with a score of 0 indicating no impairment. The HADS is also widely used to measure the level of anxiety and depression and comprises 14 items: 7 associated with anxiety (HADS-A) and 7 associated with depression (HADS-D). The HADS-A and HADS-D scores ranged from 0 to 21, and are in the range 8-10 for doubtful cases and >=11 for definite cases. For the present case, we continued the pharmacological treatment, nutritional supplement therapy, patient education, and pulmonary rehabilitation and included 2.5 g of Ninjin'yoeito to be taken 3 times a day before meals.
After administration of Ninjin'yoeito, physical examination and blood tests such as electrolytes, liver function tests, and renal function test were performed to evaluate the side effects of Ninjin'yoeito administration. However, no side effects were detected. A significant improvement in symptoms, including increased appetite and alleviation of mood disorders and weight loss, was observed 1 month after initiating Ninjin'yoeito administration. Body weight and muscle mass continued to increase, and after 6 months of Ninjin'yoeito administration, the body weight increased by 8 kg compared with that prior to Ninjin'yoeito administration. Body composition assessed using bioelectrical impedance (InBody 720; Biospace, Tokyo, Japan) showed increasing muscle mass and no change in the body fat percentage (Figure 1). The patient's KCL, CAT, and HADS scores increased over time (Figure 2), and his status improved from frailty to non-frailty. Written informed consent was obtained from the participant for the publication of this case report. | kampo medicine, ninjin'yoeito therapy, anorexia, chronic obstructive pulmonary disease, frailty | Not supported with pagination yet | null |
PMC4510255_01 | Male | 24 | A 24-year-old male presented to the hospital with four-day history of moderate left sided chest pain radiating to the back. The chest pain got worse with deep inspiration. He denied fever, chills, cough, hemoptysis, night sweats, weight loss, and recent travel. Past medical history was significant for three episodes of left lower lobe pneumonia in the past 6 months. He was treated initially with ceftibuten and azithromycin and then with a course of oral levofloxacin and most recently with amoxicillin-clavulanic acid for recurring symptoms of cough, pleuritic chest pain, and subjective fever. Currently, he was taking meloxicam as needed for chest pain. Past surgical history included right inguinal hernia repair five years ago. There was no family history of cancer, early death, or cardiac disease. He had immigrated from Guatemala four years ago and was single and unemployed. He denied any high-risk sexual behaviors or drug abuse in the present or past. He drank two beers about once or twice per week and denied smoking history. His differential diagnoses at this point include lung abscess, tuberculosis infection, foreign body aspiration, HIV with opportunistic infection, congenital immunodeficiency states, and congenital developmental anomaly of the lung.
On examination, he was tachycardic with a pulse rate of 101/min and was tachypneic at 22/min. Rest of the physical examination including respiratory examination was normal. Labs revealed complete blood counts of 14 x 109/L with 75% neutrophils. Basic metabolic panel and liver function tests were normal. Urine legionella antigen was negative, as well as antibodies to human immunodeficiency virus. His chest X-ray showed left lower lobe opacity. He was started on ceftriaxone and azithromycin for community acquired pneumonia and was admitted to the floor. Tuberculin skin test was positive with 18 mm induration at 72 hours. Interferon gamma release assay was negative. Blood cultures demonstrated no growth for 5 days.
CT angiogram of thorax showed 9 cm well-defined area of low attenuation in the left lower lobe (Figure 1) with infiltrates inside. This lesion demonstrated a dedicated pulmonary artery and pulmonary vein (Figure 2); these vessels were emerging from the hilar region. No systemic arteries or anomalous arterial supply was identified within the lesion. There was no pleural involvement or abnormal lymphadenopathy. A radiologic diagnosis of congenital pulmonary airway malformation (CPAM) was made. Review of previous chest X-rays and computed tomography (CT) of the thorax from the time of his previous episodes of pneumonia revealed various degrees of consolidation in left lower base in this particular area (Figure 3). CT abdomen pelvis did not show any abnormal intra-abdominal masses or pathology but showed some hepatic steatosis.
As his CT images were highly suggestive of congenital cystic lung lesion, surgical excision was planned to prevent further episodes of pneumonias. Bronchoscopy prior to the surgery revealed normal segmental airways in the left lower lobe. Initially left thoracoscopy was tried; however posterolateral thoracotomy was required for better visualization of the involved anatomy. Upon direct visualization, the complete lobe was involved in chronic inflammation. The lesion had no abnormal arterial supply from aorta or below the diaphragm and was connected through air passages. Left lower lobectomy was done. On gross examination, a relatively well-demarcated lesion with a 1.5 x 1.5 cm thin walled cyst with inspissated mucus within and multiple air filled microcysts at the peripheral aspect of the cyst was noted (Figure 4). Microscopic examination revealed larger cyst with columnar ciliated epithelium (Figure 5) and dispersed bronchiole-like structures within the alveolated parenchyma (Figure 6). The pathologic diagnosis was consistent with type 2 CPAM. There was no major surgical complication. He developed a small hydro pneumothorax postoperatively, which resolved on its own. Patient has been doing well 12 months after the diagnosis. | null | Not supported with pagination yet | null |
PMC8247685_01 | Male | 14 | A 14-year-old boy was presented in outpatient department with severe kyphotic deformity of the thoracic spine and complete loss of power of both lower limbs. The patient had a history of a progressively increasing kyphotic deformity since the age of 4 years, almost 4-5 months back, he started developing weakness of both legs.
On physical examination, bossing of the thoracic cage was observed with short abdomen and both iliac crest almost touching the ribs [Figure 1a]. There was a prominent kyphotic hump at the thoracic level, the lower extremities had 0/5 power bilaterally along with spasticity. Reflexes of knees and ankles were exaggerated and Babinski sign was positive. Flexion contracture of 40 was observed in both knees.
Radiographic picture of spine showed severe kyphosis of 141 from T1 to T10 thoracic vertebrae on lateral view with diffuse paraspinal calcifications, most likely representing a granulomatous lesion [Figure1b]. MRI revealed acute angle kyphotic deformity appreciated at the upper-mid dorsal spine due to multiple deshaped dorsal vertebrae (starting from T1 down till T10), resulting in significant canal narrowing posteriorly with cord compression and compressive myelopathic changes. Abnormal marrow signals were appreciated in vertebrae with pathological reduction in their heights, with indistinct/eroded adjacent end plates and involved intervening discs, suggesting squeal of chronic disco vertebral osteomyelitis (caries spine).
Pathological necrotic tissue was also appreciated in pre- and paravertebral spaces at the affected levels. Similarly, variable sized paraspinal collections were identified with areas of low-intensity signals/signal void suggested chronic calcified component [Figure 2]. Blood work-up was within normal limits.
Distraction using a modified halo-pelvic distraction assembly was planned to stretch out the soft tissues aiming to decrease the severity of the deformity and compression on the spinal cord and to improve the neurology.
Pelvic ring was substituted with two lateral arches which allowed the patient to lie supine in bed.
Supra-acetabular region was chosen for half pin placement which provided a sturdy anchorage and gave a strong construct.
Muscles were not pierced for the placement of wires or pins that minimized the risk of infection and pain.
The assembly construct had four rods, two of them were placed anterolateral and the other two were posterolateral. The aim was to provide balanced distraction forces so that the sagittal or coronal balance should not be affected.
An assembly was prepared with the following modifications:
A halo ring according to the head size was chosen and connected to the head with 06 threaded pins.
A total of four Ilizarov half pins were used in the pelvic assembly. Two Ilizarov half pins of 6 mm each were passed in the supra acetabular area one on both sides. Anterior inferior iliac spine was approached through blunt dissection after giving a 2 cm incision, almost 2 cm below and medial to the anterior superior iliac spine (ASIS) on both sides. The outer cortex at anterior inferior iliac spine was drilled with a 4 mm drill bit and a 6 mm half pin was passed using a T handle.
The 2nd site for half pin placement was about 10 cm posterior to the ASIS. After making a small incision, the outer cortex was drilled and a 6 mm half pin was passed in between the inner and outer tables of the iliac bone on both sides using a T handle. Both half pins on either side were connected to an Ilizarov arch using male posts and rancho cubes. Both arches were connected with each other through two threaded rods to strengthen the construct [Figure 3].
Distraction device consisted of four threaded rods, two anterolateral and two posterolateral connecting pelvic assembly to the halo assembly.
Distraction was started on the 1st postoperative day at the rate of 3 mm per day divided in three intervals of 1 mm each. On the 5th postoperative day, the patient started to move his right foot and started to feel touch sensations in his right leg. Distraction was continued at this constant pace of 3 mm per day for 35 days. The patient was closely monitored for his progress by getting weekly X-rays of the spine and measuring the trunk height and kyphotic angle.
After 35 days of distraction, rib hump and thoracic knuckle markedly improved and Cobb angle reduced from 141 to 56 [Figure 4] and the patient height increased up to 8 cm. Power of the legs improved to 2/5 bilaterally.
At this time, resection of vertebral bodies, thorough debridement and stabilization using a vertebral standalone cage through anterior approach, was planned and surgery was performed by the senior author (AA). A cage was placed from T1 to T10 vertebral body after debridement [Figure 5]. After the definitive surgery, kyphotic angle was reduced to 46 .
GeneXpert analysis of the tissue revealed multidrug-resistant tuberculosis. Postoperatively, the patient is doing well and put on 2nd line antituberculous therapy. | halo-pelvic distraction, kyphosis, spine | Not supported with pagination yet | null |
PMC6554557_01 | Female | 70 | Chronic kidney disease is a major global health problem with an increasing prevalence. By 2040, it is estimated that CKD will have become the fifth leading cause of death. This increasing CKD burden is driven in part by aging population structure (CKD is ~8x more common in adults > 70 years old compared to persons < 40 years of age). Diabetes and hypertension are common risk factors for kidney damage and are therefore major contributors to the increased CKD prevalence.
There is a marked gender imbalance in CKD with a higher incidence (11.0 vs. 9.6 per 1,000 person-years) and higher prevalence (16.0% vs. 12.4%) in women. Nevertheless, women have a lower risk of CKD progression and men are more likely to develop ESRD.
Chronic kidney disease is a complex heterogeneous disease, with contributions from both genomic and environmental factors. CKD heritability has been estimated to be high (30-75%). CKD can be identified by well-established clinical biomarkers such as SCr levels, eGFR, albuminuria, or UACR. Unfortunately, these clinical biomarkers are limited in their utility to predict individual risk of CKD or likelihood for later progression to ESRD. Major efforts have been made to understand the heritability in CKD but the causal pathways remain incompletely understood. Four major approaches have been proposed to uncover the missing heritability; exploration of rare variants, increased samples sizes, study of molecular factors not involving variants in the DNA sequence and consideration of whether family studies overestimated heritability risk. In CKD, meta-analyses of GWAS have provided a useful and relatively inexpensive strategy to increase the statistical power by combining data summaries from different individual GWAS, helping to attenuate the issue of small sample size and identifying many genetic loci associated with CKD and/or kidney function traits. Rare variants in UMOD, SHROOM3, solute carriers, and E3 ubiquitin ligases have also been associated with CKD, eGFR or SCr. However, these genetic markers do not account for all the susceptibility to CKD, therefore other factors must be contributing to the missing heritability. Part of the missing heritability may correspond to genetic interactions (epistasis), rather than to missing variants. Telomere length is a biological factor that has been associated with CKD prevalence and/or CKD progression in a small number of studies. Structural variants, such as CNVs, insertions, deletions, inversions and translocations are, in general, poorly covered in commercial arrays and may explain part of the missing heritability. Mitochondrial proteins, encoded by nuclear genes, and specific mtDNA encoded genes have also been associated with CKD. The sex chromosomes, often excluded from GWAS studies, may help explain gender imbalances in CKD.
In this review, we outline some recent findings on molecular biomarkers for CKD (telomeres, CNVs, mtDNA variants, X and Y chromosomes) that typically have received less attention than single nucleotide polymorphisms (SNPs) present on, or imputed from, GWAS arrays. These less commonly studied biomarkers may be part of the "missing heritability" for CKD.
Telomeres are specialized nucleoprotein complexes that help protect the ends of linear chromosomes. There are inter-individual and intra-individual differences in the length of telomeres. Shorter telomere length has been associated with multi-system diseases, early life stressors, increasing chronological age and all-cause mortality (Figure 1). The majority of studies have analyzed relative telomere length in peripheral blood leukocytes, but telomere length differs between tissues within a single individual, with greater heterogeneity in telomere length evident in older people. Telomere length has a reported heritability of 28-82%, however, not all genetic factors or environmental influences on telomere length are known. Meta-analysis of telomere length may help confirm discovery associations across multiple collections, however, this is challenging with different wet-lab techniques (such as time at sample collection, storage and processing of biological material, absolute compared to relative telomere length evaluation, platform employed) and in silico analyses (such as normalization, controls, covariates, association, and correction tools) having significant effects on the reported measurements. There is also limited traditional epidemiological evidence exploring the mechanistic basis or causality of reported associations.
Nonetheless, there is evidence that telomere length is associated with disease states, particularly age-related diseases, beyond the most commonly studied cancers. Conflicting reports have been published for the association of telomere length with renal disease, however, most publications, albeit in relatively small sample sizes with modest significance values, report that shorter telomere length is associated with renal dysfunction. Shorter telomeres have been reported as associated with progression of CKD (defined as a doubling of baseline SCr and/or ESRD), in the MMKD (n = 59 patients had confirmed CKD progression) and CRISIS (n = 105 patients had confirmed CKD progression) studies, with the effect size strengthened by smoking and the presence of diabetes. Telomere shortening has been associated with IgAN in 177 patients, but not in 30 patients with DKD or 30 patients with FSGS compared to 83 controls. A study examining DNA from peripheral blood and urine in 15 patients with IgAN showed shorter telomere length correlated with declining renal function. Multiple studies have been performed for DKD, with the majority linking shorter telomere length to the development and progression of kidney disease in people with both type 1 (, 273 patients, 176 patients, 21 progressed) and type 2 diabetes (, 168 patients, 17 patients, 501 patients, 691 patients). Shorter telomere length is associated with diabetic complications and all-cause mortality. The Heart and Soul Study is a longitudinal cohort of individuals with stable coronary heart disease; shorter telomere length at baseline and more rapid telomere shortening over 5 years were associated with reduced kidney function, but these changes were not significant when accounting for age. It is noteworthy that the largest study published considered less than 1,000 individuals, which provides limited power to draw robust conclusions in this era of mega-consortia studying the genetics of CKD.
Premature telomere shortening is associated with duration of dialysis treatment in terms of months to years. A cross-sectional study of 175 hemodialysis patients reported shorter telomere length in men with CKD, despite women having an older average age in this cohort; association of shorter telomeres was also observed with increasing age and male sex. Shorter telomeres were associated with CKD in 203 Japanese hemodialysis patients compared to 203 age and sex-matched controls without CKD, with shorter telomeres also associated with new onset cardiovascular events. A less reactive immune system is associated with healthy aging in the general population and ESRD enhances premature immunological aging with shorter telomeres observed in 137 patients with ESRD compared to 144 individuals without kidney disease.
Histologically normal and abnormal human kidney tissue samples from 24 individuals highlighted age-related shorter telomere length with telomeres typically shorter in the cortex than in the medulla. Premature senescence is an important feature of renal fibrosis that accelerates when cells are exposed to stressful environments such as more ROS and higher glucose. Increasing age and sex related telomere shortening is observed in kidneys, with shorter telomeres observed in male rats. Multiple animal models of kidney disease show telomere shortening associated with renal dysfunction, however, a careful experimental design is required for accurate telomere measurement. Exploring renal ischemia/reperfusion injury in wild-type and telomerase deficient mice also suggests that shorter telomeres impair recovery from acute kidney injury. Severe renal failure induces telomere shortening with rapid telomere loss observed during kidney transplantation in a rat model of chronic rejection. Tucker and colleagues demonstrated that high-intensity interval training was beneficial protecting against telomere erosion in a rat model of CKD.
Large-scale studies using carefully collected biological samples with harmonized phenotypes and analysis protocols will help determine the true association of telomere length for CKD. Potential therapies exist to minimize premature telomere shortening, but further work is needed to define the mechanistic links between telomere length and kidney function.
Copy number variants are genetic structural variants which involve DNA regions being deleted or duplicated. This can occur throughout the genome affecting stretches of DNA ranging from kilo- to mega-base pairs in length and can result in abnormal gene amplification. CNVs can be both inherited and arise de novo, and are increasingly being recognized as a significant source of genetic variation relating to both population diversity and disease, including renal diseases, neuropsychiatric diseases, and cancer.
There is often uncertainty about the genetic basis of CKD in pediatric patients, but recent studies have indicated that chromosomal microarrays have the potential to partly address this. assessed 419 children enrolled in the CKD in children (CKiD) study alongside 21,575 children and adults who had undergone microarray genotyping for non-CKD studies. CNV disorders were identified in 31 children with CKD and 10 known pathogenic genomic disorders were detected including HNF1B deletion at 17q12. A further 12 pathogenic genomic imbalances were identified using this technique, distributed evenly among patients diagnosed with congenital and non-congenital forms of CKD. Overall, large gene-altering CNVs were more common in the CKiD population compared with the controls (38 vs. 23%), but the specific genetic alterations identified in several of the individuals would require personalized recommendations in future healthcare.
Copy number variants have been linked to CAKUT. In a study by, DNA from 178 Australian children who presented with any abnormality associated with CAKUT was screened using SNP arrays. In total, CNVs were identified in 18 children, of which 11 children presented with genomic disorders of unknown significance. Of these 11 participants, four were reported as having duplications of 1q23.1, 4p16.1, 7q33, and 8q13.2q13.3 regions, containing genes NEPH1, SLC2A9, AKR1B1, and EYA1, respectively. Each of these genes have previously been associated with renal abnormalities.
In an investigation undertaken by, seven children with CAKUT were assessed from three unrelated families using array comparative genomics hybridization. Of these participants, one reportedly had ureterovesical junction obstruction and a 1.4 Mb deletion at 17q12, containing two genes, HNF1B, which has been previously associated with CAKUT, and ACACA.
A recent study published by, suggested whole exome sequencing (WES) as a viable method to detect CNVs in individuals with CAKUT. These investigators performed WES in 112 individuals from 62 families, to identify SNVs and CNVs in 35 genes previously related to CAKUT. They identified a de novo triplication in one family at 22q11, and overall, 6.5% of the individuals assessed in this investigation were shown to have pathogenic CNVs.
Posterior urethral valves are one of the most common causes of CKD in children. assessed the phenotypic effects of and relationship between renal outcomes and CNVs in 45 boys with PUV. In total, 13 CNVs were identified in 12 boys, two of which, at positions 3p25.1p25.2 and 17p12, were pathogenic in nature. Additionally, those CNVs identified which were > 100 kb in size, were significantly associated with earlier onset of renal failure in children with PUV.
Nephronophthisis (NPH) is a Mendelian genetic disease, which often leads to ESRD by around 13 years of age. sought to investigate the prevalence of NPH in adult-onset ESRD, through assessment of the CNVs in the NPHP1 gene (>90 kb) because a homozygous full gene deletion is a prominent cause of NPH. These investigators assessed 5,606 adult renal transplant recipients, 26 of whom showed evidence of the homozygous NPHP1 deletion, compared to none of the 3,311 controls. Despite this, only 12% of the patients with the homozygous NPHP1 gene deletion were clinically diagnosed with NPH.
Copy number variants have also been investigated in association with IgAN, which is the most common cause of primary glomerulonephritis. The multi-allelic CNV in the defensin alpha 1 and alpha 3 gene locus (DEFA1A3) was assessed in two independent IgAN cohorts of Chinese Han individuals. This locus can present as tandem repeats of a 19kb DNA stretch, containing one copy of either DEFA1 or DEFA3, and several bi-allelic polymorphisms. The protein products of DEFA1A3, human neutrophil peptides 1-3, are abundant neutrophil granule proteins and function in the regulation of both the complement system and pro-inflammatory cytokine production. Each of these have been previously linked with IgAN.
Evaluation of the presence of CNVs yields potentially useful clinical information, especially for pediatric individuals with CKD.
Copy number variants in the human genome are likely to contribute to healthy development, but have additionally been linked to several human diseases. The molecular mechanisms that trigger the formation of CNVs are not fully understood, but recurrent CNVs with common breakpoints reportedly arise through unequal meiotic or non-allelic homologous recombination. Recent evidence has suggested that de novo and non-recurrent CNVs may develop following either replicative errors, chromosome shattering or chromothripsis.
Replication stress occurring during DNA replication has been linked to the collapse of the DNA replication fork and creation of a single-ended double strand break. It has been considered that this could result in a high frequency of de novo CNVs. Both the fork collapse and strand break could result in the activation of damage checkpoint and repair pathways to correctly reactivate replication, thus preventing the creation of structural variants. However, CNVs are understood to be created if this reactivation occurs in an incorrect location using a template switch, or when an incorrect repair occurs, which joins two distant DNA breaks and causes a large deletion. Any present mutations which inhibit the ability of the cell to accurately respond to a collapsed fork, are thought to ultimately increase the formation of CNVs.
In the last decade, GWAS have become essential for investigating the genetic contribution to CKD, with over 50 germline genetic loci identified as biomarkers of kidney disease risk or associated with SCr, cystatin-C and/or microalbuminuria. The UMOD gene, coding for uromodulin, the most abundant urinary protein, is the gene with most of the consistently replicated genetic associations. Several common UMOD variants (rs12917707, rs4293393, rs11864909, rs13329952) are associated with both CKD and eGFR. More recently, the higher frequency in ESRD of another common UMOD variant (rs13333226), has been confirmed in 638 Chinese patients with ESRD and 366 controls. Several common variants in the myosin heavy chain type II isoform A (MYH9) gene have been associated with non-diabetic ESRD in African Americans. Common variants in APOL1 are also associated with non-diabetic ESRD. Common variants in ELMO1 gene have been associated with DKD and its progression to ESRD in several populations, although in this case with less consistency. A more recent meta-analysis of GWAS, including data from 133,413 individuals and subsequently replicated in 42,166 individuals, identified 24 new loci associated with eGFR (BCAS1, AP5B1, A1CF, PTPRO, UNCX, NFKB1, TP53INP2, KCNQ1, CACNA1S, WNT7A, TSPAN9, IGFBP5, KBTBD2, RNF32, SYPL2, SDCCAG8, ETV5, DPEP1, LRP2, SIPA1L3, INHBC, ZNF204, SKIL, and NFATC1). The trans-ethnic meta-analysis showed that 12 loci had fully consistent effect direction on eGFR across European, Asian and African individuals (SDCCAG8, LRP2, IGFBP5, SKIL, UNCX, KBTBD2, A1CF, KCNQ1, AP5B1, PTPRO, TP53INP2, and BCAS1). Regarding other measures of kidney function, a variant rs1801239 in the CUBN gene was proposed as a predictor of UACR and microalbuminuria in a meta-analysis of 63,153 individuals of European ancestry, and another variant in the same gene, rs10795433, has been associated with UACR in 5,825 individuals of European ancestry with diabetes compared to 46,061 without diabetes. A recent discovery GWAS of UACR in 382,500 unrelated European participants of the UK Biobank, a population-based cohort, reported 33 common variants, 20 of them sharing a consistent direction of effect with the study by, including CUBN, HOTTIP, LOC101927609, NR3C2, ARL15, SHROOM3, MAPKBP1, ICA1L, SNX17, LRMDA, SBF2, SPATA5L1, FUT1/IZUMO1 genes and additional variants in chromosomes 1, 2, 7, 14, and 15: rs10157710, rs12032996, rs1276720, rs17158386, rs2023844, rs2472297, rs4410790, rs6535594, rs702634, rs7654754, rs8035855, rs10207567, rs1047891, rs4665972, rs13394343, rs67339103, rs17368443, rs4288924, rs1145074, and rs838142. This GWAS also identified 11 common novel associations in CUBN, PRKCI, EFNA3-EFNA1, MIR548AR-LOC646736, COL4A4, SPHKAP-PID1, INC01262-FRG1, RIB1-LINC00861, and BAHCC1 genes. UACR had previously been associated with another common variant in SHROOM3 (rs17319721) in a meta-analysis of 31,580 and 27,746 Caucasian patients, although it did not reach GWA significance (pdiscovery = 1.9 x 10-6).
Although GWAS have successfully identified SNPs associations for the different traits associated with CKD, most of them are common DNA variants of small effect size. The proportion of phenotypic variance of eGFR explained by the 24 novel loci and the 29 previously identified by Pattaro et al. was 3.22%, therefore of limited help in CKD prediction.
An alternative to the concept of SNPs as single biomarkers is the use of PGRS, which provide individual estimates of the risk of presenting a determinate trait calculated from the combination of specific risks associated to SNPs. However, PGRS may provide only a partial solution in complex diseases. A recent analysis of 32 highly relevant traits related to five disease areas in 13,436 subjects of the Lifelines Cohort reported only 10.7% of the common-SNP heritability of these traits was explained by the different weighted PGRS, compiled from genome-wide significantly associated index SNPs based on previous GWAS. The percentage of variance explained by the PGRS for SCr, composed of three SNPs of high imputation quality (R2 > 0.5) was 0.2% for both weighted and unweighted PGRS. Addition of one low-quality SNP increased the variance up to 0.21% (weighted PGRS). For the eGFR PGRS, composed of 33 SNPs (high-quality), the percentage of variance was 1.6% for unweighted PGRS and 1.8% for the weighted PGRS. Addition of 19 low-quality SNPs increased the variance up to 2.01% (weighted PGRS). There were no high-quality SNPs associated with UACR, so it was not possible to construct this PGRS. The inclusion of one low-quality SNP explained 0.12% of the variance with both weighted and unweighted PGRS. The PGRS for urate, composed of 20 SNPs (high-quality), explained from 2.0 to 4.2%, depending if either an unweighted or weighted PGRS was considered. Addition of eight low-quality SNPs increased the variance up to 4.52% (weighted PGRS).
Next generation sequencing has an increasing role for both research and diagnosis of kidney disease. Recently, a NGS panel for a spectrum of genetic nephropathies, covering 301 genes, was designed and validated in a CLIA-approved laboratory. The assay showed excellent performance characteristics and was able to provide a specific molecular pathogenesis-based diagnosis in 46% of biopsies studied. An NGS panel covering all coding and regulatory regions of UMOD identified 119 genetic variants in 23 ESRD patients (compared to 22 controls without renal disease). Ninety of those variants were SNPs, 60 of them with minor allele frequency greater than 5%. Linkage disequilibrium allowed 20 SNPs to capture 100% of the alleles with a mean R2 of 0.97, providing a set of independent SNPs suitable for association analysis in larger cohorts.
Whole-exome sequencing provided a diagnosis in 22 out of 92 adults with CKD of unknown cause, familial nephropathy or hypertension (22/92; 24%). The confirmation of the clinical diagnosis by WES allowed the appropriate genetic counseling and screening for the family members of some affected patients and helped in clarifying or entirely reclassified the disease in other cases. WES also identified PARN haploinsufficiency as a new genetic cause of CKD in this study. The PARN gene encodes a poly(A)-specific ribonuclease which mediates the post-transcriptional maturation of the telomerase RNA component (TERC) and causes telomere disorders. Exome sequencing has recently identified 11 loci (p < 1 x 10-4) in eight genes (PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1) associated with T2DM-ESRD in 2476 cases and 2057 non-nephropathy control individuals of African American origin. However, exome data from 7974 self-identified healthy adults has recently demonstrated an implausibly high rate of candidate pathogenic variants for kidney and genitourinary diseases (1.4%), much higher than the prevalence of genetic renal/genitourinary disorders, even after stringent filtering criteria (removal of indels and minor allele frequency cutoffs of < 0.01% and <0.1% for dominant and recessive disorders, respectively). This overestimation of potential pathogenic variants may increase the burden of uncertain diagnoses and medical referrals rather than alleviate it, therefore minimizing the utility of exome sequencing in clinical practice.
Mitochondria are organelles which generate ATP through OXPHOS and thus represent the primary energy source for normal function of the cell and body. The majority of mitochondrial proteins are encoded by nuclear genes. However, mitochondria also have their own circular genome 16,569 base pairs long that contains 37 genes which encode 13 proteins of the electron transport chain essential for OXPHOS along with two rRNAs and 22 tRNAs. Mitochondrial dysfunction in kidney tissue may severely impact renal health and has previously been implicated in CKD development.
If mitochondrial metabolism is adversely affected by genetic variants it can result in kidney disease, sometimes as part of a wider clinical disorder. Somatic mtDNA mutations may be associated with aging, resulting in decline of mitochondrial function in older individuals. Increased levels of mtDNA mutations have previously been associated with several disorders including various forms of kidney disease (Figure 2).
Mitochondrial dysfunction can occur via a number of pathways, for example persistent hyperglycemia (associated with diabetes) results in increased tubular oxygen consumption, and in turn leads to hypoxia of the kidney tissue. Mitochondrial dysfunction can be associated with increased electron leakage from the respiratory chain during OXPHOS, which results in ROS being generated which can cause kidney injury including direct damage to DNA. Genetic variation in mtDNA (Figure 2) or nuclear genes (Figure 3) which influence mitochondrial function may impair respiratory chain complex activities leading to an increase in production of ROS resulting in a negative feedback loop, increasing mitochondrial dysfunction, OXPHOS defects and ROS generation along with a reduction in ATP production which leads to increased oxidative stress which may lead to uncontrolled autophagy, mitophagy, and further ROS production. Mitochondrial dysfunction, ROS generation and the resulting dysregulation of autophagic mechanisms may also lead to an upregulation of the intrinsic pathway of apoptosis which in turn leads to inflammation and fibrosis in the renal tubules and glomeruli.
Despite the mitochondrial genome being widely ignored in relation to CKD, a number of studies have identified mitochondrial genomic loci associated with specific forms of renal disease (Table 1). SNPs within MT-HV2, MT-CO1, and MT-CO2c have been associated with IgAN; the A3243G point mutation in the leucineUUR tRNA gene (MT-TL1) was identified in patients with FSGS, other forms of renal disease and in a male with a history of MELAS syndrome including kidney cancer, who rapidly developed renal failure after removal of the cancerous kidney. In general, mtDNA biomarkers have not been considered as potential biomarkers in association studies, therefore most findings concerning the mitochondrial genome in relation to CKD come from case reports. The MT-TW tRNA (m.5538 G > A) mutation was identified as causing FSGS in a male. The (m.547 A > T) and tRNAPhe (m.616 T > C) mutations were found in patients suffering from inherited tubulointerstitial kidney disease, who did not display typical symptoms of mitochondrial disease. A novel mutation in mtDNA (09155 A > G) was described in a Caucasian female with a history of renal disease, and symptoms of Maternally inherited deafness and diabetes (MIDD). Mutations in nuclear genes associated with mitochondrial function have also been associated with renal disease. The P99L mutation in the BCS1L gene was found in a female infant suffering from Neonatal Toni-Debre-Fanconi Syndrome, including renal tubulopathy. R45C and R56X mutations in the BCS1L gene were described in two siblings suffering from congenital lactic acidosis, including renal tubulopathy, and nine different mutations in FBXL4 were identified in nine individuals suffering from mitochondrial encephalomyopathy including renal tubular acidosis.
Despite the limited published literature, the known significance of the mitochondrial genome with relation to renal function and the multiple case reports relating to individuals suffering from renal dysfunction associated with mutations in mitochondrial or mitochondrial-associated genes, suggest that there exists considerable potential for genetic mutations, resulting in mitochondrial dysfunction, to contribute toward CKD.
In CKD research, despite the efforts of extensive GWAS and other genomic analyses in this area, a "blind spot" still exists in the form of X- and Y-chromosome analysis. Fifty-three of the 3,643 publications found in the online GWAS catalog (hosted by the National Human Genome Research Institute-European Bioinformatics Institute) examined CKD and/or kidney-associated traits. Over 450 genome-wide associations (p < 5 x 10-8) with renal disease and/or related traits were found at 140 loci across the genome (Table 2).
As depicted in Table 2, the number of associations per chromosome is the lowest for chromosome Y (no associations) and the fourth lowest number of associations for chromosome X (four associations). This is not surprising for chromosome Y. Historically thought of as a "genetic wasteland", association analyses usually exclude the Y-chromosome. Indeed, in the 53 studies examining renal disease/traits, only one included the Y-chromosome in the association analysis. Given that the Y-chromosome is the smallest and contains the fewest number of genes per number of base pairs, the lack of significant associations in this study is not unexpected.
However, for a chromosome of its size and gene content, the small number of associations found between X-chromosome SNPs and renal disease/traits raises questions as to why there are so few reported. Indeed, the only chromosomes with fewer reported associations are chromosomes 14 and 21, both of which are smaller and contain fewer genes than chromosome X. The lack of reported associations with sex chromosome SNPs could be due to a true lack of association or under-representation of sex chromosomes in GWAS.
Of the 53 GWAS in renal disease/traits, 10 are unclear as to whether X- and Y-chromosome SNPs were included in association analysis. Over half (62%) of the studies did not report sex chromosome association results, with many actively excluding the X- and Y-chromosomes from the association or meta-analysis stages. Of the 10 studies (18%) that explicitly state that the X-chromosome analysis was included, only one study found associations between X-chromosome SNPs and renal traits (SCr and eGFR) that reached genome-wide significance. Two SNPS, rs12845465, and rs5987107, were both associated with SCr and eGFR (p < 5 x 10-8). In only one study does Y-chromosome analysis appear to be included, where no SNPs reached genome-wide significance.
Therefore, with less than 20% of studies reporting X-chromosome results and Y-chromosome exclusion almost ubiquitous, it is not surprising that very few sex chromosome SNPs have shown association in studies of renal disease/traits. A possible explanation for sex chromosome exclusion is that traditional imputation methods call for the use of autosomes only. Even now that methods of X-chromosome imputation have been introduced, greater expertise is required and the X-chromosome is imputed separately from the autosomes, and these issues may lead some researchers to simply exclude it. The lack of reported analysis of X-chromosome SNPs in renal disease then leads to its exclusion from meta-analysis, as X-chromosome results are not common between all included studies. Poor genotyping of X-chromosome SNPs may also account for a reduced number of significant associations. Evidence has suggested that removal of X-chromosome SNPs during quality control is significantly more likely, due to a higher rate of chromosomal anomalies or missing call rate than autosomal SNPs. However, despite the successful imputation of the X-chromosome, chromosome Y lags behind. Despite recent efforts, haplogroup-based Y-chromosome imputation is still not widely used, with authors opting to instead use only directly genotyped SNPs.
The lack of sex chromosome inclusion in CKD GWAS may be one reason that the relationship between sex and CKD incidence/progression is so unclear. By regularly excluding these chromosomes from renal GWAS, we may miss SNPs that infer either increased CKD risk or protection to one gender in particular.
Traditionally, a greater risk of CKD incidence and progression to ESRD was associated with males. While current evidence still supports an increased rate of progression in men to ESRD, the risk inferred by gender on incidence of CKD is unclear. A study which used several definitions of incidence found that when using eGFR-based definitions of CKD (<60 ml/min/1.732), incident CKD was significantly higher in women than men (p = 0.02), but when using a minimum increase in SCr to detect CKD, men had a significantly higher incidence (p = 0.001). Gender adjustment occurs in eGFR calculation, which may explain this difference. A study conducted to develop a CKD risk score also found that female sex was associated with prevalent CKD (p = 0.02), as did a Turkish population study (p < 0.001). Additionally, a comprehensive review revealed that 38 studies found CKD was more prevalent in women, while 13 found it was more prevalent in men. Therefore, while women seem to make up a larger proportion of the individuals affected by CKD, affected men seem to progress at a much faster rate, highlighting the difference in the way that CKD affects men and women.
Clinical evidence and recent literature support a link between the sex chromosomes and impaired renal function. Arising as a result of a mutation in COL4A5 on chromosome X, Alport syndrome is caused by impaired production or function of collagen in various basement membranes throughout the body, including in the glomerulus. The condition is characterized by hearing loss, ocular abnormalities and progression to ESRD, where up to 30% of women reach ESRD by age 60 and the majority of affected males will require transplant or dialysis by their late twenties. | chronic kidney disease, copy number variants, mitochondria, single nucleotide polymorphisms, telomeres, whole exome sequencing | Not supported with pagination yet | null |
PMC8696155_01 | Male | 5 | A 5-year-old boy initially presented with headache, right eye pain, and vomiting, to a rural district hospital in the State of Sabah, East Malaysia on Borneo island. The boy also experienced difficulty in walking, blurring of vision, and fluctuating consciousness 1 month before admission. There was a significant (but unquantified) loss of weight and anorexia. He completed his bacille Calmette-Guerin (BCG) vaccination but missed all scheduled shots after his first birthday because of poor family support. On examination, a Glasgow Coma Scale (GCS) of 9 was documented (E2V2M5) with left lateral strabismus. The pupils were unequal (4 mm/3 mm) and sluggish. Power in all four limbs was 4/5 (Medical Research Council scale) with normal reflexes. Babinski was downgoing, and Kernig's sign was not elicited.
The boy was transferred to our center for further evaluation and treatment. Non-contrast CT brain showed acute hydrocephalus with cerebral edema. Subsequently, an external ventricular drain was inserted. Intra-operatively, the opening pressure was high, and outflowing cerebrospinal fluid (CSF) was clear and colorless.
Magnetic resonance imaging of the brain revealed diffuse enhancing nodular leptomeningeal thickening, especially at the basal cisterns (Figure 1). No intra-axial lesion was present. Small non-enhancing cystic lesions were seen along the leptomeningeal surface (Figure 2B1), and no restricted diffusion was depicted. A diagnosis of tuberculous meningitis was considered, and an extensive TB workup was undertaken. The positive results from that battery of tests were a high erythrocyte sedimentation rate (ESR) of 90 mm/h and elevated CSF protein with normal CSF glucose levels. Otherwise, the Mantoux test was negative, and the blood, CSF, and CSF TB cultures showed no organism. The CSF for acid-fast bacilli as well as CSF GeneXpert were also negative. CSF latex agglutination was negative for streptococcus Group B, haemophilus influenzae, streptococcus pneumoniae, neisseria meningitidis, and escherichia coli. Both gastric lavage for acid fast bacilli stain and gastric lavage for GeneXpert were negative.
Smear-negative TB was considered after reviewing the biochemical and imaging findings. Using the Composite Reference Standard (CRS) criteria, this child was classified as probable TB. A standard anti-TB regimen was started consisting of isoniazid, rifampicin, pyrazinamide, and ethionamide. Intravenous dexamethasone was prescribed during the first 2 weeks of admission and was subsequently changed to oral administration.
The boy's condition improved considerably after 14 days, and he was well enough to undergo a comprehensive ophthalmology examination. He had a visual acuity of 1/60 in the right eye, and there was no light perception in the left eye. A positive right afferent pupillary defect was detected. Ophthalmoscopy showed normal macula bilaterally.
Both his parents were screened and found to be negative for TB. He was discharged well after a 4-week hospital stay.
One month later, he presented again with vomiting, unsteady gait, and anorexia. The follow-up MR brain study revealed exuberant nodular leptomeningeal enhancement that was more extensive than the initial study (Figure 1). Also, the previously seen cystic lesions have increased in size and number (Figures 2B2,C). MR spectroscopy (single voxel placed at the thickened tentorium cerebelli) showed a markedly elevated choline:creatine ratio of 4.34 and absence of a singlet peak at 3.8 ppm (Figure 3). A biopsy sample was obtained and sent for histopathological examination (HPE). Transcranial approach at the right Keen's point was used to obtain the biopsy sample. The patient incidentally needed a revision of his external ventricular shunt at that time, so dural tissue was obtained via the Burr hole just prior to the shunt revision.
Histopathological examination (HPE) revealed a moderately cellular neoplastic proliferation with background desmoplastic and myxoid changes seen from the hematoxylin and eosin (H&E) stain slides (Figure 4A). The cells were fairly monomorphic with mild nuclear pleomorphism displaying enlarged round to oval nuclei with fine chromatin and inconspicuous nucleoli (Figure 4B). Occasional mitosis was seen (Figure 4C). The Ki-67 proliferation rate was high, accounting for about 80% (Figure 4D). Immunohistochemical (IHC) studies showed that the tumor cells were positive for S100 and synaptophysin (Figures 4E,F). Given these findings, the boy was diagnosed with DL-GNT.
A family conference was held to counsel the parents on possible treatment options. The parents decided to opt for palliative treatment. The patient succumbed to the illness 3 months later, 22 weeks in total, after diagnosis. | mr spectroscopy, diffuse leptomeningeal glioneuronal tumor, imaging, meningitis, tuberculosis | Not supported with pagination yet | null |
PMC7398405_01 | Male | 18 | An 18-year-old man was admitted to our department showing the symptoms of blurriness. A 1-year history was reported on blurriness and visual indistinctness that had progressively worsened over the past 2 weeks. He has a record of tuberculosis and takes anti-TB drugs on a regular basis. Neurologic examinations at the time of admission revealed no focal neurologic deficits except for oculomotor paralysis. Magnetic resonance imaging (MRI) indicated that the diameter of intracranial segment in the left internal carotid artery was significantly dilated, the inner diameter was approximately 14 mm, the left anterior cerebral artery, and the starting point of the MCA were slightly dilated as well, and the structure of the left cavernous sinus area lacked clarity. There was a circular liquid signal shadow spotted under the inner wall of the left maxillary sinus, the diameter of which was about 16 mm (Fig. 1). Further cerebral angiography indicated that the left internal carotid artery GSA was about 48.61 mm x 23.40 mm in size, 4.65 mm in diameter of proximal vessels, and 3.16 mm in diameter of distal vessels (Fig. 2).
His family was informed of these conditions and signed a consent form prior to the operation. The balloon occlusion test conducted previous to surgery indicated that the anterior communicating artery was open and the contralateral internal carotid artery had a good compensatory blood supply, as a result of which direct trapping of the parent artery was taken as an alternative method. However, ipsilateral MA has a potential of further growth which could lead to paralysis of facial nerve compression, which is due to higher blood flow to the external carotid artery. His family members rejected this traumatic treatment method and thus the insertion of stents was chosen to reconstruct the original structure of the vessel. Therefore, the following surgery was performed: antiplatelet therapy (100 mg aspirin + 75 mg clopidogrel daily) was carried out at least 3 days prior to the operation, and he underwent surgery after being diagnosed with anesthesia. Firstly, a LEO (6.5 mm x 75 mm) stent was put through an Echelon-10 catheter located in the MCA, and then the stent was released at a slow pace and completely through the GSA. Meanwhile, the head was anchored at the distal end of the parent artery. Subsequently, the trans 300 floppy guidewire was switched to the marksman on the MCA. The Tubridge flow diverter (6.5 mm x 45 mm) was easily placed into the designated position where it was attached to the LEO stent that was well anchored before. With the assistance of X-ray, the Tubridge flow diverter was slowly released to overlap with the LEO stent wall and the aneurysm neck was completely covered. Ultimately, digital subtraction angiography (DSA) revealed obvious retention of contrast agent in GSA, and three-dimensional vascular reconstruction demonstrated that the walls of the parent artery were reconstructed by both Tubridge and LEO stent (Fig. 3). Then, the guide catheter to the external carotid artery was replaced, liquid glue (50%, 1.5 ml) was injected, and three coils were released through the microcatheter. Finally, the right femoral artery with an 8F Angio-Seal vascular occlude was blocked. The patient needed to avoid stent thrombosis by taking aspirin for a long period of time, although the thrombo-elastography (TEG) test indicated that arachidonic acid inhibition rate (AA%) and inhibition rate on ADP receptor of clopidogrel (ADP%) were within the normal range. After a follow-up observation for 1 year, DSA revealed that the aneurysms were almost completely occluded and the abnormal serpentine channels disappeared. Meanwhile, the MA disappeared as well. The two stents overlapped in the parent artery with excellent adhesion, and no stenosis or displacement was discovered. Three-dimensional revascularization indicated a significant reduction in aneurysm volume, and the mass effect was reduced as shown by CT scan (Fig. 4). | giant serpentine aneurysm, leo stent, mandibular aneurysm, tubridge flow diverter | Not supported with pagination yet | null |
PMC9683972_01 | Male | 5 | A 3.5-year-old male was referred to our tertiary center, Estella Clinic for Children with Cancer and Blood Diseases, Manado, Indonesia, due to pallor and enlarging abdomen and neck mass noticed over the last year. The mother also mentioned recurrent fever and diarrhea for the previous two years. The patient's weight was 9.4 kg and his height was 76 cm (weight for age <P3, height for age <P3, and weight for height P15-50). Physical examination showed anemia, breathing difficulty, enlarged unilateral neck, lymph node with a diameter of 3 cm, enlarged liver 7 cm below the costal margin, spleen length 10 cm, and peripheral edema. He was diagnosed with tuberculosis and treated with triple tuberculostatic therapy; probably, this was a false diagnosis and JMML being the cause of his symptoms.
The initial routine blood test showed a hemoglobin content of 6.4 g/dl, white blood cell counts of 315.62 x 103/muL, neutrophils of 180.5 x 103/muL, lymphocytes of 23.4 x 103/muL, monocytes of 77.93 x 103/muL, and platelets of 17 x 103/muL. Blood smears showed normocytic anemia and leukocytosis with various stages of cell maturation, i.e., 10% suspected blast, 17% myelocyte, and 17% metamyelocytes, with a thrombocytopenic crisis. The HbF level was 5.8%. BCR-ABL gene tested negative. Chest X-ray and echocardiography were within normal limits. An abdominal ultrasound showed enlargement of the liver, spleen, peripancreatic, and paraaortic lymph nodes.
Our patient was diagnosed with juvenile myelomonocytic leukemia, accompanied by cachexia. Considering that HSCT was not able to be done in our center, the lack of financial possibilities to seek treatment abroad, and the complex condition of the patient, the family agreed to do palliative treatment to keep him in a reasonably good clinical condition for as long as possible. He had received hydroxyurea shortly before the diagnosis of JMML was made. The patient was treated with oral 6-mercaptopurine (6-MP) and subcutaneous cytarabine. The treatment plan consisted of 4 cycles of a 4-weeks regimen of 3 weeks 6MP daily and 1 dose of cytarabine weekly, with one week of no chemotherapy. Doses were to be increased if well tolerated, but to be decreased, if counts dropped too low. 6-MP was given daily, started with a dose of 10 mg/m2/day, and increased 20% every cycle, if tolerated, until a maximum of 20 mg/m2/day. Subcutaneous cytarabine 10 mg/m2 was given every week, except for the very first week. The chemotherapy was well tolerated, and the patient's general condition was improving; his weight increased to 10.2 kg. He survived a bout of COVID infection with a mild cough and a positive COVID antigen test. There was no fever, bleeding signs, or breathing difficulty. Four weeks after receiving 6-MP, the white blood cell count decreased to 10.6 x 103/muL, and the spleen size was half of the original size (categorized as a complete clinical response). The 6-MP dose was increased by 20% in the second cycle and was also well tolerated. The patient continued the chemotherapy at home until week 16, and chemotherapy was stopped, but 16 weeks after the diagnosis of JMLL, he developed severe thrombocytopenia, endophthalmitis, and sepsis and passed away. The protocol of palliative chemotherapy for JMML at our center and the patient's laboratory findings during treatment are shown in Table 1. | null | Not supported with pagination yet | null |
PMC6942708_01 | Male | 47 | A 47-year-old male born in the Philippines who immigrated to the US approximately 2 years ago presents to a gastroenterologist with symptoms of abdominal pain, unintentional 60 lb weight loss over the past 6 months, fatigue, and diarrhea without hematochezia. A CT scan of the abdomen showed only nonspecific colitis of the ascending colon and descending colon. He had a colonoscopy which showed segmental areas of inflammation and deep ulcerations at the hepatic flexure and in the ascending colon with edema, granularity, and loss of vascularity (Figure 1). The terminal ileum was not intubated during this procedure. Pathology showed severe lymphoplasmacytic infiltration, marked architectural distortion, and chronic inflammation without granulomas. The patient was diagnosed with Crohn's disease and was treated with prednisone and mesalamine. However, his symptoms progressively worsened over the next three months, so his treatment was escalated. He was tested for latent tuberculosis infection (LTBI) with the Quantiferon gold assay, which returned indeterminate and a subsequent tuberculin skin test (TST) was negative. Chest X-ray did not show any evidence of active or prior TB infection, so the patient was thus presumed to be TB negative and started on the TNF-alpha inhibitor infliximab. One month later, the patient presented with worsening abdominal pain, diarrhea, fatigue, and new fevers, claiming that his symptoms had significantly worsened since starting the infliximab. He was in shock with a blood pressure of 73/51 mmHg and laboratory results were notable for white blood cell count of 8.7 x 109/L (normal 3.4-9.6 x 109/L) with bandemia, albumin 1.5 g/dL (normal 3.5-5.0 g/dL), lactic acid 5.3 mmol/L (normal 0.5-1 mmol/L), and a cholestatic liver function pattern. He was treated for septic shock with broad-spectrum IV antibiotics and vasopressors, but required intubation due to clinical deterioration. CT imaging revealed ascites, large bilateral pleural effusions, and multiple hypodense lesions within the liver with an obstructing mass at the confluence of the bile ducts. Diffuse full-thickness small and large bowel wall thickening along with increased attenuation involving the terminal ileum and cecum was present. A workup for infection was pursued with liver lesion biopsy, thoracentesis, and paracentesis. These studies were negative for malignant cells, but were positive for numerous acid-fast bacilli (AFB). A repeat CT was performed where it was seen that the patient developed intraperitoneal free air and fistulas requiring exploratory laparotomy (Figure 2). Surgery revealed extensive adhesions associated with dense granulomatous disease and perforation of the small bowel and right colon. A hemicolectomy and small bowel excision was performed with pathology of the terminal ileum and right colon showed extensive caseating and noncaseating granulomatous inflammation that stained positive for AFBs in a skip lesion pattern consistent with intestinal tuberculosis (ITB). The patient was diagnosed with disseminated TB and started on anti-mycobacterial therapy with significant improvement in his clinical condition. After discharge, he no longer complained of diarrhea, weight loss, or abdominal pain on two month follow-up. The diagnosis of Crohn's Disease was no longer considered and removed from his medical history. | null | Not supported with pagination yet | null |
PMC3690727_01 | Female | 49 | A 49-year-old Caucasian female presented with generalized arthralgias and recurrent diffuse pruritic maculopapular lesions over her face, torso, and upper extremities. The patient suffered outbreaks with variable intensity almost in a daily basis over the past five years with no identifiable triggering factors.
The patient mentioned that the lesions cleared up in 24 hours, leaving no marks or scars, while new lesions appeared daily.
Her past medical history was significant for transfusion related hepatitis C, diabetes mellitus type 2, depression, chronic pancreatitis, and malnutrition.
Previous surgeries included pancreatic cyst removal at age 11, tonsillectomy/adenoidectomy, tubal ligation, and appendectomy.
She had a 35 pack/year history of smoking, with remote history of inhaled crack cocaine use. She denied alcohol or other illicit drug use.
Review of systems revealed unintended weight loss of about 20 pounds over a 6-month period, diffuse abdominal pain, generalized weakness, night sweats, and subjective recurrent low-grade fevers not associated with the onset of her skin lesions.
Her family history was noncontributory (father deceased at the age of 70 because of heart disease, mother had diabetes mellitus and coronary artery disease, and her brother and daughter had good health).
The initial physical examination revealed diffuse pruritic maculopapular lesions over her face, thorax, and upper extremities (Figure 1), sparing her palms, soles, and mucous membranes. Also mild hepatosplenomegaly was found.
Her laboratory studies showed marked leukocytosis of 48.6 with neutrophils of 97.8% with elevated D-dimer and erythrocyte sedimentation rate (ESR) (Table 1).
She was started on broad-spectrum antibiotics that were discontinued 72 hours after the admission when infections were ruled out.
Antinuclear antibodies, rheumatoid factor, anticitrullinated peptide antibodies, human immunodeficiency virus enzyme-linked immunosorbent assay (ELISA), Venereal Disease Research Laboratory (VDRL), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg), hepatitis B e antigen (HBeAg), and cryoglobulins were found to be negative or within normal limits.
Serum protein electrophoresis showed monoclonal gammopathy; SPEP showed gamma region asymmetric spike consistent with monoclonal gammopathy. UPEP showed oligoclonal gammopathy involving IgG, IgM kappa, and lambda (IgM: 552 mg/L).
Biopsy of her skin lesions showed neutrophil rich cells admixed with eosinophils consistent with chronic urticaria. A right groin excisional lymph node biopsy showed reactive lymphoid hyperplasia with plasmacytosis.
Bone marrow biopsy showed a hypercellular marrow with plasmacytosis and myeloid predominance and was reported as negative for malignancy.
Based on the clinical presentation and laboratory results the diagnosis of Schnitzler syndrome was made. As proposed by Lipsker et al. the diagnosis of this entity requires 2 major criteria and a minimum of 2 minor criteria. She had 2 major criteria (chronic urticarial rash/intermittent fever and monoclonal IgM) plus at least 5 minor criteria (arthralgias, bone pain, lymphoadenopathy, hepato- and/or splenomegaly, and elevated ESR and/or leukocytosis).
She was started on high dose of corticosteroids, nonsteroidal anti-inflammatory drugs, and antihistamines with partial remission of her symptoms and she was discharged home (Figure 2).
Anakinra was added to her regimen for several weeks with an excellent response; however due to economical constrains treatment was discontinued, and her symptoms partially recurred. | null | Not supported with pagination yet | null |
PMC6813411_04 | Female | 6 | Patient 4 (submandibular lymph node abscess, 6 weeks) was a 1-year-old girl with AR CGD (NCF1 delta GT). She was diagnosed with a bilateral submandibular fistulising lymph node abscess. Surgical drainage revealed the presence of Burkholderia cepacia. DHR test showed 17-25% of cells with residual NADPH oxidase function on a low level, as the shift of DHR-positive cells (DeltaGeoMean MFI) corresponded to only 1.9% of the shift observed in healthy control cells.
A deep frozen control lymph node sample of a non-CGD patient presenting recurrent lymph node hyperplasia was kindly provided by the tissue biobank of the Institute of Pathology and Molecular Pathology of University Hospital Zurich.
Tissues were transported and homogenized as described in the Materials and Methods section "cytokine and chemokine analysis." To avoid sampling errors, >50% of tissue was processed for flow cytometry analysis and cytokine quantification. Tissue-derived cells and ex vivo-primed macrophages were blocked with FcR blocking reagent (MACS, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) and stained with the antibodies as follows. Anti-human CD14 PC7 (clone RMO52), anti-human CD209 (DC-SIGN)-PE (clone AZND1), anti-human CD14 PC7 (clone RMO52) were from Beckman Coulter International S.A., Nyon, Switzerland. Anti-human CD15 V500 (HI98), anti-human CD57 FITC (HNK-1), anti-human CD56 PE (B159 RUO), anti-human CD8 V450 (RPA-T8) and anti-human CD8 V450 (RPA-T8) were from BD Bioscience, Eysins, Switzerland. Anti-human CD3 Alexa Fluor 700 (UCHT1), anti-human Valpha24Jalpha18 TCR PE-Cyanine7 (6B11), and anti-human CD206 (MMR) eFluor 450 (clone 19.2) were from eBioscience, Eysins, Switzerland. Anti-human CD4 PerCP (OKT4), anti-human CD19 Brilliant Violet 605 (HIB19), anti-human CD163 PerCP/Cy 5.5 (clone GHI/61) anti-human CD86 Brilliant Violet 605TM (clone IT2.2) were from BioLegend, Lucerna-Chem AG, Luzern, Switzerland. Anti-human Mer APC (clone 125518) were from R&D Systems, Bio Techne AG, Zug, Switzerland. Cells were washed, fixed with 2% formaldehyde in PBS, measured by GalliosTM flow cytometer and analyzed by Kaluza software (Beckman Coulter International S.A., Nyon, Switzerland).
Volume of pus samples were determined and diluted to separate cells from supernatant by centrifugation. Solid tissues were kept in PBS on ice for up to 1 h until >50% of samples were weighed and homogenized with a syringe piston on a Petri-dish. Remaining tissue was removed by filtration (70 mum cell strainer). For flow cytometry analysis, cells were separated from supernatant by centrifugation. Supernatant was stored at -80 C until cytokine quantification in duplicates by 18plex Immunoassay (Cat. No. EPX180-12165-901, eBioscience, Thermo Fisher Scientific AG, Basel, Switzerland) and MILLIPLEX MAP KIT (Cat. No. HCYTOMAG-60K, MILLIPORE, Merck AG, Zug, Switzerland) according to manufacturers' instructions for quantification of G-CSF, GM-CSF, IFN-gamma, MDC, TNFalpha, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-21, IL-22, IL-23, and IL-27. Cytokines concentrations are expressed in ng/ml of undiluted tissue.
Paraffin-embedded slides were dewaxed and stained with rabbit anti-human IL-18 (LS-C313164, Lifespan Biosciences, LabForce AG, Muttenz, Switzerland) and mouse anti-human CD68 (clone 514H12, Novocastra Laboratories Ltd., Newcastle upon Tyne, UK), followed by donkey anti-rabbit FITC (711-095-152, Jackson ImmunoResearch Ltd., MILAN ANALYTICA AG, Rheinfelden, Switzerland), donkey anti-mouse Cy3 (715-165-150, Jackson ImmunoResearch Ltd., MILAN ANALYTICA AG, Rheinfelden, Switzerland) followed by mouse anti-FITC Alexa488 (200-542-037, Jackson ImmunoResearch Ltd., MILAN ANALYTICA AG, Rheinfelden, Switzerland) and 4',6-Diamidin-2-phenylindol (DAPI) staining conducted by Sophistolab AG (Muttenz, Switzerland).
Slides were analyzed by confocal microscopy (model TCD SP8, Leica Geosystems Holdings AG, Glattbrugg, Switzerland) with original magnification x40. Acquired images were processed using ImageJ.
Immunohistochemistry was perfomed by Sophistolab AG (Muttenz, Switzerland) on Leica BondMax instruments using Refine HRP-Kits (Leica DS98000, Leica Microsystems Newcastle Ltd., Newcastle upon Tyne, UK) according to manufacturer's instructions. Paraffin-slides were dewaxed, penetrated, and stained with rabbit anti-human IFN-gamma (LS-B7487, Lifespan Biosciences, LabForce AG, Muttenz, Switzerland), visualized by HRP Refine Kit (DS9800, Leica Microsystems GmbH, Wetzlar, Germany). Images were then analyzed with a bright-field microscope (Axiovert S100TV, Carl Zeiss Vision Swiss AG, Feldbach, Switzerland).
Monocytes were isolated from mononuclear cells after FICOLL (Ficoll-Paque PLUS, GE Healthcare AG, Glattbrugg, Switzerland) density gradient centrifugation, followed by magnetic bead-based positive selection (CD14 human microbeads, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) according to manufacturer's description. Cells were cultured (2.8 x 105 cells/well) in PRIMARIA 24 wells plate (Becton Dickinson AG, Allschwil, Switzerland) in RPMI supplemented with Octaplas SD 10% (Octapharma AG, Lachen, Switzerland), 2 mM sodium pyruvate, 2 mM L-glutamine, 10 mM HEPES, and M-CSF 100 ng/ml (research grade, MACS, Miltenyi Biotec GmbH, Bergisch Gladbach, Germany) for 7 days.
Macrophages were either kept in culture for 24 h in a fresh differentiation medium (M0 macrophages), or stimulated with IFN-gamma (50 ng/ml, e-Bioscience, Thermo Fisher Scientific AG, Basel, Switzerland) and LPS (10 ng/ml, Sigma-Aldrich GmbH, Buchs, Switzerland) for M1 priming, IL-4 (20 ng/ml, ProSpec-Tany TechnoGene Ltd., Ness Ziona, Israel) for M2a, in wells pre-coated with human IgG (5 mug/cm2, Sigma-Aldrich GmbH, Buchs, Switzerland), and supplemented with LPS (100 ng/ml, Sigma-Aldrich GmbH, Buchs, Switzerland) for M2b, or supplemented with IL-10 (100 ng/ml, Sanofi Genzyme, Vernier, Switzerland) and M-CSF (100 ng/ml, MACS, Miltenyi Biotec, GmbH, Bergisch Gladbach, Germany) for M2c. For cytokine/chemokine analysis, supernatants were centrifuged, and aliquots were stored at -80 C. After 24 h of stimulation, macrophages were detached with EDTA and analyzed by flow cytometry analysis.
Supernatants from 24 h un-primed M0, or from 24 h M1, M2a, and M2c primed macrophages were removed, cells were washed with PBS without detachment, and re-primed for 72 h by incubation with priming stimuli (described in 24 h Priming of Macrophages). Ninty six hours after initial priming corresponding to 72 h after repriming, supernatants were centrifuged and stored at -80 C for cytokine/chemokine quantification.
Statistical analysis was performed as indicated by ANOVA with post hoc Bonferroni correction using SPSS (Version 22, IBM), and graphs were prepared using GraphPad Prism Software (Version 5.0a; GraphPad Software, La Jolla, California, USA). | il-18/ifn-γ loop, chronic granulomatous disease, hyperinflammation, macrophage priming, macrophage re-priming | Not supported with pagination yet | null |
PMC9380982_01 | Unknown | 18 | This study intends to present a different way of introducing IT into the classroom, applied in practice in an educational environment, in classes of primary level students (around 12 to 18 years old), and their schools. Although it is not an educational methodology, the proposed didactics, which use IT through robotics or programming, aim to be non-invasive. Besides, it intends not to cause an abrupt cultural change and reduce the reactivity in using IT resources in classrooms. It works on connecting the IT resources-Robotics/Programming with the students' out-of-class worldview and their personal and collective perspectives.
Instead of suddenly inserting IT into the classroom, we try to get students to "let their imagination run wild". They are instigated to give a new way : their way : to discover and experience new concepts using IT resources. Observing what they know or would like to know about IT using robotics and programming was essential. Such approach can be helpful for students with different educational needs (Erdem, ; Olakanmi et al., ).
Particularly, this view explores the idea that robotics (and its coupled programs) is part of the POP world of these students. It is seen in cartoons (from The Jetsons to Steven Universe), movies, heroes or villains of comic books, and music. Even those living in adverse socioeconomic conditions have heard of or been aware of some hero robots, such as Transformers. Thanks to media marketing, these students know about robots and the programs that control them.
One concept applied was to seek the worldview of these students regarding the world of IT. For this application, it was important to make the students present their common ways and visions of what they understand about IT. Before introducing an IT resource, they may consider what IT can offer them in the classroom. It enables them to build their perspective about this universe.
For this study, Gestaltism (Greenwood, ) was perceived as knowledge to help build new ways to discover, experiment, or create educational content. It adds different worldviews about a theme (in this case, IT). It helped to capture the development of learning environments more connected to the universe of these students. The Gestalt Approach strand values subjectivity, uniqueness, responsibility, and experience. It focuses on the perception of existence in front of a holistic environment. It was not the objective of the study to propose a hermetic methodology to apply and verify perceptions of the developed projects.
The Gestalt approach was chosen not to be bound by closed "liturgies" for an educational method. It was used to obtain the students' perceptions and worldviews. As the focus of this approach is on form, participation, and the sum of perceptions, unformatted conversations within the classroom were used to work on the development of educational resources with robotics. It can be seen as equivalent to a qualitative approach for this kind of didactics.
This way of capturing these perceptions comes from the students and teachers involved in the development processes of the new IT resources. They valued spontaneity so that it was possible to scrutinize the scope, influence, and curiosity regarding robotics and IT, from their point of view, without a strictly academic view. An attempt was made to shape these spontaneous insights into the topic by collecting these informal observations.
This research environment focused on a set of schools in Rio de Janeiro (Brazil) in classes from 5th to 9th grades (de Praga Baiao & Batista, ). It has been ongoing research since 2013. One of the authors has worked in these teaching units, facilitating information collection and the application's design.
The formatting of what was observed followed one of the maxims of Gestaltism, which states that the parts' total union makes a fundamental difference from a simple sum. By building this new form, it was possible to introduce these students to the vision of IT with robotics and programming. Thus, the product, created and driven by the students' perceptions, became a standard component in the classroom and a friendly pedagogical resource created, admitted, and planned by them, reducing reactivities.
The idea is to verify how much the Gestalt approach can help produce educational resources associated with IT. As this study deals with creative actions, the proposal uses the IT area that most deals with creations that use imagination and that can be materialized: robotics.
Monsores et al. show an example of the experience of using the gestalt approach to construct educational resources using IT principles. It is only a part of the biggest educational project that uses robotic, gestalt approach and programming to production, by the own students, educational resources.
This study shows the application of this approach to building IT-based teaching resources. It is separated into an introduction, an overview of Gestaltism, robotics, and programming, a review of case studies of the application of the Gestalt approach in other educational situations, and the application of the didactics proposed in this study in different classrooms, and a conclusion.
Although the terms are not precisely synonymous, Gestaltism (or Gestalt Psychology, or Gestalt Approach) privileges the notion of configuration or form, understanding the phenomenon as an organized totality and not as a mere sum of elements. It is a theory of psychology that emphasizes perception and postulates that the principle of brain functioning is holistic, parallel, and analogical, with personal trends (Greenwood, ).
It also focuses on the idea that human perception is not only observing and interpreting what is contained in the universe around us but is also influenced by several particular and group motivations and expectations (Greenwood, ). Therefore, its focus is on the idea of an active, relational subject and not simply a receiver of information so that the teaching/learning relationship makes all the difference.
Gestaltism did not emerge as a pedagogical method such as constructivism (Ariza & Baez, ; Asoodar et al., ), Paulo Freire's pedagogy (Giroux, ), or Skinner's behaviorism (Watters, ). It is a theory of psychology that emerges as a reaction to associationism, combating the idea of fragmentation of perception. It has been applied in various scientific areas, from economics (Beisser, ), to theology (Thomas et al., ), communication and advertising, and the arts in general (Parsons et al., ).
However, few works present it as a model for creating new educational practices in schools. The example of Pill & Hyndman gives Gestaltism and its applicability in the school setting, highlighting the value of this approach is spontaneous learning. By conceiving perception as a dynamic and integrated process, Gestaltism can provide education resources from actions of creativity (Monsores et al., ).
A robot is a term used for the products of robotics. This field aims to study and develop automated or autonomous technological tools to accomplish specific tasks through specific programming. The first mention of the term robot appeared many years ago in a play produced by Capek about an automaton mechanism that performed specific tasks. Today, the field of robotics draws on knowledge of mechanics, electronics, computing, mathematics, physics, and automation (Niku, ).
A robotic system is composed of mechanical parts manipulated by integrated circuits (microcontrollers). They are programmed to interpret signals from actuators, motors, and sensors and produce movements or automatic responses to stimuli (Niku, ). It aims to produce autonomous tools to assist or replace more complex human tasks. It includes constructions, deactivating bombs or mines in war zones (Mukh, ), performing geoprocessing (Hanisch et al., ), assisting in medical operations (AlQarzaie & AlEnezi, ), and other tasks. Figure 1 presents some models of robots or robotic tools associated with education.
Today, there is greater popularization and better access to instruments capable of developing these tools due to the emergence of lower-cost interfaces composed of cheaper microcontrollers and an entirely didactic apparatus for accessing and programming their functions. Among these new interfaces are the boards of the Arduino family (Chang & Chen, ) or Raspberry (Kingstan & Suchithra, ), which allow people without prior familiarity with this field of technology to have the ability to develop prototypes of mobile robots or automation, much more quickly.
Most robotic instruments work with more sophisticated programming algorithms, such as Deep Learning or Fuzzy Logic. They monitor specific situations, such as watching air quality in large cities, environmental sensing, and checking for disease outbreaks, among other applications requiring more robust programming. Among the programming languages that work with robotics, we have C, java, C++, phyton, and each microcontroller's assemblies (Kim et al., ; Al-Shanoon & Lang, ). Regarding the application of robots and programming in an educational environment, there is the work of Monsores et al., in which a methodology based on Gestaltism is emphasized to build educational robotic resources. Besides, the result of Sisman et al. also shows the application of constructivism to work on the effects of robotics training on children's spatial ability and attitude toward collaborating in science, technology, engineering, and mathematics (STEM).
In work by Mahdi et al., robotics and educational programming are analyzed from the teacher's point of view, looking at how the influence of the IT tool affects a new education perspective. Panskyi & Rowinska work presents an innovative approach to organizing the out-of-school teaching of programming in middle childhood. Yepes et al. show how UAVs can assist in teaching engineering subjects, indicating that the support of robotic resources helps fix diverse learning.
It has chosen robotics as an area in which the use of the gestalt approach would be appropriate to learn IT since it is an area in which students can materialize, in a concrete way, the resources they have developed. It is essential to point out that the Gestalt approach does not deal with knowledge absorption as in constructivism. The latter is one of the widely-adopted teaching methods, whereas the former emphasizes the form of each one's perception of the world (Pill & Hyndman, ; Skottun & Kruger, ).
The beginning of applying the educational method using Gestaltism with robotics and programming, with a bias towards the production of pedagogical and didactic resources to awaken interests in new knowledge, has as its starting point the obtaining of the students' particular visions about IT. One motivation issue for choosing robotics as the prominent IT area in this study was that by studying robotics, students could concretely visualize an object with form, and Gestalt Therapy is the psychology of form (Monsores et al., ; Skottun & Kruger, ).
By encouraging students to use their imagination and creativity to produce an IT resource that has a form that can be touched and even modified, the association with Gestalt Therapy is seamless. The didactic work using this application of psychology results in a comfortable learning environment. The motivation is to give shape to the senses of imagination and creativity in an accessible point of view, without any hermetic methodological formatting, to develop and create their resources, plan how they will be used and for what they will be used (Thomas et al., ; Skottun & Kruger, ).
In this type of practice, the teachers/researchers conduct and organize the meetings and activities. Still, they do not induce or influence the students, who are the main protagonists of the activities and the influencing agents for the classes (Greenwood, ; Skottun & Kruger, ). | education, gestalt, technology | Not supported with pagination yet | null |
PMC4334046_01 | Male | 38 | A male patient of 38 years old, born in a rural area of the Trujillo state (Venezuela), where the seroprevalence to T. cruzi was 19.2-23.8% and the main triatomine vector was Rhodnius prolixus came to the emergency unit of the Caracas University Hospital with fever, generalized seizures, and progressive neurological impairment (day 0), whose symptoms appeared a week before admission (day 7). The patient was living in La Guaira city (Vargas state, Venezuela) where the mortality rate due to HIV-AIDS was the second highest of Venezuela in 2009 (10.5 deaths x 100,000 inhabitants) and an outbreak of oral Chagas disease occurred in Chichiriviche de la Costa in the same year, affecting 54 children and causing 3 deaths by acute heart failure.
Patient also reported to be bisexual with a promiscuous lifestyle and to have an HIV+ diagnosis. The physical examination revealed a body temperature of 38-39 C and a CD4+ T-lymphocytes count of <200 cells/mm3 (<14%) (AIDS C3 stage). According to the National Program of AIDS and Sexually Transmitted Infections of the Ministry of Health, the patient should have been treated with antiretrovirals, but, due to difficulties in obtaining these drugs, the patient was not following a retroviral therapy. The patient was hospitalized and a computed tomography (CT) of head was done revealing two rounded SOL ring-shaped in the frontal region and basal nuclei (CT images not shown). As a consequence of neuroimaging results, a presumptive diagnosis of toxoplasmosis was given to the patient, for which he received an empirical treatment with 200 mg of pyrimethamine in the first day and 75 mg/day since the second day, in combination with 100 mg/kg of body weight/day (4-6 g/day) of sulphadiazine (day 1). Since patient did not show improvement of his health condition, a lumbar puncture was done to obtain samples of cerebrospinal fluid (CSF) (day 4) which were cytologically studied. Because results from CSF cytology showed few parasitic flagellate protozoans morphologically compatible with trypomastigotes of Trypanosoma sp., the treating physicians consulted the departments of immunology and tropical medicine in order to confirm the diagnosis and to modify the treatment.
The characteristic morphology of flagellates and the epidemiological nexus of patient in Trujillo state (a Chagas' disease endemic area), without a specific diagnosis, allowed physicians not only to reformulate the case as probable infection of the CNS by Trypanosoma cruzi but also to start a specific treatment with Nifurtimox (6 mg/kg of body weight/day for 60 days in two daily fractions) due the absence of Benznidazole (day 7). The patient had a torpid evolution, without a favourable response to treatment, and died 3 days after the treatment beginning (day 10). Autopsy was done 1 hour after his death, according to the standards protocols at Jose A. O'Daly Institute for Pathology (Faculty of Medicine, Central University of Venezuela), in order to perform the corresponding pathological studies and confirmation of the pathological diagnosis at electron microscopical and molecular level by PCR. | null | Not supported with pagination yet | null |
PMC4531652_01 | Male | 66 | A 66-year-old man was referred to our hospital for evaluation of mild fever, blood-streaked sputum and chest discomfort for 7 days prior to admission. At five months before admission, a cough with minimal episodes of bloody sputum had developed. At that time, chest radiographs were said to be unremarkable. He denied having shortness of breath, wheezes, weight loss or night sweats. He works as a fisherman and has not smoked for 1 year but has a 30-pack-year history of tobacco use. His medical history was significant for cholecystectomy and laminoplasty for herniation of nucleus pulposus five years previously. His family history was noncontributory.
On presentation, the patient appeared to be in no distress, relatively. His blood pressure was 110/70 mmHg; heart rate 78 beats /min; respiratory rate 23 breaths /min; body temperature 37.60 C. Examination of the lung revealed slightly reduced breath sounds over the right lower lung. Cardiac examination revealed a regular rhythm without murmurs. Findings of the abdominal examination were normal and the extremities were without clubbing, cyanosis or edema.
The laboratory tests were as follows: WBC count, 15.7x103/uL with 78% neutrophils, 13% lymphocytes, 7% monocytes, 1% eosinophils and others 1%; Erythrocyte sedimentation rate, 44 mm/h; hemoglobin, 14.4 g/dL; hematocrit, 41.4%; platelet count, 313x103/uL. Other laboratory findings including liver function, blood glucose level, renal function, electrolytes and urine microscopy, were all within normal limits. Arterial blood gas analysis on room air revealed a pH of 7.459, Pco2 of 36.8 mmHg and Po2 of 76.9 mmHg. The chest radiograph obtained at the time of admission showed a round mass in the right lower lobe (Figure 1). The chest CT scan performed at the referring hospital confirmed the presence of a 4x4 cm-sized, smoothly marginated, soft tissue density with central lower density in the right lower lobe.
An initial diagnosis of subclinical infectious disease or necrotizing solitary mass was made; the patient was treated with empirical antibiotics. However, mild fever and blood-tinged sputum persisted despite the use of broad-spectrum antibiotics. The lesion looked larger on a chest radiograph. The patient still felt well, apart from the mild fever. Sputum culture findings were negative for bacteria and fungus. Tuberculosis smear was negative and cultures were pending. Sputum cytology testing results were also negative.
The chest CT scan documented a slightly increased size of the mass, with more increased extent of the central low density compared with the previous chest CT and no mediastinal or hilar lymphadenopathy (Figure 2). The patient declined bronchoscopy and therefore, percutaneous fine needle aspiration was performed. Only blood without pus was aspirated and the results of aspirates were negative for routine bacterial Gram's stain and culture, including acid-fast bacilli and fungi, thus ruling out infectious process.
To define the exact etiology of the radiologic findings, thoracoscopic wedge biopsy of the left lower lobe demonstrated the mass to be contained within the lateral basal segment and the medial basal segment of the left lower lobe. On gross section, the mass was 10x9x7 cm in size, sharply circumscribed and smoothly contoured. It had no involvement to the chest wall and no endobronchial component, but extended centrally to hilar areas. Light microscopic examination demonstrated a tumor composed of malignant epithelial components and mesenchymal components. The carcinomatous components consisted of poorly differentiated squamous cell carcinoma and the sarcomatous components were considered chondroid sarcoma in the light of microscopic findings (Figure 3). Light microscopic immunohistochemical analysis showed that the tumor cells in the carcinomatous component reacted with anti-epithelial membrane antigen (EMA) antibody and the tumor cells in the sarcomatous component reacted with anti-vimentin antibody (Figure 4). He underwent workup for distant metastasis, the findings of which were unremarkable. Therefore, left lower lobectomy was performed with lymph node dissection. There was no microscopic evidence of lymph node metastases making this the international TNM stage lb (T2N0M0) lesion.
After surgical resection, mild fever and blood-tinged sputum disappeared. His postoperative course was uneventful without major complication. At 6-month follow-up, there remains no evidence of metastasis or tumor recurrence | null | The chest CT shows a large cystic mass with central low density and no mediastinal or hilar lymphadenopathy. |
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PMC5389975_03 | Male | 5 | White male, born in 2001, a full sibling of Case 2. BCG-vaccinated during the first month of life. At age 4 months, he had regional suppurative adenitis ipsilateral to the BCG vaccine site and was treated with Isoniazid (10 mg/kg/day) for 6 months with good clinical response. At age 5 years, when his older brother (Case 2) was diagnosed with histoplasmosis, he presented with multiple cervical lymphadenopathies and fever. He was treated with ketoconazole (400 mg/day). Treatment was interrupted 7 months later without recovery. At age 6 years, he was hospitalized with cervical lymphadenopathies and was treated with Amphotericin B without regression. At age 8 years, he was hospitalized with asthenia, anorexia, abdominal pain and cervical adenopathies, and evolved hepatic and splenic enlargements, respiratory distress, persistent fever, pericardial and pleural collections and splenic abscess, which demanded drainage and resection, respectively. Laboratory studies showed leukocytosis (26,900 cells/mm3; 14% bands, 80% segments, 5% lymphocytes) with normal platelet count (297,000/mm3), AST (38 U/L), ALT (25 IU/L), AP (342 IU/L), and altered albumin (2.30 g/dL), globulin (3.60 g/dL); total bilirubin (7.80 mg/dL); and direct bilirubin (6.60 mg/dL). The Wade, PAS and Giemsa stains of lymph nodes and spleen were negative. The PAS and Wade stains of the pericardial membrane were negative. The culture of bone marrow aspirate was positive for Salmonella choleraesuis. Besides antibacterial therapy (40 mg/kg/day of Vancomycin and 30 mg/kg/day of Meropenem), Rifampin (10 mg/kg/day), Isoniazid (10 mg/kg/day), and Pyrazinamide (20 mg/kg/day) were administered due to polyserositis and the unconfirmed possibility of household contacts with tuberculosis. Immunological evaluation revealed: hyper-IgE (902 and 2,848 IU/mL (RV at 87 IU/ml) in two separate evaluations as well as elevated values for IgG = 3,150 mg/dL (RV: 572-1,474), IgA = 943 mg/dL (RV: 34-305), IgM = 223 mg/dL (RV: 32-208), and T cell markers (CD4 = 955 cells/mm3 (17%), CD8 = 1,348 cells/mm3 (24%), CD4/CD8 = 0.7. Three months after suspension of the tuberculostatics, there was a recrudescence of cervical lymphadenopathy with fistulization despite the absence of fever and inflammatory signs. Cultures of ganglion aspirate were negative for bacteria, acid-fast bacilli, and fungi. Histopathology of cervical lymph nodes was negative for intracellular microbes. He received experimental treatment with Trimethoprim/Sulfamethoxazole for 5 months with complete recovery and prophylaxis with the same medication for 6 months. After the interruption of prophylaxis, he developed a left infracostal large abscess (Figure 1C), which was drained and found negative on culture. He was empirically prescribed with Ciprofloxacin (40 mg/kg/day) for Salmonella and Clarithromycin (15 mg/kg/day) for mycobacteria for 6 months. He is currently on prophylaxis with Trimethoprim/Sulfamethoxazole and is free of symptoms. | ifn-γ, il-12rβ1 deficiency, mendelian susceptibility to mycobacterial diseases, founder stop-gain mutation, impaired receptor, signal peptide | Not supported with pagination yet | null |
PMC8260863_01 | Male | 16 | A 16 year old male with a history of hereditary haemorrhagic telangiectasia presented initially to an outpatient clinic with nine months of progressive exertional nausea and dry heaving. Symptoms were most severe after intense exercise. The physical exam was unremarkable and no superficial abdominal collaterals were seen. Cardiology and allergy and immunology consultants attributed the symptoms to motion sickness. Stress echocardiogram and interrogated labs were unrevealing. The patient was given antihistamines with poor relief of symptoms.
Two years later while playing basketball, the patient re-presented to an outside hospital with sudden onset of nausea, back pain, and bilateral calf pain and swelling. Computed tomography (CT) venography demonstrated occlusive DVT bilaterally from the common iliac to the popliteal veins. The infrahepatic IVC was not visualised and replaced with collateral veins. Hypercoagulability workup was negative and the patient did not have a history of DVT. The patient underwent catheter directed thrombolysis and mechanical thrombectomy with improved symptoms and was discharged on anticoagulants. However, he was re-admitted within 24 hours with recurrent bilateral iliofemoral vein thrombosis and worsening lower extremity pain and oedema. He was transferred to the present authors' institution for further management.
Pre-intervention CT venogram confirmed extensive lower extremity DVT, partial absence of the intrahepatic IVC, complete absence of infrahepatic IVC, and dilated thrombosed paraspinal collateral veins draining into enlarged azygos and hemiazygous veins (Fig. 1). The patient was taken to the interventional radiology suite daily for three consecutive days.
On the first day, bilateral lower extremity venography was performed via posterior tibial vein access, demonstrating a clot burden from the bilateral posterior tibial veins to the common iliac veins (CIVs) (Fig. 2A). The IVC was not visualised from the confluence of the CIVs and no significant abdominopelvic collaterals were identified (Fig. 2B). Mechanical thrombectomy with Angiojet (Boston Scientific, Marlborough, MA, USA) was performed bilaterally in the iliac, femoral, popliteal, and posterior tibial veins with marginal success. Cragg-McNamara infusion catheters (Medtronic, Minneapolis, MN, USA) were placed bilaterally, terminating at the confluence of the CIVs, and tPA was infused at 0.5 mg/h in each catheter for 24 hours.
On the second day, repeat venography demonstrated near complete resolution of thrombus throughout both lower extremities and the outflow azygos vein (Fig. 3A). Within 10 minutes of terminating tPA, there was re-thrombosis of the azygos and CIVs (Fig. 3B). Thus, infusion catheters were again placed and tPA infusion was restarted. Given the rapid re-thrombosis, the patient agreed to an attempt at IVC reconstruction to restore venous outflow.
On the third day under general anaesthesia and with the patient in the supine position, venography of the proximal intrahepatic IVC was performed via a right internal jugular vein access, demonstrating complete occlusion of the infrahepatic and distal intrahepatic IVC (Fig. 4A). Venography was performed at the confluence of the CIVs via bilateral common femoral vein access, revealing a small remnant of the IVC (Fig. 4B). Recanalisation of the IVC was performed through this diminutive stub in a caudal to cranial direction using a variety of sharp recanalisation techniques, including a 16 gauge Colapinto needle (Cook Medical, Bloomington, In, USA), back end of a 0.035 Amplatz Super Stiff guidewire (Boston Scientific), and 9 and 12 French vascular sheath dilators as bougies. The atretic IVC was traversed from both the right internal jugular vein and common femoral vein accesses using a 0.035 Roadrunner wire (Cook Medical) and 0.035 Quick-Cross catheter (Spectranetics, Colorado Springs, CO, USA). The right renal vein was catheterised and venography was performed, confirming that the recanalised vessel was the IVC (Fig. 4C). A snare was used to gain body floss access and venoplasty of the atretic IVC was performed from the confluence of the CIVs to the infrahepatic IVC with a 10 mm balloon. Intravascular ultrasound (IVUS) was performed from the right atrium down through the IVC and bilateral common and external iliac veins, revealing extensive synechiae within the IVC and bilateral common and external iliac veins. Venoplasty with 16 mm and 24 mm balloons was performed in the IVC followed by repeat venography and IVUS that showed a reduction in synechiae and venous collaterals with significant recoil throughout the atretic IVC. Two overlapping 24 mm x 70 mm Wallstents (Boston Scientific) were placed in the recanalised IVC, starting in the intrahepatic IVC down to the iliac confluence. These were dilated to 24 mm and repeat venography and IVUS was performed. Two kissing 18 mm x 90 mm Wallstents were placed starting at the caudal aspect of the inferior 24 mm Wallstent and ending in each CIV. The IVC end of the 18 mm Wallstents was dilated to 14 mm and the common iliac end was dilated to 16 mm (Fig. 4D and E). Final venography and IVUS demonstrated a widely patent reconstructed IVC with good wall apposition of the stents (Fig. 4F and G).
The patient was discharged on post-operative day four on enoxaparin 80 mg SC BID (1 mg/kg), and clopidogrel 75 mg PO daily for one month. At the one month clinic visit, CT venography demonstrated a patent reconstructed IVC and bilateral iliac veins (Fig. 5, Supplemental Video 1). The patient was transitioned to lifelong apixaban 5 mg PO BID and aspirin 81 mg PO daily. He reported complete resolution of exertional nausea and denied lower extremity pain or swelling at the one and seven month post-procedural clinic visits and remains asymptomatic at 2.5 years of follow up. The patient will be seen annually going forward. | deep venous thrombosis, endovascular intervention, ivc agenesis, ivc atresia, ivc reconstruction, post thrombotic syndrome | Not supported with pagination yet | null |
PMC5735603_01 | Female | 27 | We report the case of a 27-year-old pregnant woman, gravida 3 para 2, who was presented to the maternity emergency unit of Princess Christian Maternity Hospital (PCMH) in Freetown at term in labor. The patient was referred from a health center for prolonged labor and arrest of descent at complete cervical dilatation despite being in active labor for the past 9 hours. She was an illiterate street trader. In terms of past obstetric history, there was a spontaneous vaginal delivery (SVD) at term of a healthy live born boy and a fresh stillbirth at term for an unknown reason. During this present pregnancy, she did not make any antenatal care visit. Therefore, blood pressure levels during pregnancy were undocumented and no obstetric ultrasound examination was performed. Her last menstrual date was unknown. Other relevant risk factors, such as gestational diabetes and infectious diseases, were also not known or documented.
Upon admission, the patient was awake and orientated and presented the following vital signs: blood pressure of 180/120 mmHg and a protein value of 3+ on urine dipstick test. Clinical examination revealed anasarca and hyperreflexia and a gravid abdomen with assumed term pregnancy and assumed singleton. The cervix was fully dilated with dystocia of labor; the presentation was cephalic. On auscultation with Pinard stethoscope, fetal heartbeat was absent. Ultrasound was not available. The findings led to the admission diagnosis of "obstructed labor with intrauterine fetal death (IUFD) and preeclampsia."
The patient was admitted to the eclamptic ward to be stabilized, and application of Hydralazine 5 mg (i.v.) every 20 minutes under close blood pressure monitoring was performed.
Under spontaneous progression of labor (no application of oxytocin), the patient was transferred to the labor ward, where one head of the yet unknown conjoined twin was born. Even though blood pressure was controlled (140/95 mmHg), the patient developed eclamptic fits. Ceasing of seizures was achieved after implementing the loading dose of the MgSO4 protocol.
The consultant obstetrician was now involved, and a new clinical assessment revealed a somnolent patient that was now stable, reflexes were low, and the blood pressure was controlled: 140/95 mmHg. The fundal height corresponded to term; there were no adequate contractions, and the fetal heart was absent. On vaginal examination, the presentation was left occiput posterior with stuck fetal head and a turtleneck phenomenon. With regard to the unknown presence of conjoined twins, the diagnosis of obstructed labor (suspicion of shoulder dystocia) and IUFD was confirmed and eclampsia was added. In an attempt to deliver the shoulders, manual extraction of both arms was performed as follows: reaching up along the dorsal shoulder blade, sweeping the humerus down, and thereby bringing the left arm out of the vagina. The same procedure was performed at the anterior shoulder for the right arm (Figure 1). Since shoulders were still not following and due to the unordinary presentation of the fetus, a second deep vaginal examination along the fetus' back was done, and further membranes were discovered. This led to the sudden and unexpected diagnosis of conjoined twins.
An emergency cesarean section under general anesthesia via a longitudinal midline incision was performed immediately. The fetus was extracted by breech, whilst the born head was repositioned vaginally by a midwife (Figure 2). External inspection of the conjoined twins after surgery revealed a female thoracopagus type that seemed to involve the heart (Figure 3). Apgar score (Appearance, Pulse, Grimace, Activity, and Respiration) was 0/0/0, and pH was generally not available. The gestational age was estimated to be about 37-39 weeks of gestation.
The MgSO4 protocol was maintained further for 48 hours, and the antihypertensive therapy was continued with Hydralazine and later changed to 3 x 20 mg Nifedipine orally. The patient was kept under close monitoring of blood pressure, reflexes, respiration rate, and input-output evaluation.
During the postpartum period, there was no reappearance of seizures, and the anasarca disappeared fully. In the absence of proper laboratory facilities, no parameters concerning the hepatic or renal status could be done. Oral antihypertensive therapy was maintained for 6 weeks. On the control visit after 8 weeks, the patient was clinically fully recovered. | null | Not supported with pagination yet | null |
PMC10315653_01 | Male | 63 | A 63-year-old man was admitted to Xiang'an Hospital of Xiamen University, Xiamen, China, for hepatitis on August 17, 2019. Five months before presentation, his physical examination yielded abnormally elevated transaminase levels ( Figure 1A ); yet, the patient reported no fatigue, anorexia, jaundice, or abdominal pain. Afterward, the patient received oral bicyclol tablets and compound glutathione for hepatoprotective treatment, but his transaminase levels continued to fluctuate above the normal level. The patient visited Xiang'an Hospital of Xiamen University for further diagnosis and treatment at this point.
The patient underwent surgical treatment for tuberculosis of the lumbar transverse process in 1984. After that, he received regular anti-tuberculosis treatment for 1 year and healed well afterward. In 2015, he underwent laparoscopic cholecystectomy due to cholecystitis. Hepatitis B was diagnosed in the same year, with normal transaminase levels, and the patient was diagnosed as being anti-HBe positive at this time ( Figure 1A , Table S1 ), indicating an inactive phase of chronic hepatitis B (CHB) infection. The patient was not treated with antiviral therapy and was followed up regularly. Anti-HBs seroconversion and clearance of serum HBsAg occurred during follow-up. HBV DNA tests were negative when abnormal liver function was found upon physical examination five months before admission(March 2019). The patient had no history of autoimmune disease and denied receiving immunosuppressive drugs. The patient, however, had traveled abroad several times, including the Philippines sixteen months before admission (April 2018), Singapore and Malaysia eight months before admission (November 2018),and Nepal three months before admission (May 2019).
After being admitted to Xiang'an hospital, the patient tested positive for anti-HEV IgM, and both serum and stool samples were positive for HEV RNA. The patient was diagnosed as being in the inactive phase of CHB and being superinfected with hepatitis E. Diagnostic test results for infectious diseases including hepatitis A, C, D and G, HIV, liver fluke, and plasmodium were all negative ( Tables S2 , S3 ). Diagnostic test results for liver-related autoantibodies, including anti-nuclear antibody, anti-mitochondrial antibody, and anti-smooth muscle antibody, were negative, and ceruloplasmin was within the normal range ( Table S2 ). His routine blood tests at admission showed a normal white blood cell count (WBC, 8.75 x 109/L), neutrophilic granulocyte count (NEU, 3.23 x 109/L), lymphocyte count (LYM, 3.87 x 109/L), and monocyte count (MON, 0.51 x 109/L) and a slightly increased basophilic granulocyte count (EOS, 1.07 x 109/L; Tables S2 , S4 ). The serum total IgM, IgG, IgA, and complement (C3 and C4) were all within the normal ranges ( Table S2 ). His CD3+ T cell count (1343/microL), CD4+ T cell count (555/microL), CD8+ T cell count (591/microL), and CD4/CD8 ratio (0.94) were also within the normal ranges, indicating that the patient showed no evidence for immune deficiency ( Table S2 ).
After the patient was admitted to Xiang'an hospital, his serum, feces, and urine samples were continuously collected for serological testing by ELISA and qRT-PCR ( Figure 1B ). Liver enzymes, including alanine aminotransferase (ALT), aspartate aminotransferases (AST), and glutamyl transpeptidase (GGT), fluctuated more than the normal range after admission, while the patient exhibited normal liver function four years (October 2015) and one year (July 2018) before admission ( Figure 1A ), indicating that his hepatitis was derived from HEV infection. HEV RNA was detected in the serum and feces of the patient at a titer above 105 IU/mL and 107 IU/mL, respectively. The patient was diagnosed with chronic hepatitis E as the patient's HEV RNA lasted for more than 6 months ( Figure 1B ). Therefore, treatment with 900 mg/d ribavirin was initiated on 170th day after admission (February 4, 2020). Subsequently, 600 mg/d of ribavirin combined with 180 microg/w of PEG-IFN was initiated three months later (April 27,2020). The transaminase and GGT levels returned to normal after 2 and 4 weeks of ribavirin treatment, respectively, indicating the recovery of the patient's liver function. Serum HEV RNA decreased below the detectable limit after 6 weeks of ribavirin treatment, while fecal HEV shedding persisted for more than 12 weeks after the start of ribavirin therapy. HEV antigen (Ag) levels in the serum and urine decreased after this treatment, consistent with the declining trend of viral RNA.
Liver puncture biopsy was performed two months after being admitted (October 2019), and this revealed the chronic active hepatitis with mild inflammation (METAVIR A1) and moderate fibrosis (METAVIR F1) ( Figure 2 ). Regional watery degeneration of liver cells, fatty degeneration of partial liver cells, scattered focal necrosis, and apoptotic bodies were all observed. ( Figure 2A ). An incomplete liver plate in the portal area was observed, with the reticular fibers proliferating and extending to the lobules, suggesting mild hyperplasia of fibrous tissue ( Figure 2B ). Immunohistochemical staining revealed scattered HBsAg positive cells ( Figure 2D ), whereas HBcAg tests were negative ( Figure S1 ). Widely distributed HEV Ag was detectable in the liver using a mouse anti-HEV capsid protein antibody (mAb #4, Figure 2C ), indicating chronic HBV superinfected with HEV.
Complete genome sequencing of HEV isolates from the patient's stool specimens at several distinct dates was performed, and three genome sequences (Genbank accession OQ801358, OQ801359, OQ801360) were successfully identified. Sequencing showed that the three hepatitis E virus strains belonged to genotype 3a, which was consistent at different sampling time ( Figure 3 ). Sequence similarity analysis of the HEV whole genome showed that these isolates were the most identical to the variant KT447526, with 97.0% similarity. Zhu et al. described that the HEV genotype 3a National University Hospital (NUH) clade represented by KT447526 and KT227528 was an endemic local lineage of HEV in Singapore. Given the fact that the patient had traveled to Singapore and that his ALT and AST levels were normal a few months before going abroad thirteen months before presentation (July 2018) ( Figure 1A ), we proposed that the patient was infected with HEV in Singapore in eight months before admission into Xiang'an hospital (November 2018).
We also tested the virulence of this HEV strain ( Figure S2 ). This strain exhibited stronger infectivity to cells in vitro than the virus isolated from an acute patient but had comparable infectivity to a strain isolated from another chronic patient. It is possible that the strain isolated from the chronic patient had replicated in the patient's body and produced adaptive mutations as we found ( Figure S3 ).
We analyzed the levels of 48 cytokines and chemokines in the patient's plasma. The patient showed type-2 (anti-helminths) immune responses, with an elevation of the type-2 antibody isotype IgE and the hallmark type-2 cytokine IL-5, which is produced by Th2 cells and ILC2s and is the most potent activator of eosinophils ( Figures 4 , S4 ). To test whether the patient was infected with helminths, we performed eukaryotic 18S ribosome amplicon and metagenome sequencing with blood samples and intestinal samples, but no parasitic pathogen was found (data not shown). Biomarkers for atopic dermatitis, including CTACK (strong correlation), IL-18 (strong correlation), and IgE (moderate correlation), were also increased, although the patient had no obvious clinical manifestations of atopic dermatitis. Moreover, the patient showed high serum total IgE at admission. Sustained higher eosinophil levels in the blood of the patient were observed as early as 2015 ( Figure 4A ); then, elevated eosinophils were confirmed by bone marrow examination four months after presentation (December, 2019) ( Table S5 ).
The patient showed decreasing serum anti-HEV IgG titer over time from over 30 WHO unit per mL (Wu/mL) before treatment to around 10 Wu/mL, along with reducing viral shedding, after four months of antiviral therapy ( Figure 4D ). The patient also exhibited a notably higher anti-HEV IgG level compared to individuals who were vaccinated with Hecolin and other acute HE patients and a medium range of IgG avidity ( Figure S5 ). The patient showed remarkably high neutralizing capacity with 50% inhibitory dose (ID50) values up to 16,634, in comparison to acute HE patients ( Figure S5C ). The patient's serum neutralizing activity also decreased over time, which was consistent with the patient's anti-HEV IgG level. In order to detect which epitopes antibody recognized were induced after chronic infection of hepatitis E virus, we employed competitive ELISA using a panel of murine mAbs that targeting diverse antigenic clusters on the capsid protein as previously described. The patient serum HEV specific antibodies predominantly recognize 8G12-like epitope ( Figure S5D ). When compared to acute hepatitis E patients, antibodies recognizing 8C11-like epitope and 8E1-epitope were relatively less dominant in chronic patient serum. These results are consistent with the predominant type of epitopes recognized by antibodies in sera from acutely infected individuals. To test for the generation of anti-HEV specific T-cell responses following infection, samples of the patient's PBMCs were collected. We stimulated PBMCs from the patient and two anti-HEV IgG negative controls with peptides derived from ORF1, ORF2, and ORF3 of HEV ( Table S6 ). HEV specific T-cell responses were detected in the patient's PBMCs, and these presented a slightly decreasing tendency but were significantly higher compared to HEV-negative controls ( Figure 4E ), indicating a mild to moderate T cell responses to HEV in the chronic HE patient. The T cell response was consistent with the patient's HEV RNA titer and IgG levels. The overview of the case's diagnosis, treatment, and follow-up process and timelines of major clinical events are summarized in Figure S6 . | chronic hepatitis b, chronic hepatitis e, hepatitis e virus, immunocompetent, travel-related | Not supported with pagination yet | null |
PMC9065430_01 | Male | 44 | A 44 years old, Saudi male, married, ex-smoker for 4 years, with a smoking index of 10 packs/year. He has Type 2 diabetes for 10 years and takes basal insulin, metformin and sitagliptin. He has dyslipidemia on statins and vitamin D deficiency.
He had a productive cough for 2 weeks with large quantities of odorless yellow sputum, with intermittent pain in the left shoulder for 3 days. He denied fever, dyspnea, hemoptysis, or diarrhea. He denied any history of choking or dental caries.
The general examination was unremarkable. Local chest examination was positive for dullness in the left upper chest with fine inspiratory rales.
Chest x-ray showed opacity in the left hilum and para-hilar area (Fig. 1a). CT chest without contrast showed a soft tissue mass in the left upper lobe (lingual) with central necrosis (Fig. 2a, b).
Since he is diabetic and pulmonary tuberculosis is relatively common in our area, he was admitted to a negative pressure isolation room until tuberculosis can be confirmed or ruled out.
He was treated with intravenous amoxicillin and clavulanic acid as a case of pulmonary abscess and further investigations were performed. Sputum for acid fast bacilli 3 samples by stain and polymerase chain reaction were negative for tuberculosis as well as sputum Grams stain and culture were negative. The situation improved at first, as the chest pain subsided and the sputum became less and whiter. He was discharged after 3 days on oral co-amoxclave and ordered to follow up in the clinic after 10 days.
After a week he came for follow-up, complaining only of hemoptysis, a small amount of bloody sputum, with no other symptoms. Subsequent chest radiograph revealed persistent opacity of the left upper lobe and CT thorax showed 2.2 x 2.5 cm subpleural cavitary nodules in the left upper lobe/lingula associated with an adjacent area of patchy languor, minimal interlobular septal thickening, and tree-in-bud nodules (Fig. 2c, d).
He underwent a CT guided lung biopsy to diagnose the etiology, possibly lung cancer, and the procedure was performed as a day case under local anesthesia without complications (Fig. 2e)
A diagnosis of inflammatory myofibroblastic tumor of the lung was rendered based on histopathology evaluation and a panel of immunohistochemistry stains (Fig. 3a-e).
Sections of the tumor sampled in the core biopsy revealed spindle cells in a background of abundant mixed inflammatory infiltrate rich in plasma cells, lymphocytes, and few eosinophils. The spindle cells are arranged in fascicles. The immunohistochemistry stains revealed that the spindle cells were positive for Actin. They are negative for pankeratin, S100, CD68 and Alk1. The plasma cells in the background are proven to be polyclonal using Kappa and Lambda immunohistochemistry staining.
A follow-up CT thorax with contrast was performed to assess the size of the mass, other lung areas, and the mediastinum preoperatively (Fig. 2-f).
A multidisciplinary team of pulmonology, oncology, thoracic surgery, and radiology was consulted and the decision was made to perform a surgical resection with a safety margin and rapid incision. A limited left thoracotomy was performed and a wedge resection with safety margin was performed. The resected lung lesion was confirmed by histopathological and immunohistochemical examinations as IMT of the lung. | inflammatory myofibroblastic tumor, lung cavity, lung mass | Not supported with pagination yet | null |
PMC7499122_01 | Male | 50 | The patient was a 50-year-old Chinese man who was diagnosed with hypertension at the age of 42 years. The patient was treated with felodipine alone after he was diagnosed with hypertension, and his blood pressure was ~140-150/90-100 mmHg with felodipine treatment. Approximately 1 month earlier, he felt dizzy and his self-measured blood pressure was found to be 190/120 mmHg. He went to the hospital and was prescribed nifedipine 30 mg three times a day, irbesartan hydrochlorothiazide (150 mg/12.5 mg) one tablet twice a day and, metoprolol 47.5 mg/day. He occasionally measured his blood pressure, which was ~130-150/80-90 mmHg.
The patient had type 2 diabetes mellitus for 6 years, and he currently took gliclazide 30 mg/d and metformin 500 mg twice a day. He was diagnosed with tuberculosis 2 months earlier. Since then, he was regularly taking ethambutol 750 mg/day, isoniazid 100 mg/day, and rifapentine 600 mg twice a day.
Due to his severe hypertension, he was referred to the endocrinology department. The laboratory test showed hypokalemia of 3.1 mmol/L (reference: 3.5-5.5 mmol/L). Two weeks after changing his antihypertensive therapy to nifedipine-controlled released tablet 30 mg/day and doxazosin 4 mg/day, laboratory tests showed a high plasma aldosterone concentration (PAC) of 17.4 ng/dl (to convert to pmol/L, multiply by 27.74), a low plasma renin concentration (PRC) of 4.2 mIU/l (to convert to pmol/L, multiply by 0.0375), and a high aldosterone/renin ratio (ARR) of 41 (ng/dl)/(mIU/l) (reference <2.0) (Table 1), which suggested PA. The saline infusion test and the captopril challenge test (Table 1) confirmed the diagnosis of PA. Adrenal computed tomography (CT) was performed, and a right adrenal nodule (13 mm in diameter) with low density was identified (Figure 1).
Physical examination revealed no full moon face, no centripetal obesity, and no skin purple skin striae. His 24-h urine-free cortisol, plasma cortisol, and plasma adrenocorticotropic hormone levels were normal (Table 1). However, 1 mg overnight and 2 mg/d for 48 h DST yielded positive results (>138 nmol/l). Plasma cortisol levels at 8 a.m. after 1 and 2 mg dexamethasone administration were 218.7 and 384.5 nmol/l, respectively (Table 1). Because some patients with Cushing's syndrome have inconsistent 24-h urine-free cortisol and DST results, subclinical Cushing's syndrome was considered in this patient, although his 24-h urine-free cortisol was not high. According to the guideline, patients younger than 35 years, with spontaneous hypokalemia, marked excess aldosterone, and unilateral adrenal lesions with radiological features consistent with a cortical adenoma on adrenal CT scan may not need adrenal vein sampling before proceeding to unilateral adrenalectomy. For this patient, given PAC and PRC levels as well as his age, adrenal venous sampling was strongly recommended but the patient refused. Laparoscopic total right adrenalectomy was performed. Three nodules were found in the right adrenal resection specimen, and only the largest nodule was observed by CT (Figure 1). Histology showed clear cells with vacuolated cytoplasm. Immunohistochemical staining for the enzymes involved in aldosterone (CYP11B2) and cortisol (CYP11B1) (Figure 2) biosynthesis suggested that all the three nodules secreted aldosterone, whereas none of them secreted cortisol. KCNJ5 mutations were found in two of the three nodules, whereas no PRKACA mutations were found (Figure 3).
One month after surgery, the patient's serum potassium was normal. The PAC decreased to 3.9 ng/dl and PRC increased to 9.2 mIU/L, resulting in a normal ARR, 0.4 (ng/dl)/(mIU/l) (Table 2). However, the patient was still found with resistant hypertension. Despite administration of nifedipine-controlled released tablet 30 mg twice a day, irbesartan hydrochlorothiazide (150 mg/12.5 mg) one tablet twice a day, and metoprolol 47.5 mg/day, his blood pressure was remained uncontrolled. In addition, 1 mg overnight DST yielded positive results (with 8 a.m. plasma cortisol levels of 369.8 nmol/l after administration of 1 mg dexamethasone). This situation disturbed the patients, and we discussed the possible cause with him. Rifapentine-induced false positive in DST as well as uncontrolled blood pressure was considered. Two months after he completed the tuberculosis treatment, 1 mg overnight DST results were negative (8 a.m. plasma cortisol levels of 29.8 nmol/l after administration of 1 mg dexamethasone). His blood pressure was well-controlled with nifedipine alone (30 mg/day). Finally, the patient was diagnosed with right APA and, he was satisfied with the treatment effect.
Informed consent was obtained from the patient for publication of the case report and accompanying images. | dexamethasone suppression tests, hypercortisolism, hypertension, primary aldosteronism, rifapentine | Not supported with pagination yet | null |
PMC4647119_01 | Male | 51 | A 51-year-old male presented with right facial pain of 2-years duration with no significant medical history. Atfirst, it was treated as a dental condition and multiple maxillary tooth extractions were performed to relive the pain. After dental treatment, the pain persisted and the patient was then diagnosed as having trigeminal neuralgia. The patient developed nocturnal right epistaxis of 6 months duration and, consequently, was referred to the Ear Nose and Throat (ENT) clinic for consultation. Nasofibroscopy was performed, which revealed a purple tumor occupying almost the entire right nostril. The left nostril was intact. CT and MRI imaging studies were performed to identify the nature of the mass.
CT imaging revealed a large expansive and infiltrative process involving the right nasal cavity, maxillary, sphenoidal, and ethmoidal sinuses [Figure 1]. The mass crossed the sphenopalatine foramen and extended to the pterygopalatine and pterygomaxillary fossa. The lesion also involved the inferior orbital fissure and oval foramen, reaching the ipsilateral parasellar region. At its largest diameter, the lesion measured 6 cm. There was moderate enhancement post intravenous administration. There was no evidence of regional lymphadenopathy.
Post intravenous contrast administration, MRI revealed a hyperintense soft tissue expansive process and intracranial invasion of the middle temporal fossa involving the cavernous sinuses [Figure 2]. The mass covered the major sphenoidal fissure involving the eyeball muscles, infiltrating the extra-conal orbital floor and showed PNS through maxillary nerve (CN V2) in the infraorbital foramen.
Following the results of the imaging studies, incisional biopsy was recommended confirming a "fragment of nasal adenoid cystic carcinoma" [Figure 3]. Based on the size and intracranial invasion of the tumor, the Head and Neck Tumor Board (HNTB) recommended palliative chemo-radiation therapy. Currently, the patient remains in treatment without any complications. | adenoid, carcinoma, computer tomography, cystic, magnetic resonance imaging, perineural, radiochemotherapy, spread | Not supported with pagination yet | null |
PMC5466596_01 | Male | 63 | A 63 year old man working as a salesman was referred to the respiratory team for clinical management of his progressive shortness of breath and deteriorating exercise tolerance that significantly worsened over the last 12 months. In terms of medical history, he mentioned an occasional left-sided pleuritic chest pain with no other exercise related pain, no peripheral swelling, no weight loss and no night sweats. He suffered for one episode of spontaneous pneumothorax on each side during the last year which was treated conservatively. He also mentioned diet controlled diabetes and hypercholesterolemia managed with Simvastatin. He is a non-smoker, he denied exposure to birds or pets, he does not have any allergies and he has no history of tuberculosis. With reference to the family history, his sister passed away from pulmonary alveolar microlithiasis at the age of 54. His 37 year old daughter is treated for hypertension and hypercholesterolemia with no evidence of lung disease. No information was available in regards of his parents. On physical examination, there were marked discrete inspiratory crackles, cyanosis and digital clubbing, while all laboratory investigations were within normal limits. His chest X-ray (Fig. 1) was suggestive of extensive interstitial bilateral lung disease and the differential diagnosis was suggested to be either a microlithiasis or an atypical infection. A high resolution computed tomography (HRCT) (Fig. 2) of the chest was performed and revealed several calcifications throughout the parenchyma, ground-glass opacities, sub-pleural cystic changes and calcified interlobular septa. Considering the findings on the CT scan, his case was discussed in our multidisciplinary meeting and patient was referred to our Department for surgical lung biopsy. After written consent was obtained from the patient, a right uniportal VATS biopsy of the lung was performed. The right lung was diffusely involved and the parenchyma was thickened with occasional superficial bulla. The postoperative course was unremarkable and the patient was discharged in stable condition on the 2nd postoperative day.
Subsequent histological examination of the specimens was performed. Section showed lung parenchyma with marked sub-pleural and interstitial fibrosis and patchy chronic inflammation. The alveolar spaces were filled with numerous calcified bodies which showed concentric lamination and radial striations (Fig. 3, Fig. 4). Microliths were also present within the areas of fibrosis (Fig. 5, Fig. 6). There was no evidence of atypia or malignancy. The diagnosis of pulmonary alveolar microlithiasis was made considering the histological features and the radiological image. Regarding the treatment plan, during a multidisciplinary meeting the conservative approach was decided with a re-evaluation period of 6 months. The option of lung transplantation was rejected due to patients' age. | genetic interstitial lung disease, pulmonary alveolar microlithiasis, vats biopsy | Not supported with pagination yet | null |
PMC4192926_01 | Male | 71 | A 71-year-old male with a past medical history of kidney transplant on immunosuppressive therapy, diabetes, and hypertension presented to the hospital with a 1-day history of headache, nausea, and vomiting. On physical examination, the patient had no focal neurological symptoms, and normal blood pressure. Initial laboratory reports showed an unremarkable cell blood count. Basic metabolic panel, liver function tests, and coagulation panel parameters were all within normal limits. Blood cultures and urine analysis were both negative. Prior purified protein derivative (PPD) tuberculin test and human immunodeficiency virus (HIV) results were negative.
Chest X-ray demonstrated a stable right upper lobe cavitary lesion that had been biopsied twice previously with nondiagnostic results. A head computer tomography (CT) was obtained, which demonstrated a cystic mass in the left cerebellum with perilesional edema [Figure 1]. Further evaluation with contrast enhanced MRI was performed that showed a well circumscribed left cerebellar hemisphere ring enhancing mass on T1 sequences with restricted diffusion, mass effect, and perilesional edema [Figure 1]. Differential diagnosis included pyogenic abscess (bacterial or fungal), neurocysticercosis, cystic glioma, or other cystic malignant/metastatic process.
The patient underwent a left posterior fossa biopsy and drainage. The lesion was well encapsulated with a frankly purulent center. Numerous acid fast bacilli were seen on acid fast stain, and cultures returned positive for mycobacterium tuberculosis [Figure 2]. Cerebrospinal fluid (CSF) cultures were also obtained, which were negative. Microbiology revealed pan sensitive mycobacterium tuberculosis and the patient was started on rifampicin, isoniazid, pyrazinamide, ethambutol (RIPE), and B6.
Follow-up MRIs were obtained 1, 4, 9, 11, and 14 months [Figures 3 and 4]. During this time, the patient was seen monthly, and had continued to show clinical improvement with treatment. After 6 months, ethambutol had been removed from the treatment regimen. Treatment with rifampicin, isoniazid, and pyrazinamide was continued in order to maximize CNS penetration, and it was noted on the 9-month MRI that the tuberculosis abscess had grown in size from 2.0 x 2.0 x 2.2 to 2.5 x 3.3 x 2.3 cm [Figure 3]. While the abscess had grown in size at 9 months, the amount of perilesional edema had decreased [Figure 4b]. At this time the patient's neurologic examination and symptoms were stable, and given the continued clinical improvement, and pan sensitive cultures, the drug regimen was not changed. Due to the increase in size, vigilant surveillance with frequent clinic visits was pursued. The 11-month follow up MRI showed that the abscess size was decreased to 1.5 x 2.2 x 1.2 cm, and on month 14, the abscess had nearly resolved [Figure 3]. | central nervous system, cerebellum, tuberculosis abscess | Not supported with pagination yet | null |
PMC10092364_02 | Female | 37 | Patient 13, a 37-year-old woman, developed an abdominal muscle rupture and was found to have an aortic aneurysm (Figure 2b-III) during her high school days, which ruptured at 32 weeks of gestation of her first pregnancy (Table 3). She underwent an aortoplasty following an emergency cesarean section, which saved her life with no sequelae but resulted in severe hypoxic ischemic encephalopathy in her daughter. During her second pregnancy, she was suspected to have vEDS because of skin translucency (Figure 2b-IV) and easy bruising in addition to the previous events. Her cultured skin fibroblasts showed a decreased amount of type III collagen production (29.5% of normal, Figure 3a), whereas mRNA-based direct sequencing of COL3A1 showed no pathogenic variants. She underwent an elective cesarean section at 32 weeks of gestation with no consequences for her or her son. Obstetricians noticed an extreme fragility in her uterine wall during the cesarean. The current NGS-based investigation revealed a heterozygous nonsense variant in COL3A1 (c.848T>A:p.Leu283*), which was not registered in gnomAD or 8.3KJPN. She began celiprolol therapy. Her daughter was bedridden with mild skin translucency and easy bruising, and her son had moderate skin translucency, easy bruising, and several occurrences of muscle rupture while playing football. Both were found to have the variant and her son has begun celiprolol therapy. | col3a1, amplification-based next-generation sequencing, copy number variations, formalin-fixed and paraffin-embedded (ffpe) samples, hereditary connective tissue disorders (hctds), vascular ehlers-danlos syndrome (veds) | Not supported with pagination yet | null |
PMC6292348_01 | Male | 56 | A 56-year-old man with AIDS for four years, non-compliant with his antiretroviral therapy (ART) presented with altered mental status and somnolence for four days. His family reported progressive weakness affecting his ambulation over a period of three weeks. There was no history of sick contacts, recent travel, animal exposure, or illicit drug use. An unintentional weight loss of about twenty pounds over the past four months was also reported. Patient had been started on ART four weeks prior to his hospital admission. Patient's home medications were elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (fixed dose combination), azithromycin and dapsone.
On physical examination, he was cachectic and somnolent, temperature was 97.5 F, blood pressure 112/74 mm Hg, heart rate 95 bpm, respiratory rate 16 with oxygen saturation 98% on room air. EKG showed sinus rhythm with premature atrial complexes and shortened QT interval (corrected 376ms).
Laboratory investigations were significant for normocytic anemia with a hemoglobin of 9.8 g/dL, leukopenia 3.3 x 103/microL, thrombocytopenia 120 x 103/microL, BUN 43 mg/dL (RI 8-20mg/dL), creatinine 2.09 mg/dL (RI 0.4-1.3 mg/dl), corrected calcium 16.49 mg/dL (RI 8.9-10.3 mg/dL), ionized calcium 7.8 mg/dL (RI 4.5-5.6 mg/dL), phosphorus 4.4 mg/dL (RI 2.4-4.7 mg/dL), and albumin 2.6 g/dL (RI 3.5-4.8 g/dL). Other notable initial laboratory findings included 25-hydroxyvitamin D level 56 ng/ml (RI 30-100 ng/ml), 1,25 dihydroxyvitamin D level 44.1 pg/ml (RI 19.9-79.3 pg/ml), parathyroid hormone (PTH) 4 pg/mL (RI 15-65 pg/mL) with PTH-related peptide levels undetectable. Of note, CD4 count was 36/mm3 and viral load was 617,000 before initiation of antiretroviral therapy.
He received intravenous fluids and pamidronate with calcitonin. His serum calcium declined to 9.8 mg/dL (RI 8.9-10.3 mg/dL), kidney function improved with BUN 39mg/dL (RI 8-20mg/dL) and creatinine 1.26 mg/dL (RI 0.4-1.3 mg/dl) by hospital day three. There was improvement in patient's mental status within one day of treatment initiation.
Serum protein electrophoresis revealed monoclonal gammopathy with Free Kappa/Lambda ratio of 1.31 (0.26-1.65) and serum Monoclonal Immunoglobulin (Ig) G was also elevated at 2359. Lactate dehydrogenase level (LDH) was 281 IU/L (RI 98-192 IU/L) and beta-2- microglobulin was 12 mg/L (RI 0.6-2.4mg/L). Whole body skeletal survey revealed no focal uptake. There was no evidence of parenchymal lung disease or mediastinal lymphadenopathy on Computerized Tomography (CT) scan of Chest (Figure 1). CT scan of Abdomen and Pelvis revealed hepatosplenomegaly with large retroperitoneal, retrocrural, and mesenteric lymphadenopathy (Figure 2(a,b)) which had an intense focal uptake on Gallium scan with no abnormal lung uptake (Figure 3). The presence of Monoclonal IgG along with hepatosplenomegaly and retroperitoneal lymphadenopathy, elevated LDH were all strongly suggestive of initial presumptive diagnosis of a lymphoproliferative disease. Lymphoma was strongly suspected and he underwent a bone marrow biopsy and lymph node biopsies twice. Bone marrow biopsy revealed mild plasmacytosis (5%), normocellular marrow (50%) with mature trilineage, no evidence of myelodysplasia, acute leukemia or lymphoma. A subsequent biopsy of the lymph nodes showed fragments of fibrous tissue with lymphohistiocytic infiltrate (Figure 4) and many acid-fast bacilli on special stain (Figure 5). Results of bone marrow biopsy and lymph node biopsy were not consistent with lymphoma which promoted investigation for other causes of hypercalcemia and lymphadenopathy. Mycobacterium tuberculosis and Mycobacterium avium complex Polymerase Chain Reaction (PCR) were also negative. Three sputum samples for acid fast bacilli (AFB) smear were negative.
Patient was initially started on Vancomycin and meropenem for presumed sepsis. As lymph node biopsy smear was positive for AFB; rifabutin, isoniazid, pyrazinamide and ethambutol were commenced as well as azithromycin for tuberculous and nontuberculous mycobacterium pending further identification. Calcium level remained within normal range and his medical condition improved. He was then discharged with medical follow up and continues to show sustained clinical improvement. However, pre-antibiotic blood cultures drawn in a sodium heparin tube subsequently grew Mycobacterium identified by genomic analysis as M. abscessus subspecies abscessus at four weeks. Bone marrow culture remained without any growth. | mycobacterium abscessus, nontuberculous mycobacterium, hypercalcemia, immune reconstitution inflammatory syndrome, retroperitoneal lymphadenopathy | Chest CT scan- Axial view: Normal parenchymal lung tissue without evidence of active chest disease or intrathoracic lymphadenopathy. |
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PMC9114778_01 | Female | 30 | The participant was a 30-year-old female with congenital bilateral limb absence. Both limbs were affected at the wrist disarticulation level. The participant reported use of single degree of freedom, direct control myoelectric prostheses with both limbs for 27 years, as well as right-hand dominance. The study was reviewed and approved by the Institutional Review Board at George Mason University. The participant provided written informed consent to participate in this study, and to include her data and identifiers in publications about the study.
The participant was fitted with thermoplastic test sockets on both residual limbs using supracondylar suspension. The sockets weighed 223 g. A TASKA Hand and Quick Disconnect Wrist (TASKA Prosthetics, Christchurch, New Zealand) and MC Standard Wrist Rotator (Motion Control Inc., Salt Lake City, UT) were mounted to the socket. The left hand was 19.3 cm long and weighed 567 g. The right hand was 20.4 cm long and weighed 680 g. The wrist rotator was 7 cm long and weighed 149 g. The batteries and on/off switch weighed 105 g. The resulting prosthesis was extremely long relative to the participant's height (149.86 cm) and residual limb length (20.5 cm for the right limb and 19.3 cm for the left limb). It was also considerably heavier than the participant's clinically-prescribed myoelectric prostheses, with much of the weight located distally due to the size of the TASKA Hand (Figure 1). The participant reported that the socket alone was well-fitted over the limb, but when the components were attached to the distal end of the socket (i.e., the TASKA Hand, wrist rotator, batteries, and on/off switch), the fit noticeably deteriorated.
A low-profile, high-frequency, linear 16HL7 ultrasound transducer weighing 11 g was mounted on the socket via a custom 3D printed bracket (Figure 1). The transducer was positioned such that it made direct contact with the volar surface of the residual limb when the prosthesis was donned (i.e., over the forearm muscle tissue of the residual limb). We acquired ultrasound images using a clinical ultrasound system (Terason uSmart 3200T, Terason, Burlington, MA) and transferred them to a PC in real-time using a USB-based video grabber (DVI2USB 3.0, Epiphan Systems, Inc., Palo Alto, CA). The video grabber digitized the images at 8 bits/pixel. Using a custom MATLAB script (MathWorks, Natick, MA), we downscaled the ultrasound images to 100 x 140 pixels before processing with a classifier, as described below.
We acquired a set of ultrasound images under various training conditions to be used as training data for a classifier (Table 1). For each acquisition, we instructed the participant to perform a forearm muscle contraction corresponding to a desired hand grasp and maintain this contraction for a specified duration. We also instructed the participant to perform contractions at a comfortable level and allowed her to rest between periods of classifier training to minimize fatigue. Note that the TASKA hand and wrist rotator were not active during classifier training.
We used linear discriminant analysis (LDA) classifiers to predict the user's desired hand grasp from the acquired ultrasound training data. While more complex classification algorithms are possible, LDA classifiers are commonly used for myoelectric control given their simple implementation, strong classification performance, and computational efficiency. As described below, we considered different classifier training strategies to account for changes to arm position and socket loading.
We trained the classifiers to recognize a set of three intended hand grasps: tripod grasp, index finger point, and rest. Any repeatable muscle deformation pattern could be mapped to these intended hand grasps, therefore we asked the participant to choose a set of muscle contractions that would be easiest to perform based on her experience using direct control myoelectric prostheses. The participant had congenital limb absence and could not reliably produce tripod grasp or index finger point, so she instead chose to produce a set of muscle contractions corresponding to wrist flexion, wrist extension, and rest (i.e., a relaxed muscle state). Within the classifiers, we mapped wrist flexion to tripod, wrist extension to point, and rest to rest.
The participant reported a deteriorated socket fit when all the distal components were attached. We therefore conducted classifier training using two separate loading conditions (Figure 1). Under the load A training condition, classifier training was performed with all the distal components attached to the socket (i.e., the TASKA Hand, wrist rotator, batteries, and on/off switch). Under the load B training condition, training was performed without the TASKA hand and wrist rotator attached to the socket. However, in this condition we temporarily attached a weight to the distal end of the socket equal to the weight of the participant's clinically-prescribed prosthetic hand (Transcarpal Hand DMC Plus, Ottobock, Duderstadt, Germany). The attached weight was designed to make the resultant socket length approximately similar to the length of the participant's clinically-prescribed prosthesis. We designed this loading condition to approximate the inertial loading and end-effector distance that the participant normally experiences using her prostheses.
We considered three classifier training strategies to account for changes to arm position during real-world prosthesis use (Figure 2). In the first strategy (i.e., the static training strategy), we recorded training data for the set of hand grasps while the participant held her arm still for 5 seconds in seven different positions. In the second strategy (i.e., the dynamic training strategy), we recorded training data for the set of hand grasps while the participant moved her arm for 5 seconds following four prescribed movement patterns. In the third strategy (i.e., the continuous dynamic training strategy), we recorded training data for a set of hand grasps while the participant moved her arm through all seven positions in a pre-defined 20-sec movement pattern. We chose this approach to minimize the total training time required and to reduce the potential impact of extraneous arm motion between data collection periods.
1) Ipsilateral Countertop: as if reaching for an object located in front of and ipsilateral to the body at waist height
2) Midline Countertop: as if reaching for an object located directly in front of the body at waist height
3) Contralateral Countertop: as if reaching for an object located in front of and contralateral to the body at waist height
4) Ipsilateral Bookshelf: as if reaching for an object located in front of and ipsilateral to the body at head height
5) Midline Bookshelf: as if reaching for an object located directly in front of the body at head height
6) Contralateral Bookshelf: as if reaching for an object located in front of and contralateral to the body at head height
7) Drinking Glass: as if reaching for an object located directly in front of the body at sternum height
We used a naming convention for the seven arm positions and four movement patterns to make it easier for the participant quickly recognize and perform the requested action. The names were selected based on a functional task related to each position or pattern. The seven arm positions for the static training strategy were chosen to cover the majority of the reachable workspace:
To maintain consistency between trials, the positions were defined relative to the participant's anatomy and displayed on a wall in front of the participant at about an arm's length away (Supplementary Figure S1).
1) Countertop Wipe: moving from Contralateral Countertop to Midline Countertop to Ipsilateral Countertop in one fluid motion
2) Lawnmower: moving from Contralateral Countertop to Drinking Glass to Ipsilateral Bookshelf in one fluid motion
3) Sliding Glass Door: moving from Contralateral Bookshelf to Midline Bookshelf to Ipsilateral Bookshelf in one fluid motion
4) Drawing Blinds: moving from Contralateral Bookshelf to Drinking Glass to Ipsilateral Countertop in one fluid motion
The four prescribed movement patterns for the dynamic training strategy were chosen to cover the seven arm positions:
The continuous dynamic training strategy was defined as a combination of the four movement patterns from the dynamic training strategy. However, the direction of the Countertop Wipe and Sliding Glass Door movement patterns were reversed so that the combined patterns could be performed continuously.
Before performing any real-time functional testing of the SMG-controlled prosthetic hand, we first examined the offline performance of classifiers using our different training strategies to account for socket loading and changes in arm positions.
For a given set of training strategies, we collected classifier training and testing data during a single session. Two repeated sets of muscle contractions were collected for the set of hand grasps during each arm position or movement pattern. For example, under the load A training condition using the static training strategy, we collected two sets of ultrasound images over two 5-sec collection periods for muscle contractions corresponding to tripod, point, and rest for each of the seven static arm positions. Note that for our offline testing, we only considered the static and dynamic training strategies and did not consider the continuous dynamic training strategy.
The order of the selected hand grasps and arm positions or movement patterns were randomized. To avoid including any transient motion at the start of the recording, we instructed the participant to assume their initial arm position and then provided two audio cues (i.e., beeps). The first beep notified the participant that their prescribed arm motion would start in 3 seconds (i.e., a preparatory period). The second beep occurred 3 seconds later to notify the participant to initiate the prescribed arm motion (e.g., by holding their arm still for static training sessions or by moving their arm for dynamic training sessions). Ultrasound images were recorded at the end of the preparatory period and continued for 5 seconds, during which the participant maintained the requested muscle contraction. After the data collection session, data for two repeated sets of muscle contractions were randomly assigned as either classifier training data or classifier testing data.
For a given set of training strategies, we built a series of LDA classifiers to predict a user's desired hand grasp from the designated training data. For sessions using the static training strategy, we built seven classifiers using training data from each of the seven static positions individually and an eighth classifier from all seven static positions collectively. Similarly, for sessions using the dynamic training strategy, we built four classifiers using training data from each of the four dynamic movement patterns individually and a fifth classifier from all four dynamic patterns collectively.
We then calculated classification accuracy by inputting the designated testing data from each static position or dynamic movement pattern into the relevant classifier. This process generated a predicted grasp for each frame of testing data, which could be compared to the true grasp. Note that because the participant held only one grasp when recording a given dataset, the true grasp was the same for each frame in that dataset. Finally, classification accuracy was calculated by summing the number of correctly-predicted frames and dividing by the number of total frames in the dataset:
Note that although data was collected for 5 seconds for both the static and dynamic training strategies, the total number of frames fluctuated between 57 or 58 across datasets.
We used the Structural Similarity Index (SSIM) to quantify differences in the ultrasound images acquired during classifier training. SSIM quantifies the similarity between two images by decomposing them into luminance, contrast, and structure components, which are compared separately between the two images. A final value between -1 and 1 is then computed as an index of similarity, where 1 represents perfect similarity. Given two images and , the index is defined aswhere , c , and are the luminance, contrast, and structure components. The components are defined as where , , , , and are the local means, standard deviations, and cross-variance, and constant . The exponents are used to adjust the relevance of each component and were defined as . To provide context to a calculated SSIM value, we determined the similarity of ultrasound images due to chance was 0.229. We determined the similarity due to chance as the average SSIM between 100 randomly generated ultrasound images (i.e., 4,950 unique comparisons). Each image was generated using random image intensity values from a Rayleigh distribution () matching a representative ultrasound image of forearm muscle tissue.
To understand the consistency of ultrasound images for repeated conditions, we assessed the similarity of the ultrasound images for the two sets of contractions collected using the same classifier training strategies and hand grasp. Similarly, to understand the uniqueness of ultrasound images for differing hand grasps, we assessed the similarity of ultrasound images for two sets of contractions collected using the same classifier training strategies but different hand grasps. For all these comparisons, we calculated the SSIM within each frame of their 5-sec training periods. We then used a t-test to compare the average SSIM values between images using the same hand grasp and images using different hand grasps.
After offline classification testing, we conducted real-time functional testing using SMG to control the TASKA hand. Commands for the predicted hand grasp were delivered to the TASKA hand via Bluetooth. During functional testing, the MC Standard Wrist Rotator was fixed in place such that hand pronation or supination could not be controlled.
We collected a new set of training data to build classifiers for functional testing. We selected classifiers using different training strategies based on our evaluation of offline performance. By considering a smaller set of classifiers during functional testing we hoped to reduce the user's burden of repeated functional testing under separate classifier strategies (e.g., to reduce fatigue). For the functional testing that involved classifiers trained using the static strategy, we included training data from all seven positions collectively. We also used a classifier built from training data collected using the continuous dynamic strategy. The functional tests were conducted immediately after training the relevant classifier (i.e., we did not train all classifiers before beginning the functional testing). Note that the TASKA hand was not attached when collecting training data during the load B training condition. However, the TASKA hand and related components were reattached to complete the functional testing.
We configured the TASKA hand to perform the three grasps executed in classifier training, including tripod, point, and rest (Figure 3). We chose to implement these three grasps because only two of the grasps would be needed to perform the functional tests (tripod and rest) and one of the grasps would not be helpful (point). Each grasp was defined to be a discrete configuration of the thumb and fingers on the TASKA hand, such that a trained classifier initiated the TASKA hand to assume that configuration (i.e., the position and velocity of the thumb and fingers during grasp transitions were set in advance and not controlled by the classifier or participant). Thus, a participant could physically implement a grasp by activating their muscles in a manner that enabled the classifier to identify the desired grasp based on the ultrasound image of muscle deformation. We defined the rest grasp such that the thumb, index, and middle fingers of the TASKA hand were partially extended and the ring and little fingers were in a closed position (Figure 3). We used this definition to prevent the ring and little fingers from inadvertently moving blocks out of their designated rows during the targeted Box and Blocks Test, as described below. For consistency, we used this definition of rest grasp during all three functional tests.
We instructed the participant to perform three functional tests involving grasping and moving one-inch wooden blocks. Each functional test included a quantifiable score related to completion speed. We also recorded the participant's performance with a video camera. Although the primary purpose was to ensure accurate quantification of the test scores, we also used comparisons of the recorded video for a general observational analysis of functional performance.
Additionally, we calculated two outcome measures to characterize the efficiency of grasp selection. First, we counted the "number of transient bouts" during each test. A transient bout was defined as an instance when the classifier predicted a grasp for less than five consecutive frames. Note that a transient bout does not necessarily indicate that a predicted grasp was misclassified, as it is possible for a user to select a grasp for a brief period (i.e., <5 frames) if desired. However, given the relatively slow, pick-and-place nature of each functional test, we consider it unlikely that a user would deliberately choose to switch grasps that quickly. This outcome measure thus serves as an indirect indicator of a classifier's ability to predict a user's intended grasp. Second, we quantified the percent of all frames that were classified as point during each functional test. Although point was not a helpful grasp during functional testing, we included it in the repertoire of available grasps so that we might examine a participant's ability to select a desired grasp from a set of grasps. Because the participant should not be selecting point to accomplish the functional tasks, these instances of point also served as an indirect indicator of a classifier's ability to predict a user's intended grasp. Note that classification of point during a functional test does not necessarily indicate that a predicted grasp was misclassified, but we consider it unlikely for a user to voluntarily select this grasp when attempting to hold a block.
The Box and Blocks Test (BBT) is a common measure of gross manual dexterity. The set-up consists of two 10-inch square compartments separated by a six-inch-tall partition (Figure 4). The compartment on the side of the arm being tested is filled with 150 one-inch wooden blocks, which are mixed such that the blocks rest in many different orientations. The test is scored by the number of blocks transported over the partition in 1 minute. Subjects may transport the blocks in any order as long as their fingertips cross the partition before releasing the block into the opposite compartment. The BBT apparatus was placed on a table set to 10 cm below the participant's right anterior superior iliac spine. The apparatus was positioned 4 cm from the proximal edge of the table with the box partition aligned with the participant's midline.
The Targeted Box and Blocks Test (tBBT) is a modified version of the BBT involving only 16 blocks. The blocks are placed in a four-by-four grid in the compartment on the side of the arm being tested (Figure 4). The blocks are numbered 1 to 16, beginning with the innermost block on the bottom row and moving across each row. Subjects must transport the blocks between the compartments in numbered order. Each block must be placed in its mirrored position in the other compartment. The test is scored by the time required to transport all 16 blocks. The tBBT was performed on the same table as the BBT with the apparatus placed in the same position described previously. Note that we made a minor modification to the tBBT apparatus by removing both compartments' outer walls (Figure 4). Because of the large size of the TASKA Hand, it collided with the walls when the participant attempted to manipulate blocks located near the edge of the compartment. Since this study was intended to demonstrate the feasibility of using prostheses controlled by SMG during functional tasks, we felt it was appropriate to remove the walls so that the tBBT could be completed more easily.
The Rainbow Test was developed for this study to evaluate grasp control over a wider variety of arm positions than is required by the BBT or tBBT (Figure 4, Supplementary Figure S2). A series of 14 squares were marked on a magnetic whiteboard following an approximate arch shape. One-inch magnetized blocks with magnets attached were placed inside each square. We instructed the participant to transport each block from the whiteboard to a collection box placed at waist height along the midline of the body. Blocks were transported in a designated order, beginning with the bottom blocks on the side ipsilateral to the prosthesis and continuing up each column. The test was scored by the time required to transport all blocks.
1) Short-term testing: The participant trained a classifier and performed the set of three functional tests in random order. The participant then repeated the set of three functional tests (presented in a new random order) for a second and third time without retraining the classifier.
2) Three-hour testing: The participant trained a classifier and then wore the socket for 3 hours. Every 30 min, the participant performed the set of three functional tasks in random order. During each break between the functional testing, the TASKA hand was turned off and the participant was able to move freely and perform normal daily activities. Although the TASKA Hand could not be actively controlled during breaks, it could still be used for passive object manipulation. The participant performed pre-defined tasks during each break (Table 2), which were staggered to require increased arm movement and socket loading over time. For this testing scenario, we used a linear regression model to reveal any changes to the outcome measures over this 3-h period.
3) Simulated donning/doffing: The participant trained a classifier and performed the set of three functional tests in random order. Next, the ultrasound transducer was removed and replaced to simulate donning/doffing of the socket. The participant then repeated the set of three functional tests in random order without retraining the classifier.
To assess whether the participant could repeatedly perform functional tasks using an SMG-controlled prosthetic hand, real-time functional performance was assessed for three separate scenarios:
End-to end system latency was approximated as the delay between the onset of volitional finger flexion in an individual without limb loss and the corresponding onset of finger flexion on the TASKA hand. We manually identified the start of each movement based on the acceleration signals (Supplementary Figure S3), and these time differences were averaged over 5 cycles. The resulting value encompasses latency associated with data acquisition, data transfer, processing, and communication with the TASKA Hand via Bluetooth.
We also calculated the processing latency for the MATLAB-based classification algorithm using all datasets recorded during real-time functional testing (see Section 2.7). The difference in successive timestamps were averaged across all files to compute the processing latency. Lastly, we computed the classification throughput as the number of predictions divided by the total elapsed time, based on the real-time functional testing datasets (see Section 2.7). | functional tasks, gesture recognition, prosthesis control, rehabilitation, sonomyography, ultrasound imaging, upper limb | Not supported with pagination yet | null |
PMC5959910_01 | Female | 67 | Here we report an extensive inflammatory skin reaction that occurred at the site of vaccination in a 67-year-old Caucasian woman following a single dose of PCV13 (Fig. 1). Prior to PCV vaccination she underwent a detailed immunological work-up at our immunodeficiency clinic because of recurrent lower respiratory tract infections. Over the past 6 years, she experienced three CAP, once with sepsis. Bacterial blood cultures and search of urinary pneumococcal and legionella antigens were performed after initiation of antibiotic therapy. No causative agent could be isolated for any of the three episodes. Patient history was remarkable for two episodes of diverticulitis, recurrent herpes labialis ("cold sore"; reactivation rate <1/year and not for several months preceding PCV administration), obesity (BMI 39 kg/m2), and non-insulin-dependent diabetes mellitus. No opportunistic infections were documented. She was not taking any immunosuppressive drugs. She had been vaccinated according to the Swiss vaccination guidelines. The last tetanus/diphtheria booster dose had been administered 17 years ago. She had never received any pneumococcal vaccine. The physical examination and CT scan imaging were normal, with no evidence for chronic pulmonary disease or lympho proliferation. Body pletysmography was normal, excluding asthma or chronic obstructive lung disease. Immunologic analysis in the clinical routine showed normal total serum IgG, IgM, IgA, and IgG1-4 subclass levels. Lymphocyte (T vs. B vs. NK cell) and B cell subset distribution (naive vs. memory vs. marginal zone-like B cells) were normal (Table 1). Functional complement screening revealed normal classical and alternative pathways (Table 1). In summary, there was no evidence of an underlying immunodeficiency that would have predisposed to the recurrent infections. Diabetes and obesity were potential risk factors.
Given the history of recurrent lower respiratory tract infections, the patient was vaccinated with PCV13 (Prevenar13, Pfizer). Three days later, she developed a progressive, extensive, and painful swelling and erythema of about 10 x 20 cm (4 x 8 inches), affecting almost all of her upper arm around the site of injection (Fig. 1a). Given the strong pain and extensive local inflammatory reaction, she received glucocorticosteroid (20 mg prednisone daily) and an antihistaminic for 4 days, with a favorable evolution. A skin biopsy obtained on day 4 following vaccination, and 46 h following the first dose of prednisone/antihistamine, showed a dense dermal and subdermal perivascular-intensified infiltration dominated by CD4+ T cells and CD68+ macrophages. This pathology is classical of a type IV delayed hypersensitivity reaction:as seen with a positive Mantoux tuberculosis skin test (Fig. 1b). CD8+ T cells were very sparse and B cells were almost completely absent (Fig. 1b). Pre-vaccine and 4 weeks post-vaccine anti-pneumococcal IgG levels were determined in a multiplexed serotype-specific assay testing a total of 14 serotypes: 7 that are included in PCV13, and 7 that are not (Fig. 1c). Seroresponses were very vigorous against all tested PCV13 serotypes plus serotypes 9N and 20, not included in PCV13. Strikingly, a very high pre-vaccination IgG titer was observed against the non-PCV13 serotype 8, suggesting prior infection with this serotype (Fig. 1c). There was a humoral response against the diphtheria carrier protein CRM197, as anti-diphtheria titers increased following PCV13 vaccination, which was not observed for an irrelevant control protein (tetanus) (Fig. 1d). Notably, this anti-diphteria titer increase was recorded before the subsequent DiTe booster dose that was given 4 weeks after the PCV vaccination.
In vitro B cell activation 2 months after PCV13 vaccination showed a strong PCV13-induced B cell proliferation and plasmablast induction, and also a high spontaneous B cell proliferation rate in the absence of exogenous antigen (Supplementary Fig. S1). In vitro T cell responses (2 months post PCV13 vaccination and 1 month post DiTe booster vaccination), as measured by directly ex vivo ELISpot and T cell proliferation assay following in vitro stimulation with DiTe and PCV vaccines were measurable, but not different from control individuals (Supplementary Fig. S2). | null | Not supported with pagination yet | null |
PMC8208083_01 | Male | 35 | A 35-year-old Chinese male with diabetes mellitus presented to Peking University Third Hospital (Beijing, China) on November 14, 2011, with progressive swelling, ulceration, and destruction of the face. The lesions had begun 2 months earlier as infiltrated rhino facial and maxillofacial erythema, with nasal obstruction, discharge, rhinorrhea, and epistaxis, which rapidly increased in size and ulcerated. The patient was initially diagnosed, in the local hospital, with periodontitis and the treatment with tooth extraction was ineffective. Next, the lesion was diagnosed with skin and subcutaneous infection in the rhino face and treatment with antibiotics was administered, but the necrotic ulcer progressively enlarged. Subsequent clinical diagnosis was made of rhino facial mycosis and the patient was treated with itraconazole, but the ulcer still progressed with the disease eroding through his hard palate, sinuses, nose, and face, resulting in destructive changes in the maxilla and mandible, with systemic manifestations of fever, weight loss, and hepatosplenomegaly. As the ulceration progressed, he was suspected as having LMG and was therefore transferred 2 weeks after to the university clinic for further diagnosis and treatment.
On examination, his left half central face was swollen, ulcerated, and destructed, and the nose, lower eyelid, chin, and upper lip were all necrotic. Black eschar covered the left side of the face with an underlying grayish pus (Figure 1A). The anterior wall of the left maxilla was perforated with a green-yellowish pus seen at the bottom of the maxilla (Figure 1B). The hard palate had patches of black, pale discoloration showed perforation (Figure 1C), and soon proceeded with complete destruction (Figure 1D). Pale gray, wool-like mycelium was observed on the necrotic tissue of the nose (Figure 1E). The patient had a normal temperature, pulse, respiration, and blood pressure. His body weight was 42 kg (20 kg less than before onset). Blood tests showed levels of hemoglobin: 90 g/L, white cells: 7.5 x 109 /L with 81.8% band cells, platelets: 433 x 109 /L, blood glucose level: 17.7 mmol/L, total iron binding capacity: 40.2 mol/L, transferrin: 147 mg/dL, prothrombin time: 14.2 s, prothrombin activity: 61.0 (80-150), alanine aminotransferase: 43 U/L, alkaline phosphatase: 394 U/L, and r-GT: 354 U/L. The tests for HIV Ab, anti-TB, EBV IgM, and syphilis were all negative. X-ray computed tomography (CT) showed left facial soft tissue deficiency, absence of left anterior bone wall of the maxillary sinus, mucosal thickening with increased density of bilateral maxillary sinus, ethmoid, sphenoid sinus, bilateral hydrothorax, and high-density fuzzy shadow in the lower part of the lungs. Meningeal enhancement was seen on MRI.
A skin biopsy was performed on the lesions of the nasal dorsum, nasal mucosa, and granuloma. The biopsied tissue was sent for lymphoma diagnosis to the authored pathologists for microbiological evaluation in our laboratory. Pathology showed inflammation, necrosis, and pleomorphic cell infiltration, with atypical hyperplasia. Angioinvasive, angiocentric, and angiodestructive characteristics were typical with "Onion-skin" lesions (Figure 2A). In immunohistochemistry, the atypical lymphoid cells were positive for NK/T cell markers (CD2+, CD3+, CD8+, and individual CD56+), cytotoxic granule associated proteins (GZMB and TIA1), and hyperplasia (Ki67+):typical of ENKTL (Figure 2). Patient was diagnosed as LMG/T cell non-Hodgkin's lymphoma at the Department of Pathology, Peking University, according to the WHO classification of mature T- and NK-cell neoplasms with negative EBER and EBV testing. | nk/t cells, rhizopus arrhizus, rhizopus oryzae, lethal midline granuloma, midline face destruction, rhino-orbital-cerebral mycosis | Not supported with pagination yet | null |
PMC10182818_01 | Female | 38 | The female child, was her mother's third fetus and second birth, with a gestational age of 38+2 weeks, and was delivered by cesarean section due to dystocia. Her parents were a non-consanguineous healthy couple, with no specific skin, oral, or perineal diseases. Her birth weight was 2980g, and her Apgar score was 6 (A+P+G+A+R=1+1+1+1+2) after 1 min. After wiping the fetal fat, it was found that her skin was slightly damaged, which did not attract enough attention. In the following two days, the aforementioned skin damage progressed to scattered coin-sized desquamation and yellow blisters. Among them, the two upper limbs were the weight, and several skin damages were observed together (See Figure 1). Scattered yellow blisters was not easily broken, and the blister fluid is turbid and purulent. There was no family history with the same features. The patient did not have fever, screaming, irritability, etc. Vital signs showed a blood pressure of 85/50 mmHg, a pulse rate of 120 beats/minute, a respiratory rate of 32 breaths/minute, and a body temperature of 38.2 C. Her body weight, height, and head circumference were all. Her laboratory results such as complete blood cell count of WBC (white blood cell) 28.0x109/L, mainly neutrophils, accompanied by increased eosinophils. RBC (red blood cell count) 4.08x1012/L, PLT (platelet) 433x109/L, liver panel: ALT (alanine aminotransferase) 19 U/L, AST (aspartate aminotransferase) 34 U/L, kidney panel: creatinine 47 mumol/L) were within normal. Her limits and respiratory etiology test results (including tuberculosis) were negative. No abnormalities were detected in the TORCH (T: Toxoplasma gondii; R: Rubella virus; C: Cytomegalovirus; H: Herpes simplex virus; O: Other pathogens), immunization series and autoimmune series examinations. No bacteria or fungi were detected in blister smears, cultures, or blood cultures. The blister culture was sterile. Convulsions occurred on the third day after birth. Head magnetic resonance imaging (MRI) showed multiple blood lesions in the brain (Figure 2). Combined with the patient's medical history, the diagnosis was considered IP. To further clarify and seek sufficient evidence, the patient was examined by a wide-angle digital retinal imaging system, suggesting that fundus fluorescein angiography showed fundus vascular loop-like changes, consistent with the fundus vascular manifestations of pigmented incontinence (Figure 3). In the meantime, the patient underwent skin biopsy, which showed that more eosinophils were aggregated in the epidermis, a small number of dyskeratocytes were scattered in the surrounding epidermis, and a small number of eosinophils and lymphocytes were infiltrated in the superficial dermis (Figure 4). To further clarify the genetic status of the patient's family, the parents and older sister of the patient underwent blood genetic testing. The results suggested that the patient had a heterozygous loss in exons 4-10 of the IKBKG gene, but the parents and older sister were normal (Figure 5). | bloch-sulzberger syndrome, nemo gene, genodermatosis, incontinentia pigment, skin disease | Not supported with pagination yet | null |
PMC6939412_01 | Female | 23 | This was a case of a 23-year old G4 P3 A3 woman at a gestational age of 39 weeks in April, 2017 who was referred to the labour ward of the University of Calabar Teaching Hospital (UCTH), Calabar, Southern Nigeria, with a history of inability to deliver her baby after 5 days in labour prior to presentation. The patient had been managed in two different traditional birth attendant (TBA) homes. The second TBA recognized that the cause of prolonged labour was abnormal lie of the fetus and attempted to correct the lie by intrauterine manipulation through the vagina. This resulted in uterine rupture and subsequent evisceration of the intra-abdominal viscus through the vagina. The loop of the small intestine was initially mistaken for umbilical cord by the TBA who pulled several lengths of it through the vagina (Figure 1). Following the failed attempt to deliver the baby and the woman's deteriorating clinical state, the patient was subsequently rushed to UCTH.
At UCTH, the patient was resuscitated. Parenteral broad spectrum antibiotics were administered. The extruded loops of bowel were wrapped in sterile guaze soaked with warm normal saline. A general surgeon was invited to take part in the management of the patient. The patient was immediately prepared and taken to theatre for emergency laparotomy.
A midline incision was made to access the peritoneal cavity. Intra-operatively, a macerated female fetus was found in the uterine cavity. There was a left postero-lateral uterine wall tear extending from the mid portion to the posterior vaginal fornix. The loops of bowel extruded through this opening. The dead fetus was extracted. About 1,200 ml of blood in the peritoneal cavity was suctioned. Total abdominal hysterectomy was performed.
The whole intestines were thoroughly examined (Figures 2 and 3); about half the length of the intestine was devitalized and therefore, resected and an end-to-end anastomosis was done. The peritoneal cavity was lavaged with warm normal saline before abdominal wall closure. Nasogastric tube was then inserted.
Post-operatively, the patient was given parenteral nutrition for 5 days. Antibiotics, analgesics and other supportive treatments were continued according to our protocols. The patient opened bowel on the eighth post-operative day. The patient was commenced on graded oral meals which the patient tolerated. Subsequent post-operative days were uneventful. The patient was later discharged home. | null | Not supported with pagination yet | null |
PMC8326066_01 | Male | 71 | A 71-year-old male presented with a 3-month history of word-finding difficulties, confusion, and left leg weakness. CT head demonstrated several ill-defined hypodense areas within the right parietal and occipital subcortical white matter. MRI of the brain demonstrated a contrast-enhancing 3.2 cm lesion in the right occipital lobe, a 1.8 cm enhancing lesion in the right precentral gyrus, and multiple smaller enhancing lesions in the right periventricular region with associated vasogenic edema but no mass effect [Figure 1a]. PET/CT showed no evidence of systemic malignancy but visualized right posterior temporal, occipital and parietal lobe lesions [Figure 1b and c]. Susceptibility-weighted angiography (SWAN) imaging demonstrated a hemorrhagic component of the right occipital lobe lesion [Figure 1d].
A needle core biopsy was obtained of the right occipital lesion, and intraoperative frozen pathology was thought to be consistent with a lymphoma. Formal pathology, however, only showed an intense inflammatory process [Figure 2a and b] comprised foamy macrophages and T-cells with scattered small B-cells. These cells were CD3 [Figure 2c], CD163, Iba1, and CD68 positive. B cell immunohistochemistry was scantly positive [Figure 2d]. The T-cell population was found to be composed of more CD4+ than CD8+ cells.
Postoperatively, he was started on high-dose dexamethasone. However, this was discontinued once the formal pathology was available. A follow-up brain MRI after 1 month demonstrated a decrease in the size of all enhancing lesions. MRI of the total spine was without evidence of disease. Dexamethasone was subsequently tapered off given initial concern for sentinel lymphomatous lesions.
CSF studies, ordered 2 months after the patient's biopsy, were unremarkable for autoimmune, bacterial, viral, fungal, parasitic, or inflammatory etiologies. CSF flow cytometry was limited by the low cellularity of the specimen but revealed a predominance of CD5+ T cells. Repeat MRI brain off of corticosteroids demonstrated an interval increase in size and conspicuity of all previously observed enhancing lesions, and the decision was made to perform an excisional biopsy of the right occipital lesion.
The patient was brought to the operating room for excisional biopsy of the right occipital lesion. He was positioned supine with his head placed in the Mayfield head holder. The field was prepped and draped, and an incision was made down to the bone. A burr hole was made, and a craniotomy was turned over the lesion as confirmed with image-guidance. There was a pale tan pink discoloration of the brain. Several biopsies were obtained, and then the lesion was resected under the microscope and sent for pathology.
Further histological analysis demonstrated areas of macrophages/lymphocytes with markedly reactive astrocytes that showed quick transition to reactive less inflamed cortex. The lymphocytic population appeared small, but polymorphous, containing scattered plasma cells. There was marked perivascular inflammation but no fibrinoid necrosis. Flow cytometric and immunohistochemical workup failed to demonstrate a definitely clonal lymphocyte population. There was no evidence of demarcated myelin loss or a vasculitic process.
Two weeks postoperatively, he had worsening behavioral outbursts, frequent mood fluctuations, poor comprehension, and worsening balance. Given the clinical deterioration, he was restarted on high-dose dexamethasone. The following MRI demonstrated post-surgical changes with significant decrease in the size of the right occipital lesion [Figure 3]. His steroids were changed to a Prednisone taper starting at 60 mg that was tapered to 20 mg over the course of 6 weeks. Upon follow-up, he was noted to have improved cognitive processing and improved left-sided weakness. Given the clinical and radiographic responsiveness to steroids in the absence of infectious, inflammatory, or neoplastic etiologies, the diagnosis of SLIPPERS was made. | clippers, cns lymphoma, neuroimmunology, slippers | Not supported with pagination yet | null |
PMC7723813_01 | Male | 60 | A 60-year-old man, who was treated at our hospital for chronic obstructive pulmonary disease for five years, was admitted for the examination of ground glass opacity (GGO) in the lower lung field and mediastinal lymphadenopathy in the computed tomography (CT), which tended to be enlarged gradually. He was a former smoker (two packs a day for thirty-two years until fifty-one years of age) and had a history of surgery for inguinal hernia. He had dry cough and slight dyspnea (modified Medical Research Council [mMRC] grade I). Fine crackles were heard in the lower lung field upon chest auscultation. The superficial lymph nodes were not palpable. Laboratory data on admission are shown in Table 1.
Blood tests showed a white blood cell (WBC) count of 7400/muL without any significant abnormalities, hemoglobin level 14.5 g/dL, platelet count 25 x 104/muL, serum total protein 6.4 g/dL, albumin 3.7 g/dL, serum creatinine 1.09 mg/dL, lactate dehydrogenase 247 IU/L, serum beta2-microglobulin 2.4 mg/L (reference value < 2.0 mg/L), soluble interleukin 2 receptor 469 U/mL, sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) 805 U/mL, angiotensin-converting enzyme (ACE) level 37.4 U/L, IgM level 791 mg/dL (reference value 33-183 mg/dL), IgG level 531 mg/dL (reference value 861-1747 mg/dL), IgA level 52 mg/dL (reference value 93-393 mg/dL), and IgE level 10 IU/mL (reference value < 170 IU/mL). In the urine test, kappa type Bence-Jones proteins (BJP) were detected. Pulmonary function tests showed obstructive ventilatory impairment, forced vital capacity (FVC) 3.94 L, FVC/predicted FVC 110.4%, forced expiratory volume in 1 s (FEV1) 2.41 L, and FEV1/FVC 61.17%. Electrocardiogram and ultrasonic cardiography were normal. An enhanced chest CT revealed emphysema dominant in the upper lung field, GGO in the lower lung field, interlobular septal thickening, mediastinal lymphadenopathy, and a soft tissue shadow in the paravertebral region (Fig. 1).
A fluorodeoxyglucose (FDG)-positron emission CT examination showed FDG accumulation in ill-defined soft tissue attenuation in the mediastinum and retroperitoneum (SUVmax = 2.5 and 2.4, respectively) (Fig. 2).
Bronchofiberscopy was performed. The recovery rate of bronchoalveolar lavage (BAL) from the right B5 was 60.0%. A BAL fluid (BALF) evaluation showed a total cell count of 4.26 x 105/mL and the differential WBC counts for macrophages, lymphocytes, neutrophils, and eosinophils were 95.0%, 3.8%, 0.9%, and 0.3%, respectively, showing normal proportion of the BALF. Among the T lymphocytes, the CD4/CD8 ratio was 1.8 and the proportion of CD1a was 1.3%, which was within the normal range. Bacterial, fungal, and acid-fast bacillus culture tests in BALF were negative. Transbronchial lung biopsy (TBLB) from the right S8 showed the infiltration of inflammatory cells, such as lymphocytes and plasma cells, in the alveolar wall.
Due to elevated serum IgM, urinary BJP and lymphadenopathy, our differential diagnoses included LPL, mucosa associated lymphoid tissue (MALT) lymphoma with plasma cell differentiation, and multiple myeloma. Bone marrow aspiration and biopsy were performed to assess bone marrow involvement. Normocellular marrow tissue with kappa predominant lymphocytes and plasma cells were obtained. The bone marrow smear showed 24.2% lymphocytes, 3.0% plasma cells, and some atypical cells. Flow cytometry suggested kappa-predominant B cells. These findings supported the diagnosis of LPL, but did not enable us to make a definitive diagnosis. To clarify the cause of the soft tissue shadow in the paravertebral region and GGO in the lower lung field, a surgical biopsy was performed from the right lower paratracheal lymph node and the right S8 of the lung. The lymph node specimen and the surrounding connective tissue revealed small lymphocytes and plasma cells between follicles (Fig. 3A). These cells were mostly positive for CD20, CD79a, and IgM, focally positive for CD138, and negative for CD3, CD5, CD10, and CD56. A few Dutcher bodies were also observed. In situ hybridization (ISH) revealed immunoglobulin light-chain restriction with an elevated kappa/lambda ratio of ten (Fig. 3B and C).
DNA was extracted from paraffin-embedded tissue and a mutation analysis using an allele-specific primer-polymerase chain reaction (PCR) confirmed MYD88 L265P mutation in lymph node specimens (a substitution of leucine with proline at amino acid position 265) (Fig. 4). G-banding was not available; fluorescence in situ hybridization (FISH) analysis of MALT lymphoma-specific translocation was negative.
In addition, eosinophilic amorphous deposits found in the lymph nodes and stroma of the fat connective tissue stained positively by Congo red, exhibited apple green color under polarized light, and were positive for AL kappa by immunohistochemistry (Fig. 5A-D).
In the lung specimens, mild emphysema and inflammatory fibrotic changes, including fibroblastic foci, were seen in the subpleural area. Besides these changes, amyloid deposition was also confirmed in the interlobular septa, and slight plasma cell infiltration was seen around amyloids. Thus, LPL with AL kappa amyloidosis was diagnosed, coexisting with interstitial pneumonia with usual interstitial pneumonia (UIP) like features.
During surgical biopsy, the lung tissue and fat connective tissue were fragile and bled easily. Due to massive bleeding, the operation was changed from video assisted thoracic surgery to thoracotomy. After surgery, the patient was moved to the respiratory care unit (RCU) with intubation for 16 days because of bleeding from the airways. After his condition improved, he was referred to another hospital. | amyloidosis, diagnosis, lymphadenopathy, lymphoplasmacytic lymphoma, myd88 mutation | Not supported with pagination yet | null |
PMC5446870_01 | Male | 23 | A 23-year-old Saudi male, known case of sickle cell disease, presented to the medical OPD in June, 2013 with one-week history of mild vague abdominal pain in the left upper quadrant associated with early satiety. On examination, the patient was conscious. His vital signs were as follows: blood pressure 110/60 mmHg, pulse rate 84/minute, and temperature 37.1 C. He had mild pallor but not jaundiced. Abdominal examination revealed massive splenomegaly (10 cm below costal margin). His investigations were as follows: WBC: 4.32, Hb: 11.3, PLT: 184, LDH: 807, TBIL: 31, Conj.Bil: 0, ALT: 39, AST: 32, and ALKP: 66. Abdominal ultrasound showed homogenous echo pattern with slightly enlarged liver (16 cm at the right midclavicular line) and smooth hepatic boarders. There were no focal lesions; spleen was confirmed to be enlarged (20 cm) with dilated portal vein.
Ultrasound portal-splenic Doppler showed the diameter of the portal vein measuring 12.5 mm in caliber. It also showed normal patent biphasic flow pattern with average velocities and normal hepatopedal flow direction with no evidence of portal vein thrombosis. The hepatic veins also displayed average normal diameter measuring 10.5 mm in caliber. It appeared patent on color Doppler interrogation displaying average velocities with no evidence of portal-systemic collateral vessels. Hematology consultation recommended splenectomy which was carried out laparoscopically with uneventful postoperative recovery.
In July 2015, the patient presented to the OPD with obstructive jaundice. On examination, he was conscious, alerted, and oriented. His vital signs were as follows: blood pressure 112/58 mmHg, pulse rate 81/minute, and temperature 36.9 C. He looked jaundiced. Abdomen (after splenectomy) was soft, lax, and nontender. His investigations were as follows: WBC 5.9, Hb: 11.2, platelet: 251, BUN: 1.2, creatinine: 52, sodium: 138, potassium 4.2, chloride 105, bicarbonate 22. TBIL: 187.7, ALP: 425 AST: 84, ALT: 54, and Direct Bil: 42.5. Abdominal ultrasound showed gallstone with signs of cholecystitis, biliary dilatation, and common bile duct (CBD) stone. Abdominal Doppler ultrasound showed patent portal vein. The patient was admitted to the hospital where ERCP was performed; sphincterotomy and CBD stone extraction were done. He developed mild pancreatitis which resolved in two days.
In October 2015, the patient presented again with abdominal pain and obstructive jaundice. His full investigations can be seen in Table 1. Abdominal ultrasound showed gallstones, cholecystitis, and dilated bile ducts (Figure 1). He underwent ERCP; cholangiogram showed a CBD stone difficult to be extracted. Balloon sphincteroplasty up to 10 mm was performed which was complicated by massive bleeding from the ampulla. The blood was just oozing and pouring from the orifice. There was no arterial bleeding. The bleeding was massive and could not be controlled. The patient went into acute hypovolemic shock (Hb dropped to 5.8 g/dl), and he was then intubated and transferred to the ICU where he was resuscitated and received six units of packed RBCs and FFPs. His condition improved after two days. Later on, he was evaluated for the cause of massive bleeding. Abdominal CT showed cavernous transformation of portal vein with splenic and portal veins thrombosis, in addition to extensive collaterals at porta hepatis and around the biliary tree (Figure 2). Upper endoscopy showed grade II esophageal varices. ERCP was successfully performed after 2 days to assess the area of bleeding and put stent to assure free drainage of the bile duct. The patient's condition improved after ERCP. He was then transferred to the medical ward where his condition was stable with no bleeding or hemoglobin drop. His LFT results were as follows: TBIL: 58.1, ALP: 156, AST: 19, ALT: 13, TP: 72, INR: 1.3, and albumin: 33. The patient was seen by general surgery and planned for laparoscopic cholecystectomy. | null | Not supported with pagination yet | null |
PMC5228691_01 | Male | 54 | A 54-year-old male presented to our department with arthritis, involving multiple joints. His symptoms started in 2007. When he first developed spontaneous arthritis of third proximal interphalangeal (PIP) joint, presented with painful swelling, accompanied by morning stiffness lasting for hours and relieved by warmth and activity. In July 2012, the above-mentioned symptoms were aggravated. Multiple arthralgia and swollen joints involved in bilateral PIP joints, wrists, elbows, knees, and ankles joints, along with a limited range of motion. He visited our hospital and was diagnosed as RA. The symptoms were relieved after starting on treatment with corticosteroids, NSAIDs (loxoprofen, celecoxib), and immunosuppressive agents (methotrexate, leflunomide). Having outpatient review and treatment regularly in our hospital, his condition was stable. At the beginning of 2015, he suffered from nontender subcutaneous nodules on the left forearm. The nodule could disappear with injection of corticosteroids. The symptoms appeared repeatedly but he paid no attention to it. Since then, he followed up with his rheumatologist intermittently. He is currently on medication with prednisone (5 mg/d), NSAID, and methotrexate (15 mg /w). During the course of disease, there was no xerostomia, xerophthalmia, rampant tooth, recurrent oral or genital ulcers, hair loss, photosensitivity, rashes, Raynaud's phenomenon, lower back pain, or talalgia. Particularly, proteinuria was present. He did not have any nocturia, oliguria, pollakisuria, urgent urination, odynuria, or gross hematuria. Defecation was normal. His body weight did not change obviously.
In mid-November 2015, the patient presented to our department of rheumatology with the complaints of the swelling and pain of multiple joints and edema of bilateral lower limbs. There were no symptoms in the respiratory, cardiovascular, and gastrointestinal systems. On examination, nontender subcutaneous nodules measuring 2 x 1.5 cm (rheumatoid nodule confirmed) over the extensor surface on the left forearm with no limitation of range of motion. Tenderness and swelling of the second and third PIP joints of right hand, the third PIP joints of left hand, bilateral knees, wrists, shoulders, and ankles were present. Pitting edema was present in the lower limbs, and bilateral palpebral edema was also present. The laboratory examination showed as follows: erythrocyte sedimentation rate 88.00 mm/h, C-reactive protein 18.8 mg/L, purified protein derivative test, tuberculosis antibody or T-cell spot test were negative, 24 hours urine protein 12.56 g/24 h, albumin 18.30 g/L (normal>40 g/L), serum total cholesterol 12 mmol/L (normal<5.7 mmol/L), triglyceride 2.37 mmol/L (normal<1.7 mmol/L), creatinine 82 mummol/L, rheumatoid factor 1280 Iu/mL, antiperinuclear factor 1:80, antikeratin antibody 1:80, anticyclic cirullinated peptide antibodies 826.2 RU/mL, human leucocyte elastase +, anti-SSA, anti-SSB, anti-SM, anti-RNP, anti-Jo1, anti-Scl70, anti-double-stranded deoxyribonucleic acid, cytoplasmic antineutrophil cytoplasmic antibody (ANCA), perinuclear ANCA, protease-3, myeloperoxidase, anti-mitochondrial antibody, and human leukocyte antigen-B27 were normal or negative.
Renal biopsy revealed glomeruli with segmental sclerosing lesions. The electrolyte microscope showed no electron-dense deposits and only visceral epithelial cell foot process effacement (Fig. 1). To stop the progressing of disease, we used methyprednisolone160 mg/4 days, human albumin 20 mg/5 days, prednisone acetate15 mg /QD, celecoxib200 mg/BID, leflunomide10 mg/QD, and other symptomatic treatment. After intensive treatment proteinuria level dropped to 7.2 g/24 h, serum albumin levels were increased to 24.9 g/L, renal function gradually returned to normal, and the patient was discharged in a stable condition.
This case report has been approved by the Ethics Committee of the Second Hospital of Shanxi Medical University and got the written consent of the patient. | null | Not supported with pagination yet | null |
PMC10482024_01 | Female | 44 | This is the case of a 44-year-old female, with a history of four vaginal deliveries, presenting to the hospital with a huge abdominopelvic mass, moderate to severe pelvic pain, and spotting and intermenstrual bleeding for the last one month. She had a history of a failed laparotomy six months back, attempted to remove the mass. There were minor episodes of heavy menstrual problems earlier. As per old operative records, a diagnosis of fibroid uterus had been made. During the attempted surgery, dense adhesions were encountered around the mass and the abdomen had to be closed without proceeding further.
In the present visit, the mass was found to be of 18 weeks size, uniformly enlarged and firm with restricted mobility. There was both a vertical and a transverse scar, resulting from the previous attempted laparotomy.
An endometrial biopsy was planned. On dilating the cervix, around 30 cc of pus was drained out, which had found no mention in the previous sonography done earlier. Escherichia coli was grown and she was treated with antibiotics according to the culture sensitivity report. Endocervical and endometrial biopsy were done to rule out malignancy or tuberculosis.
Magnetic resonance imaging (MRI) showed a normal uterus and endometrium. A mass, possibly a myoma with a well-defined collection was seen possibly arising from the posterior lower uterine segment and cervix. The draining tract was seen to open into the cervix [Figure 1a-c]. Kidneys and ureters were normal. The correct diagnosis was, however, made only after the surgery. A relaparotomy was planned. Due to the previous failed surgery, she insisted on a panhysterectomy.
On laparotomy, an 18 cm x 15 cm x 9 cm mass was seen arising from the pelvis, behind a normal sized uterus. Cornual structures were normal. Dense bowel adhesions were present between the bowel, uterus, and the mass. Adhesiolysis was done followed by pan hysterectomy. The mass was found to be a fibroid arising from the posterior aspect of the cervix [Figure 2].
In the postoperative period, she started developing high-grade fever from the third postoperative day. A small stitch line infection and urinary tract infection were diagnosed and treated, but she remained febrile. Sonography on day 7 was normal. High-grade fever persisted in spite of higher antibiotics. On day 12, she complained of some dirty discharge for which her vault stitches were dilated and around 30 cc blood mixed discharge was drained from the pelvis. Subsequent to the drainage, the fever finally resolved. Culture showed that it was an aseptic collection, possibly because of the prior antibiotics.
On HPE [Figure 3], grossly, the uterus was normal. Cervix measured 5 cm x 2 cm x 1 cm. A large capsulated leiomyoma measuring 18 cm x 15 cm x 9 cm was seen arising from the posterior wall of the cervix. On cutting open through the leiomyoma a cavity/diverticulum of 4cm in diameter was found, which was communication with the endocervical canal. It was filled with pus-like material admixed with blood. On microscopy, the sections were taken from the diverticulum near the lumen of the endocervical canal and the diverticulum wall adjacent to leiomyoma. Sections from both the diverticula showed endocervical glands embedded in fibrocollagenous tissue and mixed inflammatory infiltrate, while subepithelial area showed smooth muscle proliferation.
The final diagnosis was given as cervical fibroid and diverticulum with inflammation. | abdominopelvic mass, infected cervical diverticulum, primary uterine diverticulum | Not supported with pagination yet | null |
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