In a thirty-seven-year-old woman, gravida 2 para 0, routine ultrasound (US) performed at 22 WG revealed severe intrauterine growth restriction and cerebral anomalies consisting of microcephaly, vermis hypoplasia and bilateral hypoechogenic zones close to the anterior horns of the lateral ventricles for which a diagnosis of porencephaly was suggested. Due to unfavorable prognosis, a medical termination of the pregnancy (TOP) was achieved at 27 WG. Four months later, the parents conceived a second child. At 22 WG, foetal growth parameters were within the normal range, but US examination at 30 WG showed severe growth restriction and recurrence of the brain lesions leading to TOP at 32 WG. Array-CGH was normal in both foetuses, as was the karyotype (46, XX and 46, XY respectively). The unrelated parents had no personal or familial medical history.
A complete autopsy was carried out in both foetuses according to standardized protocols with the informed written consent of the parents in accordance with the French law and after approval by our local ethical committee (Supplementary material S Methods with additional references). Foetal weights were below the 3rd percentile. Neither craniofacial particularities nor macroscopical and histological visceral abnormalities were noted. In the first foetus, histological examination of the ovaries did not reveal any ovarian dysgenesis and the density of primordial follicles appeared to be similar to what observed in two 27 WG control ovaries. Brain weight was 88 g in the first foetus and 153 g in the second foetus. Infratentorial weights were 4.3 g and 6 g, corresponding to a developmental age of 22 and 26 WG respectively, in favour of microcephaly with cerebellar hypoplasia. In the second foetus, brain gyration was delayed with almost no secondary sulci (Fig. a and b). Cerebellar foliation was also delayed, the tertiary folia being still absent. On coronal sections, periventricular pseudo-cysts were observed within the ganglionic eminences close to the caudate nuclei (Fig. c). Cerebellar abnormalities consisted in poorly convoluted dentate nuclei and a five-layered cerebellar cortex in the two foetuses (Fig. d). Luxol-phloxin stains were entirely negative in the brainstem of the second foetus (Fig. e) compared with an age-matched control brain (Fig. f). No pycnotic or foamy oligodendrocytes were observed within and around the dentate nuclei (Fig. g and h). At the supratentorial level, no gaps in the glia limitans were observed. The cortical plate was depleted in neurons mainly in layer III but no microcolumnar dysplasia was noted, arguing against a disruption of cortical plate cytoarchitectony which could result from impaired migration or neuron positioning. In the second case, the pyramidal morphology of neurons in layers III and V was not apparent, indicative of immaturity as pyramidal morphology is easily recognizable 26 WG onward. In the second case, histological examination of the eyes was normal using routine stainings.
Vimentin immunohistochemistry did not make it possible to find radial glia or glia limitans abnormalities, and GFAP immunolabelings revealed some accumulation of reactive astrocytes around the periventricular cavities. But whatever the location, i.e., surrounding the cavities or at a distance from them, astrocyte morphology was similar. No differences in shape or number of GFAP-positive Muller cells between the affected foetus and an age matched control eye were observed. Conversely, it displayed a decreased number of mature astrocytes in the cerebellar white matter. Their severely altered morphology consisted of underdeveloped processes compared with an age-matched control (Fig. a and b). Their cytoplasms exhibited no alpha-B crystallin accumulation. Immunolabelings using the intermediate filament nestin, a marker of radial glial cells confirmed the presence of numerous immature astrocytes by comparison with the control brain (Fig. c and d). Even though Olig2 immunolabeling revealed no significant differences pre-oligodendrocyte number, an increased number of PDGFRα-positive oligodendrocyte precursors was observed (Fig. e and f). Bergmann glia was virtually absent (Fig. g and h). Calbindin immunoreactivity was weak in Purkinje cells, the density of which was reduced with almost no associated immunolabelling of Golgi II neurons and stellate cells (Fig. i and j).
Whole Exome Sequencing (WES) (detailed procedures in Supplementary material SMethods with additional references and S Missense variant considered in this study), allowed for the identification of two compound heterozygous missense variants in the EIF2B5 gene (NM_003907.2) in the two foetuses: c.468C > G p.Ile156Met and c.1165G > A p.Val389Met. Each parent was heterozygous for one of the two variants which are absent in the GnomAD, ESP and in the dbSNP databases. Contrary to the deleterious p.Ile156Met variant which has already been reported in a patient with VWMD [], the p.Val389Met is novel. This variant has a CADD score of 29.6 and is predicted as damaging using SIFT, Mutation Taster and Polyphen-2 prediction tools []. No deleterious variants were found in the other currently known genes involved in other leukodystrophies.


In July 2014, a 57-year-old Caucasian woman with a family history of metastatic CRC in a younger brother underwent a screening colonoscopy that revealed adenocarcinoma of the right ascending colon. Preoperative computed tomography (CT) at the time showed enlarged lymph nodes in the right colonic mesentery and a 6.3-mm solitary pulmonary nodule in the right lower lobe, without evidence of clear distant metastatic disease. She underwent a robotic-assisted laparoscopic right hemicolectomy in August 2014. Pathologic examination revealed a 3.5-cm grade 2 tumor invading through the muscularis propria into the pericolonic adipose tissue and a positive mesenteric margin with four tumor deposits. There was lymphovascular and perineural invasion noted, with involvement of four to sixteen lymph nodes. There was an additional incidental finding of an 0.55-cm well-differentiated neuroendocrine (carcinoid) tumor of the appendix. She was pathologically staged with pT3, pN2a, pMX stage IIIB adenocarcinoma of the right ascending colon, which was found to be KRAS mutation-positive with microsatellite instability, and pT1a appendiceal well-differentiated stage IA neuroendocrine carcinoma.
Further staging workup with positron emission tomography-CT (PET-CT) in September 2014 revealed a persistent solitary pulmonary nodule in the right lower lobe that did not characterize metabolically. Adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was started, and a restaging PET-CT in March 2015, after completion of 10 cycles of adjuvant therapy, showed complete resolution of the previously seen right lower lobe pulmonary nodule. Of note, there was symmetrical increased metabolic activity in the thyroid gland reported at this time, suggesting possible underlying multinodular goiter.
Restaging PET-CT in September 2015 revealed a metabolically active and enlarging pulmonary nodule in the right lower lobe consistent with metastatic disease, and subsequent biopsy confirmed metastatic colonic adenocarcinoma. At this time, she was reclassified as stage IV disease, KRAS-positive with microsatellite instability. The patient underwent a wedge resection of the right lower lobe of the lung and excision of a station 9 right lymph node in November 2015, with subsequent pathologic examination confirming metastatic colonic adenocarcinoma and a solitary benign lymph node.
Restaging CT scans from June 2016 through August 2017 showed the appearance and subsequent enlargement of two subcentimeter right and left upper lobe pulmonary nodules, with PET-CT confirming metabolic activity in bilateral apical lung fields and in a level III left neck lymph node. Of note, a diffusely enlarged thyroid with diffuse increased PET activity was noted on this scan, and maintained to be suggestive of multinodular goiter. The patient completed a four-day regimen of stereotactic body radiation therapy, and adjuvant therapy with fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI) was started, with 10 cycles completed by March 2018.
In July 2019, the patient presented with complaint of a neck mass and difficulty swallowing. She underwent fine-needle aspiration of the thyroid isthmus and a left lobe nodule identified on ultrasound, with both tissue samples pathologically identified as papillary thyroid cancer (Figure ).
The patient underwent a total thyroidectomy in August 2019, and pathologic analysis of the gross specimen confirmed two foci of metastatic colonic adenocarcinoma at the posterior surgical margin with a background of chronic lymphocytic thyroiditis (Figure ). The foci were determined to be 4.3 and 1.5 cm in size, and found to involve one of two right paratracheal lymph nodes.
Neoplastic origin was confirmed with immunohistochemical staining techniques, with the cells staining positive for cytokeratin 20 (CK20) and CDX-2, and negative for cytokeratin-7 (CK7), transcription termination factor 1 (TTF-1), and paired box gene 8 (PAX-8), consistent with a primary colonic malignancy (Figure ).


An 8.5 yr old, 30.7 kg male neutered Golden Retriever presented to Purdue University Veterinary Teaching Hospital (PUVTH), for referral evaluation of a 5-year history of intermittent vomiting, regurgitation, and loose stool. Review of primary care veterinarian medical records revealed that control of intermittent gastrointestinal signs was achieved with empirical metronidazole (16.2 mg/kg PO q 12) and metoclopramide (0.65 mg/kg PO q 12). The patient had also chronically received deracoxib (2.44 mg/kg PO q 24), sucralfate (1 gram PO q 12), tramadol (1.62 mg/kg PO q 12), and methocarbamol (16.2 mg/kg PO q 8) for pain management related to osteoarthritis and intervertebral disc disease. Six weeks prior to admission to PUVTH, the referring veterinarian discontinued the deracoxib when gastrointestinal clinical signs began to worsen. The patient otherwise had no past pertinent medical history, was up-to-date on core vaccinations, and received regular preventative healthcare which included an annual fecal analysis. The patient had a regular travel history to central Canada.
At presentation, the owner reported increasing lethargy and weight loss (5 kg) occurring over a six-week duration. The patient's appetite increased following a change from dry to canned food; however, no correlated changes in gastrointestinal clinical signs were reported. The patient had a complete blood count, biochemical profile, thyroid level, thoracic and abdominal radiographs, and a barium upper gastrointestinal tract contrast study prior to referral. No abnormalities were noted on laboratory analyses, thoracic radiographs, or abdominal radiographs. Barium contrast study revealed residual fluid retained within the stomach and suspected pyloric thickening.
Upon intake at PUVTH, physical examination was unremarkable. Initial diagnostic workup included the following: a complete blood count, blood chemistry, urinalysis, resting cortisol, cobalamin, folate, trypsin-like immunoreactivity (TLI), abdominal radiographs, and ultrasound. No abnormalities were identified with these first-line diagnostics. Thoracic radiographs revealed fluid opacity in the caudal esophagus consistent with either esophagitis, esophageal reflux, or less likely a mass lesion.
Due to the persistence of gastrointestinal clinical signs and the lack of a definitive diagnosis on initial evaluation, the patient underwent endoscopic esophagogastroduodenoscopy (EGD). Static photographs are provided from performed EGD (). Endoscopic evaluation of the esophagus revealed mild, circumferential, and shallow irregularities in the esophageal mucosa (). The gastric mucosa had a diffuse patchy erythema with white-colored mucosa noted in the fundus and pyloric antrum (). The pylorus was hypermotile and was easily traversed with the gastroscope. Immediately following passage through the pylorus, a circumferential dilatation between the pyloric opening and a duodenal stricture distal to the pyloric opening was noted. The stricture was estimated to be approximately 6 cm past the pylorus as measured by the endoscope. The 5 mm diameter opening of the stricture prevented further passage of the scope (). The visible duodenal mucosa had a slightly granular texture throughout. Biopsies were taken at the stricture site and proximal duodenum and the stomach. The histopathology results were consistent with fibrosis and mild lymphoplasmacytic inflammation.
Following EGD, a contrast (barium) upper gastrointestinal study was performed using static radiographs and fluoroscopy. Fluoroscopic evaluation revealed the barium passing through the pyloric canal, into the proximal duodenum, prior to identifying a stenotic segment of the proximal duodenum proximal to the cranial flexure. The barium pooled proximally to the stenotic area of the duodenum showing a “beak sign”. The stenotic areas and “beak-sign” are well visualized on the provided radiographs as well (Figures and ).
Proximal gastrointestinal ultrasound following administration of the barium allowed for visualization of a focal narrowing of the lumen of the proximal duodenum aborad to the pylorus and orad to the cranial duodenal flexure. Orad to the narrowing, the focal widening of the proximal duodenum could be visualized. Summary of imaging findings were consistent with a proximal duodenal stricture.
Based on tentative diagnosis of the benign duodenal stricture, the dog underwent an abdominal exploratory surgery, stricture correction, and full-thickness gastrointestinal biopsies. A proximal duodenal stricture was confirmed at the time of surgery with a large amount of omental and mesenteric adhesions present. The biopsy and enterotomy taken at the stricture site were closed in a transverse fashion (4-0, PDS) to relieve the stricture and attempt to confirm a benign cause of stricture formation. Biopsies from the jejunum and ileum were also collected. Analysis of the biopsies revealed transmural granulomatous and lymphoplasmacytic enteritis at the site of stricture with focal mucosal ulceration and hyperplasia. Additional peritonitis was noted and attributed to a likely partial rupture at the stricture site. These findings were consistent with a benign, proximal duodenal stricture. The jejunal and ileal biopsy findings were unremarkable.
The dog recovered uneventfully from surgery and at the two-week postoperative recheck was free of clinical signs. Initially, it was planned that after the full-thickness biopsies of the stricture were obtained, the dog would return for a more aggressive surgical correction (e.g., Billroth 1 for surgical margins if neoplastic) if indicated. However, based on the observed clinical response, it was deemed unnecessary. Resolution of clinical signs was achieved for 18 months postoperatively with dietary therapy utilizing a highly digestible diet (Hill's Prescription Diet i/d Digestive Care); at which time, the dog was euthanized following acute collapse, hemoabdomen, and a suspected hemangiosarcoma based on masses identified by abdominal ultrasound (liver and spleen) and cytology (liver).


A 56-year-old man with history of type 2-diabetes mellitus presented to our facility with few days' history of subjective fever, body aches, nonproductive cough, and left-sided pleuritic chest pain that increases with deep inspiration. The patient is known to have recurrent infected skin cyst with methicillin-resistant Staphylococcus aureus (MRSA). The cyst is located over the thoracic back, which required incision and drainage in the past. A few years prior to his current presentation, a vascular surgery with stent placement was performed on the right upper extremity due to vascular stenosis.
Physical exam upon arrival revealed no heart murmur. Lungs auscultation; coarse breath sounds with no wheezing. Abdomen without tenderness or distention. Lower extremities with no erythema or ulcerations; pulse is palpable in all four extremities. An infected skin cyst lesion was found over the thoracic back which was lanced at bed side. A very thick purulence was exposed from the cyst. A specimen was sent to the microbiology laboratory for culture, which grew MRSA sensitive to sulfamethoxazole/trimethoprim, clindamycin, tetracycline, and vancomycin with minimum inhibitory concentration (MIC) ∼1 mg/ml. It was intermediate to levofloxacin.
Vital signs were blood pressure 147/85, temperature 98.7 Fahrenheit (F), heart rate of 97 per minute, and respiratory rate 18 per minute. The laboratory findings were as the follows: white blood cells count 17 K/UL, creatinine 0.7 mg/dl, sodium 128 mg/dl, and platelet count 205.
Radiographic study with chest X-ray () showed development of multifocal regions of nodular appearing infiltration within both lungs and possible small amount of bilateral pleural fluid.
Computed tomography (CT) scan () angiogram of the chest was performed, and it showed patchy lung infiltration in both sides compatible with pneumonia. Also, there was mediastinal and bilateral hilar lymphadenopathy.
Blood culture was collected and sent to microbiology which resulted as positive with Gram-positive cocci and that grew MRSA which was sensitive to vancomycin with MIC ∼1 mg/ml, sulfamethoxazole/trimethoprim, clindamycin, tetracycline, and intermediate to levofloxacin.
The patient was initially started on intravenous (IV) vancomycin, IV ceftriaxone, and IV azithromycin, and then the antibiotic adjusted to only IV vancomycin, after obtaining the blood culture result. A transthoracic echo showed no valvular vegetation. The patient continued to be bacteremic with MRSA despite being on antibiotic/vancomycin. The antibiotic was exchanged to IV daptomycin and IV linezolid and IV ceftaroline.
Extensive workup was done to determine the hematogenous focus of infection which is seeding the pathogen into the blood stream. Lumber spine magnetic resonance imaging (MRI) showed no diskitis, osteomyelitis, or epidural abscess. Upper and lower extremities Doppler ultrasound showed no deep venous thrombosis or any arterial stenosis in all 4 extremities. CT scan of abdomen and pelvis with and without contrast did not reveal any intra-abdominal source of infection. Transesophegal echo (TEE) was performed. However, no valvular vegetation or valvular abnormalities were observed, but the pulmonic valve was not well visualized.
Blood culture persistently was positive with MRSA, even after the antibiotic was exchanged. Repeated CT scan chest without IV contrast reveals progression in lung pneumonia and increase in size of the existing nodules and cavitations, as well as multiple new nodules. Due to the high concern of cardiovascular system focal infection, another TEE was performed after one week after the first one. At this time, a large mass compatible with vegetation was seen over the pulmonic valve measured ∼1.9 × 0.9 cm ().
Due to uncontrolled source of infection, persistent bacteremia, and the size of the vegetation, the patient was evaluated by cardiothoracic surgery team; then, the patient underwent pulmonary valve replacement using a LivaNova extra-large sutureless valve.
Peroperative note: a large vegetation was involving the pulmonic valve, which was adherent to the pulmonary artery itself (Figures and ).
Tissue valve culture came back positive for MRSA, sensitive to vancomycin MIC 1 mg/ml, and resistant to levofloxacin. Repeated blood culture showed sterile blood. The patient was discharged home on IV vancomycin with goal vancomycin trough level 15–20 mg/ml for a total of 6 weeks via the central line. Repeated CXR after completion of the course of therapy showed total resolution of all lung nodules ().


A 58-year-old myopic woman visited our clinic, complaining of blurred vision and symptomatic floaters in her left eye for 3 months. Ophthalmologic examination revealed significant Elsching pearl like PCO in her left eye and VF like a thick string in the posterior segment of the vitreous cavity(Fig. a). The BCVA of her left eye was 8/20. She had no history of any systemic disease and drug intake. Two years ago she had undergone phacoempulsification and IOL implantation in her left eye, preoperatively she had − 6.50DS myopia with her left eye and the axial length of her left eye was 26.81 mm. We performed vitreous and retina examination on her left eye by slit-lamp biomicroscopy with Goldman’s three mirror contact lens to rule out peripheral retinal tears and degeneration. By Goldmann three-mirror lens, we clearly saw the partial posterior vitreous detachment (PVD) at posterior fundus and the VF was approximately 4-5 mm in front of the optic disc(Fig. b). The patient was eager to improve the visual acuity and remove the floaters in her left eye. At that time, we considered that the patient’s residence was far away from our clinic. In order to reduce the number of visits of the patient, we decided to complete Nd:YAG laser capsulotomy and Nd:YAG laser vitreolysis in one time. After signing the informed consent, Nd:YAG capsulotomy was performed first, followed by Nd:YAG laser vitreolysis immediately. In order to decrease the symptoms of floaters after Nd:YAG capsulotomy, we used the cross incision method for Nd:YAG capsulotomy. The diameter of Nd:YAG capsulotomy was about 6 mm(Fig. a), the power was set from 1.6 to 3.0 mJ, and the total power was 34 mJ. Then we swithed the offset to the anterior to avoid the damage of the retina and optic disc behind the VF. We used the professional vitreous laser lens (the type: KARICKHOFF25mm OFF-AXIS) for vitreolysis. During the vitreolysis the energy ranged from 3.0–4.5 mJ for a value that fully vaporized the VF(Fig. b) and the total power of vitreolysis was 130 mJ. In the process of Nd:YAG laser vitreolysis we found the fiber around the floaters were shaking violently. The whole timing of the two laser treatment was about 15 min. After the laser treatment, the patient immediately complained of a prominent darking and flashing sensation with her treated eye, but the patient’s complaint did not catch our attention and we did not have a timely retinal examination on her. Seven days later, she came back to our clinic complaining of rapid vision loss in her left eye and dark shadows in her lower visual field. We found her BCVA of the left eye was down to finger count at 2 ft. We found retinal detachment (RD) at the upper and nasal retina and involved the macular fovea, and two large holes in the upper retina about 4DD in diameter (Fig. ). She immediately underwent a vitrectomy, retinal reattchment and silicone oil tamponade surgery for her left eye. Six months later silcone oil removal was arranged on her, and the BCVA in her left eye gradually improved to 10/20 and maintained during a 1-year follow-up period.


A 17-year-old African-American male with SCD presented to his primary care physician
with a 1-month history of severe occipital head pain, left facial numbness, and left
eye droop. His SCD had previously caused several emergency department admissions for
pain and sickle cell crisis. Magnetic resonance imaging (MRI) was ordered to rule
out a possible skull infarct secondary to a sickle cell crisis. The MRI image did
not show an infarction, but the patient’s left maxillary sinus was completely
opacified and enlarged compared to the contralateral side. He was referred to
otolaryngology for further evaluation.
The patient presented to otolaryngology clinic with sinusitis and occipital pain. The
physical examination was normal, but nasal endoscopy demonstrated medialization of
the uncinate and medial maxillary wall within the left nasal cavity. There were no
polyps or purulence noted on either side. A noncontrast computed tomography (CT) was
ordered and revealed opacification and expansion of the left maxillary sinus that
occluded the ostiomeatal unit consistent with a fungal ball (). Due to the persistent
symptoms and unknown etiology of the sinus lesion, the patient was scheduled for
endoscopic sinus surgery. Intraoperatively, the maxillary sinus was noted to filled
with spiculated osseous tissue (). A routine maxillary antrostomy was performed and specimens
were collected for pathology. No drilling or special techniques were required.
Pathology demonstrated erythroid hyperplasia with blood cells of all 3 hematopoietic
lineages intermixed with fragments of bone ().
The patient was observed postoperatively without complications and discharged home.
He has not experienced any subsequent episodes of facial pressure or pain since the
surgery. Nevertheless, he continues to have frequent exchange transfusions and
struggles with pain management for his underlying SCD.


A 49 years-old woman with ten-year recurrent non-bloody watery diarrhea and abdominal pain came to our observation in 2015. No family history of gastrointestinal disorders was detected. A full ileocolonscopy performed 5 years before (no biopsies collected) was normal, leading to a diagnosis of an irritable bowel syndrome, so managed with symptomatic drugs without significant clinical benefit. She had also an history of repeated endoscopic sinus surgery (ESS) because of polyps’ recurrence, aspirin-exacerbated respiratory disease and severe eosinophilic asthma with frequent exacerbations, requiring short courses of oral corticosteroids. Over the years, it appeared that oral steroids induced also a complete relief of gastrointestinal symptoms, with a relapse at withdrawal. Therefore, the patient had repeated steroids exposure, developing dependence and several side-effects.
At admission to our department, she complained watery diarrhea (5–6 bowel movements/day) preceded by abdominal pain. Her vital signs were: SpO2 95% (room air), Temperature 35.8 °C, Heart Rate 100 bpm, Respiratory Rate 18/m, Blood Pressure 108/60 mmHg.
Physical examination was significant only for mild tenderness in the mesogastric area with intact bowel sounds. No organomegaly was found. Visual analog scale (VAS) score for abdominal pain was moderate/severe (60). Besides elevated peripheral blood eosinophil (0.38 × 109/L) laboratory tests were unremarkable. Stool examinations were negative for parasitic, bacteria and clostridium difficile infections. Pulmonary functional tests revealed a Forced Expiratory Volume in the first second (FEV1) of 63% (of predicted value), Asthma Control Test (ACT) score was 13, Sino-Nasal Outcome Test (SNOT-22) was 93, Lund–Mackay (LM) score was 20. Baseline mean OCS dose was 15 mg of prednisone per day. Four OCS requiring asthmatic exacerbations occurred during the previous year.
An ileocolonscopy revealed a normal aspect of the mucosa of each explored segment, except for a small polyp (2 mm) in the rectum, that was removed. Biopsies collected from apparently normal mucosa showed instead an important linfoplasmacellular and granulocytic infiltrate in the lamina propria with a predominance of eosinophils (Fig. a, b).
Moreover, no significant findings emerged from gastroscopy, but biopsy specimens, collected in antrum, showed as well as the linfomonocytic and eosinophil granulocytic infiltrate disrupting the glandular structures (Fig. c).
According to the immunopathogenetic mechanisms of the diseases and in order to spare oral steroids, in 2017, we started treatment with subcutaneous MEP at the standard dose of 100 mg every 4 weeks, using the severe eosinophilic asthma schedule.
As expected, blood eosinophil count was reduced after the first administration, and became lower and lower during the next 48 weeks (30 cells/mm3). After 3 months, patient experienced a significant improvement of sinusitic, respiratory as well as gastrointestinal symptoms. FEV1 and SNOT-22 were evaluated at 6 and 12 month, showing a global improvement (75% and 95%; 51 and 21 respectively). ACT raised to 23. LM score reduced to 8 at month 12. VAS score for abdominal pain reduced to 20 after 3 months so gradually all oral corticosteroids were successfully reduced by patient. After 6 months, patient was in steroid-free clinical remission with a stool frequency of 1–2 movements/day of normal feces (type 3 according to the Bristol stool chart) and a complete resolution of abdominal pain. BMI (Body Mass Index) reduced from 28 to 23 and none asthma exacerbation occurred during the first year of treatment and until the last follow-up evaluation (24 months) [].
Endoscopies were repeated in order to obtain new biopsy specimens, showing a remission of the disease in term of eosinophilic inflammation, glands where normal and neither reactive hyperchromatic changes, nor mucin depletion can be appreciated (Fig. d–f).
Basophils activation was evaluated after 12 months of MEP, using the surface molecules CD203c, CD63 and CD125, showing a reduction of activation percentages. Results are shown in Fig. a, b []. Serum IL-5 levels (R&D Systems; sensitivity: 0.29 pg/ml) were measured at baseline and after 3, 6 and 12 months of treatment and are shown in Fig. . Serum IL-5 was non-quantifiable at baseline and showed an increase with peak on 6 months as expected and previously demonstrated by Pouliquen et al. in 2015 (Fig. c) [].


Male, 27 years old, woodworker, who was admitted to the Department of Neurology of Zhongda Hospital on April 18th, 2019, because of a cough with fever for 12 days and headache for 4 days. Twelve days prior to admission, he presented with a cough and fever of up to 38.0°C, without expectoration or headache, and accepted antibiotic treatment for 3 days at a community-based hospital (specific medication was unknown). The cough and fever symptoms did not improve. Then he returned to his hometown. The doctors at the local community hospital administered azithromycin intravenously. At the same time, oral antipyretics were administered. Four days prior to hospital admission, the patient developed a headache and his temperature increased to 39.0°C, accompanied by nausea and vomiting. One day later, he was admitted to Xuzhou First People's Hospital. Brain magnetic resonance imaging (MRI) showed space-occupying lesions in the right basal ganglia, with obvious local edema (, before admission). Blood routine: white blood cells (WBC) 15.27 * 109/L, neutrophils 67.8%. After treatment with an antibiotic, the symptoms worsened, and his left limb muscle strength decreased. For further treatment, he was transferred to the NICU of the Department of Neurology of Zhongda Hospital on April 18. The patient was previously healthy, had a history of smoking for 10 years (10 cigarettes/day), had no history of immunosuppressive drug use, and had no other special abnormalities. On examination, Temperature 37.8°C; heart rate 66 beats/ min; respiratory rate 18 breaths/min; blood pressure, 107/62 mmHg; weight, 60 kg; and body mass index, 20.8 kg/m2. General examination showed no lesions of the nose, paranasal sinuses, orbits, or skin. Physical examination showed normal consciousness, left-sided central facial paralysis, muscle strength four out of five in the left upper and lower limbs, and the left-sided pathological reflex (Babinski sign) and meningeal irritation were positive. Blood routine tests were reexamined: WBC 15.42 * 109/L; neutrophil 12.92 * 109/L; neutrophil ratio 83.81%; lymphocyte ratio 9.32%. Lumbar puncture was operated: CSF pressure 220 mm H2O, light yellow, total cell count: 160 * 106/L; white cell count: 60 * 106/L; red blood cell count: 100 * 106/L, lobulated nucleus cells: 40%; monocyte: 60%. Biochemistry of CSF: Cl−: 123.8 mmol/L (120.0 ~ 130.0 mmol/L), glucose: 1.96 mmol/L (2.50 ~ 4.50 mmol/L), protein: 2557.9 mg/L (120 ~ 600 mg/L). No bacteria or fungi were found in blood, sputum and urine cultures. Tests for viruses were performed, with no positive results (including hepatitis B virus, hepatitis C virus, human immunodeficiency virus, treponema pallidum). The patient was empirically treated with meropenem (2 g, q8h) because of concern for bacterial meningoencephalitis. Glycerol fructose and mannitol were also used to reduce intracranial pressure. On the night of admission, a brain plain scan and enhanced MRI showed lesions in the right basal ganglia and frontotemporal lobe, and a new lesion in the left basal ganglia was found (, after admission). Magnetic resonance angiography of the head did not reveal evidence of stenosis or thrombosis of any major intracranial blood vessels. We then called the consultation of a neurosurgeon, and a diagnosis of brain abscess was made. Considering the incomplete formation of the abscess capsule, conservative treatment was recommended. We then adjusted our treatment plan as follows: imipenem (0.5 g, q6h), vancomycin (1,000 mg, q12h), and ornidazole (0.5 g, q12h). On the second day of admission, the patient developed altered consciousness, Glasgow Coma Score (GCS) of 5 (1 + 1 + 3). The diameter of the bilateral pupils was not equal: 3.5 mm on the right side, 2.1 mm on the left side, indicative of symptoms of cerebral hernia. Brain and chest computed tomography (CT) examinations revealed bilateral basal ganglia lesions with a right basal ganglia hemorrhage broken into the ventricle (, left) no abnormalities were found by chest CT. We then contacted the neurosurgeon again. Under general anesthesia, the patient underwent an emergency decompressive craniectomy and resection of the lesion of the right basal ganglia. A large amount of gray-yellow-red brain tissues with dark red blood clots was observed, and some brain tissues were removed for pathological biopsy. After surgery, the patient was transferred to ICU. Meropenem combined with vancomycin for anti-infective treatment was continued, and mannitol was also continued to reduce intracranial pressure. Endotracheal intubation and ventilator-assisted breathing therapy were also administered. On the same day, the CSF in the ventricular drainage tube was examined. No bacteria or acid-fast bacilli were detected by Gram staining. On the third day, the patient was still comatose, with a GCS score of 5 (1 + 1 + 3). The body temperature remained high, reaching 38.8°C. On the fourth day, we stopped meropenem and ceftriaxone was administered empirically. Meanwhile, we carried out NGS of the CSF etiology. The symptoms of cerebral hernia worsened further: bilateral pupil diameter increased, right pupil diameter 5 mm, left pupil diameter 3 mm. The light reflex disappeared. Re-examination of the brain CT showed that brain tissue swelling was more severe than before (, right). On the sixth day, the brain tissue histopathological results showed a large number of infiltrated neutrophils and abscesses formation, and fungal hyphae and spores were found in surrounding necrotic brain tissues, which tended to be Mucor (). Meanwhile, the results of NGS were obtained, suggesting Rhizopus microspore infections. No bacteria, viruses, mycoplasma, chlamydia, Mycobacterium tuberculosis complex or other pathogenic microorganisms were detected. We then stopped ceftriaxone and vancomycin, and added amphotericin B lipid formulation (5 mg/kg) and posaconazole (200 mg q6h). Unfortunately, the patient's condition continued to deteriorate during the night of April 24th. The bilateral pupil diameters both increased to 5 mm, and the light reflex completely disappeared. On the seventh day, the patient's family members stopped treatment, and the patient died on the sixth day after discharge.


A 66-year-old female presented with an acute onset of right upper quadrant abdominal pain and near syncope. Her medical history was notable for remote subarachnoid hemorrhage and aneurysm, with sequelae including incomplete quadriparesis and hydrocephalus requiring ventriculoperitoneal (VP) shunt, extensive bifrontal encephalomalacia, and dysphagia. Due to her history of brain injury, she was unable to give further details about her new onset abdominal pain.
On initial physical examination, vital signs were blood pressure 100/65 mmHg and heart rate 130 beats/min, and she was afebrile. There was no scleral icterus. Her abdomen was distended, exhibiting diffuse tenderness throughout her abdomen, worse in the right upper quadrant with voluntary guarding.
Laboratory test results were significant for elevated white blood cell 18 K/cmm, lactate 8 mmoL/L, and C-reactive protein 58 mg/L. Her liver function labs, including her total bilirubin, were all within normal limits. Abdominal ultrasonography suggested acute cholecystitis with a positive sonographic Murphy’s sign. A subsequent CT scan of the abdomen and pelvis showed cholelithiasis with gallbladder wall enhancement and thickening, with pericholecystic fluid, also consistent with acute cholecystitis; the CT scan also showed lateral and inferior perihepatic fluids, due to gallbladder perforation (Figure ).
Given her clinical decompensation with severe sepsis upon arrival to the medical intensive care unit (MICU) that evening, she was immediately and empirically started on both vancomycin and piperacillin/tazobactam, even prior to general surgery examining the patient. Ultimately, general surgery deemed her a poor surgical candidate, given her comorbidities, probable gallbladder perforation complicated by peritonitis, and her clinical decompensation with severe sepsis
Interventional radiology was consulted for an intra-abdominal drain placement, but due to a decompressed, perforated gallbladder, only a perihepatic drain was able to be placed on the second day of arrival to the MICU. Bile fluid from the perihepatic drain was obtained for cultures approximately one day after initiating antibiotics. The drain produced turbid fluid with gram-positive rods on stain. Although her cerebrospinal fluid did not show any bacterial infection, her VP shunt was externalized since it coursed through the site of infection. With the perihepatic drain placement, she clinically improved with regard to her mentation, abdominal pain, and leukocytosis; however, she continued to have high-output drainage in excess of 700 cc/daily of perihepatic fluid, initially turbid and subsequently clear and bilious. To redirect the high-output flow of bile, gastroenterology performed an endoscopic retrograde cholangiopancreatography-guided biliary sphincterotomy and stent placement, retrieving five gallstones from the gallbladder, and placing two stents, one in the common bile duct and one in the cystic duct (Figure ). Perihepatic drain output dramatically declined thereafter, and the patient continued to improve clinically.
On day 7 of her hospital stay in the ICU, her bile fluid culture, which was collected from the perihepatic drain approximately one day after initiating antibiotics, grew only Lactobacillus paracasei, which was resistant to vancomycin, cefotaxime, and metronidazole, but sensitive to piperacillin/tazobactam. Vancomycin was discontinued after a total of seven days. A repeat CT scan of abdomen showed diminished perihepatic fluid and signs of improved inflammation, and piperacillin/tazobactam was stopped after a total of 11 days.
Overall, the patient continued to improve each day with the perihepatic drain in place, and while on piperacillin/tazobactam.
Prior to transferring out of the ICU, the patient had her perihepatic drain successfully removed. Fortunately, her VP shunt remained sterile throughout this process and was eventually removed due to the patient demonstrating minimal output of cerebrospinal fluid and showing no signs of hydrocephalus on CT head. She spent a total of four weeks in the ICU and was transferred to the medicine floor without recurrence of her symptoms and with her mentation back to her baseline. Notably, the patient and her family had previously been recommended to have cholecystectomy but had declined.


A 13-months old Sudanese male presented with low grade fever and irritability. He was diagnosed with acute otitis media and placed on oral amoxicillin. Fever and irritability initially resolved but on day 7 of amoxicillin, fever (102°F) returned along with leukocytosis (20,000 cells/μL). Intramuscular ceftriaxone was given but within 24 h, he had developed vomiting, right arm weakness, worsening irritability, and persistent fever. Because of the onset of neurologic symptoms, a CT scan of the brain was performed and showed a large left parietal brain mass with midline shift and cerebral edema (). He underwent emergent left parietal craniotomy and evacuation of the brain abscess. Cultures yielded methicillin-susceptible Staphylococcus aureus (MSSA). He was treated with intravenous ceftriaxone for 6 weeks. He had resolution of the infection and complete resolution of neurologic symptoms. His previous history included a 36-weeks' gestation to consanguineous Sudanese parents. He was monitored in the neonatal intensive care unit for the first 4 days of life due to low birth weight. In the first year of life, he had two episodes of cellulitis, involving the lower leg and upper eyelid. Both episodes resolved with oral antibiotics. This patient's 4-year-old brother also had recurrent cellulitis and cutaneous abscesses at sites of minimal trauma for a toddler (upper back, face, abdomen).


A 33-year-old man was referred to our rheumatology department in 2003 because of low back pain accompanied by tenderness of the knees and small joints of the wrists. Since the axial pattern of affection dominated the clinical presentation at that time and the patient was HLA B27 positive, he was diagnosed with ankylosing spondylitis with accompanying peripheral arthritis. Low-dose glucocorticoids and methotrexate (15 mg weekly) were introduced, leading to significant improvement of signs and symptoms, as well as decline in the number of swollen and tender peripheral joints within the following months. Basal blood pressure values were normal (128/76 mmHg) while the estimated glomerular filtration rate (eGFR) was 99.8 mL/min/1.73 m2.
Despite initial improvement, the following time course was marked by aggravation of signs and symptoms consistent with peripheral polyarthritis, leading to a diagnosis of seronegative RA in 2005, fulfilling the 1987 classification criteria []. Methotrexate was continued, now in combination with sulfasalazine (2 grams daily) being replaced with leflunomide (20 mg daily) after several months. Despite combined treatment with conventional disease-modifying agents (DMARDs) and concomitant use of low-dose glucocorticoids, the patient suffered from a persistently active disease with a 28-joint disease activity score calculated using the erythrocyte sedimentation rate, ESR (DAS28-ESR) of 5.52. This prompted the initiation of adalimumab (40 mg subcutaneous every other week), while methotrexate was continued at a lower dose (10 mg weekly). This treatment strategy led to a satisfactory clinical response and reduction of DAS28-ESR to 2.66.
In 2006, the patient developed a psoriatic rash of the palms and soles, which was successfully treated with topical therapy. In the same year, the patient developed arterial hypertension (175/94 mmHg), for which an ACE inhibitor was introduced.
In 2011, the patient was still in stabile remission of his rheumatic condition (s) while continuously taking the biological drug; however, routine urinalysis unexpectedly revealed microscopic hematuria (urine sediment E 20–30 erythrocytes and 66–73% dysmorphic erythrocytes), accompanied by non-nephrotic proteinuria (2.25 g in daily urine, dU) with eGFR of 56 mL/min/1.73 m2. Urine cytology revealed no urothelial atypia, and urine was negative for M. tuberculosis. The erythrocyte sedimentation rate (ESR) was increased (64 mm/h) as well as the C-reactive protein (CRP) level (18.3 mg/L). The complete blood count was unremarkable, as well as blood urea nitrogen (BUN) (5.0 mg/dl) and serum electrolytes. Serum creatinine was increased (137 μmol/l), as well as total cholesterol (5.7 mmol/L), LDL-cholesterol (3.52 mmol/L), and triglycerides (2.78 mmol/L). Antinuclear, anti-neutrophil cytoplasmic, and anti-glomerular basement membrane antibodies (ANA, ANCA, and GBM, respectively) were negative. Serum protein electrophoresis, immunoelectrophoresis, and immunofixation were normal as well as serum complement levels (C3 and C4). Screening for hepatitis B, hepatitis C, and HIV (human immunodeficiency virus) were negative. On ultrasonography, both kidneys were of normal size with hyperechogenic parenchyma.
Percutaneous kidney biopsy was performed, and its results are shown in Figures and .
On light microscopy, diffuse mesangial hypercellularity was observed in all glomeruli, whereas global sclerosis was established in 1 of 15 glomeruli (6.66%). The tubules demonstrated degenerative changes while there were no changes on arteries. A moderate mononuclear infiltrate and mild fibrosis was noted in the interstitium. Immunofluorescence microscopy revealed mild mesangioproliferative changes. Electronic microscopy showed eosinophil infiltrates mostly in the mesangium, while several subendothelial and subepithelial eosinophil deposits were seen in the capillaries. In some glomeruli, there were signs of podocyte loss. Electronic microscopy also revealed glomerulonephritis with diffuse mesangial deposits and several subendothelial and subepithelial deposits compliant with glomerulonephritis caused by circulating immune complexes. The findings were in concert with the diagnosis of IgAN. There were no elements of diabetic nephropathy. The patient's MEST-C score was M1, E0, S1, T2, and C0.
Treatment with adalimumab and medium-dose glucocorticoids (prednisone 20 mg) was continued as well as an ACE inhibitor. Over the next two years, the patient was in a state of low disease activity (DAS28 3.08) of his RA, with progression of chronic kidney disease (eGFR 35.3 mL/min/1.73 m2) and persistent proteinuria (2.26 g/dU). This prompted discontinuation of adalimumab and a further increase in the dose of glucocorticoids (prednisone 60 mg), with the intention to control the renal disease.
Due to the increased prednisone dose, the patient gradually developed cushingoid features including type 2 diabetes mellitus; he was diagnosed in 2014. A slight improvement in kidney function (eGFR 44.1 mL/min/1.73 m2) and proteinuria (1.60 g/dU) allowed for a reduction of the prednisone dose to 40 mg. Of note, the patient's blood pressure was unremarkable, often being 120/80 mmHg or even less.
In 2015, the patient's kidney function was without further deterioration (eGFR 42.2 mL/min/1.73 m2) and without progression of proteinuria. Diabetes was not adequately controlled, and the patient also experienced a relapse of his RA; so, rituximab was introduced in 2016. Unfortunately, the drug had to be discontinued after three cycles due to lacking efficacy and an increase in proteinuria from 0.78 to 2.04 g/dU. After discontinuation of rituximab, a decision was made to commence treatment with baricitinib, an oral selective JAK inhibitor. This finally led to the achievement of a low disease activity state of RA. However, the patient still continued to have persistent proteinuria of 1.9 g/dU, with no further decline in the eGFR.


A 27-year-old woman was referred in 2007 to our rheumatology department because she had tenderness of her feet and knees with normal levels of acute phase parameters. Nine years before this referral, she was diagnosed with diabetes type 1 with consequent mild retinopathy and neuropathy.
Given that she had no swollen joint, an expectative approach was initially taken, and she was treated with NSAIDs. However, in early 2009, she developed symmetrical peripheral polyarthritis consistent with a diagnosis of seronegative RA, and she was put on low-dose methylprednisolone (8 mg qd) and weekly methotrexate (15 mg). Due to suboptimal response, sulfasalazine (2 grams daily) was added to the aforementioned regimen. Her blood pressure values were normal (122/64 mmHg), while her estimated glomerular filtration rate (eGFR) was 103.2 mL/min/1.73 m2. Although low disease activity was achieved in the following months, she again started to develop active disease with swollen and tender joints of her hands, feet, and knees. A pattern of persistently active disease with a DAS28-ESR exceeding 5.00 led to the decision to start the patient on golimumab (50 mg subcutaneously, once monthly) in 2012. Achievement of sustained clinical remission allowed the discontinuation of glucocorticoids, while the dose of methotrexate was also gradually tapered, and the drug was finally stopped in 2013. Around that time, the patient developed arterial hypertension (160/90 mmHg), with an intact renal function.
In 2015, the patient was still in persistent remission of her rheumatic disease. Routine screening of her 24 h urine revealed albuminuria of 420.53 mg/dU and proteinuria of 0.47 g/dU. The findings were accompanied by a history of oscillatory hypertension and occasional ankle oedema. Laboratory tests revealed the following: hemoglobin: 11.7 g/dl, hematocrit: 37%, white blood cell count: 7.1 × 109/L, platelet count: 247 × 109/L, BUN: 4.9 mg/dl, serum creatinine: 61 µmol/L, eGFR 112.8 mL/min/1.73 m2, albumin: 34.6 g/L, cholesterol: 4.6 mmol/L, triglycerides 0.61 mmol/L, and LDL-cholesterol: 2.36 mmol/L. Serum electrolytes were within normal limits. The erythrocyte sedimentation rate (ESR) was 20 mm/h, while the level of C-reactive protein (CRP) was normal. Serum protein electrophoresis and classes of immunoglobulins (IgG, IgA, and IgM) were within normal limits. Immunological screening (comprised of complement components C3 and C4, anti-neutrophil cytoplasmic antibodies, antinuclear antibodies including extractable nuclear antigens, and anti-glomerular basement membrane antibodies) was also unremarkable. Screening for hepatitis B and C, as well as HIV) was negative. On ultrasonography, both kidneys were of normal size, with a hyperechogenic parenchyma.
Percutaneous kidney biopsy was performed, and the pathohistological findings are shown in Figures and .
On light microscopy, diffuse mesangial hypercellularity was demonstrated in all glomeruli, whereas a perihilar segment of sclerosis was established in 1 of 17 glomeruli (5.88%). Degenerative changes were seen in the tubules, while segmental intimal deposits were described in the arteries. There were no signs suggestive of interstitial inflammation and/or fibrosis.
Immunofluorescence microscopy showed diffuse IgA, moderate C3, and lambda light chains, and low IgM and kappa light chains deposits in the mesangium while there were no IgG, C1q, and fibrin deposits. Moderate C3 deposits were described in the arteries. Electronic microscopy revealed eosinophil infiltrates mostly in the mesangium and several subendothelial and subepithelial eosinophil deposits in the capillaries. Loss of podocytes was described in some of the glomeruli. There were no elements of diabetic nephropathy. The biopsy findings were consistent with IgAN class II, with a MEST-C score being M1, E1, S1, T2, and C0.
Given the remarkable and sustained response of RA to golimumab, the biological drug was continued, with the addition of an ACE inhibitor. During 2016, the patient was still in clinical remission of her RA with a stabile kidney function (eGFR 60.2 mL/min/1.73 m2), but proteinuria increased to 3.0 g/dU. This led to the decision to discontinue golimumab and start the patient on oral cyclophosphamide (50 mg bid) with 40 mg of prednisone. Three months later after introduction of Endoxan, proteinuria dropped to 1.03 g/dU (partial remission); thus, cyclophosphamide was replaced with azathioprine (50 mg bid), with gradual tapering of prednisone. It is noteworthy that the kidney function did not decline over the follow-up period (eGFR 62.5 mL/min/1.73 m2), while proteinuria continued to gradually improve (to 0.65 g/dU), despite inadequately controlled glycemia (provoked due to relatively high doses of prednisone). Such an improvement allowed for a further tapering of prednisone. In the following year, rituximab was introduced as a biological disease-modifying agent to control rheumatoid arthritis (1 gram on days 0 and 14, repeated every 6 months). Given that it was found reasonable to expect that rituximab may serve as a sound option for the maintenance of remission of the patient's renal disease, azathioprine was discontinued. In the following course (after three cycles of rituximab), the patient continued to be in clinical remission of her RA, but also achieved a complete decline in proteinuria to 0.09 g/dU with normal kidney function (eGFR was 73.3 mL/min/1.73 m2) and good blood pressure control (<130/90 mmHg).


A 48-year-old woman was referred to our rheumatology department in 2004 due to tenderness of her small joints of the wrists and knees, accompanied by morning stiffness of the lower back. Four years prior to the first visit, she was diagnosed with diabetes type 2. After initial workup, she was diagnosed as undifferentiated polyarthritis and was treated with NSAIDs and medium- to low-dose prednisone with good response and relief of symptoms. In 2009, she was finally diagnosed as seropositive rheumatoid arthritis with high titers of both RF and anti-CCP antibodies. She was put on 15 mg of methotrexate weekly, as well as sulfasalazine 2 grams daily.
In 2011, RA was still clinically active with increased inflammatory parameters and high DAS28-ESR of 7.09, so methotrexate was increased to 25 mg once a week but without considerable clinical effect. Therefore, a TNF-α inhibitor was introduced; she was started on adalimumab (40 mg subcutaneous every other week) with methotrexate 25 mg once weekly. She continued to take low-dose prednisone (up to 7.5 mg daily), achieving a satisfactory clinical response and reduction of DAS28-ESR to 2.28.
However, in 2015, she again started developing clinically active disease, but with normal inflammatory parameters. In 2016, she developed increased inflammatory markers with development of puffy pretibial edema and microcytic anemia. Laboratory tests showed hemoglobin: 10.5 g/dl, hematocrit: 33%, mean corpuscular volume: 73.2 fL, white blood cell count: 13.3 × 109/L, platelet count: 297 × 109/L, BUN: 8.5 mg/dl, serum creatinine: 81 µmol/l, eGFR: 68 mL/min/1.73 m2, albumin: 31.0 g/L, cholesterol: 5.6 mmol/L, triglyceride: 1.65 mmol/L, and LDL-cholesterol: 3.59 mmol/L. Serum electrolytes were within normal limits. Proteinuria was 4.55 g/dU. Erythrocyte sedimentation rate (ESR) was 100 mm/h, CRP 45.9 mg/L. Serum complement levels (C3 and C4), ANA, ANCA, and anti-glomerular basement membrane (GBM) antibodies were all unremarkable. Serum protein electrophoresis revealed polyclonal hypergammaglobulinemia while immunofixation was normal. Screening for hepatitis B, hepatitis C, and HIV was negative. On ultrasonography, both kidneys were of normal size, with hyperechogenic parenchyma.
Percutaneous kidney biopsy was performed; results of the histopathological analyses are shown in Figures and .
Light microscopy revealed diffuse mesangial hypercellularity with segmental formation of nodules in all glomeruli, whereas global sclerosis was established in 5 of 22 glomeruli (22.7%). Degenerative changes were demonstrated in the tubules, while the findings in the arterioles included concentric intimal hyalinosis and moderate intimal fibrosis with elastosis. There was no mononuclear infiltrate but fibrosis was present in interstitium.
Immunofluorescence microscopy showed diffuse IgA, moderate C3 and lambda light chains, and low IgM and kappa light chain deposits in the mesangium while there were no IgG and C1q deposits. Moderate C3 deposits were detected in the arteries. Electronic microscopy showed osmiophilic deposits mostly in the mesangium and paramesangium deposits. Glomerular basal membranes were a bit thicker without osmiophilic deposits, with stationary thicker internal lamina rara. Podocyte loss was described in some of the glomeruli. Therefore, a diagnosis of diabetic nephropathy with superimposed IgAN was established, prompting the decision to discontinue adalimumab. The patient's MEST-C score was M1, E1, S1, T2, and C0. The cause of microcytic anemia was two polyps of the colon which were removed. At that time, the patient developed arterial hypertension (170/90 mmHg) and an ACE inhibitor was introduced, with the aim to control hypertension and to control the proteinuria. Arthritis was suboptimally controlled with low-dose steroids. The patient continued to have nephrotic-range proteinuria, as well as high disease activity of her RA. This prompted the decision to target both patient's conditions with a single agent, rituximab, administered in 4 cycles. This led to remission of arthritis, as well as a pronounced decline in proteinuria to 0.13 g/dU, with a stabile kidney function, which was sustained through the following period (eGFR 65 mL/min/1.73 m2).


A 60-year-old male with a congenital absence of the inferior vena cava (IVC) ( presented with symptomatic, persistent AF (, with resulting cardiomyopathy related to his tachyarrhythmia. His associated comorbidities included diabetes, deep vein thrombosis, obesity, and severe venous insufficiency with chest and abdominal wall varicosities. His exertional dyspnea and dilated left ventricular dysfunction (ejection fraction: 20%) prompted referral for possible combined surgical and electrophysiological treatment.
Following careful review in our multidisciplinary AF center, we elected to perform an open full Cox maze IV procedure. The ascending aorta and superior vena cava (SVC) were cannulated within purse-string sutures and umbilical tape placed around the SVC. Next, cardiopulmonary bypass was initiated. The right pulmonary veins were ablated with seven applications using the Isolator Synergy bipolar radiofrequency (RF) clamp (Atricure, Mason, OH, USA). After initiating cardiopulmonary bypass, with intermittent SVC occlusion while the heart continued beating, we ablated the left pulmonary veins six times and confirmed entrance block.
Under cardioplegic arrest, we opened the left atrium and connected the pulmonary veins with roof and floor lesions between the respective superior and inferior veins using the cryoICE® cryoenergy instrument (Atricure, Mason, OH, USA). We then initiated a cryo lesion into the left atrial appendage and to the P2 leaflet of the mitral valve annulus. We further created an epicardial cryo lesion at the mitral valve annulus and a right transatrial lesion across the floor of the interatrial septum, respectively.
We excluded the left atrial appendage with a 45-mm Atricure clip (Atricure, Mason, OH, USA). Two RF ablations were then created across the middle of the posterior left atrium to further segment this large region of tissue. After completing the left-sided lesion, we closed the left atrium and released the cross-clamp. While the heart was beating, we created cryolesions to the tricuspid valve at both the anterior and posterior leaflets. A connecting lesion was made across the floor of the right atrium into the coronary sinus to connect to the transseptal lesion. We then used bipolar energy to create a lesion from the SVC to the IVC.
After closing the right atrium, a Webster® deflectable decapolar catheter (Biosense Webster, Diamond Barr, CA, USA) was placed into the coronary sinus through a separate purse-string suture and verified by fluoroscopy. Next, a second purse-string suture was placed in the right atrium and a percutaneous needle was positioned through the right atrial free wall, across the intra-atrial septum and into the left atrium using transesophageal echocardiography guidance. Using the Seldinger technique, a 9-French, 16-cm Radifocus® Introducer sheath (Terumo, Somerset, NJ, USA) was then positioned across the septum and secured with a purse-string suture to the right atrial free wall.
An endocardial three-dimensional (3D) map of the left atrium was constructed using the Rhythmia HDx™ hardware and software (Boston Scientific, Natick, MA, USA) and with fusion of computed tomography (CT) images (. We created an epicardial electroanatomical map using the same mapping system by manipulating the catheter around the epicardial surface (. These maps revealed complete isolation of the posterior wall of the left atrium and the pulmonary vein pedicle. There was complete block across the mitral isthmus. This demonstration of the endocardial and epicardial completeness of the Cox maze IV procedure indicated no necessity to add further RF lesions to complete the operation (.
The patient had an uneventful postoperative course and remained in normal sinus rhythm with first-degree atrioventricular block throughout his hospital stay. He continued on home-dose amiodarone, and coumadin was restarted prior to discharge. At the six-month follow-up, the patient remained on amiodarone and coumadin while demonstrating resolution of his AF. His follow-up transesophageal echocardiogram demonstrated improved left ventricular function (ejection fraction: 48%), with no significant change in his left atrial size (left atrial ejection fraction was not documented).


Patient 1 was a 50-year-old woman (height 1.55 m, weight 82 kg, BMI 34.1 kg m-2) with severe steroid-dependent allergic asthma who demonstrated no therapeutic response to omalizumab. The patient had never smoked. Disease onset had occurred in early childhood, with remission from age 15–25. The patient had a history of severe pulmonary exacerbations requiring mechanical ventilation and tracheostomy, despite regular treatment with high-dose oral and inhaled corticosteroids and LABA. In August 2015, the patient underwent bone marrow aspiration and received a single dose of autologous BMMCs intravenously. Measured variables were performed before treatment and periodically up to 1 year after BMMC transplantation (Table ). Whole-body 99mTc-BMMC scintigraphy was performed 2 h after administration and demonstrated a normal biodistribution of labeled cells, with greater uptake in the liver, lungs (especially the right), heart, blood pool, kidneys, and bladder (Fig. ). Over the following days, the patient experienced improvement of respiratory symptoms but developed sinus tachycardia, requiring a reduction in LABA dose. A mild increase in ventilation of all zones of the right lung was also observed 120 days after BMMC transplantation. Asthma control was successfully achieved with half of the prior dose of inhaled corticosteroids and LABA for up to 12 months after BMMC transplantation. Self-perceived QoL score significantly improved on day 7 after the procedure and remained steady over 1 year of follow-up (Fig. ). Lung function and 6MWD measurements remained stable throughout.


Patient 2 was a 58-year-old woman (height 1.53 m, weight 75 kg, BMI 32.0 kg m-2) with severe steroid-dependent allergic asthma who also failed to respond to omalizumab. Disease onset had occurred in early childhood; there had been no remission. The patient had mild bronchiectasis without chronic infection and had never smoked. IgE testing for Aspergillus fumigatus was negative on multiple occasions. The patient was on regular high-dose oral and inhaled corticosteroids plus LABA and had a history of multiple hospital admissions due to pulmonary exacerbations. In November 2015, bone marrow aspiration was performed, and the patient received a single dose of autologous BMMCs intravenously and was periodically followed for a year (Table ). Corticosteroids and LABA were continued. Whole-body 99mTc-BMMC scintigraphy performed 2 h after cell infusion demonstrated a normal biodistribution of labeled cells, with greater uptake in the liver, lungs, heart, blood pool, kidneys, and bladder (Fig. ). Thirty days after the procedure, asthma control was achieved, and the patient demonstrated better exercise tolerance as well as a reduction in corticosteroid requirements. During the following months, the patient had three pulmonary exacerbations, each requiring an increase in the dose of oral corticosteroids and prescription of antibiotics. No significant changes in ventilation or perfusion from baseline were observed on day 120 post-BMMC transplantation. Over the 1-year follow-up period, her asthma remained partially controlled. Lung function, 6MWD, and self-perceived QoL score improved slightly up to 30 days after BMMC transplantation (Table , Fig. ). On day 60, these parameters declined, which remained stable thereafter.


Patient 3 was a 58-year-old woman (height 1.58 m, weight 56 kg, BMI 22.4 kg m-2) with severe non-allergic asthma. Disease onset occurred at age 47; the patient had never smoked. She had dyspnea with minimal exertion despite regular treatment with high-dose inhaled corticosteroids, LABA, and a long-acting muscarinic antagonist. Severe obstruction was also observed on spirometry, with a positive bronchodilator test. In December 2016, the patient underwent bone marrow aspiration and received a single dose of autologous BMMCs intravenously. Lung function remained stable throughout the follow-up period. Asthma control, QoL score, and 6MWD improved slightly over the first 30 days after BMMC transplantation and remained stable up to day 180 (Table , Fig. ). Thereafter, a mild increase in breathlessness was reported, but without the need to change baseline treatments. At 1-year follow-up, asthma symptoms were partially controlled, and both self-perceived QoL and 6MWD had improved from baseline.
In the first trimester of 2020, all patients were alive, with a significant reduction in the number of hospital admissions during their respective follow-up periods compared to before BMMC transplantation. Patient 2 had a pneumonia episode in 2019, however, recovered well. More recently, both patients 1 and 2 were using only an oral inhalation solution of formoterol fumarate plus budesonide, while patient 3 was using two oral inhalation solutions (formoterol fumarate/beclometasone and tiotropium bromide).


A 49-year-old female with a past medical history of EB, long-standing hypertension, and rheumatoid arthritis presented to the emergency department (ED) with right groin pain of one-hour duration after falling on her right side. After the fall, the patient was not able to bear weight and remained in a sitting position until she was taken to the ED. On the next day, she underwent a successful open reduction and internal fixation (ORIF) for her right hip without complications (Figure ).
Over the course of three months after the procedure, she experienced worsening of the pain accompanied by skin necrosis and total collapse of the femur head (Figure ).
After that, the patient was scheduled to undergo a right THA. Before the surgery, a dermatology consult was obtained and approved the patient for surgery as long as there was careful and gentle handling of the skin during the application of povidone-iodine in the preoperative skin preparation. Furthermore, the dermatological team advised that only experts in anesthesia should proceed with intubation for surgery in order to avoid causing a mucosal injury in such a patient with fragile skin. A preoperative 2 g dose of the cefazolin IV was given along with the induction of anesthesia. The THA surgery was performed using a cementless (Zimmer, Warsaw, IN) prosthesis and fixated via cannulated screws (Figure ).
The surgical wound was closed with a 2-0 nylon thread using a vertical mattress interrupted suture technique with gel, and no adhesive tape was used during wound closure. Vancomycin 500 mg IV and imipenem/cilastatin 500 mg IV were given for four days postoperatively. Postoperative pain control consisted of 10 mg morphine over six hours, 1 g of paracetamol given intravenously every six hours, and a 400-g dose of gabapentin given at bedtime. The pain score before the surgery was 10/10 and 5/10 immediately after the THA surgery. For a period of 25 days after the surgery, the patient did not complain of any pain. Upon follow-up, sutures were removed, and no surgical wound infection, rashes, or lacerations were noted.


The patient was a 30-year-old man who presented with primary infertility having had 5 years of regular unprotected intercourse. He visited our center for his reproductive problem. Female factors were excluded. Two routine semen analyses, performed according to the World Health Organization guidelines [], revealed severe oligozoospermia. The known causes of male infertility, including obstructive causes, infectious factors, genitourinary injury factors, chromosomal abnormalities, and AZF microdeletions, were excluded. Family genetic history and information about personal habits were collected using a questionnaire survey. The patient’s medical history was unremarkable for infertility risk factors. Physical examination revealed normal penis and pubic hair. The patient’s endocrine status was assessed by electrochemiluminescent immunoassays for reproductive hormone levels including luteinizing hormone, follicle stimulating hormone, testosterone, and estradiol. The patient chose intracytoplasmic sperm injection (ICSI) as the treatment for his primary infertility. He agreed to participate in the research and signed informed consent. The present study was approved by the Ethics Committee of the First Hospital of Jilin University.


The proband was a 13-day-old female, the second child of healthy non-consanguineous parents. She was born as the first of fraternal twins at 37 weeks via cesarean section due to reduced heart rate of the twins. Her birth weight was 2.4 kg (<10th p). Her older brother and the other neonate twin were both normal, and there was no relevant medical family history. After birth, she required a laryngeal mask to pressurize the oxygen. The treatment relieved her cyanosis. She was then immediately transferred to the local neonatal intensive care unit where she was intubated and ventilated. She was also treated with anti-infectious and excitatory respiration center drugs (nalmefene hydrochloride injection). However, the effect was poor. She failed to extubate after multiple attempts due to carbon dioxide retention. The patient was hospitalized in our neonatal intensive care unit for dyspnoea for 13 days with failure to extubate for 1 day.
The patient had a full-term appearance, a weight of 2.35 kg, poor response to physical examinations, weak crying, labored breathing, shortness of breath, and a positive three-concave sign. Both lungs were clear on auditory percussion. Neither obvious wet nor dry rattling was heard. The heart rate was strong, and no obvious murmurs were heard in the precordial region. There was no abdominal guarding upon palpation, and abdominal rumbling was weak. There was reduced movement of the limbs, decreased muscle tone and absent primitive reflexes.
The results of routine blood examination were as follows: white blood cell count 27.90 × 109/L, erythrocyte count 3.61 × 1012/L, hemoglobin 113.0 g/L, platelet count 390 × 109/L, percentage of neutrophils 55.8%, and percentage of lymphocytes 32.8%. The levels of inflammatory markers were as follows: procalcitonin 0.390 ng/mL and C-reactive protein 7.60 mg/L. The N-terminal pro b-type natriuretic peptide level was 1,334.00 pg/mL. The prostigmine test was positive. The fungal glucan level was 405.05 pg/mL. The myocardial enzyme levels were as follows: creatine kinase 70.00 U/L and creatine kinase isoenzyme 20.10 U/L. The chest plain film indicated a double-lung texture growing thick and heavy, and CT images showed an increasing density of patchy shadows with blurry margins, which was consistent with the manifestations of pneumonia (). No abnormalities were found on cranial MRI (). In regard to brain function, the upper and lower peaks were generally normal, but the differences in the sleep-wake cycle were not obvious. The acetylcholine receptor antibody level was 0.045 mmol/L (within the normal range).
Upon transfer to our neonatal intensive care unit, the patient's oxygen saturation decreased frequently and at times was accompanied by convulsions. Subsequently, the patient was intubated for mechanical ventilation, was fed milk through a nasogastric tube and later showed difficulty in weaning from the ventilator. We administered a neostigmine (0.05 mg/kg) intramuscular injection, which relieved the dyspnoea and improved her feeding. We then orally administered pyridostigmine (5 mg/kg) to replace the intramuscular injection, which controlled her dyspnoea. We did not observe any side effects from these drugs. Later, she was weaned successfully from mechanical ventilation and could gradually breathe independent of oxygen therapy. However, episodes of dyspnoea accompanied by cyanosis and decreased oxygen saturation occurred upon reducing the dosage of pyridostigmine. We failed to make a definitive diagnosis at the initial stage of treatment due to rejection of genetic testing by the family members. She was transferred to a hospital with better equipment and treatment capacity, according to the parent's wishes, where she died.
In consideration of the clinical course of the neonate, we suspected that she had CMS. To explore the potential genetic etiology, we communicated with the patient's parents repeatedly and ultimately obtained informed consent for genetic tests 15 days after admission. The genetic testing was performed when she was 28 days old (2018-05-14). Two milliliters of peripheral blood was extracted from the proband and her parents. The blood was sent to Cipher Gene LLC, and the following tests were conducted. Whole exome sequencing was performed on the proband and her parents using the Illumina NovaSeq 6000 platform. Agilent SSELXT Human All Exon V6 was used to capture and construct the library, and a paired-end sequencing strategy was used. CNV-Seq was performed on the proband using the Illumina NovaSeq 6000. A TruSeq Library Construction Kit was used to capture and construct the library, and a paired-end sequencing strategy was used. CNV-Seq indicated a 4.9 Mb deletion [10q11.22-10q11.23 (chr10: 46123781-51028772)], which contained the whole CHAT gene (). The whole-exome sequencing validated by Sanger sequencing indicated that the patient carries a hemizygous mutation in exon14 of CHAT (c.1976A>T, p.Gln659Leu), which is inherited from her father ().


A 40-year-old Chinese Han male presented to the emergency room of Peking Union Medical College Hospital with the chief complaints of nausea, vomiting and anuria. He had been in his usual health until approximately 10 days ago, when he took 500 mg paracetamol to alleviate a headache. Later in the day, nausea and vomiting developed without fever, rash, edema or gross hematuria. During the next week, his blood creatinine level increased gradually from normal to 700 μmol/L, followed by a decrease in urine output. The day before admission his urine volume was only 40 mL/day. His plasma creatine kinase levels were constantly normal.
He had a 12-year history of hypertension, with the highest blood pressure ever observed being 150/110 mmHg. His blood pressure was well controlled with amlodipine (below 140/90 mmHg). He had no significant past or family history of kidney diseases. The patient is a military man and has a comprehensive health checkup every year. A health checkup performed 1 months before the onset of his symptoms showed that his routine urine test and serum creatinine level were normal. He had been taking part in long-distance running almost every day for some years, and running approximately ten kilometers each day. Although he sweated a lot, he insisted on not drinking water during or within one hour after the exercise, aimed at “losing weight”.
Physical examination revealed an anxious appearance. He was hypertensive with a blood pressure of 148/108 mmHg (without taking his anti-hypertensive medicine on that day), respiratory rate of 20 breaths/min, and heart rate of 70 beats/min. His oxygen saturation was 97% in room air. His body mass index was 24.6 kg/m2. No other findings were remarkable.
His serum creatinine level was 860 μmol/L, and the urea was 12.49 mmol/L. Urinalysis showed that the white blood cell count was 15 cells/mL and red blood cell count was 80 cells/mL (only 30% were dysmorphic). Protein excretion rate was 250 mg/24 h. Ultrasound of the urinary system showed enlarged kidneys (right kidney 13.3 × 6.6 × 7.3 cm; left kidney 14.2 × 6.5 × 6.1 cm).
The patient underwent ultrasound-guided transdermal renal biopsy. Acute tubular necrosis (ATN) was diagnosed, characterized by dilated tubules lined by flattened tubular cells, effacement of the proximal tubule brush border, distal tubule casts, and interstitial edema under the light microscopy. No tubular crystals were identified by polarized light microscopy. The glomerulus and blood vessels were largely normal (Fig. ). Immunofluorescence and electron microscopy supported the diagnosis of ATN.
After 7 weeks of dialysis, his baseline creatinine decreased to 300 μmol/L, and serum electrolytes were normal. His urine volume increased to more than 3 L/day.
The patient’s creatinine declined continuously and stabilized at 45 μmol/L after discharge from hospital. His urinalyses were also normal. He restricted his salt and calorie intake, and started long-distance running once again, without taking enough water. He had lost 10 kg within the next year. His blood pressure kept normal without antihypertensive therapy. One year after the first discharge, a routine health checkup showed that his creatinine had increased to 150 μmol/L, and he was re-admitted to our hospital.
His routine urine test and urine sediment analysis were normal. Protein excretion rate was 420 mg/24 h. Laboratory tests including complete blood count, serum uric acid, serum immunoglobulins, complements, anti-neutrophil cytoplasmic antibodies, anti-nuclear antibodies, anti-glomerular basement membrane antibody, erythrocyte sedimentation rate and C-reactive protein were all normal. Serum tumor markers and serum immunofixation electrophoresis were also normal. Ultrasound showed that both kidneys had shrunk (right kidney 9.5 × 5.7 × 4.4 cm; left kidney 10.4 × 5.6 × 5.5 cm). Artery ultrasound including renal, carotid, lower extremity and mesenteric arteries showed no evidence of stenosis or thrombosis.
Renal biopsy was performed for the second time. Nine of 25 glomeruli showed global sclerosis, and the basement membrane in non-sclerotic glomeruli had variable thickening and wrinkling. Patchy tubular atrophy and interstitial fibrosis were observed. The arteriolar wall was thickened and the vascular lumen was narrowed (Fig. ), and no tubular crystals were found under polarized light. Immunoglobulins and complements were not observed in the tubulointerstitium, glomeruli, nor blood vessels under immunofluorescence. Electron microscopy showed no abnormalities.
Considering the patient’s history of long-distance running, ischemic changes in renal biopsy, and exclusion of other likely causes of CKD, especially vascular diseases, chronic dehydration-associated kidney disease similar to MeN was suspected. The patient underwent CKD management including regular monitoring, blood pressure control and lipid control. During the follow-up period, the patient’s creatinine fluctuated between 150 and 180 μmol/L.


A 75-year-old woman with a medical history of hypertension presented at another institution with fecal occult blood, and a colonoscopy showed a type II tumor in the sigmoid colon. She was referred to our hospital for tumor resection, where colonoscopy determined that the tumor was located 23 cm from the anal verge. Histopathology of a biopsy specimen revealed a moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed sigmoid colon wall thickening. Regional lymph node metastasis was suspected, but no evidence of distant metastasis was observed. A blood examination revealed an elevated carcinoembryonic antigen (CEA) concentration (32.7 ng/ml). Following a diagnosis of cancer of the sigmoid colon, clinical stage IIIb [cT4a, N1b, M0], a laparoscopic sigmoid colectomy was performed without complications. The postoperative histopathological examination revealed a moderately differentiated to mucinous adenocarcinoma. Three of the 16 retrieved lymph nodes contained malignant cells. Finally, the cancer was classified as stage IIIb [pT4a, pN1b, M0]. The patient recovered uneventfully and was discharged 10 days after the surgery. Following the diagnosis of stage III colorectal cancer, the patient was recommended to receive adjuvant chemotherapy with CAPOX starting 4 weeks after surgery. The selected regimen consisted of capecitabine (1,000 mg/m2 orally twice daily) for 14 days and L-OHP (130 mg/m2 intravenous infusion) on the first day of each cycle, with a periodicity of 3 weeks over 3 months (four cycles). The anticancer drug dosage was reduced to 80% because of the patient's age. The patient had postoperative physical weakness and appetite loss, and also received 7.5 g of NYT daily throughout the course of adjuvant chemotherapy. She did not report any events of peripheral loss of appetite, general fatigue, peripheral neuropathy, neutropenia, or febrile neutropenia. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. She has not experienced any recurrence during a 1-year postoperative follow-up.


The patient was a 58-year-old Japanese woman who visited the Department of Dentistry and Oral Surgery, Tsuyama Central Hospital (Okayama, Japan) at the end of May 2018, complaining of a painful right maxillary premolar gingiva and ulcer for the most recent 2 weeks. The patient had had RA for 10 years and had been treated with several immunosuppressive drugs, including MTX (2 mg/week for 6 months and 4 mg/week for 6 months) and prednisolone (PSL: 2 mg/week for 10 years).
On clinical examination, a right submandibular lymph node was swollen, with pain. The intraoral examination showed swelling with necrotic ulcer formation of the right maxillary gingiva in the canine to the first molar region. There was no exposure of perilesional alveolar bone. The perilesional premolar showed mild mobility with occlusal and percussion pain (). A blood examination revealed EBV infection (EBV viral capsid antigen IgG = 320, IgM < 10, IgA < 10, and EBV nuclear antigen = 80).
There was no obvious bone destruction with lesion anywhere as shown by dental radiographs and head and neck computed tomography (CT). Lymph node swellings were not detected except for the right submandibular lymph node. However, chest CT indicated the presence of a nodular mass that was suspected to be a malignant lung tumor of the bilateral lungs, and S8 of the inferior lobe of the right lung was the largest. Fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) indicated the presence of increased uptake in the right maxilla (maximum standardized uptake value: SUVmax = 5.85) and bilateral lungs (S8 of the inferior lobe of the right lung SUVmax = 4.94) but no uptake in the right submandibular lymph node ().
We performed a biopsy based on a suspicion of MTX-LPD since the patient had been treated with MTX to treat RA for approximately one year. Hematoxylin and eosin staining showed a high degree of atypical large-sized lymphocyte infiltration with a background of inflammatory cell infiltration in the submucosal stroma. Immunohistochemistry staining showed that the atypical large-sized lymphocytes were positive for CD20 and negative for CD3, CD5, and CD10; the Ki-67 labeling index was high. The result of EBV-encoded small RNA in situ hybridization (EBER-ISH) was positive, and the histopathological diagnosis was EBV-positive diffuse large B-cell lymphoma (DLBCL) ().
It was not possible to make a diagnosis of bilateral lung lesions because the patient refused an endoscopic biopsy, but a hematologist and respiratory medicine physician at another hospital indicated that the lung lesion was also MTX-LPD. From the results obtained in these examinations, we diagnosed MTX-LPD that had developed ectopically and was expressed at the same time in the maxillary gingiva and bilateral lungs.
We consulted the patient's primary physician, and the patient's treatment with MTX was then discontinued. Two weeks after the discontinuation of MTX, the ulcer and swelling in the gingival lesion were reduced, and the swelling and pain in the right submandibular lymph node had resolved.
The size of the nodular mass at the bilateral lungs also began to reduce. At 4 weeks after the discontinuation of MTX, we confirmed that the ulcer had disappeared completely, but the perilesional alveolar bone was exposed due to shedding of the necrotic gingiva. At 5 weeks, the exposed alveolar bone necrosed, and we removed sequestrum along with the premolar of the patient under local anesthesia.
At 2 weeks after this surgery, the wound was covered by normal epithelium, and the lesion had completely disappeared. The nodular mass at the bilateral lungs had also completely disappeared. The patient's RA had slightly worsened with joint pain, but her rheumatologist maintained good control of the symptoms with analgesics without a change to another drug for RA. At 15 months since the withdrawal of MTX, the patient was in a good condition without recurrence.


A 32-year-old female with opiate use disorder and bipolar depression, presented with acute onset of abdominal pain and non-bloody diarrhea for the past two days. Two weeks before hospitalization, she was prescribed lamotrigine at a drug rehabilitation center for bipolar disorder. On physical examination, her vital signs were with normal limits. Apart from dry mucous membranes and mild generalized abdominal tenderness, her physical exam was unremarkable. Our initial working diagnosis included opiate withdrawal associated with diarrhea vs viral gastroenteritis. She was managed conservatively with intravenous fluids. However, diarrhea worsened and it became bloody. She subsequently developed fever, facial edema and a red, violaceous maculopapular rash on her arm. An initial concern for invasive bacterial gastroenteritis led to the initiation of intravenous broad-spectrum antibiotics. Unfortunately, her symptoms worsened and the rash spread to more than 50% of her body. Labs were significant for leukocytosis (17 x 109/L, reference range: >11 x 109/L), eosinophilia (43%, reference range: <6%) and atypical lymphocytosis (18%, reference range <5%). Her liver function tests (LFTs) were within normal limits. The remaining blood work was normal including chemistry and thyroid profile. Stool studies were negative for invasive pathogens, including parasites. Given the unrelenting bloody diarrhea, a colonoscopy with biopsy was done and this showed pancolitis with prominent eosinophilic infiltrates (Figure ).
A skin biopsy was undertaken to assess the rash and this revealed vacuolar interface dermatitis, perivascular lymphocytic infiltrate with eosinophils, consistent with a morbilliform rash (Figure ).
A diagnosis of DRESS syndrome was made based on a “regiSCAR” score of 6. The drug lamotrigine was presumed to be the cause of her symptoms and was stopped. She received a course of systemic steroids after which her diarrhea, rash, and eosinophilia resolved.


A 27-year-old man with a past medical history significant for AIDS, KS, and latent syphilis came to the ED complaining of persistent fatigue, fever, chills, night sweats, diffuse headaches, and a productive cough with white sputum. He was found to have a persistent temperature of up to 40.1 degrees Celsius, and tachycardia. His initial physical exam demonstrated fine crackles at the bilateral lower lung lobes. His initial laboratory workup revealed leukocytosis with a white cell count of 5.6 x 109/L, mild anemia with a hemoglobin of 10.6 g/dL, thrombocytopenia with a platelet count of 61 × 109/L, coagulopathy with a prothrombin time of 19.6 s, INR of 1.8, normal lactic acid at 0.9 mmol/L, and elevated pro-calcitonin at 1.95 μg/L. A chest X-ray revealed prominent pulmonary interstitial markings. CT chest, abdomen, and pelvis showed hepatosplenomegaly with diffuse lymphadenopathy, which was concerning for malignancy and, or disseminated infection (Figure ).
Initially, his presentation was thought to be due to sepsis of unknown etiology. Therefore, empiric therapy with piperacillin-tazobactam, linezolid, acyclovir, and fluconazole was started. Infectious diseases and hematology-oncology teams were consulted to aid in the patient's management. Despite empiric therapy, the patient continued to have high daily fevers and night sweats. Subsequently, antibiotics were changed to vancomycin and ceftriaxone. Infectious workup, including coccidiosis-specific antibodies and cerebrospinal fluid testing, returned negative, and therefore, fluconazole and acyclovir were discontinued.
Meanwhile, during admission, the patient developed diarrhea and pancytopenia for which cytomegalovirus (CMV) colitis was diagnosed and treatment with valganciclovir initiated. Esophagogastroduodenoscopy (EGD) was performed, showing an 0.8 cm hyperemic patch along the lesser curvature of the stomach (Figure ). A biopsy from the lesion was taken, and a single new gastric KS was seen after the histopathological examination (Figure ,B). The immunoperoxidase stain was positive for HHV-8 (Figure ).
Throughout his stay, labs were pertinent for anemia, which required blood transfusions, hypergammaglobulinemia, elevated C-reactive protein (CRP), low cluster of differentiation 4 (CD4) count of 173 cells/mm3, undetectable HIV RNA, and an elevated procalcitonin. Bone marrow biopsy was performed and was negative for malignancy, and no organisms identified on lymph node biopsy. Moreover, blood and urine cultures described no growth. The patient eventually underwent a left clavicular lymph node biopsy, which showed a plasma cell variant CD with B-cell lymphoma (Bcl)-2-negative, Bcl-6-positive, and positive immunostaining for HHV-8 with a high HHV-8 viral load at 196 copies/mL (Figure -E).
He was started on rituximab and liposomal doxorubicin for MCD and KS, respectively. Unfortunately, the patient had a severe anaphylactic reaction to rituximab, and this recurred despite pretreatment with dexamethasone; hence we could not proceed with this treatment. Then, tocilizumab therapy was considered, and upon initiation of therapy, the patient's symptoms, vital signs, and laboratory derangements began to improve. Subsequently, the patient was discharged from the hospital on tocilizumab therapy and was prescribed valganciclovir for his CMV. Repeat CT scans showed a near-complete treatment response with decreased lymphadenopathy throughout and hepatosplenomegaly. His laboratory values continued to improve upon follow-up. Since his discharge home 14 months ago, the patient has not been re-admitted to the hospital, and he continues to follow-up regularly with his HIV specialist and the oncology clinic. He has tolerated the tocilizumab well, and his symptoms have entirely resolved.


A 38-year-old Caucasian male with a past medical history significant for right plantar fasciitis suffered multiple lower extremity injuries following a motor vehicle rollover accident (MVA) while an active duty army non-commissioned officer serving in Iraq. Of note, he was an active, long-time cigarette smoker at the time of injury. Injuries to bilateral lower extremities were sustained from the MVA, including of the right lower leg, right foot and ankle, left knee, and left lower leg. Open joints were suspected in the right ankle and left knee. A left torus fibular fracture and a right malleolus fracture were confirmed on a plain radiograph. The patient underwent initial debridement and two-incision, four-compartment fasciotomies for compartment syndrome. Screening for traumatic brain injury was negative. Following stabilization and evacuation, first to Germany and then to the United States, the acute injuries were treated with serial debridements, delayed primary closures, and open reduction and internal fixation of fractures with plates and screws. Eventually the last remaining untreated injury was a 7 x 6 cm (42 cm2) right dorsolateral ankle wound with multiple exposed extensor tendons.
Intermediate treatment of the wound included serial debridements and local wound care followed by the application of bilayer collagen-GAG matrix (Integra® Meshed Dermal Regeneration Template, Integra LifeSciences, Plainsboro, NJ) one week post-injury. The patient was pessimistic about all traditional treatments options, such as STSG, cross-leg flap, and free-tissue transfer for both donor site morbidity and functional outcome reasons. His goal was to regain normal ankle, foot, and toe function with minimal downtime and a quick return to active duty. Following a comprehensive discussion of treatment options, he chose to pursue treatment with AHSC for coverage of the remaining exposed tendons and epithelial closure due to the minimal donor site impact (5 cm linear groin incision) and the potential for functionally normal skin.
Approximately six weeks post-injury and five weeks following application of bilayer collagen-GAG matrix, a 5 x 2 cm elliptical harvest of full-thickness skin, including a small amount of subcutaneous fat, was taken from the right groin (Figure ) and shipped to an FDA-registered biomedical manufacturing facility, where it was processed into AHSC.
AHSC was returned six days after harvest and applied evenly across the wound seven days after harvest (Figure ) following sharp debridement. Following application of AHSC, the wound was dressed with silicone sutured to the wound margin, covered in petrolatum gauze, and bolstered with portable negative pressure wound therapy (Figure ). Both the harvest and application were performed in an ambulatory setting under local anesthesia. The injured ankle was immobilized in a posteriorly based thermoplastic splint, and the patient was non-weight bearing on the right, walking on crutches. Silicone was used as the primary dressing layer for 2.5 weeks after AHSC application, allowing enough time for vascular soft tissue to regenerate and cover the remaining exposed tendons. After 2.5 weeks, the primary dressing was switched to a silver non-adherent dressing (Silverlon® Wound Contact Dressing, Argentum Medical LLC, Geneva, IL) covered with an adhesive foam followed by compression with an elastic bandage (ACETM Elastic Bandage, 3M, St. Paul, MN). Nine weeks after the application of AHSC, the wound was completely closed and remained closed at most recent follow-up 16 weeks after AHSC application (Figure ).
The percent area reduction of the wound at two weeks, six weeks, seven weeks, and nine weeks postoperative was 79%, 85%, 99%, and 100%, respectively. Out of the original 42 cm2 wound, there was only one small 1 cm2 (2.4% of original wound area) central area with mild thickening and scar formation, which did not result in functional limitations. The remainder of the wound was covered with pliable, sensate skin that had normal capillary refill. There was no restriction in tendon gliding (Video ). The patient was taken out of the splint at eight weeks and cleared for unrestricted weight-bearing and activity at 12 weeks. Because of normal sensation and wound contour, he was able to wear normal combat boots, perform light and office-based military duties, and pursue unrestricted physical therapy. His rehabilitation trajectory is consistent with a full recovery and unrestricted military duty by nine months post-injury.


A 30-year-old male presented to the hospital for new-onset seizures, left hand erythema with tenderness, and right knee swelling. He was diagnosed with acquired immunodeficiency syndrome (AIDS) three years prior with inconsistent use of his home prophylactic trimethoprim / sulfamethoxazole medication and antiretroviral therapy. Two years prior to presentation, he was diagnosed with septic arthritis of the third digit on the left hand. Synovial fluid cultures grew S. schenckii and he was discharged on itraconazole; however, he had not been compliant. He was readmitted to the same hospital for septic arthritis of the left knee, cultures grew S. schenckii again, and the patient was instructed to restart itraconazole. However, he continued to struggle with medication compliance. Of note, he has not been to any endemic area for fungal infections.
On admission, laboratory testing was notable for CD4+ count of 64 cells/µL and HIV-1 viral load of 247 copies/mL. Left hand imaging was suspicious for acute on chronic osteomyelitis primarily originating from the 3rd digit of the left hand (Figure ). Magnetic resonance imaging (MRI) of the brain with contrast was obtained, and showed multifocal irregular ring-enhancing lesions with surrounding edema (Figure ). Given his history of HIV infection, the differential diagnosis now included intracranial toxoplasmosis, cryptococcosis, histoplasmosis, aspergillosis, tuberculosis, and primary central nervous system (CNS) lymphoma. However, when considered with the patient’s clinical presentation and history, sporotrichosis disseminated to the CNS was more likely. Cerebrospinal fluid (CSF) analysis by lumbar puncture was non-diagnostic. Craniotomy was performed for mass resection and diagnosis. Intraoperative cytology by squash preparation of the resected left parietal brain mass was negative for a primary or secondary CNS malignancy (Figure , squash HE). Immunohistochemical (IHC) staining of the resected brain abscess revealed an extensive neutrophilic infiltration and necrosis (Figure , HE). Grocott's methenamine silver (GMS) staining was positive for abundant oval, spherical, and cigar shaped yeast in the sampled tissue (Figure , GMS).
Gram stain of left parietal brain abscess specimens only showed a few neutrophils and fungal elements. No acid-fast bacilli (AFB) were seen on AFB smear, fluorescent staining, and culture. No fungal elements were observed on fungus smear or culture. Gram stain of right parietal brain abscess specimens showed few neutrophils only. No organisms or fungal elements were observed on gram stain or smear. In contrast to the aforementioned specimens, two out of two fungal cultures were positive for S. schenckii colonies. Histopathology and gram stain on CSF fluid was primarily acellular with no bacteria or fungi isolated (Figure , CSF). CSF meningitis/encephalitis panel was negative. Serum immunologic testing for cytomegalovirus, as well as bacterial and fungal cultures, was negative. This IHC, special staining, and microbiologic profile supported disseminated S. schenckii to the brain, rather than a primary or secondary CNS malignancy, or another opportunistic infection.
His home antiretroviral medication (bictegravir / emtricitabine / tenofovir) was resumed, and trimethoprim / sulfamethoxazole was started prophylactically. Oral itraconazole was continued until S. schenckii was identified in the brain via culture. Intravenous liposomal amphotericin B dosed at 5 mg/kg/d (or 350 mg per dose) was started and continued for six weeks. He was transitioned to twice-daily oral itraconazole 200 mg on the day of hospital dismissal with instructions to continue for one year, then de-escalate to a once daily regimen indefinitely.