title: Intraperitoneal Photodynamic Therapy Causes a Capillary-Leak Syndrome

text: Background: In patients undergoing intraperitoneal (IP) photodynamic therapy (PDT), the combination of aggressive surgical debulking and light therapy causes an apparent systemic capillary-leak syndrome that necessitates significant intensive care unit (ICU) management after surgery. Methods: From May 1997 to May 2001, 65 patients underwent surgical debulking and PDT as part of an ongoing phase II trial for disseminated IP cancer. Perioperative data were reviewed retrospectively, and statistical analyses were performed to determine whether any identifiable factors were associated with the need for mechanical ventilation for longer than 1 day and with the occurrence of postoperative complications. Results: Forty-three women and 22 men (mean age, 49 years) were treated. Operative time averaged 9.8 hours, and mean estimated blood loss was 1450 mL. The mean crystalloid requirement for the first 48 hours after surgery was 29.3 L, and 49 patients required blood products. Twenty-four patients were intubated for longer than 24 hours, with a mean of 8.3 days for those intubated longer than 1 day. The median ICU stay was 4 days. Overall, 110 complications developed in 45 (69%) of the 65 patients. Significant complications included 6 patients with acute respiratory distress syndrome, 28 patients with infectious complications, and 4 patients with anastomotic complications. Statistical analyses revealed that surgery-related factors were significantly associated with these complication outcomes. Conclusions: Patients who undergo surgical debulking and IP PDT develop a significant capillary-leak syndrome after surgery that necessitates massive volume resuscitation, careful ICU monitoring, and, frequently, prolonged ventilatory support.


title: The use of immunoglobulin in bone marrow transplantation

text: The role of bone marrow transplantation is to restore lymphohematopoietic function of a recipient whose marrow has been destroyed, either by disease or by the preparative therapy employed in an attempt to eradicate the patient's lymphohematopoietic malignancy. The restoration of lymphohematopoietic function through the donor graft occurs in stages, requires several months, and is often not completed until 1 to 2 years after transplantation. These sequential steps of immuno-reconstitution are associated with a number of definable and predictable immune deficiencies and seem to be responsible for the pattern of complications that emerges after transplantation. Most of these complications are either the result of, or associated with, infections that also occur in an almost predictable pattern. In the various phases of immune deficiency following sequentially after transplantation, the humoral immune system is greatly affected, thus raising the possibility that passively administered antibodies in the form of immune globulin therapy might be beneficial in all phases of the marrow transplant procedure. This paper attempts to summarize the use of immune globulin preparations in clinical bone marrow transplantation, showing the rationale for and some of the results of therapeutic immune globulin administration.


title: Combined Resection and Radiofrequency Ablation for Advanced Hepatic Malignancies: Results in 172 Patients

text: Background: Resection combined with radiofrequency ablation (RFA) is a novel approach in patients who are otherwise unresectable. The objective of this study was to investigate the safety and efficacy of hepatic resection combined with RFA. Methods: Patients with multifocal hepatic malignancies were treated with surgical resection combined with RFA. All patients were followed prospectively to assess complications, treatment response, and recurrence. Results: Seven hundred thirty seven tumors in 172 patients were treated (124 with colorectal metastases; 48 with noncolorectal metastases). RFA was used to treat 350 tumors. Combined modality treatment was well tolerated with low operative times and minimal blood loss. The postoperative complication rate was 19.8% with a mortality rate of 2.3%. At a median follow-up of 21.3 months, tumors had recurred in 98 patients (56.9%). Failure at the RFA site was uncommon (2.3%). A combined total number of tumors treated with resection and RFA >10 was associated with a faster time to recurrence (P = .02). The median actuarial survival time was 45.5 months. Patients with noncolorectal metastases and those with less operative blood loss had an improved survival (P = .03 and P = .04, respectively), whereas radiofrequency ablating a lesion >3 cm adversely impacted survival (HR = 1.85, P = .04). Conclusions: Resection combined with RFA provides a surgical option to a group of patients with liver metastases who traditionally are unresectable, and may increase long-term survival.


title: Management of Fulminant Hepatitis B

text: PURPOSE OF REVIEW: Acute HBV infection and acute exacerbations of chronic HBV infection can cause acute liver injury (ALI) or fulminant hepatitis (FH). At this stage, spontaneous survival is poor, less than 25%. The purpose of this review is to provide an overview of specific management of patients with HBV-ALI/FH. RECENT FINDINGS: Acute HBVinfection and acute exacerbations of chronic HBVinfection can cause acute liver injury (ALI) or fulminant hepatitis (FH). Spontaneous survival at this stage is poor. It is urgent to distinguish between these two entities so that antiviral therapy can be initiated rapidly. Although the indications for antiviral therapy are clear for HBV reactivation, there is no true consensus regarding ALI/FH related to acute HBV infection. The global management of HBV-related FH does not differ from that implemented for other causes of FH, i.e. close cardiorespiratory and neurological monitoring, treatment with acetylcysteine, organ support in the event of organ failure (haemodynamic, renal, respiratory) and albumin dialysis. Liver transplantation remains the only alternative when certain criteria for a poor prognosis are met. A recurrence of HBV infection on the graft can be prevented post-transplant by the administration of HBIG and antiviral therapy for HBV, the modalities varying depending on the risk of recurrence.


title: High-vs low-dose cytarabine combined with interferon alfa in patients with first chronic phase chronic myeloid leukemia. A prospective randomized phase III study

text: A prospective randomized phase III study was performed to evaluate whether intensified cytarabine would induce a higher response rate and longer event-free interval as compared to low-dose cytarabine in chronic myeloid leukemia (CML). One hundred and eighteen patients with CML in early chronic phase entered the study. Twenty-eight out of 32 patients assigned to group A received two cycles of a combination of intensified cytarabine and idarubicin followed by interferon alfa (IFN-α) maintenance, 28 patients in group B received standard treatment by a combination of low-dose cytarabine and IFN-α. Forty-nine patients with a human leukocyte antigen-identical sibling donor proceeded to allogeneic stem cell transplantation (allo-SCT) and nine patients were excluded from the analysis. Hematological response was observed in 97% of the patients in group A vs 86% of the patients in group B during the first year of treatment. In group A, 16 patients (50%) achieved a major cytogenetic response, which compared to seven patients (25%) with a major cytogenetic response in group B. With a median follow-up of 58 months (range 34–76), event-free survival was not significantly different between arms A and B. The estimated 5-year survival rate was 56% in the intensified arm and 77% in the low-dose arm (P = 0.05). Recipients of allo-SCT showed a 5-year estimated survival rate of 55%. Although intensified cytarabine induced a higher initial percentage of major and complete cytogenetic responses, responses were not sustained by IFN-α maintenance therapy.


19. Jahrestagung der GfH, ÖGH und SGMG, 8.-10. April 2008 in Hannover: Abstracts mit Autorenindex


title: Hospitalization of newborns and young infants for chickenpox in France

text: Chickenpox is often considered more severe during the first year of life, but its course is usually mild during the first 3 months of life, presumably owing to the persistence of maternal antibodies. Hospitalization and intravenous acyclovir therapy are generally restricted to severe cases but also systematically recommended in newborns in France, irrespective of the clinical severity of the infection. This recommendation was launched in 1998 when Varicella zoster virus (VZV)-specific immunoglobulins were not available in the country and has remained unchanged since. The aim of this prospective observational study was to describe complications of varicella infection in a population of 745 children hospitalized for varicella before 1 year of age, with a specific focus on newborns. Complications occurred in 65% of cases. They were very rare before the age of 1 month (10%) but their incidence then increased progressively with age and probably the disappearance of maternal antibodies: 42% (1–2 months), 66% (3–5 months), 70% (6–8 months), and 79% (9–12 months). Conclusion Chickenpox is usually mild in newborns because most of them are protected by VZV maternal antibodies. Unless the absence of maternal VZV immunity is demonstrated, newborns with mild chickenpox should not require antiviral therapy.


title: Strategy for antibiotic therapy in febrile neutropenic patients on selective antibiotic decontamination

text: In a non-randomized prospective study the need for broad-spectrum antibiotic therapy was evaluated in selectively decontaminated neutropenic patients with fever. Fifty-two adult patients with a neutrophil count < 0.5 × 10(9)/l suffered 77 febrile episodes while receiving oral antibiotics for selective decontamination. Antibiotic treatment was only initiated if additional clinical signs or the microbiological culture results pointed to the likelihood of an infection. Treatment was either empirically based (broad-spectrum) or specific (narrow-spectrum). If a causative agent was identified, therapy was adjusted accordingly. If evidence of infection was lacking after 72–96 hours, the antibiotics were discontinued, and these patients were reexamined meticulously and repeatedly. For the 40 episodes without confirmed infection, the median duration of therapy was three days (range 0–13 days) and the survival rate 100 %; for the 37 episodes with confirmed infection, the median duration of therapy was 12 days (range 1–49 days, p<0.0001) and the survival rate 85 %. After adjustment of therapy the final regimen was broad-spectrum in only 18 % of treated episodes. None of the six deaths could be attributed to the withholding or stopping of broad-spectrum therapy. It is concluded that in febrile neutropenic patients on selective decontamination a standard therapy regimen with prolonged administration of broad-spectrum antibiotics is not necessary. After initial intervention antibiotic therapy can safely be tailored to the needs of the individual patient.


title: The effect of common bovine respiratory diseases on tidal breathing flow-volume loops

text: In order to better understand the bovine breathing pattern, tidal breathing flow-volume loops (TBFVL) were analyzed in 24 healthy cattle of different body weights (range: 37–660 kg) (Group A) and in 28 cattle suffering from the common respiratory diseases: verminous bronchitis (Group B); shipping fever (Group C); acute respiratory distress syndrome (Group D); respiratory syncytial virus pneumonia (Group E); organophosphate poisoning (Group F); and necrotic laryngitis (Group G). Respiratory airflow and tidal volume were measured with a breathing mask-Fleisch pneumotachograph assembly. TBFVL were traced from these values using a computerized method. All the loop indices proposed by Amis and Kurpershoek (1986a) were calculated from 5 representative breathing cycles for each of the 52 animals. The TBFVL shapes and indices were relatively constant in most healthy cattle and were not correlated with the body size. When compared to normal values, animals with moderate respiratory syndromes (Groups B and C) had a more flattened shape to their TBFVL. On the other hand, in most cattle with severe respiratory pathologies (Groups D, F and G) expiration tended to be biphasic with the peak expiratory flow (PEF) occurring significantly later than in healthy animals. Both PEF and peak inspiratory flow were increased in all the pathological conditions. The TBFVL indices were more frequently and more severely changed during expiration than during inspiration.


46. ARBEITSTAGUNG für Pädiatrische Forschung Göttingen 25.- 26. Februar 2009


Bosentan as Rescue Treatment in Refractory Hypoxemia and Pulmonary Hypertension in a Patient with ARDS and H7N9 Influenza Virus Infection


title: Undetectable Interleukin (IL)-10 and Persistent IL-8 Expression Early in Hyaline Membrane Disease: A Possible Developmental Basis for the Predisposition to Chronic Lung Inflammation in Preterm Newborns

text: We are interested in determining whether premature birth alters expression of counterregulatory cytokines which modulate lung inflammation. Production of proinflammatory cytokines tumor necrosis factor α, IL-1β, and IL-8 is regulated in part by the antiinflammatory cytokine IL-10. For preterm newborns with hyaline membrane disease, deficiencies in the ability of lung macrophages to express antiinflammatory cytokines may predispose to chronic lung inflammation. We compared the expression of pro- and antiinflammatory cytokines at the mRNA and protein level in the lungs of preterm and term newborns with acute respiratory failure from hyaline membrane disease or meconium aspiration syndrome. Four sequential bronchoalveolar lavage (BAL) samples were obtained during the first 96 h of life from all patients. All patients rapidly developed an influx of neutrophils and macrophages. Over time, cell populations in both groups became relatively enriched with macrophages. The expression of proinflammatory cytokine mRNA and/or protein was present in all samples from both patient groups. In contrast, IL-10 mRNA was undetectable in most of the cell samples from preterm infants and present in the majority of cell samples from term infants. IL-10 concentrations were undetectable in lavage fluid from preterm infants with higher levels in a few of the BAL samples from term infants. These studies demonstrate that1) IL-10 mRNA and protein expression by lung inflammatory cells is related to gestational age and 2) during the first 96 h of life neutrophil cell counts and IL-8 expression decrease in BAL from term infants, but remain unchanged in BAL samples from preterm infants.


title: Rheumatherapie und Lungentoxizität

text: Rheumatic diseases are treated with manifold different drugs that can potentially be pneumotoxic. Adverse effects of drug therapy may induce a wide variety of bronchopulmonary and pleural disorders, which can have a life-threatening course. These side effects rarely have pathognomonic features; therefore, drug-induced diseases are relevant differential diagnoses of pulmonary manifestations of rheumatic diseases, infections, and other independent genuine pulmonary diseases. Diagnosis is based mainly on verification of a compatible disease pattern and exclusion of differential diagnoses, as well as on assessment of the temporal relationship and the consequences of drug abstention.


title: BK papova virus pneumonia following hematopoietic stem cell transplantation

text: BK papova virus infection is frequently seen after bone marrow transplantation as a causative agent of hemorrhagic cystitis. We report an 8-month-old child with osteopetrosis who died of a severe interstitial pneumonia after receiving an unrelated umbilical cord transplant. On autopsy, BK virus was detected in the lung tissue using immunofluorescence assay, cell culture and PCR. No other pathogens were recovered. BK virus infection should be considered as a cause of interstitial pneumonia in children undergoing transplantation.


Tuberculosis complicated by ARDS


title: ECMO for pulmonary rescue in an adult with amiodarone-induced toxicity

text: Amiodarone is a highly effective antiarrhythmic agent. Unfortunately amiodarone-induced pulmonary toxicity is described for medium-long term therapy. We describe a case of a 65-year-old man admitted to our department for breathlessness and with a history of recurrent episodes of atrial fibrillation for which he had been receiving amiodarone (200 mg/day) since 2008. Despite diuretic therapy, along with aspirin, statins and antibiotics the patient continued to complain of severe dyspnea and had a moderate fever. Thus, diagnostic hypotheses different from acute cardiac failure were considered, in particular non-cardiogenic causes of pulmonary infiltrates. Following suspicion of amiodarone-induced pulmonary toxicity, the drug was discontinued and corticosteroid therapy was initiated. Due to the deterioration of the clinical picture, we proceeded to intubation. After few hours from intubation we were forced to institute a veno-venous extracorporeal membrane oxygenation due to the worsening of pulmonary function. The patient’s clinical condition improved which allowed us to remove the ECMO after 15 days of treatment. Indications for use of ECMO have expanded considerably. To our knowledge this is the first successful, reported article of a veno-venous ECMO used to treat amiodarone-induced toxicity in an adult. In patients with severe but potentially reversible pulmonary toxicity caused by amiodarone, extracorporeal life support can maintain pulmonary function and vital organ perfusion at the expense of low morbidity, while allowing time for drug clearance.


title: Rheumatologic emergencies

text: Rheumatological conditions can sometimes present as emergencies. These can occur due to the disease process or infection; contrary to what many people think, rheumatologic emergencies like a pain, rheumatic crisis, or attack gout do not compromise the patient's life. This article mentioned only true emergencies: catastrophic antiphospholipid syndrome (cAPS), kidney-lung syndrome, central nervous system (CNS) vasculitis, anti-Ro syndrome (neonatal lupus), and macrophage activation syndrome (MAS). The management of above emergencies includes critical care, immunosuppression when indicated, and use of a diagnostic flowchart as well as fast laboratory profile for making decisions. Anticoagulants have to be used in the management of antiphospholipid syndrome. A good understanding of these conditions is of paramount importance for proper management.


title: Severe H1N1-infection during pregnancy

text: H1N1 is known to induce fulminant courses in youths and young adults. We report the case of a 24-year gravida 4 para 2 with singleton pregnancy admitted to obstetrical unit for fever up to 38°C during the 20th week of a so far uncomplicated pregnancy. Ultrasound examination and urine test was inconspicuous. Throat complaints were initially relieved during antibiotic therapy, but the patient developed dyspnea with progressing signs of cyanosis. Intubation was necessary on the fifth day because of decreasing oxygen saturation. Coincidentally, progressive pancytopenia and increased inflammatory activity was recorded. Echocardiography, blood cultures, and bronchial lavage brought no pathological findings, but CT revealed acute respiratory distress syndrome and hepatomegaly. Recent human immunodeficiency virus, cytomegalic virus, herpes simplex virus, classical influenza and parainfluenza infections were excluded. An H1N1-infection was confirmed by PCR on the sixth day. The antiviral therapy was changed from zanamivir to oseltamivir. Extracorporeal membrane oxygenation was necessary due to insufficient oxygen saturation by mechanical ventilation. Until this time, pregnancy seemed to be unimpaired, but a sudden spontaneous expulsion of the fetus occurred on the seventh day (weight 460 g, no anomalies detectable). Curettage post abortem was not necessary. As a result of the antiviral therapy, H1N1-DNA was not detectable at day 16. Despite all endeavors, the respiratory situation could not be improved significantly; the patient additionally developed multiorgan failure during the time course and died on the 28th day of treatment. The recent case illustrates a very dangerous and imposing course of an H1N1-infection during pregnancy.


title: Determinants of stated willingness to pay for public goods: A study in the headline method

text: Respondents were shown brief statements (“headlines”) referring to various threats to the environment or to public health, and other public issues. An intervention to deal with each problem was also introduced by a single sentence. Some respondents were asked to indicate their willingness to pay for the interventions by voluntary contributions. Others indicated their opinion of the intervention on a conventional rating scale, rated the personal satisfaction of contributing to it, or rated the importance of the problem. Group averages of these response measures were obtained for a large set of issues. Computed over issues, the rank-order correlations between the different measures were very high, suggesting that group averages of WTP and of other opinion statements are measures of the same public attitudes. Observed preference reversals and violations of monotonicity in contributions are better explained by a concept of attitude than by the notion of economic value that underlies the contingent valuation method. Contributions and purchases do not follow the same logic. Possible implications for the contingent valuation method are discussed.


Inhaled nitric oxide in patients with the acute respiratory distress syndrome secondary to the 2009 influenza A (H1N1) infection in Canada


title: Evaluation of penicillin G in the prevention of streptococcal septicaemia in patients with acute myeloid leukaemia undergoing cytotoxic chemotherapy

text: The efficacy of penicillin G was evaluated in the prevention of infections caused by streptococci in patients receiving remission induction or intensive consolidation treatment for acute myeloid leukaemia. Between 1980 and 1988, 29 episodes of streptococcal septicaemia occurred in 139 treatment events. All patients received as prophylaxis regimen ciprofloxacin (n=38) or a combination of polymyxin B with nalidixic acid (n=42) or neomycin (n=59). Six patients died of streptococcal septicaemia despite adequate antibiotic treatment. The high incidence of streptococcal septicaemia lead to the administration of penicillin G in addition to ciprofloxacin as prophylaxis regimen during the 14 days immediately following cytotoxic chemotherapy. Only two episodes of streptococcal septicaemia were documented after addition of penicillin G to the prophylaxis regimen (n=76, p<0.001). Both patients had an uneventful recovery after treatment with vancomycin. Patients receiving penicillin G prophylaxis experienced fever during 17 % of the time and received antimicrobial therapy during 20 % of the time per treatment event compared with 27 % and 32 % respectively of this time in patients receiving no streptococcal prophylaxis (p<0.001). Penicillin G prophylaxis was associated with an increased incidence of fever of unknown origin and more frequent isolation of aerobic gram-negative bacteria in surveillance cultures. Penicillin G in combination with ciprofloxacin proved to be highly successful in preventing infections caused by streptococci and in reducing infection-related mortality and morbidity.


title: Infection and replication of avian influenza H5N1 virus in an infected human

text: The highly pathogenic avian influenza H5N1 viruses usually cause severe diseases and high mortality in infected humans. However, the tissue tropism and underlying pathogenesis of H5N1 virus infection in humans have not been clearly elucidated yet. In this study, an autopsy was conducted to better understand H5N1 virus distributions in tissues of infected humans, and whether H5N1 virus can replicate in extrapulmonary tissues. We found that the lungs had the higher viral load than the spleen, whereas no detectable viruses in tissues of heart, liver, kidney, large intestine, small intestine, or brain. Specifically, the viral load was higher in the left lung (7.1 log10 copies per ml) in relation to the right lung (5.7 log10 copies per ml), resulting in more severe pathological damage in the left lung, and lung tissues contained both positive- and negative-stranded viral RNA. However, there existed a low level of H5N1 viruses in the spleen (3.8 log10 copies per ml), with the absence of positive-stranded viral RNA. Our results indicate that replication of H5N1 viruses mainly occurs in the lungs, and the degree of lung damage is highly correlated with the viral load in the lungs. The low-load viruses in the spleen might be introduced through blood circulation or other ways.


title: Die Diagnose der Sepsis

text: The early diagnosis of sepsis is mandatory for the further reduction of mortality due to sepsis. Current findings exist that accentuate the role of the time factor, comparable with acute myocardial infarction or with ischemic stroke. On the other hand, there are no generally accepted diagnostics for sepsis, realizing the demands of early diagnosis and based on the physician’s experience. The diagnostics start with the recognition of the inflammatory reaction caused by infection (at least 2 of 4 criteria of inflammatory reaction have to be fulfilled). This definition has high sensitivity, but remarkably lower specificity and it leads either to too frequent admissions or only to hospitalization in case of a complicating organ failure. Making a careful history and knowledge about sepsis are essential for the out-patient department physicians. In addition to the varying pictures of sepsis, the clinicians have laboratory findings available, most of all procalcitonin. Patients have to be considered as septic with a serum PCT level higher than 1 ng/ml particularly when clinical signs do not exclude sepsis and in cases of positive blood cultures. Initially PCT is a product of macrophages if the defense reaction starts, but it becomes an infection marker, when the serum PCT level declines less than the half life falls.


title: Infections in neutropenic patients I: Aetiology

text: Improvement in supportive care including the introduction of new antibiotics, antiviral and antifungal agents and haematopoietic growth factors have all contributed to a decreased chemotherapy-related mortality and morbidity in cancer patients. However, infections/septic shock during neutropenia still constitutes a major threat to these patients. Most patients develop fever during neutropenia and in 20–40% a manifest bacteremia is documented. In patients with prolonged neutropenia, the risk for fungal infections is increased. The spectrum of bacterial, fungal and viral infections in the neutropenic patient is reviewed.


title: Infections in Cirrhosis

text: PURPOSE OF REVIEW: Patients with cirrhosis are at high risk of developing serious infections. Bacterial infections remain the most common cause of morbidity and mortality in these patients. This review is focused on the prevalence of infections in those with cirrhosis, including multidrug-resistant (MDR) pathogens, pathogenesis of infection-related acute-on-chronic liver failure (ACLF), current treatment recommendations, and prophylactic strategies in patients with cirrhosis. RECENT FINDINGS: Recent epidemiological studies have noted an emerging prevalence of MDR bacterial infections and associated with poor prognosis, and a high rate of treatment failure and mortality. Therefore, new recommendations on empirical antibiotic use based on epidemiological data have been developed in order to improve outcomes. SUMMARY: Spontaneous bacterial peritonitis (SBP) and urinary tract infection (UTI) are the most frequent infections followed by pneumonia, cellulitis, and bacteremia, while pneumonia carries the highest risk of mortality. The incidence of MDR bacterial infections has been increasing, especially in healthcare-associated settings. Second infections that develop during hospitalization, multiple organ failures, and high MELD score are associated with poor survival. Preventive measures, early diagnosis, and adequate treatment of infections are essential key concepts in minimizing morbidity and mortality in patients with cirrhosis.


title: Appropriate dose reduction in induction therapy is essential for the treatment of infants with acute myeloid leukemia: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group

text: Infants (<1 year old) with acute myeloid leukemia (AML) are particularly vulnerable to intensive cytotoxic therapy. Indeed, the mortality rate was high among infants enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 study, which prompted us to temporarily suspend patient enrollment and amend the protocol. Forty-five infants with AML were enrolled. For patients aged <2 years, drug doses were adjusted for body weight. Following the protocol amendments, doses for infants were reduced by a further 33 % in the initial induction course. Six infants died during the induction phase (including five early deaths), mainly due to pulmonary complications. The 3-year probability of overall survival (pOS) in all 45 infants [55.9 %, 95 % confidence interval (CI) 37.9–70.6 %] was significantly lower than that of patients aged 1 to <2 years (77.0 %, 95 % CI 62.7–86.3 %) and those aged ≥2 years (74.7 %, 95 % CI 69.2–79.4 %) (P = 0.037), mainly due to the higher non-relapse mortality rate in infants. No early deaths occurred after the protocol amendments, and the 3-year pOS of the 17 infants enrolled thereafter was 76.4 % (95 % CI 48.8–90.4 %). In conclusion, appropriate dose reduction is essential to avoid early deaths when treating infants with AML.


title: Significance of apoptotic cell death in systemic complications with severe acute pancreatitis

text: In severe acute pancreatitis, multiple organ failure in the early stage after onset, and sepsis in the late stage, due to infection of pancreatic or peripancreatic devitalized tissue, contribute to its high mortality. In analogy with sepsis, evidence has accumulated of the significance of apoptotic cell death in the systemic manifestations associated with acute pancreatitis. Since we identified apoptosis-inducing activity in pancreatitis-associated ascitic fluid in 1995, a number of investigators, including our group, have reported, through animal experiments, that apoptosis occurred in the parenchymal cells constituting organs, such as alveolar epithelial cells in the lung, renal tubular cells in the kidney, and hepatocytes in the liver, and this apoptosis was involved in organ dysfunction with severe acute pancreatitis. Moreover, through clinical and experimental investigations, apoptosis has been revealed to be involved in the mechanism of infectious complications in acute pancreatitis. Namely, apoptosis in lymphatic tissues and peripherally circulating lymphocytes is involved in the impairment of cellular immunity, and apoptosis in gut epithelial cells is implicated in bacterial translocation. These results suggest that apoptotic cell death may play a considerable role in affecting mortality and morbidity in severe acute pancreatitis. Control of apoptosis could be a potent strategy for improvement of the clinical outcome in severe acute pancreatitis.


title: Clinical characteristics of adult patients with influenza-like illness hospitalized in general ward during Influenza A H1N1 pandemic 2009/2010

text: OBJECTIVE: To investigate clinical and laboratory features of patients with Influenza A H1N1 virus infection hospitalized during 2009/2010 pandemic. METHODS: Prospective observational study comparing clinical and laboratory characteristics of Influenza A H1N1 positive and negative patients with influenza-like illness (ILI). RESULTS: From October 21, 2009 to February 14, 2010 196 ILI patients were admitted, of which 66 tested positive for Influenza A H1N1. The patients with H1N1 infection were younger (43 years vs. 65 years; P < 0.01), more patients were pregnant (P < 0.01), had allergies (P < 0.05) or, asthma (P < 0.01). H1N1 positive patients were more often febrile (91% vs. 72.9%; P < 0.01) and had a higher prevalence of headache (31.8% vs. 18.5%; P < 0.05). Lower values of C-reactive protein (88 pg/dl vs. 126 pg/dl; P < 0.01), procalcitonine (0.42 µg/l vs. 3.98 µg/l; P < 0.05), leukocyte count (7.4*10(9)/l vs. 11.7*10(9)/l; P < 0.01) and higher values of troponin (0.162 µ/l vs. 0.146 µg/l; P < 0.01) were found in H1N1 positive patients. More bacterial infections were found in H1N1 negative group (68.8% vs. 89.2%; P < 0.05). CONCLUSIONS: In this study patients infected with Influenza A H1N1 differed from H1N1 negative ILI patients in several clinical and laboratory characteristics. The same was observed also by other investigators. The results of the study suggest some other specific features, such as a higher incidence of headache and higher values of troponin in Influenza A H1N1 infected patients.


title: Potential of plants to produce recombinant protein products

text: Plants have great potential as photosynthetic factories to produce pharmaceutically important and commercially valuable biomedicines and industrial proteins at low cost. The U.S. Food and Drug Administration (U.S. FDA) has approved the drug Elelyso (taliglucerase alfa) produced by carrot cells for treatment of type 1 Gaucher’s disease in 2012. The commercial potential of biomedicines produced by molecular farming has dramatically improved due to the success of an experimental drug called ZMapp, which has immunological activity in Ebola patients. A cocktail of three monoclonal antibodies was produced in tobacco (Nicotiana benthamiana) plants (Chen and Davis 2016). At present, very few drugs made by this technology have been approved by worldwide authorities such as the U.S. FDA. However, plants have been proposed as a novel paradigm for commercial production of proteins over the next decade. In recent years, leading researchers on molecular farming have given more priority to the area of animal-free therapeutic proteins such as parenteral and oral vaccines. Although plant-based platforms have considerable advantages over traditional systems such as bacterial and animal systems, there are several obstacles to commercial-scale production, especially with regards to improving the quality and quantity of plant-produced biologics and industrial materials. One of the biggest barriers to commercialization of this technology is the intense scrutiny of these new plant varieties by regulatory agencies and the public as well as the high costs associated with their regulatory approval.


title: Feasibility of conditioning with thymoglobulin and reduced intensity TBI to reduce acute GVHD in recipients of allogeneic SCT

text: Murine studies using anti-T-cell antibodies for conditioning in allogeneic SCT demonstrate engraftment with low rates of GVHD. On the basis of this preclinical model, we conditioned 30 patients with advanced hematologic malignancies with rabbit antithymocyte globulin (ATG) and TBI, to reduce rates of fatal acute GVHD. Patients were enrolled in two sequential groups: cohort 1 received ATG 10 mg/kg in divided doses (days −4 to −1)+200 cGy TBI (n=16), and cohort 2 received ATG (days −10 to −7)+450 cGy TBI (n=14). Median donor blood chimerism for the combined group was 94, 93 and 93% in the first, second and third months after transplant. Only three developed grade II acute GVHD despite 43% of patients receiving unrelated donor transplants. One-year survival was 71±11 and 54±14%, respectively, in recipients of related and unrelated donor SCT. Donor lymphocyte infusions were needed in 12 patients for the management of relapse and for mixed donor–recipient chimerism in 4 patients. We conclude that 10 mg/kg ATG and TBI allows engraftment with a low risk of acute GVHD; however, further dose optimization of ATG is required to achieve a balance between GVHD and disease relapse.


title: Research progress on human infection with avian influenza H7N9

text: Since the first case of novel H7N9 infection was reported, China has experienced five epidemics of H7N9. During the fifth wave, a highly pathogenic H7N9 strain emerged. Meanwhile, the H7N9 virus continues to accumulate mutations, and its affinity for the human respiratory epithelial sialic acid 2–6 receptor has increased. Therefore, a pandemic is still possible. In the past 6 years, we have accumulated rich experience in dealing with H7N9, especially in terms of virus tracing, epidemiological research, key site mutation monitoring, critical disease mechanisms, clinical treatment, and vaccine development. In the research fields above, significant progress has been made to effectively control the spread of the epidemic and reduce the fatality rate. To fully document the research progress concerning H7N9, we reviewed the clinical and epidemiological characteristics of H7N9, the key gene mutations of the virus, and H7N9 vaccine, thus providing a scientific basis for further monitoring and prevention of H7N9 influenza epidemics. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at 10.1007/s11684-020-0739-z and is accessible for authorized users.


title: Does Crimean-Congo Hemorrhagic Fever Cause a Vasculitic Reaction with Pulmonary Artery Enlargement and Acute Pulmonary Hypertension?

text: PURPOSE: Crimean-Congo hemorrhagic fever (CCHF) is a viral tick-borne illness. Although its etiopathogenesis is not clearly understood, it is known to be a Nairovirus. We aimed to examine the viral effects of intense systemic inflammation and vascular damage on the pulmonary vascular beds and lung tissues. METHODS: A total of 45 patients who were diagnosed with CCHF were considered for this retrospective study. In this patient group, those whose lungs had been visualized via thoracic computer tomography (CT) were entered into the study. Diameters of the pulmonary trunk, main pulmonary arteries, atria, and ventricles were measured. Study group measurements were compared with the control group, which included patients with normal thoracic CT. RESULTS: Overall, 90 patients were enrolled in the study, with 45 patients in the study group and 45 in the control group. In the study group, the man-to-woman balance was 3/2. The average age in the study group was 54.07 ± 17.91 years. In comparing the average diameters of pulmonary arteries in the study and control groups, the study group’s average pulmonary artery diameter was significantly larger than the control group (p < 0.001). CONCLUSIONS: The increase in diameters of the pulmonary trunks and main pulmonary arteries due to CCHF was first shown in this current study. Moreover, due to our findings, it should be noted that with the rise in pulmonary artery diameter in CCHF, pulmonary hypertension can appear acutely, and this condition can be significantly alter clinical course and follow-up of the viral illness.


title: HIV infection with concomitant cerebral toxoplasmosis and disseminated histoplasmosis in a 45-year-old man

text: Although disseminated histoplasmosis is a common opportunistic infection in HIV patients in endemic areas, it is not widely known in Japan. We report a rare case of a man from Ghana infected with HIV who was hospitalized in Japan and who suffered from coinfection with cerebral toxoplasmosis and disseminated histoplasmosis. The diagnosis of cerebral toxoplasmosis was confirmed by a brain biopsy, and the therapy for the disease resulted in almost complete resolution of the brain lesion. However, fever of unknown origin continued for 2 weeks, and disseminated histoplasmosis was diagnosed by examination of a blood smear and by the detection of the histoplasma genome in the peripheral blood by means of polymerase chain reaction. The isolate was confirmed to be Histoplasma capsulatum var. duboisii. Therapy with amphotericin B was initiated, and no histoplasma genome in the peripheral blood was detected 3 days later. Unfortunately, the patient died after 10 days from acute respiratory syndrome. This case highlights that histoplasmosis should be included in the differential diagnosis of opportunistic infections in AIDS patients when patients have a history of travel to or arrival from endemic areas.


title: Effect of granulocyte colony-stimulating factor (G-CSF) on chemotherapy-induced oral mucositis

text: In this study, the ability of granulocyte colony-stimulating factor (G-CSF) to treat or prevent chemotherapy-induced oral mucositis in patients with advanced breast cancer was evaluated. A total of 14 patients who received intra-arterial (i.a.) adriamycin (ADM) preoperatively were divided into two groups according to whether or not G-CSF was given. Thus, group A (n=7) was given G-CSF and group B (n=7) was not. G-CSF therapy reduced both the incidence and duration of ADM-induced oral mucositis, and a positive correlation was also seen between the incidence of mucositis and ADM-induced leukopenia (<2,000/mm(3)). Group A was further divided into two subgroups according to whether G-CSF was given after or before the leukopenia had dropped below 2,000/mm(3): group A-1 (n=3) and group A-2 (n=4), respectively. ADM-induced mucositis was observed in two of the three patients in group A-1, but in none of the four patients in group A-2. These results strongly support the idea that G-CSF can effectively treat and prevent ADM-induced oral mucositis.


title: Immunosuppression following surgical and traumatic injury

text: Severe sepsis and organ failure are still the major causes of postoperative morbidity and mortality after major hepatobiliary pancreatic surgery. Despite recent progress in understanding the immune conditions of abdominal sepsis, the postoperative incidence of septic complications after major visceral surgery remains high. This review focuses on the clinical and immunological parameters that determine the risk of the development and lethal outcome of postoperative septic complication following major surgery and trauma. A review of the literature indicates that surgical and traumatic injury profoundly affects the innate and adaptive immune responses, and that a marked suppression in cell-mediated immunity following an excessive inflammatory response appears to be responsible for the increased susceptibility to subsequent sepsis. The innate and adaptive immune responses are initiated and modulated by pathogen-associated molecular-pattern molecules and by damage-associated molecular-pattern molecules through the pattern-recognition receptors. Suppression of cell-mediated immunity may be caused by multifaceted cytokine/inhibitor profiles in the circulation and other compartments of the host, excessive activation and dysregulated recruitment of polymorphonuclear neutrophils, induction of alternatively activated or regulatory macrophages that have anti-inflammatory properties, a shift in the T-helper (Th)1/Th2 balance toward Th2, appearance of regulatory T cells, which are potent suppressors of the innate and adaptive immune system, and lymphocyte apoptosis in patients with sepsis. Recent basic and clinical studies have elucidated the functional effects of surgical and traumatic injury on the immune system. The research studies of interest may in future aid in the selection of appropriate therapeutic protocols.


title: Respiratory syncytial virus infection in infants with acute leukemia: a retrospective survey of the Japanese Pediatric Leukemia/Lymphoma Study Group

text: Respiratory syncytial virus (RSV) can cause life-threatening complications of lower respiratory tract infection (LRTI) in young children with malignancies, but reports remain limited. We performed a retrospective nationwide survey to clarify the current status of RSV disease among infants with hematological malignancies. Clinical course, treatment, and outcome of patients with hematological malignancies who suffered from RSV infections at the age of <24 months during anti-tumor therapy from April 2006 to March 2009 were investigated by sending a questionnaire to all member institutions of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). Twelve patients with acute leukemia were identified as having experienced RSV disease. The primary diseases were acute myeloid leukemia (n = 8) and acute lymphoblastic leukemia (n = 4). RSV infection occurred pre- or during induction therapy (n = 8) and during consolidation therapy (n = 4). Eight patients developed LRTI, four of whom had severe pneumonia or acute respiratory distress syndrome; these four patients died despite receiving intensive care. In our survey, the prognosis of RSV disease in pediatric hematological malignancies was poor, and progression of LRTI in particular was associated with high mortality. In the absence of RSV-specific therapy, effective prevention and treatment strategies for severe RSV disease must be investigated.


title: Zelluläre Pathophysiologie der pulmonalen Hypertonie

text: Pulmonary hypertension comprises a group of diseases with heterogeneous etiology characterized by an increase of hydrostatic pressure in the pulmonary vascular bed. While secondary pulmonary hypertension predominantly results from acute or chronic left ventricular failure, characteristic gene defects or predisposing risk factors lead to various forms of primary pulmonary hypertension. Despite its diverse pathogenesis, pulmonary hypertension exhibits a uniform cellular pathophysiology in the pulmonary microcirculation. The dysfunction of lung vascular endothelial cells, which are the front line in response to hemodynamic changes in the pulmonary circulation, is the pathophysiological driving force of pulmonary hypertension. Endothelial dysfunction is characterized by a reduced production of vasodilative, anti-proliferative mediators and an increased release of vasoconstrictive, proliferative factors. This apparent imbalance not only enhances pulmonary vasoconstriction, but supports pathologic remodeling processes in the vascular intima and media. In addition, the pulmonary endothelium recruits platelets and leukocytes, thus, contributing to further release of vasoconstrictive and proliferative mediators and characteristic thrombus formation. These endothelium-derived pathomechanisms amplify each other, further enhance pulmonary vascular resistance, and finally result in fixation of the hypertensive state. Hence, pulmonary hypertension not only describes an alteration of lung hemodynamics, but comprises a complex set of pathophysiological events in both lung parenchymal cells and circulating blood cells. For development of new therapeutical strategies, the multifactorial character of the disease should be considered.


title: Neurological Management of Fulminant Hepatic Failure

text: Acute liver failure (ALF) is uncommon in the United States, but presents acutely and catastrophically, often with deadly consequences. Hepatic encephalopathy, cerebral edema, elevated intracranial pressure, and intracranial hemorrhage due to coagulopathy are common occurrences in patients with ALF. Appropriate management of multi-system organ failure and neurological complications are essential in bridging patients to transplant and ensuring satisfactory outcomes.


title: Nichtinvasive Beatmung bei Kindern mit akuter respiratorischer Insuffizienz

text: Noninvasive ventilation (NIV) may be used to treat pediatric acute respiratory failure. Recent improvements in ventilator technology and availability of nasal and full face masks for infants and children have simplified the use of NIV even in the smallest children. Mainly patients with hypercapnic respiratory failure may benefit from noninvasive ventilation. There is some evidence available that supports the use of NIV in viral bronchiolitis, asthma and acute on chronic respiratory failure in patients with neuromuscular or chronic pulmonary disease. Furthermore, noninvasive ventilation is beneficial during prolonged weaning from invasive ventilation and to treat upper airway obstructions. Children suffering from hypoxic respiratory failure, such as community-acquired pneumonia and acute respiratory distress syndrome do not benefit from NIV. Due to possibly relevant side effects and the possibility of rapid deterioration in gas exchange in failure of NIV, invasive ventilation should be readily available; therefore, treatment with noninvasive ventilation for acute respiratory failure in children should be initiated on the pediatric intensive care ward.


title: Clinical features, complications and atypical manifestations of children with severe forms of dengue hemorrhagic fever in South India

text: OBJECTIVE: To review clinical features and outcome of children with severe forms of dengue hemorrhagic fever (DHF) presenting to a pediatric intensive care unit (PICU) with particular focus on clinical presentation and outcome. METHODS: Retrospective chart review of patients admitted to the Pediatric Intensive Care Unit (PICU) of a referral children's hospital in South India with DHF over 1.5 years (2001–January 2003). RESULTS: Of 858 patients with dengue fever/DHF admitted to the hospital during the study period, 109 cases with severe forms of disease required PICU admission, of which 9 patients died. 77 were under 5 years of age. The commonest indication for PICU admission was persistent shock (39 patients) followed by requirement for positive pressure ventilation in 29 patients (10 of whom had Acute Respiratory Distress Syndrome [ARDS]) and neurological symptoms in 24 patients. An important finding was the presence of diastolic dysfunction in 3 children. Six deaths of refractory shock included 4 who had ARDS and DIC and 2 who had shock with DIC 3 patients had abdominal compartment syndrome (ACS) has not been previously described in children with DSS and may lead to fluid refractory shock if not corrected. All patients had thrombocytopenia which was a defining feature of the syndrome, while 74 were also coagulopathic and 6 had severe fatal DIC. Hepatic dysfunction was more severe in children with prolonged shock, however, only a fifth of cases (5/24) with neurological manifestations were in shock. Other significant reasons for neurological presentation included cerebral edema, and encephalopathy secondary to hepatic dysfunction. 2 children had features of Acute Disseminated Encephalomyelitis (ADEM), previously only described in adults with dengue. CONCLUSION: It was found that complications such as DIC, diastolic dysfunction, abdominal compartment syndrome, ARDS and hepatic dysfunction were more frequent in severe established shock. However, most neurological events were unrelated to the perfusion status. Children referred late were harder to resuscitate. There were 9 PICU deaths (case fatality rate of 8.35%). Severe refractory shock, DIC, ARDS, hepatic failure and neurological manifestations singly or in combination were the commonest causes of death in the present study.


RSV Infection—An Immune Balancing Act: Commentary on the article by Bem et al. on Page 650


title: H1N1 Influenza Pandemic of 2009 Compared With Other Influenza Pandemics: Epidemiology, Diagnosis, Management, Pulmonary Complications, and Outcomes

text: Influenza pandemics are complex events that have occurred frequently throughout human history, three during the past century alone. Now the world is facing the first 21st century pandemic, and the comparison among them is essential to identify common epidemiologic patterns, clinical characteristics, and outcomes. The evolution of medicine, including diagnostic and treatment options, the critical care advances, and global responses are new interventions that could modify the general outcome of the pandemic. Learning from past and current events could lead to a plan for prompt and efficient response in future pandemics and may be help us to predict the unpredictable.


title: Regulated nuclear localisation of the yeast transcription factor Ace2p controls expression of chitinase (CTS1) in Saccharomyces cerevisiae

text: The yeast transcription factor Ace2p regulates expression of the chitinase gene CTS1 in a cell cycle-dependent manner. Nuclear localisation of Ace2p is restricted to late M and early G1 phases of the mitotic cell cycle. We show here that this nuclear localisation is directly associated with regulation of CTS1 expression. Using a version of Ace2p tagged with a c-myc epitope, we show that the protein is excluded from the nucleus of cells during most phases of the mitotic cell cycle. A mutant derivative in which one threonine and two serine residues, which are candidate phosphorylation sites, were replaced by alanine (to mimic constitutive dephosphorylation) is localised in the nucleus throughout the cell cycle. The mechanism of localisation of Ace2p therefore involves regulation of its phosphorylation state, and closely resembles that used by the homologous transcription factor Swi5p. The wild-type Ace2 protein associates with Cdc28p in vivo, suggesting this may be the kinase that mediates the phosphorylation event. The stability of the protein is greatly reduced in a mutant that is constitutively localised to the nucleus, but is restored in a deletion derivative which remains in the cytoplasm. Ace2p is therefore controlled throughout the cell cycle at three levels: transcription, nuclear localisation, and proteolysis.


title: Evidence for the Use of Intravenous Immunoglobulins—A Review of the Literature

text: Intravenous immunoglobulins (IVIg) were first introduced in the middle of the twentieth century for the treatment of primary immunodeficiencies. In 1981, Paul Imbach noticed an improvement of immune-mediated thrombocytopenia, in patients receiving IVIg for immunodeficiencies. This opened a new era for the treatment of autoimmune conditions with IVIg. Since then, IVIg has become an important treatment option in a wide spectrum of diseases, including autoimmune and acute inflammatory conditions, most of them off-label (not included in the US Food and Drug Administration recommendation). A panel of immunologists and internists with experience in IVIg therapy reviewed the medical literature for published data concerning treatment with IVIg. The quality of evidence was assessed, and a summary of the available relevant literature in each disease was given. To our knowledge, this is the first all-inclusive comprehensive review, developed to assist the clinician when considering the use of IVIg in autoimmune diseases, immune deficiencies, and other conditions.


title: Development of reliable artificial liver support (ALS)-plasma exchange in combination with hemodiafiltration using high-performance membranes

text: A new artificial liver support system (ALSS) consisting of plasma exchange (PE) in combination with hemodiafiltration (HDF) using high-performance membranes of polymethyl metacrylate (PMMA) and cellulose triacetate (CTA) was developed to efficiently remove middle molecules from plasma and treat fulminant hepatic failure (FHF) complicated, by the onset of hepatic coma. Twenty-seven patients with FHF due to viral hepatitis, two with type A (HA), nine with type B (HB), and 16 with type non-A, non-B (NANB) underwent therapy with this new ALSS over the last five years. Three patients, with an exacerbation of chronic HB and 15/16 with type NANB hepatitis were treated with interferon (IFN) also. Of these, 25 patients (92.6%), regained consciousness and 15 (55.6%) [1/2 (50%) with type A, 6/9 (66.7%) with type B and 8/16 (50%) with type NANB hepatitis] survived Including four patients who survived with intensive, care and plasma exchange alone, 19/31 (61.3%) patients survived. Because of its biocompatibility, both survivors and nonsurvivors could be sustained with the ALSS without complications for long periods (19.3 days for the survivors and 32.4 days for nonsurvivors). With this ALSS the ability to sustain life for such prolonged periods allows hepatic regeneration to occur and result in patient survival. It is anticipated that this new ALSS will not only be of value in cases of fulminant hepatic failure but that it may also play a role in sustaining life for those, awaiting liver transplantation.


title: Anemia and Transfusions in Patients Undergoing Surgery for Cancer

text: Preoperative, operative, and postoperative factors may all contribute to high rates of anemia in patients undergoing surgery for cancer. Allogeneic blood transfusion is associated with both infectious risks and noninfectious risks such as human errors, hemolytic reactions, transfusion-related acute lung injury, transfusion-associated graft-versus-host disease, and transfusion-related immune modulation. Blood transfusion may also be associated with increased risk of cancer recurrence. Blood-conservation measures such as preoperative autologous donation, acute normovolemic hemodilution, perioperative blood salvage, recombinant human erythropoietin (epoetin alfa), electrosurgical dissection, and minimally invasive surgical procedures may reduce the need for allogeneic blood transfusion in elective surgery. This review summarizes published evidence of the consequences of anemia and blood transfusion, the effects of blood storage, the infectious and noninfectious risks of blood transfusion, and the role of blood-conservation strategies for cancer patients who undergo surgery. The optimal blood-management strategy remains to be defined by additional clinical studies. Until that evidence becomes available, the clinical utility of blood conservation should be assessed for each patient individually as a component of preoperative planning in surgical oncology.


title: Personalized medicine in severe influenza

text: Existing therapies against infectious diseases may only be effective in limited subpopulations during specific phases of diseases, incorporating theranostics, and there is a clear need to individualize different therapeutic approaches depending on the host. Influenza A virus infection evolves into a severe respiratory failure in some young adult patients, related to an exaggerated inflammatory response. Mortality rates remain high despite antiviral treatment and aggressive respiratory support. The influenza A virus (IAV) infection will induce a proinflammatory innate immune response through recognition of viral RNA by Toll-like receptor (TLR) 7 and retinoic acid-inducible gene 1 (RIG-I) molecules by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB route). Anti-inflammatory therapies focused on modulating this inflammatory response to “all patients” have not been satisfactory. Steroids should be avoided because they do not improve survival and promote superinfections. Since clinical judgment has often been proven inadequate, interest in the use of biomarkers to monitor host response and to assess severity and complications is growing. It is well known that, if used appropriately, these can be helpful tools to predict not only severity but also mortality. We need more biomarkers that predict host response: it is time to change lactate measurement to proteomics and transcriptomics. Theranostics describes an approach covering both diagnosis and coupled therapy. Death is usually a fatal complication of a dysregulated immune response more than the acute virulence of the infectious agent. Future research demonstrating the usefulness of adjunctive therapy in a subset of critically ill patients with IAV pneumonia is an unmet clinical need.


title: The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

text: PURPOSE OF THE REVIEW: The main goal of this article is to discuss how the development of state-of-the-art technology has made it possible to address fundamental questions related to how the renin-angiotensin system (RAS) operates within the brain from the neurophysiological and molecular perspective. RECENT FINDINGS: The existence of the brain RAS remains surprisingly controversial. New sensitive in situ hybridization techniques and novel transgenic animals expressing reporter genes have provided pivotal information of the expression of RAS genes within the brain. We discuss studies using genetically engineered animals combined with targeted viral microinjections to study molecular mechanisms implicated in the regulation of the brain RAS. We also discuss novel drugs targeting the brain RAS that have shown promising results in clinical studies and trials. SUMMARY: Over the last 50 years, several new physiological roles of the brain RAS have been identified. In the coming years, efforts to incorporate cutting-edge technologies such as optogenetics, chemogenetics, and single-cell RNA sequencing will lead to dramatic advances in our full understanding of how the brain RAS operates at molecular and neurophysiological levels.


title: The use of laparoscopy in abdominal emergencies

text: Background: The purpose of this article is to describe our experience using laparoscopy in the management of emergent and acute abdominal conditions. Methods: Between March 1997 and November 2001, 277 consecutive minimally invasive procedures were performed for various nontrauma surgical emergencies. The indications for operation were nonspecific abdominal pain in 129 cases (46%), peritonitis in 64 cases (23%), small bowel obstruction in 52 cases (19%), complications after previous surgery or invasive procedures in 24 cases (9%), and sepsis of unknown origin in 8 cases (3%). Results: Laparoscopy obtained a correct diagnosis in 98.6% of the cases. In 207 patients (75%), the procedure was completed laparoscopically. An additional 35 patients (12.5%) required a target incision. The remaining 35 patients (12.5%) underwent formal laparotomy. The morbidity rate was 5.8%. No laparoscopy-related mortality was observed. Conclusions: For patients with abdominal emergencies, the laparoscopic approach provides diagnostic accuracy and therapeutic options, avoids extensive preoperative studies, averts delays in operative intervention, and appears to reduce morbidity.


title: Lactic Acidosis in a Newborn With Adrenal Calcifications

text: A patient is reported who presented in the newborn period with an unusual combination of congenital lactic acidosis and bilateral calcifications in the adrenal medulla, visible on standard abdominal x-ray and ultrasound examination. At birth, the proband was hypotonic and dystrophic. She developed respiratory insufficiency, cardiomegaly, and hepatomegaly and died at the age of 38 d. Examination of postmortem heart muscle revealed multiple areas of myocardial infarction with dystrophic calcifications. In the medulla of the adrenal glands, foci of necrosis and calcifications, and in the liver, multiple zones of necrosis and iron deposition were detected. Biochemical analysis in heart muscle revealed a decreased activity of complex IV of the oxidative phosphorylation (OXPHOS) and in liver a combined deficiency involving the complexes I, III, IV, and V. The findings were suggestive of a defect in biosynthesis of the mitochondrially encoded subunits of the OXPHOS complexes. Extensive analysis of the proband's mitochondrial DNA revealed neither pathogenic deletions and point mutations nor copy number alterations. Relative amounts of mitochondrial transcripts for the ribosomal mitochondrial 12S rRNA (12S) and mitochondrial 16S rRNA (16S) were significantly increased suggesting a compensatory mechanism involving the transcription machinery to low levels of translation. The underlying molecular defect has not been identified yet.


title: Early use of beta-blockers attenuates systemic inflammatory response and lung oxygenation impairment after distal type acute aortic dissection

text: We have reported that serum C-reactive protein (CRP) elevation is an independent predictor of lung oxygenation impairment (LOI) after distal type acute aortic dissection (AAD). Systemic activation of the inflammatory system after aortic injury may play a role in the development of LOI. The aim of this study is to clarify the effect of beta-blockers on systemic inflammation and the development of LOI after distal type AAD. A total of 49 patients, who were admitted with distal type AAD and treated conservatively, were examined. White blood cell (WBC) count, serum CRP level, and arterial blood gases were measured serially. Forty patients received beta-blocker treatment within 24 h of the onset, while 9 patients received no beta-blocker treatment. Maximum WBC count, maximum CRP level, lowest PaO(2)/FiO(2) (P/F) ratio, and patient background were compared between the two groups. There was no difference between the groups according to age, sex, coronary risk factors, blood pressure, serum level of CRP, WBC count, and oxygenation index on admission. Beta-blocker treatment was associated with lower maximum WBC count (P = 0.0028) and lower maximum serum CRP level (P = 0.0004). The minimum P/F ratio was higher in patients with beta-blocker treatment than in those without (P = 0.0076). Multivariate analysis revealed that administration of a beta-blocker was an independent negative determinant of LOI (P/F ratio ≤200 mmHg). In conclusion, early use of beta-blockers prevented excessive inflammation and LOI after distal type AAD, suggesting a pleiotropic effect of beta-blockers on the inflammatory response after AAD.


title: Impact of herpes simplex virus detection in respiratory specimens of patients with suspected viral pneumonia

text: BACKGROUND: Respiratory infection and failure is a commonly encountered problem in intensive care unit (ICU) patients. However, despite the accumulating body of evidence to suggest that herpes simplex virus type 1 (HSV-1) is associated with pneumonia, the exact role played by this virus in this process is still not fully understood. Therefore, to identify patients at risk, we have conducted a case–control study to characterize patients with HSV-1-positive pneumonia. PATIENTS AND METHODS: Between 2007 and 2009, all patients with suspected viral pneumonia were tested for the presence of herpes viruses using a PCR assay approach with respiratory specimens. To identify possible associations, risk factors, and impact of HSV, HSV-1-positive ICU patients (n = 51) were compared to age-, gender-, and department- and season-matched HSV-negative patients (n = 52). RESULTS: HSV-positive patients differed significantly from the HSV-negative ones only in terms of time of mechanical ventilation (13 vs. 6 days, respectively; p = 0.002). Subgroup analysis in the patients aged >60 years and in those without bacterial detection revealed a similar trend (p = 0.01 and p = 0.004, respectively). Mortality did not differ between the groups or between the HSV-1-positive patients treated with aciclovir and those who were not. A viral load >10E+05 geq/ml was associated with mechanical ventilation (20/21 vs. 17/29; p = 0.004), acute respiratory distress syndrome (ARDS; 19/21 vs. 18/29; p = 0.005), sepsis (18/21 vs. 14/29; p = 0.008), detection of a bacterial pathogen in the same specimen (10/21 vs. 4/29; p = 0.01) and longer ICU stay (25 vs. 30 days; p = 0.04). CONCLUSION: Despite several associations with high viral load, the clinical outcome of HSV-1-positive ICU patients did not differ significantly from the clinical outcome of HSV-negative patients. This finding indicates that HSV-1 viral loads in respiratory specimens are a symptom of a clinically poor condition rather than a cause of it. Longitudinal and therapy studies are therefore needed to distinguish between HSV-1 as a causative pathogen and HSV-1 as a bystander of pneumonia/ARDS.


Abstracts of oral presentations and posters


title: Upregulated Tim-3/galectin-9 expressions in acute lung injury in a murine malarial model

text: Malaria is the most relevant parasitic disease worldwide, and severe malaria is characterized by cerebral edema, acute lung injury (ALI), and multiple organ dysfunctions; however, the mechanisms of lung damage need to be better clarified. In this study, we used Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) to elucidate the profiles of T cell immunoglobulin and mucin domain-3 (Tim-3) and its ligand galecin-9 (Gal-9) in the development of ALI. Mice were injected intraperitoneally with 10(6) PbANKA-infected red blood cells. The lungs and mediastinal lymph nodes (MLNs) were harvested at days 5, 10, 15, and 20 post infections (p.i.). The grade of lung injury was histopathologically evaluated. Tim-3- and Gal-9-positive cells in the lungs and MLNs were stained by immunohistochemistry, and the messenger RNA (mRNA) expressions of Tim-3, Gal-9, and related cytokines were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Bronchoalveolar lavage fluid (BALF) analyses were performed from days 18 to 20 p.i. The results showed that the pathological severities in the lungs were increased with times and the total protein level in the BALFs was significantly elevated in PbANKA-infected mice. The numbers of Gal-9(+) and Tim-3(+) cells in the lungs were significantly increased, and the mRNA levels of both Gal-9 and Tim-3 in the lungs and MLNs were over-expressed in PbANKA-infected mice. In conclusion, our data suggested that Tim-3/Gal-9 may play a role in PbANKA-induced ALI.


title: How Physical Exercise Influences the Establishment of Infections

text: During exercise, leucocytes are recruited to the blood, and if muscle damage occurs the cytokine level is enhanced. After prolonged, intense exercise the number of lymphocytes in the blood is reduced, and the function of natural killer cells is suppressed; furthermore, secretory immunity is impaired. During this time of immunodepression, often referred to as ‘the open window’, the host may be more susceptible to micro-organisms bypassing the first line of defence. This is of interest to top athletes who perform frequent severe exercise. Clinical observations regarding an increased risk of infections in top athletes are compatible with this model. However, in those performing regular moderate exercise the immune system will often be temporarily enhanced and this will protect these individuals from infections.


title: High-Frequency Oscillatory Ventilation in Pediatric Acute Hypoxemic Respiratory Failure: Disease-Specific Morbidity Survival Analysis

text: BACKGROUND: Multiple ventilatory strategies for acute hypoxemic respiratory failure (AHRF) in children have been advocated, including high-frequency oscillatory ventilation (HFOV). Despite the frequent deployment of HFOV, randomized controlled trials remain elusive and currently there are no pediatric trials looking at its use. Our longitudinal study analyzed the predictive clinical outcome of HFOV in pediatric AHRF given disease-specific morbidity. METHODS: A retrospective 8-year review on pediatric intensive care unit admissions with AHRF ventilated by HFOV was performed. Primary outcomes included survival, morbidity, length of stay (LOS), and factors associated with survival or mortality. RESULTS: A total of 102 patients underwent HFOV with a 66 % overall survival rate. Survivors had a greater LOS than nonsurvivors (p = 0.001). Mortality odds ratio (OR) for patients without bronchiolitis was 8.19 (CI = 1.02, 65.43), and without pneumonia it was 3.07 (CI = 1.12, 8.39). A lower oxygenation index (OI) after HFOV commencement and at subsequent time points analyzed predicted survival. After 24 h, mortality was associated with an OI > 35 [OR = 31.11 (CI = 3.25, 297.98)]. Sepsis-related mortality was associated with a higher baseline FiO(2) (0.88 vs. 0.65), higher OI (42 vs. 22), and augmented metabolic acidosis (pH of 7.25 vs. 7.32) evaluated 4 h on HFOV (p < 0.05). CONCLUSION: High-frequency oscillatory ventilation may be safely utilized. It has a 66 % overall survival rate in pediatric AHRF of various etiologies. Patients with morbidity limited to the respiratory system and optimized oxygenation indices are most likely to survive on HFOV.


title: Severe adenovirus pneumonia in immunocompetent adults: a case report and review of the literature

text: Adenovirus is a frequent cause of mild self-limiting upper respiratory tract infection, gastroenteritis, and conjunctivitis in infants and young children. Fatal infections (severe pneumonia progressing to respiratory failure, septic shock and/or encephalitis) are rare among immunocompetent adults. We report a case of severe adenovirus pneumonia in a young immunocompetent male who presented with sudden onset respiratory distress that progressed rapidly to respiratory failure and made a successful recovery on supportive measures. Systematic review of the literature identified 14 cases of severe adenovirus pneumonia (defined as respiratory failure requiring ventilatory support at any point during the course of illness) in otherwise healthy immunocompetent adults both in epidemic and community settings. We describe the clinical characteristics, radiological features, and outcome of identified cases.


title: Neuraminidaseremmers voor de behandeling van influenza

text: Een influenza-infectie ontwikkelt zich jaarlijks opnieuw bij ongeveer 20% van de wereldbevolking. Ofschoon vaccinatie de uitgelezen strategie is om influenza te voorkomen, kan in geval van een pandemie deze strategie tekortschieten omdat er gewoon te weinig vaccin voorradig is. In die situatie zijn effectieve antivirale middelen onmisbaar. Antivirale middelen verdienen om deze reden een plaats in de behandelstrategie van een influenza-epidemie.


title: Which patients should be tested for viruses on bronchoalveolar lavage fluid?

text: Bronchoalveolar lavage (BAL) is a major diagnostic tool in lung diseases, including viral respiratory infections. We aimed to better define the situations where viral tests should be performed on BAL fluid (BALF). We retrospectively studied all cases where viral tests [immunofluorescence, immunocytochemistry, viral culture, and/or polymerase chain reaction (PCR)] were performed on BALF during a period of 1 year (2008) in our institution. We compared the characteristics of patients with virus-positive versus virus-negative BALF. Of the 636 BALF samples sent to the microbiology laboratory, 232 underwent viral tests. Of these, 70 (30 %) were positive and identified 85 viruses: herpes simplex virus (HSV)-1 (n = 27), cytomegalovirus (CMV, n = 23), Epstein–Barr virus (EBV, n = 18), human herpesvirus (HHV)-6 (n = 12), respiratory syncytial virus (RSV, n = 3), rhinovirus (n = 1), and adenovirus (n = 1). The variables associated with positive viral tests on univariate analysis were immunosuppression [human immunodeficiency virus (HIV), corticosteroids >10 mg/day for ≥3 weeks, or other immunosuppressive therapy], ground-glass attenuations on computed tomography (CT) scanning, late-onset ventilator-associated pneumonia (VAP), and durations of (i) hospital stay, (ii) intensive care unit (ICU) stay, and (iii) mechanical ventilation before BAL (p < 0.01 for each comparison). On multivariate analysis, only immunosuppression [odds ratio (OR) 6.4, 95 % confidence interval (CI) [2.8–14.3], p < 0.0001] and ground-glass attenuations (OR 3.7, 95 % CI [1.8–7.7], p = 0.0004) remained associated with virus-positive BAL. None of the viral tests performed on BALF for the initial assessment of diffuse infiltrative lung disease (n = 15) was positive. PCR improved the diagnostic yield of viral tests on BALF by 50 %. Testing for viruses on BALF should be mostly restricted to immunocompromised patients with acute respiratory diseases and/or patients with unexplained ground-glass attenuations on CT scanning.


title: Use of Leukoreduced Blood Does Not Reduce Infection, Organ Failure, or Mortality Following Trauma

text: BACKGROUND: Leukoreduced (LR) blood has been demonstrated to reduce morbidity and mortality in high-risk surgical patients, but not in trauma patients. The objective of the present study was to determine the effect of LR blood on morbidity and mortality. We hypothesized that the use of LR blood does not improve outcome in trauma patients. METHODS: This study was a retrospective cohort analysis of trauma patients transfused at a level 1 Trauma Center from 2001 to 2004. Between 2002 and 2003, LR blood was transfused. Prior to that time and subsequent to it, non-leukoreduced (NLR) blood was transfused. This created two historical comparison groups. Data collected included patient demographics, units of blood transfused, intensive care unit (ICU) and hospital days, ventilator days, injury severity score (ISS), mortality, presence of acute respiratory distress syndrome (ARDS), and infectious complications. A multiple organ dysfunction syndrome (MODS) score was calculated. RESULTS: The distribution of patients was as follows: 284 patients received only NLR blood, 153 received only LR blood, and 58 received at least one unit of each. The mean ISS was similar (NLR: 26, LR: 24; P > 0.1). No differences were seen between groups in units transfused (6.2 vs. 5.5), number of ICU days (8.2 vs. 9.0), number of hospital days (16.9 vs. 18.6), number of ventilator days (6.1 vs. 5.7), incidence of ARDS (8.3% vs. 8.5%), MODS score (5.5 vs. 5.9), mortality rate (15.1% vs. 15.7%), or infection rate (36% vs. 30%) (P > 0.1). CONCLUSIONS: This study represents the largest series comparing trauma patients who received either LR or standard blood transfusions. The use of LR blood does not improve outcome in trauma patients.


title: Nucleic Acid-Based Therapeutics for Pulmonary Diseases

text: Nucleic acid-based therapeutics present huge potential in the treatment of pulmonary diseases ranging from lung cancer to asthma and chronic pulmonary diseases, which are often fatal and widely prevalent. The susceptibility of nucleic acids to degradation and the complex structure of lungs retard the effective pulmonary delivery of nucleic acid drug. To overcome these barriers, different strategies have been exploited to increase the delivery efficiency using chemically synthesized nucleic acids, vector encapsulation, proper formulation, and administration route. However, several limitations regarding off-target effects and immune stimulation of nucleic acid drugs hamper their translation into the clinical practice. Therefore, their successful clinical application will ultimately rely on well-developed carriers and methods to ensure safety and efficacy. In this review, we provide a comprehensive overview of the nucleic acid application for pulmonary diseases, covering action mechanism of the nucleic acid drugs, the novel delivery systems, and the current formulation for the administration to lungs. The latest advances of nucleic acid drugs under clinical evaluation to treat pulmonary disorders will also be detailed.


title: Side Effects of Cytokines Approved for Therapy

text: Cytokines, currently known to be more than 130 in number, are small MW (<30 kDa) key signaling proteins that modulate cellular activities in immunity, infection, inflammation and malignancy. Key to understanding their function is recognition of their pleiotropism and often overlapping and functional redundancies. Classified here into 9 main families, most of the 20 approved cytokine preparations (18 different cytokines; 3 pegylated), all in recombinant human (rh) form, are grouped in the hematopoietic growth factor, interferon, platelet-derived growth factor (PDGF) and transforming growth factor β (TGFβ) families. In the hematopoietin family, approved cytokines are aldesleukin (rhIL-2), oprelvekin (rhIL-11), filgrastim and tbo-filgrastim (rhG-CSF), sargramostim (rhGM-CSF), metreleptin (rh-leptin) and the rh-erythropoietins, epoetin and darbepoietin alfa. Anakinra, a recombinant receptor antagonist for IL-1, is in the IL-1 family; recombinant interferons alfa-1, alfa-2, beta-1 and gamma-1 make up the interferon family; palifermin (rhKGF) and becaplermin (rhPDGF) are in the PDGF family; and rhBMP-2 and rhBMP-7 represent the TGFβ family. The main physicochemical features, FDA-approved indications, modes of action and side effects of these approved cytokines are presented. Underlying each adverse events profile is their pleiotropism, potency and capacity to release other cytokines producing cytokine ‘cocktails’. Side effects, some serious, occur despite cytokines being endogenous proteins, and this therefore demands caution in attempts to introduce individual members into the clinic. This caution is reflected in the relatively small number of cytokines currently approved by regulatory agencies and by the fact that 14 of the FDA-approved preparations carry warnings, with 10 being black box warnings.


This journal issue contains abstracts that have been accepted for presentation as the 8th Annual Conference of the International Society for Quality of Life Research (ISOQOL)


title: A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation

text: In a 22-year-old male with a 10-day history of fever, painful swelling in the left groin, and abdominal complaints, emergency surgery was performed because of spontaneous splenic rupture. At histology, a cellular infiltrate of intermediate-sized atypical lymphocytes was seen in the splenic white pulp, staining for T-cell markers. In addition, CD30 and anaplastic lymphoma kinase 1 (ALK) were diffusely positive, thus, representing a case of anaplastic large cell lymphoma (ALCL), T-cell, ALK-positive, small cell monomorphic variant. ALK-positive ALCL patients generally bear a much better prognosis than patients with T-cell lymphomas, unspecified, or ALK-negative ALCL. Therefore, besides the very unusual clinical presentation, this case highlights the importance of immunostaining for CD30 and ALK in all T-cell lymphomas. This report is the first extensive description of ALK-positive ALCL involvement of the spleen.


title: Lipid peroxidation in Gram-negative bacteremia modulates the risk for septic shock and infections by resistant Klebsiella pneumoniae

text: Controversies in outcomes with the parenteral administration of antioxidants as adjuvant therapies led to the measurement of malondialdehyde (MDA), a product of lipid peroxidation, in serum collected from 120 patients with primary Gram-negative bacteremia during the first 24 h from sepsis onset. MDA was measured by the thiobarbiturate assay, followed by high-performance liquid chromatography (HPLC) analysis. After receiver operator characteristic (ROC) curve analysis, patients were divided into those with high levels of MDA and low levels of MDA. The primary endpoint was the association of the level of MDA with septic shock. The level of MDA as an index of neutrophil function and associations with outcome and with infections by carbapenem-resistant Klebsiella pneumoniae were the secondary endpoints. In total, 63 patients had high and 57 had low MDA levels; 27% and 49.1%, respectively, had septic shock (p = 0.015). The rate of the concentration of MDA to the total neutrophil count was used as an expression of neutrophil function; this was lower among patients with septic shock. The odds ratio (OR) for death among patients without septic shock and low level of MDA was 4.00; this was 0.48 for patients with septic shock (p = 0.020 between the two ORs). The OR for resistance to carbapenems among patients with bacteremia by K. pneumoniae and low level of MDA was 7.50 (p = 0.011 compared to patients with bacteremia by other pathogens). Low level of circulating MDA is associated with susceptibility to septic shock and infections by carbapenem-resistant K. pneumoniae.


Subject Index to Volume 45 (2008)


title: MMP-8 Genotypes Influence the Inflammatory Response in Human Endotoxemia

text: Clinical studies have reported associations between MMP-8 genotypes and clinical outcomes without exploring underlying mechanisms. This study aims to understand the influence of the rs1940475 SNP on downstream chemokine and cytokine response in human endotoxemia. Rs1940475 was genotyped in 44 healthy Caucasian males, who were challenged with an intravenous bolus of 2 ng/kg lipopolysaccharide (LPS). Plasma levels of tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, and macrophage inflammatory protein (MIP)-1α were measured at baseline and 2, 4, 6, and 24 h after LPS infusion with high-sensitivity enzyme immunoassays. Peak TNF levels at 2 h after LPS infusion were significantly higher in subjects with AA genotype compared to subjects with AG or GG genotypes (185 pg/mL [IQR, 154–234] vs. 94 pg/mL [IQR, 65–125] vs. 107 pg/mL [IQR, 80–241], respectively; p = 0.03 between groups). Peak IL-6 levels were trend-wise higher in subjects with AA genotype compared to those with AG or GG genotypes (566 pg/mL [IQR, 294–644] vs. 278 pg/mL [IQR, 184–539] and 329 pg/mL [IQR, 240–492], respectively; p = 0.15 between groups). In contrast, peak MIP-1α at 2 h was highest in GG genotype carriers compared to those with AG or AA genotypes (602 pg/mL [IQR, 449–727] vs. 389 pg/mL [IQR, 375–490] and 510 pg/mL [425–813], respectively; p < 0.03 between groups). AA genotype carriers had highest peak TNF and IL-6 levels after LPS challenge, whereas peak MIP-1α levels were highest in GG carriers. This indicates that the rs1940475 SNP modifies the host response to inflammatory stimuli, which may in part explain previously shown associations with clinical outcomes.


title: Acute respiratory distress syndrome induced by H9N2 virus in mice

text: H9N2 avian influenza viruses have repeatedly caused infections in swine and humans in some countries. The purpose of the present study was to evaluate the pulmonary pathology caused by H9N2 viral infection in mice. Six- to eight-week-old BALB/c mice were infected intranasally with 1 × 10(4) MID(50) of A/Chicken/Hebei/4/2008(H9N2) virus. Clinical signs, pathological changes and viral replication in lungs, arterial blood gas, and cytokines in bronchoalveolar lavage fluid (BALF) were observed at different time points after infection. A control group was infected intranasally with noninfectious allantoic fluid. H9N2-infected mice exhibited severe respiratory syndrome, with a mortality rate of 60%. Gross observations showed that infected lungs were highly edematous. Major histopathological changes in infected lungs included diffuse pneumonia and alveolar damage, with neutrophil-dominant inflammatory cellular infiltration, interstitial and alveolar edema, hemorrhage, and severe bronchiolitis/peribronchiolitis. In addition, H9N2 viral infection resulted in severe progressive hypoxemia, lymphopenia, and a significant increase in neutrophils, tumor necrosis factor-α and interleukin-6 in BALF. The features described above satisfy the criteria for acute respiratory distress syndrome (ARDS). Our data show that H9N2 viral infection resulted in ARDS in mice, and this may facilitate studies of the pathogenesis of future potential H9N2 disease in humans.


title: Multiple organ failure – the discrepancy between our scientific knowledge and understanding and the management of our patients

text: The excitement of molecular biology and of genetic knowledge and their possibilities must be balanced against our limitations in using this information for the care of our patients. There is a great discrepancy between what we know and what we can do. There are many reasons for this. A major one is that science must simplify/reduce the variables in experimentation and then generalize in terms of a specific factor or effect, whereas patients are complex with variables that we do not yet understand completely. This powerful science is now teaching us about the genetic diversity in both susceptibility and outcome of disease, and the diversity in life experiences and antigen exposures. Clinicians have tried to lump together and treat in a similar way many diverse human diseases. This has not worked well. Pancreatitis and perforated diverticulitis both produce inflammation and sepsis, but they are different processes and may both lead to multiple organ failure. This lumping together has contributed to the failure of so-called magic bullets. There are new contributors to organ damage. Gender, lifestyle and prior disease differences also complicate the care of patients. Despite this, we are slowly and gradually improving the care of our surgical patients by careful pre-, intra- and postoperative support and better, simpler and safer operations.


title: Construction of enhanced transcriptional activators for improving cellulase production in Trichoderma reesei RUT C30

text: Enhancing cellulase production in Trichoderma reesei is of great interest for an economical biorefinery. Artificial transcription factors are a potentially powerful molecular strategy for improving cellulase production in T. reesei. In this study, enhanced transcriptional activators XYR1VP, ACE2VP, and ACE1VP were constructed by linking the C terminus of XYR1, ACE2, or ACE1 with an activation domain of herpes simplex virus protein VP16. T. reesei transformants T(XYR1VP), T(ACE2VP), and T(ACE1VP) showed improved cellulase and/or xylanase production. T(XYR1VP) has a cellulase-free phenotype but with significantly elevated xylanase production. Xylanase I and xylanase II activities [U/(mg biomass)] increased by 51% and 80%, respectively, in T(XYR1VP) in comparison with parental strain RUT C30. The filter paper activity of T(ACE2VP) in the Avicel-based medium increased by 52% compared to that of RUT C30. In the Avicel-based medium, T(ACE1VP) manifested an 80% increase in FPase activity and a 50% increase in xylanase activity as compared to those of RUT C30. Additionally, when pretreated corn stover was hydrolyzed, crude enzymes produced from T(ACE1VP) yielded a greater glucose release than did the enzymes produced by parental strain RUT C30. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40643-018-0226-4) contains supplementary material, which is available to authorized users.


title: Pathophysiology of fatty acid oxidation disorders and resultant phenotypic variability

text: Fatty acids are a major fuel for the body and fatty acid oxidation is particularly important during fasting, sustained aerobic exercise and stress. The myocardium and resting skeletal muscle utilise long-chain fatty acids as a major source of energy. Inherited disorders affecting fatty acid oxidation seriously compromise the function of muscle and other highly energy-dependent tissues such as brain, nerve, heart, kidney and liver. Such defects encompass a wide spectrum of clinical disease, presenting in the neonatal period or infancy with recurrent hypoketotic hypoglycaemic encephalopathy, liver dysfunction, hyperammonaemia and often cardiac dysfunction. In older children, adolescence or adults there is often exercise intolerance with episodic myalgia or rhabdomyolysis in association with prolonged aerobic exercise or other exacerbating factors. Some disorders are particularly associated with toxic metabolites that may contribute to encephalopathy, polyneuropathy, axonopathy and pigmentary retinopathy. The phenotypic diversity encountered in defects of fat oxidation is partly explained by genotype/phenotype correlation and certain identifiable environmental factors but there remain many unresolved questions regarding the complex interaction of genetic, epigenetic and environmental influences that dictate phenotypic expression. It is becoming increasingly clear that the view that most inherited disorders are purely monogenic diseases is a naive concept. In the future our approach to understanding the phenotypic diversity and management of patients will be more realistically achieved from a polygenic perspective.


title: Cytologische untersuchungen an tumoren mit unterschiedlichem klinischen verhalten

text: Five tumours removed from the larynx and the pharynx have been examined. The results of cytophotometric survey of the DNA content were compared with that of the cellkinetic and histological investigation as well as the clinical progress. A distinct correlation between the position of DNA-Stem-line in the aneuploid region and the development of the tumours was observed. The cellkinetic and cytophotometric results showed that the irradiated cells remained in the G (2)-Phase for a long period.


title: Infectious and Immunologic Phenotype of MECP2 Duplication Syndrome

text: MECP2 (methyl CpG binding protein 2) duplication causes syndromic intellectual disability. Patients often suffer from life-threatening infections, suggesting an additional immunodeficiency. We describe for the first time the detailed infectious and immunological phenotype of MECP2 duplication syndrome. 17/27 analyzed patients suffered from pneumonia, 5/27 from at least one episode of sepsis. Encapsulated bacteria (S.pneumoniae, H.influenzae) were frequently isolated. T-cell immunity showed no gross abnormalities in 14/14 patients and IFNy-secretion upon ConA-stimulation was not decreased in 6/7 patients. In 6/21 patients IgG(2)-deficiency was detected – in 4/21 patients accompanied by IgA-deficiency, 10/21 patients showed low antibody titers against pneumococci. Supra-normal IgG(1)-levels were detected in 11/21 patients and supra-normal IgG(3)-levels were seen in 8/21 patients – in 6 of the patients as combined elevation of IgG(1) and IgG(3). Three of the four patients with IgA/IgG(2)-deficiency developed multiple severe infections. Upon infections pronounced acute-phase responses were common: 7/10 patients showed CRP values above 200 mg/l. Our data for the first time show systematically that increased susceptibility to infections in MECP2 duplication syndrome is associated with IgA/IgG(2)-deficiency, low antibody titers against pneumococci and elevated acute-phase responses. So patients with MECP2 duplication syndrome and low IgA/IgG(2) may benefit from prophylactic substitution of sIgA and IgG. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10875-015-0129-5) contains supplementary material, which is available to authorized users.


title: Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies

text: Forty-one patients were studied at set times after allogeneic blood stem cell transplantation (alloBSCT) for recovery of lymphocyte numbers and function. Cells were mobilized with G-CSF from HLA-matched related donors and cryopreserved. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate; G-CSF was administered post-transplant. Median time to absolute lymphocyte count (ALC) ⩾500/μl was 17 days vs 41 and 49 days in historical alloBMT patients with G-CSF (n = 23) or no cytokine (n = 29) post-transplant, respectively (P < 0.0001). CD4/CD8(+) ratio was 1.9 on day 28 after alloBSCT, then gradually declined to 0.8 at 1 year due to more rapid CD8(+) cell recovery. Mean phytohemagglutinin-induced T cell responses were lower than normal on day +28 (P < 0.05), then tended to recover towards normal values. Natural-killer cytotoxicity remained low from day +28 to 1 year post-alloBSCT, but considerable lymphokine-activated killer cytotoxicity was induced from cells already obtained on day +28. Faster lymphocyte recovery correlated with better survival in alloBSCT patients (median follow-up 287 days, P = 0.002), ALC recovery was not affected by acute GVHD, CMV infections or doses of infused cells. ALC recovery did not correlate with survival in either historical alloBMT group. These data suggest that after alloBSCT lymphocyte reconstitution is faster than after alloBMT, and that quicker lymphocyte recovery predicts better survival in the alloBSCT setting.


2018 CIS Annual Meeting: Immune Deficiency & Dysregulation North American Conference


title: Cytopathology or immunopathology? The puzzle of cytomegalovirus pneumonitis revisited

text: Various hypotheses have been proposed to explain why cytomegalovirus pneumonitis (CMV-P) is frequent and severe in bone marrow transplant patients while remaining rare and mild in HIV infected patients. One hypothesis suggests that CMV-P is an immunopathological condition that is common in bone marrow transplantation (BMT) under the effects of an abnormally regenerating immune system that reacts against CMV infected lung tissue. Such a hypothesis implicates CD4 T lymphocytes as one of the critical cell populations involved in immunopathology and also suggests that this process would be aborted by CD4 T cell deficiency in HIV infection. However, studies correlating the onset of CMV-P with lymphocyte reconstitution following BMT have revealed that CD4 cells are present at very low frequencies in the blood during the early period after transplantation when most cases of CMV-P occur. Furthermore, studies directly investigating bronchoalveolar lavage cell types during episodes of CMV-P in BMT patients have also failed to demonstrate significant CD4 involvement and, instead, have emphasized a predominance of natural killer (NK) cells and CD8 cells. These findings serve as the basis for questioning the validity of a CD4-driven immunopathological model of CMV-P in BMT. On the other hand, a variety of experimental and clinical observations support the protective role of CMV-specific CD3(+) CD8 T lymphocytes against CMV in both immunocompetent individuals and BMT patients. In a murine BMT model, adoptive transfer of syngeneic BM cells was associated with massive increases in lung CD8 cells which resulted in the resolution rather than the exacerbation of existing CMV-P. In the light of these findings a more plausible hypothesis for CMV-P in BMT is that during the early period after transplantation adequate protective CD8 responses are absent and an uncontrolled CMV proliferation is allowed to develop. Once a critical viral load is reached a cytokine ‘storm’ may be triggered in the lung tissue that aggravates direct CMV-associated cytopathic effects. Likely candidates for this process would include the release of tumour necrosis factor-alpha (TNF-α) from alveolar macrophages stimulated by interferon-gamma (IFN-γ) released from NK cells that are reconstituted early after BMT. Bone Marrow Transplantation (2000) 26, 591–597.