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.


title: Amiodarone-Induced Pulmonary Toxicity—A Fatal Case Report and Literature Review

text: Amiodarone is a widely used and very potent antiarrhythmic substance. Among its adverse effects, pulmonary toxicity is the most dangerous without a causal treatment option. Due to a very long half-life, accumulation can only be prevented by strict adherence to certain dosage patterns. In this review, we outline different safe and proven dosing schemes of amiodarone and compare the incidence and description of pulmonary toxicity. Reason for this is a case of fatal pulmonary toxicity due to a subacute iatrogenic overdosing of amiodarone in a 74-year-old male patient with known severe coronary artery disease, congestive heart failure and ectopic atrial tachycardia with reduced function of kidneys and liver but without preexisting lung disease. Within 30 days, the patient received 32.2 g of amiodarone instead of 15.6 g as planned. Despite early corticosteroid treatment after fast exclusion of all other differential diagnoses, the patient died another month later in our intensive care unit from respiratory failure due to bipulmonal pneumonitis.


title: Rheumatologische Notfälle an der Grenze zur Intensivmedizin

text: In rheumatological practice situations repeatedly occur where critical problems which need to be quickly addressed in order to prevent permanent damage to the patient. The focus of this article is on rapidly progressive inflammatory diseases, severe side effects of many medications and complications of infections during immunosuppressive treatment.


title: Extrakorporale Membranoxygenierung (ECMO) im Erwachsenenalter

text: Despite ongoing discussions, ECMO (extracorporeal membrane oxygenation) has become an important part of treatment options in acute lung injury and ARDS (acute respiratory distress syndrome) even in adults. On the other hand, none of the two RCT (randomized controlled trial) studies resulted in reduced letality of the artificial lung therapy when compared to convention treatment. Both authors concluded, that ECMO is not recommended in ARDS. Meanwhile experience with ECMO in adults is extensive in various institutions worldwide, exceeding 1000 patients by the end of 2001. Growing experience and improved technical equipment reduce the rate of technical complications substantially. However, for different reasons ECMO incidence in adults is progressively decreasing in recent years. Inclusion and exclusion criteria vary among different ECMO centers. Potential reversibility of lung injury and persisting life-threatening gas exchange disorder under maximal conventional therapy are commonly seen as requirements for ECMO therapy. ECMO criteria are Murray lung injury score >3.5 (chest x-ray, PaO(2)/FiO(2)-index, static compliance C(stat), PEEP), Morel-classification >3 (chest x-ray, AaDO(2)/FiO(2)-index, C(stat), PEEP), AaDO2 >600mmHg, intrapulmonal shunt Q(S)/Q(T) >30%, and increase in extravascular lung water >15 ml/kg bodyweight. Commonly accepted absolute contraindications are (1) severely consuming disorders with poor prognosis, (2) CNS damage with poor prognosis, (3) advanced chronic lung disorders, and (4) progressive multiple organ failure. Relative contraindications are immunosuppresion, active bleeding, age over 60 years, and days on mechanical ventilation. In our experience, early contact to an ECMO reference center can optimise early identification of patients which benefit from ECMO, as well as treatment and transportation modalities, and improves outcome. Due to high technical and personal requirements and decreasing incidence in the adult sector, ECMO should be limited to a small number of reference centers with substantial experience in extracorporeal circulation.


title: Simvastatin attenuates the lipopolysaccharideinduced inflammatory response of rat pulmonary microvascular endothelial cells by downregulating toll-like receptor 4 expression

text: OBJECTIVE: The therapeutic potential of simvastatin as an anti-inflammatory agent was explored by investigating its effect on the lipopolysaccharide (LPS)-induced inflammatory response in rat pulmonary microvascular endothelial cells (RPMVECs). METHODS: RPMVECs were isolated and the mRNA and protein levels of different toll-like receptors (TLR) were assessed by qRT-PCR and western blotting. The LPS-induced expressions of TLR4, TNF-α and iNOS were analyzed in RPMVECs treated with different concentrations of simvastatin for different times. NF-κB activation was examined by immuofluroscence, luciferase reporter assay and western blotting. RESULTS: TLR4 is abundantly expressed in RPMVECs, and its expression is induced by LPS stimulation. Simvastatin inhibited LPS-induced TLR4 expression at the mRNA and protein levels in a time-dependent manner (p<0.01), and alleviated inflammation in RPMVECs by inhibiting the release of inflammatory factors such as TNF-α and iNOS. Further study indicated that simvastatin significantly attenuated NF-κB activity by inhibiting the degradation of IκB-α. Pretreatment with pyrrolidine dithiocarbamate (PDTC) and knock-down of TLR4 expression by RNA interference down-regulated the LPS-induced inflammatory response in RPMVECs. CONCLUSION: Simvastatin inhibits the LPS-induced inflammatory response in RPMVECs by down-regulating TLR4 expression, suggesting its role as a potential inhibitor of LPS-induced inflammation


title: Combined blockade of angiotensin II and prorenin receptors ameliorates podocytic apoptosis induced by IgA-activated mesangial cells

text: Glomerulo-podocytic communication plays an important role in the podocytic injury in IgA nephropathy (IgAN). In this study, we examine the role of podocytic angiotensin II receptor subtype 1 (AT1R) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. Polymeric IgA (pIgA) was isolated from patients with IgAN and healthy controls. Conditioned media were prepared from growth arrested human mesangial cells (HMC) incubated with pIgA from patients with IgAN (IgA-HMC media) or healthy controls (Ctl-HMC media). A human podocyte cell line was used as a model to examine the regulation of the expression of AT1R, PRR, TNF-α and CTGF by IgA-HMC media. Podocytic nephrin expression, annexin V binding and caspase 3 activity were used as the functional readout of podocytic apoptosis. IgA-HMC media had no effect on AngII release by podocytes. IgA-HMC media significantly up-regulated the expression of AT1R and PRR, down-regulated nephrin expression and induced apoptosis in podocytes. Mono-blockade of AT1R, PRR, TNF-α or CTGF partially reduced podocytic apoptosis. IgA-HMC media activated NFκB, notch1 and HEY1 expression by podocytes and dual blockade of AT1R with PRR, or anti-TNF-α with anti-CTGF, effectively rescued the podocytic apoptosis induced by IgA-HMC media. Our data suggests that pIgA-activated HMC up-regulates the expression of AT1R and PRR expression by podocytes and the associated activation of NFκB and notch signalling pathways play an essential role in the podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Simultaneously targeting the AT1R and PRR could be a potential therapeutic option to reduce the podocytic injury in IgAN. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10495-015-1117-1) contains supplementary material, which is available to authorized users.


title: A case of pulmonary toxicity associated with G-CSF and doxorubicin administration

text: The cytokine growth factor, G-CSF (granulocyte colony-stimulating factor), is commonly used in oncologic practice and is generally believed to be a safe agent to administer. We describe here a case of pulmonary toxicity associated with the concurrent administration of G-CSF and doxorubicin. We contend that G-CSF contributed to the life-threatening lung injury in our patient, and discuss additional reports in the literature of pulmonary toxicity associated with the use of this agent.


title: Die nosokomiale Pneumonie: State-of-the-Art

text: Nosocomial pneumonia is among the most frequent infections in the intensive care unit with high morbidity and mortality. The decisive factor for treatment failure is inadequate previous antibiotic treatment. Broad spectrum and sufficiently high dosed initial treatment is crucial. To prevent further resistances, the antibiotic treatment must be evaluated early. Depending on the treatment success, treatment has to be changed or terminated. Deescalation is possible and sensible after three days. A treatment period of seven days should not routinely be exceeded. The treatment recommendations should be adapted to local resistances and the local statistics of frequent pathogens. A further factor for treatment decision-making is the risk analysis of the patient (previous treatment, stays in hospitals or nursing homes, concomitant diseases).


title: Feeding intolerance due to connatal tuberculosis in a prematurely born infant

text: A prematurely born infant had three episodes of feeding intolerance in the first three weeks after birth. In the post-partum period, his mother, who was from the Ukraine, had a respiratory arrest; unusually, a high-resolution computerised tomograph demonstrated miliary tuberculosis (TB). As a consequence, and due to the continuing ill health of the infant, gastric aspirates were sent from the infant. Acid fast bacilli were seen on microscopy. Variable nucleotide tandem repeat analysis of acid fast bacilli facilitated the rapid diagnosis of connatal TB. We conclude that connatal TB should be considered in a prematurely born infant poorly responsive to standard management and whose mother falls into a high-risk group.


title: Coccidioidomycosis in adolescents with lupus nephritis

text: Coccidioidomycosis, a fungal infection endemic in the southwestern United States, can cause life-threatening infections in immunosuppressed patients. We report the contrasting cases of two adolescents with lupus nephritis, treated with intravenous pulse cyclophosphamide and daily oral corticosteroids, who developed pulmonary coccidioidomycosis. One patient developed a fatal form of fulminant disseminated coccidioidomycosis, while the other patient developed a solitary pulmonary Coccidioides immitis abscess which was responsive to intravenous liposomal amphotericin and fluconazole therapy. Because serologies and initial X-ray studies can be negative, definitive diagnostic studies including bronchioaveolar lavage and needle aspiration should be performed when there is clinical suspicion of coccidioidomycosis in an immunocompromised patient. Immunosuppressed patients with coccidioidomycosis should receive early intravenous amphotericin therapy and may benefit from long-term suppressive antifungal therapy to prevent relapse.


title: Vascularized Composite Allotransplantation: Medical Complications

text: The objective of this review is to summarize the collective knowledge regarding the risks and complications in vascularized composite tissue allotransplantation (VCA), focusing on upper extremity and facial transplantation. The field of VCA has entered its second decade with an increasing experience in both the impressive good outcomes, as well as defining challenges, risks, and experienced poor results. The limited and selective publishing of negative outcomes in this relatively new field makes it difficult to conclusively evaluate outcomes of graft and patient survival and morbidities. Therefore, published data, conference proceedings, and communications were summarized in an attempt to provide a current outline of complications. These data on the medical complications of VCA should allow for precautions to avoid poor outcomes, data to better provide informed consent to potential recipients, and result in improvements in graft and patient outcomes as VCA finds a place as a therapeutic option for selected patients.


High-Frequency Transduction of Antibiotic Resistance in Pseudomonas aeruginosa by a Wild-Type Bacteriophage with Restricted Specificity for Recipient Strains


title: Medikamenteninduzierte parenchymatöse Lungenerkrankungen

text: Drug-induced alveolitis/pneumonitis and lung fibrosis are comparatively frequent manifestations of drug-induced damage to the respiratory system. These side effects rarely have pathognomonic features. Therefore, they are relevant differential diagnoses of naturally occurring pulmonary diseases. Side effects of drug therapy may mimic much of the clinical-radiological-pathological pattern of interstitial lung diseases; however, precise figures on the frequency of medicamentous induction of interstitial lung disorders are lacking. The diagnostics are based mainly on verifying a compatible disease pattern, excluding differential diagnoses, and assessing the temporal relationship and the consequences of drug abstention. Reexposure is rarely indicated. Strict elimination of the responsible drugs is the most important therapeutic measure. Additional drug therapy, mostly with glucocorticosteroids, may be indicated. This article summarizes the spectrum of drug-induced disorders of the lung parenchyma.


title: Prepubertal vaccination of mice against experimental infection of the genital tract with type 2 herpes simplex virus

text: Pre-pubertal immunisation of mice with a formalin-inactivated type 1 and 2 herpes simplex virus vaccine conferred a level of life-long protection against primary type 2 genital infection. Protection levels were better with type 1 vaccine and strikingly influenced by vaccine dosage where a one-hundred-fold reduction from the standard vaccine dosage diminished protection to insignificant levels. Vaccine efficacy was not significantly affected by the method of virus inactivation, the number of immunisations or the age of the mouse at immunisation. Vaccination conferred better protection than previous type 2 genital infection; this may be a consequence of a higher antigenic dose, more acceptable antigenic presentation or to a perversion of the immune response in a latently infected animal to homologous virus challenge.


title: Analysis of Low Molecular Weight Substances and Related Processes Influencing Cellular Cholesterol Efflux

text: Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing ‘biological oxidations’ activate cholesterol efflux and the substances influencing ‘Signaling by GPCR and PTK6’ inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.


title: Adhesion molecules in lung diseases

text: The human body possesses highly specialized cellular defense mechanisms that, when activated pathologically, can induce a number of immunologic disorders. For a normal cellular immune response, the following conditions must be fulfilled: (1) accumulation of white blood cells, (2) their diapedesis through the vessel walls of the inflammatory area affected by an injurious agent, and (3) normal cellular effector functions in the tissue. This cascade of inflammatory processes has recently been shown to be regulated by a group of molecules that are termed adhesion molecules and consist of three subfamilies: selectins, the immunoglobulin supergene family, and integrins. The cellular functions influenced by adhesion molecules include, among others, cytotoxic T-cell responses, CD4-dependent activation of B lymphocytes by T lymphocytes, activation of granulocytes and macrophages, phagocytosis of opsonized particles by monocytes, macrophages, and granulocytes, antigen-presenting function of macrophages, their antibody-dependent cytotoxicity, initiation of a respiratory burst by white blood cells, and activation of fibroblasts. Studies performed in recent years have shown that pathogenetically relevant changes in the expression and function of adhesion molecules are involved in a variety of pulmonary diseases. These changes include the accumulation and activation of alveolar macrophages in smokers, experimentally induced bronchial hyperreactivity in bronchial asthma, accumulation of eosinophils in allergic rhinitis, bleomycin-induced pulmonary fibrosis, binding of viruses and bacteria to respiratory mucosa, and various mechanisms of acute damage to pulmonary parenchyma. Though their role in tumor development is still unclear, adhesion molecules are obviously involved in determining the route and organotropism of metastases. Further studies of the function of adhesion molecules in pulmonary diseases will contribute to our understanding of the pathomechanisms of these diseases and, through the development of specific antibodies, may provide attractive new therapeutic approaches to problems for which treatment is not yet available


title: The Cytokine Response to Physical Activity and Training

text: Cytokines are soluble glycoproteins that are produced by and mediate communication between and within immune and nonimmune cells, organs and organ systems throughout the body. Pro- and anti-inflammatory mediators constitute the inflammatory cytokines, which are modulated by various stimuli, including physical activity, trauma and infection. Physical activity affects local and systemic cytokine production at different levels, often exhibiting striking similarity to the cytokine response to trauma and infection. The present review examines the cytokine response to short term exercise stress, with an emphasis on the balance between pro- and anti-inflammatory mechanisms and modulation of both innate and specific immune parameters through cytokine regulation. The effects of long term exercise on cytokine responses and the possible impact on various facets of the immune system are also discussed, with reference to both cross-sectional and longitudinal studies of exercise training. Finally, the validity of using exercise as a model for trauma and sepsis is scrutinised in the light of physiological changes, symptomatology and outcome, and limitations of the model are addressed. Further studies, examining the effect of exercise, trauma and infection on novel cytokines and cytokine systems are needed to elucidate the significance of cytokine regulation by physical activity and, more importantly, to clarify the health implications of short and long term physical activity with respect to overall immune function and resistance to infection.


title: Der Leukämiepatient auf der Intensivstation

text: Patients with leukemia are prone to critical illness at some time during their disease and their therapy that requires critical care. A number of these patients will have the opportunity to receive curative treatment and have an excellent probability of long-term remission if supported through a crisis. Complications that cause critical illness can be categorized as related to disease or those caused by therapy. The present review is focused on the description of the types of complications requiring intensive care, on specific aspects of the application of critical-care techniques, on organization of the intensive care unit in the context of leukemia and on ethical considerations.


title: Is there a clinical difference between influenza A and B virus infections in hospitalized patients?: Results after routine polymerase chain reaction point-of-care testing in the emergency room from 2017/2018

text: PURPOSE: The clinical presentation, complications and mortality in molecularly confirmed influenza A and B infections were analyzed. METHODS: This retrospective observational single-centre study included all influenza positive patients older than 18 years who were hospitalized and treated at the flu isolation ward during 2017/2018. The diagnosis was based on point-of-care tests with the Alere(TM). RESULTS: Of the 396 patients tested positive for influenza, 24.2% had influenza A and 75.8% influenza B. Influenza A patients were younger (median age 67.5 years vs. 77 years, p < 0.001), were more often smokers (27.7% vs. 16.8%, p = 0.021), had chronic pulmonary diseases more frequently (39.6% vs. 26.3%, p = 0.013), presented with a higher body temperature (38.6 °C vs. 38.3 °C, p = 0.004), leucocyte count (8 G/L vs. 6.8 G/L, p = 0.002), C‑reactive protein (CRP) level (41 mg/l vs. 23 mg/l, p < 0.001) and had dyspnea more often (41.7% vs. 28%, p = 0.012). Influenza B patients had an underlying chronic kidney disease in 37% vs. 18.8% (p < 0.001) and presented with vomiting on admission more frequently (21.7% vs. 11.5%, p = 0.027). Influenza A patients were admitted for 8 days vs. 7 days (p = 0.023). There were no differences in the rate of complications; however, 22 (5.6%) patients died during the hospital stay. The in-hospital mortality was higher in influenza A patients (8.3% vs 4.7%, p = 0.172). CONCLUSION: Some differences were found between influenza A and B virus infections but symptoms were overlapping, which necessitates polymerase chain reaction point-of-care testing for accurate diagnosis. Influenza A was a more severe disease than influenza B during the period 2017/2018.


title: Development of common variable immunodeficiency in IgA- and IgG2-deficient patients with systemic lupus erythematosus

text: BACKGROUND: There have been few reports on children who developed common variable immunodeficiency (CVID) in association with immunoglobulin A (IgA) and IgG2 deficiencies and systemic lupus erythematosus (SLE). CASE-DIAGNOSIS/TREATMENT: Our patient experienced nephrotic syndrome and acute respiratory distress syndrome (ARDS) caused by influenza A/H1N1 virus infection at 5 years of age. A diagnosis of IgA and IgG2 deficiency and SLE was made on the basis of severe proteinuria, hematuria, hypocomplementemia, high anti-DNA antibody and antinuclear antibody (ANA) titers, and malar rash. However, these clinical signs and symptoms and laboratory features disappeared after the administration of methylprednisolone pulse therapy and prednisolone. For the 5 years following the initial treatment for SLE, the patient experienced a number of infections and had a low serum total IgG level; she was eventually diagnosed with CVID. The administration of intravenous immunoglobulin (IVIG) was required to prevent subsequent infections, and no relapse of SLE was observed. CONCLUSION: We report the development of CVID in an IgA- and IgG2-deficient patient with SLE on the basis of multiple episodes of infection. To prevent the development of CVID in IgA- and IgG2-deficient patients with SLE, it is important to prevent immune dysregulation by the avoidance of infections through the use of IVIG therapy.


title: Was sind die Indikationen für Rescue-Verfahren?: Rheumatische Systemerkrankungen auf der Intensivstation

text: Severe, organ-threatening and life-threatening manifestations of inflammatory rheumatic diseases, such as diffuse alveolar hemorrhage in the context of small vessel vasculitis, sometimes inadequately respond to immunosuppressive treatment. In the case of an immanent or already occurring organ failure, immunosuppressive treatment may need to be supplemented with rapidly effective rescue treatment procedures. Due to the rarity of many rheumatic diseases, the evidence for the use of rescue treatment, such as plasmapheresis, extracorporeal membrane oxygenation (ECMO) and the administration of intravenous immunoglobulins (IVIG), is relatively low for many indications. The use of plasmapheresis is considered useful in acute anti-glomerular basement membrane (GBM) disease (Goodpasture’s syndrome) or catastrophic antiphospholipid antibody syndrome (APS). The use of ECMO treatment may be considered for persistent respiratory failure despite mechanical ventilation due to diffuse alveolar hemorrhage or acute respiratory distress syndrome (ARDS). Administration of IVIG is indicated for acute cardiac involvement in Kawasaki’s disease and may be considered in catastrophic APS and refractory myositis.


docid: hylleesx

title: A case of novel swine influenza A (H1N1) pneumonia complicated with virus-associated hemophagocytic syndrome

text: Influenza related to complications such as pneumonia and encephalitis have sporadically been reported. However, influenza A (H1N1)-virus-associated hemophagocytic syndrome (VAHS) has rarely been reported. A 39-year old woman complained of high fever and was referred to us. Chest infiltrations in both lungs and a positive polymerase chain reaction (PCR) for novel swine-origin influenza A (H1N1) in bronchial alveolar lavage fluid (BALF) specimen was confirmed and she was diagnosed with influenza A (H1N1) pneumonia. Pancytopenia was found, and hemophagocytic syndrome (HPS) was diagnosed by bone marrow aspiration. Following intravenous administration of antiflu drug and combination therapy of steroid pulse and erythromycin IV, the patient’s respiratory dysfunction and lab data gradually improved and she was discharged on day 21. Whereas secondary HPS related to viral infections such as Epstein–Barr virus, cytomegalovirus, and human herpesvirus type 6 are commonly seen, H1N1 pneumonia complicated with secondary VAHS is rare.


title: Pneumocystis jirovecii (Pj) quantitative PCR to differentiate Pj pneumonia from Pj colonization in immunocompromised patients

text: Conventional polymerase chain reaction (PCR) in respiratory samples does not differentiate between Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii (Pj) colonization. We used Pj real-time quantitative PCR (qPCR) with the objective to discriminate PCP from Pj colonization in immunocompromised patients. All positive Pj qPCR [targeting the major surface glycoprotein (MSG) gene] obtained in respiratory samples from immunocompromised patients presenting pneumonia at the Grenoble University Hospital, France, were collected between August 2009 and April 2011. Diagnoses were retrospectively determined by a multidisciplinary group of experts blinded to the Pj qPCR results. Thirty-one bronchoalveolar lavages and four broncho aspirations positive for the Pj qPCR were obtained from 35 immunocompromised patients. Diagnoses of definite, probable, and possible PCP, and pneumonia from another etiology were retrospectively made for 7, 4, 5, and 19 patients, respectively. Copy numbers were significantly higher in the “definite group” (median 465,000 copies/ml) than in the “probable group” (median 38,600 copies/ml), the “possible group” (median 1,032 copies/ml), and the “other diagnosis group” (median 390 copies/ml). With the value of 3,160 copies/ml, the sensitivity and specificity of qPCR for the diagnosis of PCP were 100 % and 70 %, respectively. With the value of 31,600 copies/ml, the sensitivity and specificity were 80 % and 100 %, respectively. The positive predictive value was 100 % for results with more than 31,600 copies/ml and the negative predictive value was 100 % for results with fewer than 3,160 copies/ml. qPCR targeting the MSG gene can be helpful to discriminate PCP from Pj colonization in immunocompromised patients, using two cut-off values, with a gray zone between them.


title: Unexplained chronic leukopenia treated with oral iron supplements

text: Case A 67-year-old woman known to have iron deficiency anemia and persistent unexplained chronic leukopenia was cared for by our medical center for about 16 years. During this period she was examined thoroughly and diagnosed to have chronic idiopathic neutropenia (also known as chronic benign neutropenia). Her iron deficiency was attributed to nutritional factors and she was non-compliant with her oral iron supplements. The patient fully received her iron supplement medication by nursing staff for two and a half months during an unexpected prolonged hospital stay after her suffering an acute ischemic cerebrovascular accident. An astonishing outcome was that in addition to having her iron deficiency anemia treated, her long-term unexplained neutropenia was also corrected. Conclusion Some patients diagnosed with chronic idiopathic neutropenia and clinically present as having unexplained chronic neutropenia might actually be suffering from a form of not yet described iron deficiency induced neutropenia.


title: Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan

text: BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is a rare immunodeficiency that is characterized by recurrent hemophagocytic lymphohistiocytosis (HLH) and splenomegaly and sometimes associated with refractory inflammatory bowel disease (IBD). Although hematopoietic stem cell transplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory compared with those for SLAM-associated protein deficiency and familial HLH. AIM: To investigate the outcomes and adverse events of HSCT for patients with XIAP deficiency, a national survey was conducted. METHODS: A spreadsheet questionnaire was sent to physicians who had provided HSCT treatment for patients with XIAP deficiency in Japan. RESULTS: Up to the end of September 2016, 10 patients with XIAP deficiency had undergone HSCT in Japan, 9 of whom (90%) had survived. All surviving patients had received a fludarabine-based reduced intensity conditioning (RIC) regimen. Although 5 patients developed post-HSCT HLH, 4 of them survived after etoposide administration. In addition, the IBD associated with XIAP deficiency improved remarkably after HSCT in all affected cases. CONCLUSION: The RIC regimen and HLH control might be important factors for successful HSCT outcomes, with improved IBD, in patients with XIAP deficiency. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10875-016-0348-4) contains supplementary material, which is available to authorized users.


title: Lung Function and Bacterial Proliferation in Experimental Neonatal Pneumonia in Ventilated Rabbits Exposed to Monoclonal Antibody to Surfactant Protein A

text: Surfactant protein A (SP-A) increases the resistance of surfactant to inhibition by plasma and other proteins. In a previous study we found that a monoclonal anti-SP-A antibody (R 5) increased the sensitivity of surfactant to inhibition by fibrinogen in vivo and in vitro. SP-A has been shown to stimulate microbial phagocytosis and killing by alveolar macrophages. We hypothesized that using R 5 to inactivate SP-A in an animal model mimicking congenital group B streptococcal (GBS) pneumonia might result in increased bacterial proliferation and a deterioration in lung function. Newborn near term rabbits were delivered by Cesarean section, anesthetized, tracheotomized, and ventilated for 5 h in a plethysmograph system allowing measurement of dynamic lung-thorax compliance. Postnatally the animals received one intratracheal injection (5 ml/kg) of R 5, nonspecific IgG, or normal saline. At 30 min all animals received a standard dose of an encapsulated GBS strain by intratracheal injection. The number of bacteria (mean log(10) CFU/g lung ± S.D.; CFU = colony forming unit) was evaluated in lung homogenates. Histologic lung sections were judged by light microscopy. Bacterial proliferation was similar in rabbits treated with the monoclonal antibody (9.33 ± 0.39; n= 14) and in control animals receiving saline (9.16 ± 0.35; n= 14) or nonspecific IgG (9.26 ± 0.31; n= 11). No significant differences were noted on the histologic analysis or in measurements of lung function. We conclude that intratracheal instillation of a monoclonal anti-SP-A antibody did not increase bacterial proliferation in GBS-infected newborn rabbits. These findings suggest that SP-A does not play an important role in protection against encapsulated GBS strains in the neonatal period.


title: Pseudallescheria boydii with Aspergillus fumigatus and Aspergillus terreus in a Critically Ill Hematopoietic Stem Cell Recipient with ARDS

text: Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-d-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.


title: Influenza Virus: A Brief Overview

text: Influenza is a major public health concern, infecting 5–15% of the global population annually. Influenza virus belongs to family Orthomyxoviridae, and has three types A, B and C. Infection by influenza virus A is most common and severe, generally found in humans. It spreads rapidly and affects human population across large geographical region within short period of time with varying degree of pathology from mild to severe. Wild aquatic birds and other animal species like birds, pigs, ferret, horses, seals, whales, mink, giant anteaters, cats and dogs are the reservoir for the influenza A virus. Influenza B and C viruses have very limited host range and appear predominantly in humans. Influenza virus gains pandemic potential through genetic reassortment called “genetic shift” with complete renewal of surface antigen and a small but gradual genetic change by mutations which make it to adapt efficiently in human population called “genetic drift”. Although, the epidemiology related to influenza infection has been studied from several years but some facts associated to disease transmission has poorly understood. This article reviews the important aspects of virological, epidemiological and clinical features related to influenza virus for better understanding of disease transmission and its pathogenesis.


Proceedings of the RAMI Intern Section Meeting


title: Clinical characteristics and predictors of mortality in 67 patients with primary pyomyositis: a study from North India

text: Primary pyomyositis is infection of the skeletal muscles in the absence of adjacent skin, soft tissue, and bone infection. This study was undertaken to look at the spectrum of clinical presentations, therapeutic interventions, and their outcomes and also to evaluate the association of various risk factors with mortality. This was a retrospective study in which the patients admitted with the diagnosis of primary pyomyositis from January 2000 to June 2007 were included. Their demographic details, clinical and laboratory data, Sequential Organ Failure Assessment (SOFA) score at presentation, treatment instituted, complications encountered, and hospital outcome were recorded. Sixty-seven patients (42 males and 25 females) with a diagnosis of primary pyomyositis were included. Median age at the time of presentation was 37 years (interquartile range = 25–50 years). Common presenting symptoms were myalgias [50 (74.62%)] and fever [49 (73.13%)]. Twenty-six patients had underlying predisposing medical conditions. The commonest muscle group involved was iliopsoas muscles in 31 (46.26%) patients. Methicillin-sensitive Staphylococcus aureus was the commonest organism isolated from the pus. Twenty-eight patients developed sepsis and seven died. On univariate analysis, there was a statistically significant association between higher SOFA score, lower Glasgow coma scale, higher pulse rate, lower blood pressure, raised blood urea, raised serum creatinine, higher serum glutamic pyruvate transaminase, raised total bilirubin at presentation, and development of sepsis during hospital stay with mortality. In our study, the patients were seen almost a decade later than those seen in other studies from the region. Evidence of organ dysfunction at presentation and sepsis was associated with increased mortality.


Case Report: Severe Interstitial Pneumonitis Secondary to Pegylated Interferon α-2b and Ribavirin Treatment of Hepatitis C Infection


title: Parasites of the small intestine

text: This paper discusses the most important parasites that inhabit the human small intestine. Beginning with the protozoa and proceeding through the various species of cestodes, nematodes, and trematodes that inhabit the human small bowel, the most important organisms are presented. Possible future developments are discussed along with pathophysiology and treatment in this phylogenic approach. Zoonotic illnesses, those diseases that by their rarity are of little import, and diseases without significant clinical or social implications are beyond the scope of this article and are not discussed.


title: Clinical studies of alveolar-capillary permeability using technetium-99m DTPA aerosol

text: Soluble radioaerosols such as technetium-99m diethylene triamine pentacetate (DTPA) permit simple quantitative studies of alveolar-capillary permeability to be performed, since the submicronic aerosols are deposited mainly at the lung periphery and are cleared across the alveolar-capillary membrane. Regional alterations in permeability can also be noted using this radionuclide technique. We have measured the pulmonary epithelial permeability in normal subjects and the alteration in smokers, in glue-sniffers, in patients with inhalation burns, in chronic obstructive pulmonary disease (COPD) and in patients with lung metastases from thyroid cancer treated with radioiodine(131)I. In the normal volunteers, the time taken for 50% of inhaled(99m)Tc DTPA to be cleared from the lungs (T1/2) was 66 minutes ± lsd of 12 mins. The smokers had a mean T1/2 of 20 mins ± lsd 4 min. In the hard-core glue-sniffing group, the majority were smokers who had stopped smoking and gluesniffing for periods varying from 1 day to 42 days, and it was possible to note the changes in clearance times against period of abstinence. In the patients with inhalation burns, there was change in lung clearance arising from pulmonary epithelial damage; these patients showed increased rate of clearance (short T1/2) with mean T1/2 of 36 min ± 1 sd of 11 mins, while the retention images revealed regional lung damage in moderately severe inhalation burns. Twenty-four patients with COPD had inhalation scans done with Tc-99m tin colloid radioaerosol, and these images were compared with the perfusion lung scans done with(99m)Tc macroaggregated albumin (MAA); in general the perfusion images matched the defects noted in the inhalation scans. The(99m)Tc DTPA clearance rate in these patients was normal i.e. T1/2 = 78 ± 14 mins. In the thyroid cancer patients with lung metastases, who had high doses of radioiodine treatment, the T1/2 values were normal or prolonged slightly, mean T1/2 = 76 min ± 23.


Inferior dislocation of the patella: an unusual cause of a locked knee


title: Perivascular Adipose Tissue: the Sixth Man of the Cardiovascular System

text: Perivascular adipose tissue (PVAT) refers to the local aggregate of adipose tissue surrounding the vascular tree, exhibiting phenotypes from white to brown and beige adipocytes. Although PVAT has long been regarded as simply a structural unit providing mechanical support to vasculature, it is now gaining reputation as an integral endocrine/paracrine component, in addition to the well-established modulator endothelium, in regulating vascular tone. Since the discovery of anti-contractile effect of PVAT in 1991, the use of multiple rodent models of reduced amounts of PVAT has revealed its regulatory role in vascular remodeling and cardiovascular implications, including atherosclerosis. PVAT does not only release PVAT-derived relaxing factors (PVRFs) to activate multiple subsets of endothelial and vascular smooth muscle potassium channels and anti-inflammatory signals in the vasculature, but it does also provide an interface for neuron-adipocyte interactions in the vascular wall to regulate arterial vascular tone. In this review, we outline our current understanding towards PVAT and attempt to provide hints about future studies that can sharpen the therapeutic potential of PVAT against cardiovascular diseases and their complications.


ITS Annual Scientific Meeting 2016


title: Invasive Aspergillus infection localized to the gastric wall: report of a case

text: Invasive aspergillosis is most commonly seen in patients with immune disorders and usually in the lung. Local invasive aspergillosis of the gastrointestinal system is quite rare. A 13-year-old female without immune deficiency presented with acute abdomen due to full-thickness necrosis of the gastric fundus. The necrotic gastric wall was excised and the stomach repaired. The pathology revealed a gastric ulcer with invading Aspergillus hyphae and spores. Aspergillosis is an opportunistic infection and its spores cannot survive in the normal gastric mucosa. The Aspergillus spores in this case probably grew on a background of gastric ulcer and caused wall necrosis and that the surgical treatment possibly provided a cure because it remained localized to the gastric wall.


title: Adult respiratory distress syndrome associated withMycoplasma pneumoniae infection

text: A 13-year-old boy is described who developed severe adult respiratory distress syndrome (ARDS), biochemical pancreatitis and skin vasculitis after an acute respiratory infection due toMycoplasma pneumoniae. The boy was mechanically ventilated for 17 days, but could be discharged in good clinical condition after 36 days of hospitalization. However, major disturbances of the lung function tests persisted, suggesting interstitial fibrosis. To the best of our knowledge, this is the first case of ARDS afterM. pneumoniae infection in childhood.


title: Intrahost emergent dynamics of oseltamivir-resistant virus of pandemic influenza A (H1N1) 2009 in a fatally immunocompromised patient

text: The oseltamivir-resistant pandemic influenza virus A (2009 H1N1) with H275Y mutation in neuraminidase (NA) has been sporadically reported, and its wide spread remains a potential threat. Here we detected the uneven distribution of H275Y mutant virus in a patient who received a 21-day long-term administration of oseltamivir. Intrahost variation of the virus showed that the H275Y mutant virus was the predominant population in both nasopharynx and right lung, whereas the oseltamivir-sensitive virus comprised half the population in the left lung. By constructing minimum spanning trees, it is proposed that the H275Y mutant might be generated primarily in the nasopharynx, then spread to the right and left lungs.


title: TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury

text: Acute lung injury (ALI) frequently occurs after liver transplantation and major liver surgery. Proinflammatory mediators released by damaged liver after liver ischemia/reperfusion (I/R) injury might contribute to this form of ALI, but the underlying mechanisms have not been well characterized. High-mobility group box protein 1 (HMGB1), a recently identified proinflammatory cytokine, was found to be significantly higher in the serum after liver I/R injury. This study investigated whether HMGB1 was involved as a stimulating factor, and whether its downstream Toll-like receptor 4 (TLR4), p38 mitogen-activated protein kinase (p38MAPK), and activator protein-1 (AP-1) signaling pathways act as mediators in the development of liver I/R injury-induced ALI. Extensive ALI and lung inflammation was induced in a rat model of liver I/R injury. Serum HMGB1 was significantly higher after liver I/R injury, and more importantly, expression of HMGB1 mRNA and protein in the lung tissue was also significantly increased. We further found that liver I/R injury enhanced the expression of TLR4 mRNA and protein, and the activity of p38MAPK and AP-1 in the lung tissue. Inhibition of TLR4 expression in the lung tissue by infection with pGCSIL-GFP-lentivirus-expressing small hairpin RNAs targeting the TLR4 gene (TLR4-shRNA lentivirus) significantly attenuated ALI, lung inflammation, and activity of p38MAPK and AP-1 in the lung tissue. These findings indicate that HMGB1 might contribute to the underlying mechanism for liver I/R injury-induced ALI and that its downstream TLR4, p38MAPK, and AP-1 signaling pathways are potentially important mediators in the development of ALI.


title: Sickle Cell Anaemia: Progress in Pathogenesis and Treatment

text: The phenotypic expression of sickle cell anaemia varies greatly among patients and longitudinally in the same patient. It influences all aspects of the life of affected individuals including social interactions, intimate relationships, family relations, peer interactions, education, employment, spirituality and religiosity. The clinical manifestations of sickle cell anaemia are protean and fall into three major categories: (i) anaemia and its sequelae; (ii) pain and related issues; and (iii) organ failure including infection. Recent studies on the pathogenesis of sickle cell anaemia have centred on the sequence of events that occur between polymerisation of deoxy haemoglobin (Hb) S and vaso-occlusion. Cellular dehydration, inflammatory response and reperfusion injury seem to be important pathophysiological mechanisms. Management of sickle cell anaemia continues to be primarily palliative in nature, including supportive, symptomatic and preventative approaches to therapy. Empowerment and education are the major aspects of supportive care. Symptomatic management includes pain management, blood transfusion and treatment of organ failure. Pain managment should follow certain priniciples that include assessment, individualisation of therapy and proper utilisation of opioid and non-opioid analgesics in order to acheive adequate pain relief. Blood selected for transfusion should be leuko-reduced and phenotypically matched for the C, E and Kell antigens. Exchange transfusion is indicated in patients who are transfused chronically in order to prevent or delay the onset of iron-overload. Acute chest syndrome is the most common form of organ failure and its management should be agressive, including adequate ventilation, multiple antibacterials and simple or exchange blood transfusion depending on its severity. Preventitive therapy includes prophylactic penicillin in infants and children, blood transfusion (preferably exchange transfusion) in patients with stroke, and hydroxyurea in patients with frequent acute painful episodes. Bone marrow and cord blood transplantation have been successful modalities of curative therapy in selected children with sickle cell anaemia. Newer approaches to preventative therapy include cellular rehydration with agents that inhibit the Gardos channel or the KCl co-transport channel. Curative gene therapy continues to be investigational at the level of the test tube and transgenic mouse models.


title: Tumor necrosis factor as a pharmacological target

text: As indicated by its name, tumor necrosis factor (TNF), cloned in 1985, was originally described as a macrophage-derived endogenous mediator that can induce hemorrhagic necrosis of solid tumors and kill some tumor cell lines in vitro. Unfortunately, its promising use as an anticancer agent was biased by its toxicity, which was clear soon from the first clinical trials with TNF in cancer. Almost at the same time TNF was being developed as an anticancer drug, it became clear that TNF was identical to a mediator responsible for cachexia associated with sepsis, which was termed cachectin. This research led to the finding that TNF is, in fact, the main lethal mediator of sepsis and to the publication of a huge number of articles showing that TNF inhibits the toxic effects of bacterial endotoxins, which are now described as systemic inflammatory response. Although the clinical trials with anti-TNF in sepsis have not been successful thus far, undoubtedly as a result of the complexity of this clinical setting, these studies ultimately led to the identification of TNF as a key inflammatory mediator and to the development of anti-TNF molecules (soluble receptors and antibodies) for important diseases including rheumatoid arthritis and Crohn’s disease. On the other side, the mechanisms by which TNF and related molecules induce cell death have been studied in depth, and their knowledge might, in the future, suggest means of improve the therapeutic index of TNF in cancer.


title: Diagnosis and prevention of rabies

text: Over a million Americans are bitten by animals every year. Since the rabies vaccine is uniformly effective and the disease is uniformly fatal when the vaccine is not given, management decisions must be made promptly.


title: HIV- und AIDS-Patienten auf der Intensivstation

text: The number of HIV-infected patients in Germany has increased steadily over time. This is due to the positive development of decreasing death rates and a nearly stable rate of new infections. This development is based on the improved prognosis for HIV/AIDS patients due to the introduction of highly active antiretroviral therapy (HAART) in 1996. Considering this, a new look at the HIV patient as a potential ICU candidate is necessary. The most common referral for ICU therapy is respiratory failure, followed by neurological disorders. In rare cases, HAART-induced side-effects require therapy in the ICU. Very few clinical trials directly compare the outcome of HIV-positive and HIV-negative patients, and most of these data were collected in the pre-HAART era. The ICU outcome does not correlate with HIV-genuine parameters, such as the CD4 cell counts. Thus, a HIV patient can benefit from ICU treatment. Regarding HAART management, open questions still exist especially considering the mechanically ventilated patient. Actually only AZT (Retrovir®) is available as an i.v. formulation. Other antiretroviral medication can only be administered after grinding the tablets. The consequenses of the altered galenic composition with regard to efficacy and development of resistance has not been sufficiently studied. This also applies to risks and benefits of interrupted therapy versus a possibly inappropriate application of HAART. In this survey we also describe possible interactions between HAART and sedative/antiepileptic/tuberculostatic etc. medication. Finally special aspects of HIV exposure in the health care setting are discussed, including essential immediate measures after an injury. Current recommendations for post-exposure prophylaxis are given.


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title: Proapelin is processed extracellularly in a cell line-dependent manner with clear modulation by proprotein convertases

text: Apelin is a peptide hormone that binds to a class A GPCR (the apelin receptor/APJ) to regulate various bodily systems. Upon signal peptide removal, the resulting 55-residue isoform, proapelin/apelin-55, can be further processed to 36-, 17-, or 13-residue isoforms with length-dependent pharmacological properties. Processing was initially proposed to occur intracellularly. However, detection of apelin-55 in extracellular fluids indicates that extracellular processing may also occur. To test for this, apelin-55 was applied exogenously to HEK293A cells overexpressing proprotein convertase subtilisin kexin 3 (PCSK3), the only apelin processing enzyme identified thus far, and to differentiated 3T3-L1 adipocytes, which endogenously express apelin, PCSK3 and other proprotein convertases. Analysis of culture media constituents from each cell type by high performance liquid chromatography–mass spectrometry and western blot demonstrated a time-dependent decrease in apelin-55 levels. This decrease was partially, but not fully, attenuated by PCSK inhibitor treatment in both cell lines. Comparison of the resulting apelin-55-derived peptide profile between the two cell lines demonstrated distinct processing patterns, with apelin-36 production apparent in 3T3-L1 adipocytes vs. detection of the prodomain of a shorter isoform (likely the apelin-13 prodomain, observed after additional proteolytic processing) in PCSK3-transfected HEK293A cells. Extracellular processing of apelin, with distinct cell type dependence, provides an alternative mechanism to regulate isoform-mediated physiological effects of apelin. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00726-018-2674-8) contains supplementary material, which is available to authorized users.


title: IL-8 Gene Variants and Expression in Childhood Asthma

text: PURPOSE: To examine the IL-8 expression levels and association of genetic variants with the risk of childhood persistent asthma prognosis. METHODS: Overall, 170 asthmatic children and 170 healthy controls were included in this case–control study. The human IL-8 serum levels were measured using ELISA. The IL-8 mRNA expression levels were assessed by a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) methods. RESULTS: The IL-8 expression at both protein and mRNA levels was found to be significantly elevated in asthmatic children compared to healthy subjects (P < 0.0001, P = 0.004; respectively). Higher levels of IL-8 mRNA are detected in subjects with moderate to severe asthma. The presence of IL8-251 A/T (rs4073) and + 781C/T (rs2227306) polymorphisms was significantly associated with an increased risk of asthma (P = 0.002, P = 0.036, respectively). In addition, we noted a significant association between these polymorphisms and an elevated risk of atopic asthma (P < 0.05). For rs2227306 SNP, the highest median level of IgE was detected for the presence of TT genotype (865 ± 99.74 IU/mL). Although, the rs4073 polymorphism conferred a higher risk to develop asthma at an advanced stage of severity (P = 0.008). The rs4073 T and rs2227306 C alleles are considered as risk factors for asthma development. The rs4073 T allele is represented also as a risk factor for asthma severity in Tunisian children. CONCLUSIONS: Both IL-8 gene and protein expression may play a key role in asthma pathogenesis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00408-017-0058-6) contains supplementary material, which is available to authorized users.


title: The outcomes of pediatric liver retransplantation from a living donor: a 17-year single-center experience

text: PURPOSE: Liver retransplantation is the only therapeutic option for patients with graft failure after liver transplantation. The aim of this study is to evaluate the outcomes of pediatric retransplantation from living donor at a single center. METHODS: Between December 1998 to August 2015, retransplantation from a living donor was performed for 14 children (<18 years of age) at Kumamoto University Hospital. The characteristics of the retransplantation recipient and the clinicopathological factors between primary transplantation and retransplantation were analyzed to detect the prognostic factors. RESULTS: In retransplantation, the operative time was longer and the amount of blood loss was greater in comparison to primary transplantation. The 1-, 3-, and 5-year survival rates from the date of retransplantation were 85.7, 85.7, and 78.6%, respectively. The rates of re-laparotomy after primary transplantation, bile leakage and postoperative bleeding after retransplantation were higher than after primary transplantation. Among the three patients who died after retransplantation, the operative time, the rate of re-laparotomy after primary transplantation and the incidence of gastrointestinal complications were higher in comparison to the surviving patients. CONCLUSION: Pediatric retransplantation from a living donor is an acceptable procedure that could save the lives of recipients with failing allografts when organs from deceased donors are scarce. To ensure good results, it is essential to make an appropriate assessment of the cardiopulmonary function and the infectious state of the patients before Re-LDLT.


title: Proteomic peptide profiling for preemptive diagnosis of acute graft-versus-host disease after allogeneic stem cell transplantation

text: Allogeneic hematopoietic stem cell transplantation is one curative treatment for hematological malignancies, but is compromised by life-threatening complications, such as severe acute graft-versus-host disease (aGvHD). Prediction of severe aGvHD as early as possible is crucial to allow timely initiation of treatment. Here we report on a multicentre validation of an aGvHD-specific urinary proteomic classifier (aGvHD_MS17) in 423 patients. Samples (n=1106) were collected prospectively between day +7 and day +130 and analyzed using capillary electrophoresis coupled on-line to mass spectrometry. Integration of aGvHD_MS17 analysis with demographic and clinical variables using a logistic regression model led to correct classification of patients developing severe aGvHD 14 days before any clinical signs with 82.4% sensitivity and 77.3% specificity. Multivariate regression analysis showed that aGvHD_MS17 positivity was the only strong predictor for aGvHD grade III or IV (P<0.0001). The classifier consists of 17 peptides derived from albumin, β2-microglobulin, CD99, fibronectin and various collagen α-chains, indicating inflammation, activation of T cells and changes in the extracellular matrix as early signs of GvHD-induced organ damage. This study is currently the largest demonstration of accurate and investigator-independent prediction of patients at risk for severe aGvHD, thus allowing preemptive therapy based on proteomic profiling. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/leu.2013.210) contains supplementary material, which is available to authorized users.


title: Fulminant blastomycosis with blastomycotic infection of a cerebral glioma: Light microscopic and ultrastructural observations

text: Except for isolated case reports, blastomycosis has not been identified as a significant problem in immunosuppressed patients. We describe an unusual case with blastomycotic infection of a cerebral glioma in a 56-year-old man who underwent radiotherapy for his tumor and died of fulminant blastomycotic pneumonia. This is believed to be the first reported case of Blastomyces dermatitidis infection of a cerebral glioma. The light microscopic and ultrastructural features of B. dermatitidis, the giant forms of which were encountered in our patient, are described, and the role of immuno-suppression due to steroid therapy in the pathogenesis of this fulminant infection are reviewed.


title: Impact of severe hematological abnormalities in the outcome of hospitalized patients with influenza virus infection

text: Although hematological abnormalities have been described among patients with influenza virus infection, little is known about their impact on the outcome of the patients. The aim of this study was to assess the frequency and clinical impact of severe hematological abnormalities in patients with confirmed influenza virus infection. This was an observational retrospective study including all adult patients with diagnosis of influenza virus infection hospitalized from January to May 2016 in our institution. Influenza virus infection was diagnosed by means of rRT-PCR assay performed on respiratory samples. Poor outcome was defined as a composite endpoint in which at least one of the following criteria had to be fulfilled: (a) respiratory failure, (b) SOFA ≥2, or (c) death. Two hundred thirty-nine patients were included. Applying the HLH-04 criteria for the diagnosis of hemophagocytic syndrome, cytopenias (hemoglobin ≤9 g/dl, platelets <100,000/μl or neutrophils <1,000/μl) were present in 51 patients (21%). Patients with hematological abnormalities showed higher SOFA scores, respiratory failure, septic shock and in-hospital mortality than the remaining patients. The composite endpoint was present in 33.3% in the cytopenias group vs. 13.3% in the group without cytopenias (p=0.001). In a multivariate analysis, variables associated with the composite endpoint were: use of steroids prior to present admission (OR: 0.12; 95% CI: 0.015–0.96, p=0.046), presence of any hematological abnormality (OR: 3.54; 95% CI:1.66–7.51, p= 0.001), and LDH>225 U/l (OR:4.45; CI:1–19.71, p=0.049). Hematological abnormalities are not uncommon among hospitalized patients with influenza virus infection, and they are associated with a poorer outcome.


title: n−3 Fatty acids, inflammation, and immunity— Relevance to postsurgical and critically III patients

text: Excessive or inappropriate inflammation and immunosuppression are components of the response to surgery, trauma, injury, and infection in some individuals and these can lead, progressively, to sepsis and septic shock. The hyperinflammation is characterized by the production of inflammatory cytokines, arachidonic acid-derived eicosanoids, and other inflammatory mediators, while the immunosuppression is characterized by impairment of antigen presentation and of T helper cell type-1 responses. Long-chain n−3 FA from fish oil decrease the production of inflammatory cytokines and eicosanoids. They act both directly (by replacing arachidonic acid as an eicosanoid substrate and by inhibiting arachidonic acid metabolism) and indirectly (by altering the expression of inflammatory genes through effects on transcription factor activation). Thus, long-chain n−3 FA are potentially useful anti-inflammatory agents and may be of benefit in patients at risk of developing sepsis. As such, an emerging application of n−3 FA is in surgical or critically ill patients where they may be added to parenteral or enteral formulas. Parenteral or enteral nutrition including n−3 FA appears to preserve immune function better than standard formulas and appears to partly prevent some aspects of the inflammatory response. Studies to date are suggestive of clinical benefits from these approaches, especially in postsurgical patients.


title: Der Einsatz von TNFα-Antagonisten bei primär systemischen Vaskulitiden

text: After the introduction of the TNFα blocking drugs Etanercept and Infliximab for the standard therapy of rheumatoid arthritis these effective substances have also been used successfully in many patients with primary systemic vasculitides, who were unresponsive to standard therapy. From pathophysiologic findings their use is justified by the prominent role of TNFα in the inflammation of small and large vessels. So far only open studies with a maximum of 20 patients and case reports are published. In summary there are reports of the successful treatment of 7 patients with rheumatoid vasculitis, 39 patients with Wegener's granulomatosis, 3 patients each with microscopic Polyangiitis, and 5 patients each with temporal Arteritis or Takayasu disease with Etanercept as well as with Infliximab. In addition, Infliximab was also used with a good response in severe Polymyalgia rheumatica in 4 cases and in one case of a cryoglobulinemic vasculitis. More than 60 patients with Panuveitis and other manifestations of Behçet's disease were treated with Infliximab or Etanercept according to preliminary reports. Because of the overall positive reports with TNFα collected in this review controlled investigations for their use in primary systemic vasculitis are necessary.


title: Einfluß des operationstraumas auf die NK-zell-aktivität beim ösophaguskarizinom nach transmediastinaler dissektion vs. transthorakaler en-bloc-resektion

text: In order to assess the impact of surgical trauma involved in the therapy of esophageal carcinoma on the cellular immune system, a perspective study was performed involving perioperative hematological parameters. The activity of natural killer cells and the serum concentrations of interleuin-2, interleukin-6 and TNF-α were measured in 12 cases of transmediastinal dissection and 10 cases of transthioracic en bloc esophageal resection and compared to values of a control group of thoracic and abdominal surgical patients with non-malignant maladies. Natural killer cells assume a central role in the non-specific immunological response in tumor patients. Their main function is the destruction of tumor cells via cytotoxic activities amplified by the release of interleukin-2 and TNF-α. Natural killer cell activity was measured prior to surgery and on postoperative days 4 and 10 using a standardized europium chloride release assay, utilizing K 562 target cells. Lymphokines interleukin-2, interleukin-6, and THF-α were also measured on postoperative days 1 and 7 using standardized ELISA assays. The activity of natural killer cells in our patient group sank significantly (P<0.05) on postoperative day 4 and likewise in the control group and both study groups, activity sank to the original values. In the control groups, natural killer cell activity averaged 45% of preoperative values, in comparison with an average of 63% following transmediastinal esophageal carcinoma resection (one cavity procedure), and transthoracic en bloc resection patients only reached 61% of preoperative values, transmediastinal dissection patients assumed 75%, and 77% was achieved by control group members. Transthoracic en bloc resection of the esophagus led to a more extreme reduction in cytotoxic cellular activity owing to the greater surgical trauma. Suppression of the immunological tumor resistance, especially in the vulnerable perisurgical pahse, can have an indirect negative effect on the manifestation risk of hematogenic metastases owing to intraoperative tumor cell dissemination resulting from tumor manipulation and may thus be prognostically relevant.


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title: Expression of inflammation-related genes in the lung of BALB/c mice response to H7N9 influenza A virus with different pathogenicity

text: H7N9 influenza A virus (IAV)-infected human cases are increasing and reported over 200 mortalities since its first emergence in 2013. Host inflammatory response contributes to the clearance of influenza virus; meanwhile, the induced “cytokine storm” also leads to pathological lesions. However, what inflammation-related response of the host for H7N9 influenza A virus infection to survival from injures of exuberant cytokine release is still obscure. In this research, expression pattern and histological distribution of inflammation-related genes, RIP3, NLRP3, IL-1β, TNF-α, Slit2 and Robo4 in the lung of BALB/c mice infected with two H7N9 IAV strains with only a PB2 residue 627 difference were investigated, as well as the histopathological injury of the lung. Results showed that significantly higher expression level of NLRP3, RIP3, IL-1β and TNF-α in H7N9-infected groups compared with the control would play a key role in driving lung pathological lesion. While the expression level of Slit2 and Robo4 in H7N9 rV(K627E) group had significantly increased trend than V(K627) which might be the main factor to inhibit the interstitial pneumonia and infiltration. Also, H7N9 induced the histopathological changes in the lung of infected mice, and RIP3, NLRP3, IL-1β, TNF-α, Slit2 and Robo4 showed cell-specific distribution in the lung. The results will provide basic data for further research on the mechanism of inflammatory response and understanding of the role of site 627 in PB2 in H7N9 IAVs infection. In addition, enhancing the resilience of the host vascular system to the inflammatory response by regulation of Slit2–Robo4 signaling pathway might provide a novel strategy for H7N9 IAVs infection.


title: Microcirculatory abnormalities in patients with severe influenza A (H1N1) infection

text: PURPOSE: This study was designed to evaluate the degree of microcirculatory abnormalities in patients with severe influenza A (H1N1) infection. METHODS: We assessed the sublingual microcirculation in seven consecutive patients with acute lung injury related to influenza A (H1N1) infection. The evaluation was carried out using sidestream dark field (SDF) imaging within the first 96 hr after the patients were admitted to the intensive care unit. Thenar oxygen saturation (StO(2)) was also measured with near-infrared spectroscopy (NIRS) during a vascular occlusion test. In addition, the Lung Injury Score (LIS) and the APACHE II and SOFA scores were recorded. RESULTS: All patients received invasive mechanical ventilation and at least one of the following adjuvant therapies: inhaled nitric oxide (n = 4), extracorporeal membrane oxygenation (n = 1), prone position (n = 4), recruitment maneuver (n = 3), and hydrocortisone 50 mg·hr(−6) (n = 6). The median time from admission to microcirculatory assessment was 21 hr. Three patients had bacterial superinfection. The median LIS and PaO(2)/F(i)O(2) were 2.5 (2.25-3.25) and 178 (158-212), respectively. Three subjects were treated with norepinephrine. During a vascular occlusion test, the microcirculation was moderately to severely compromised with a NIRS ascending slope of 2.39%·sec(−1) (1.75-2.67%·sec(−1)), 66% (60-86%) of perfused small vessels in the sublingual microcirculation, and a microvascular flow index of 1.9 (1.3-2.6). The degree of microcirculatory abnormalities detected by the NIRS and SDF imaging techniques was correlated with the severity of the disease, as reflected by the SOFA and APACHE II scores. CONCLUSIONS: The microcirculation as assessed by SDF imaging and NIRS techniques was compromised in patients with acute respiratory distress syndrome (ARDS) and influenza A (H1N1) infection.


title: Nosocomial infections in pediatric intensive care units

text: Nosocomial infections are a significant problem in pediatric intensive care units. While Indian estimates are not available, western PICUs report incidence of 6–8%. The common nosocomial infections in PICU are bloodstream infections (20–30% of all infections), lower respiratory tract infections (20–35%), and urinary tract infections (15–20%); there may be some differences in their incidence in different PICUs. The risk of nosocomial infections depends on the host characteristics, the number of interventions, invasive procedures, asepsis of techniques, the duration of stay in the PICU and inappropriate use of antimicrobials. Most often the child had endogenous flora, which may be altered because of hospitalization, are responsible for the infections. The common pathogens involved areStaphylococcus aureus, coagulase negativestaphylococci, E. coli Pseudomonas aeruginosa, Klebsiella, enterococci, andCandida. Nosocomial pneumonias predominantly occur in mechanically ventilated children. There is no consensus on the optimal approach for their diagnosis. Bloodstream infections are usually attributable to the use of central venous lines; use of TPN and use of femoral site for insertion increase the risk. Urinary tract infections occur mostly after catheterization and can lead to secondary bacteremia. The diagnostic criteria have been discussed in the review. With proper preventive strategies, the nosocomial infection rates can be reduced by up to 50%; handwashing, judicious use of interventions, and proper asepsis during procedures remain the most important practices.


title: Transplantation of highly purified peripheral blood CD34(+) cells from HLA-mismatched parental donors in 14 children: evaluation of early monitoring of engraftment

text: HLA-mismatched family members may represent an important cell source for patients that require stem cell transplantation but lack both a matched sibling donor and a closely matched unrelated donor. We report the outcome of 19 transplantations from HLA two- or three- loci mismatched parental donors in which 14 pediatric patients with hematological malignancies or other disorders, received a median of 21.5 × 10(6) (range, 5.4–58) highly purified CD34(+)peripheral blood stem cells (PBSC), as well as 4.7 × 10(4) (range, 0.4–12) donor T cells per kg body weight. T cell depletion was performed using a two-step CD34-positive selection on two different magnetic beads devices. Ten of 14 patients presented with rapid myeloid engraftment. The four patients who presented with graft failure (two non-engraftments, two rejections) received a second stem cell graft and one a third. Graft rejection was detected early by polymerase chain reaction (PCR) analysis of FACS-sorted T cells. Eight of the 14 patients are still alive after a median observation period of 15.6 months (range, 3–31.3) with full donor chimerism in all hematopoietic cell lineages. No acute organ graft-versus-host disease (GVHD) and no chronic GVHD have occurred. One patient experienced relapse of leukemia. We conclude that transplantation of allogeneic PBSC from haploidentical donors will open new perspectives for pediatric patients for whom an HLA-matched stem cell graft is not available. Close monitoring of recipient and donor hematopoiesis might be of clinical value, to recognize early engraftment or rejection.


title: Extracorporeal life support for immune reconstitution inflammatory syndrome in HIV patients with Pneumocystis jirovecii pneumonia

text: Patients with immunosuppression from human immunodeficiency virus (HIV) have been traditionally considered poor candidates for extracorporeal membrane oxygenation (ECMO) because of high in-hospital mortality and poor long-term survival. Highly active antiretroviral therapy (HAART) has improved survival rates in compliant HIV patients and reversible severe respiratory failure may warrant ECMO in this group. Immune reconstitution inflammatory syndrome (IRIS) involves excessive inflammatory response to a pathogen with paradoxical clinical deterioration following HAART initiation and may present as severe respiratory failure. Patients with IRIS supported on ECMO have been infrequently reported in literature. We report two HIV-positive patients who developed acute respiratory distress syndrome from IRIS necessitating successful veno-venous ECMO as salvage therapy.


title: Approach to neuromuscular disorders in the intensive care unit

text: Neuromuscular disorders increasingly are recognized as a complication in patients in the intensive care unit (ICU) and represent a common cause of prolonged ventilator dependency. The distinct syndromes of critical illness myopathy, prolonged neuromuscular blockade, and critical illness polyneuropathy (CIP) may arise as a consequence of sepsis, multi-organ failure, and exposure to various medications—notably, intravenous corticosteroids and neuromuscular blocking agents—but the pathophysiology of these disorders remains poorly understood. More than one syndrome may occur simultaneously, and the distinctions may be difficult in a particular patient, but a specific diagnosis usually can be established after careful clinical, electrodiagnostic, and, when necessary, histological evaluation. For example, asthmatics requiring treatment with corticosteroids and neuromuscular blocking agents may develop an acute myopathy characterized by generalized weakness, preserved eye movements, elevated creatine kinase levels, and myopathic motor units on electromyography (EMG). Muscle biopsy demonstrates distinctive features of thick (myosin) filament loss on ultrastructural studies. Conversely, those with a prolonged ICU course that is complicated by episodes of sepsis with failure to wean from the ventilator, distal or generalized flaccid limb weakness, and areflexia probably have CIP. EMG in these patients demonstrates reduced or absent motor and sensory potentials with neurogenic motor units. Prolonged neuromuscular blockade most commonly occurs in patients with renal failure who have received prolonged infusions of neuromuscular blockers. There is severe flaccid, areflexic paralysis with normal sensation, facial weakness, and ophthalmoparesis that persists for days or weeks after the neuromuscular blockers have been discontinued. Repetitive nerve stimulation shows a decrement of the compound muscle action potential and, in most cases, establishes a disorder of neuromuscular transmission. With the recent epidemic of West Nile virus infection, a clinical syndrome of acute flaccid paralysis with several features indistinguishable from poliomyelitis has emerged. This article critically examines the clinical, electrophysiological, and pathological features of these and other acute neuromuscular syndromes that arise in the context of ICU care and summarizes the current understanding of the pathophysiology and treatment of these disorders.


title: Transjugular intrahepatic portosystemic shunt in the treatment of portal vein thrombosis: a critical review of literature

text: Reports of successful transjugular intrahepatic portosystemic shunt (TIPS) surgery in patients with portal vein thrombosis (PVT) are considered anecdotal owing to the technical difficulty of the procedure and potential procedure-related complications. A literature review was undertaken to determine the feasibility and safety of TIPS in the treatment of PVT. All studies in which TIPS was attempted in patients with PVT were identified by searching through the PUBMED and MEDLINE databases. A total of 424 PVT patients undergoing TIPS were reported in 54 articles. The success rate of TIPS insertion was 67–100% in 19 case series. Further, 85 patients with portal cavernoma underwent successful TIPS insertions. Three therapeutic strategies of TIPS placement were used: (1) TIPS placement followed by portal vein recanalization via the shunt, (2) portal vein recanalization via percutaneous approaches followed by TIPS placement, and (3) TIPS insertion between a hepatic vein and a large collateral vessel without portal vein recanalization. Four approaches were used to access the portal vein: transjugular, transhepatic, transsplenic, and transmesenteric. Intra-abdominal hemorrhage secondary to hepatic capsule perforation was lethal in only three patients. No episode of pulmonary embolism was reported. Other procedure-related complications were reversible. The overall incidence of shunt dysfunction and hepatic encephalopathy was 8–33% and 0–50%, respectively. In conclusion, the reviewed studies uniformly support the feasibility and safety of TIPS for PVT even in the presence of portal cavernoma. Further, several major issues that remain unresolved are discussed.


title: Studies on histoplasmosis IV. Elution characteristics of the Histo-inhibitory factor (HIF)

text: The histo-inhibitory factor (HIF) derived from homogenates of liver or kidney from hamsters infected withHistoplasma capsulatum has been fractionated by column chromatography. It shows maximum absorption at 280 mµ, has a molecular weight of 142,000 and can be eluted from DEAE-cellulose or DEAE-Sephadex A—50 with 0.02 M phosphate — 4 M sodium chloride (1 : 1) HIF can be eluted fromHistoplasma yeast cells at pH 10.0, thus a greater number of positive cultures from chronic histoplasmosis could be expected to result from pretreatment of clinical specimens in glycine buffer pH 10.0 prior to culture.


title: Non-neoformans Cryptococcal Infections: a Systematic Review

text: Non-neoformans cryptococci have been generally regarded as saprophytes and rarely reported as human pathogens. However, the incidence of infection due to these organisms has increased over the past 40 years, with Cryptococcus laurentii and Cryptococcus albidus, together, responsible for 80% of reported cases. Conditions associated with impaired cell-mediated immunity are important risks for non-neoformans cryptococcal infections and prior azole prophylaxis has been associated with antifungal resistance. The presence of invasive devices was a significant risk factor for Cryptococcus laurentii infection (adjusted OR = 8.7; 95% CI = 1.48–82.9; p = 0.003), while predictors for mortality included age ≥45 years (aOR = 8.4; 95% CI = 1.18–78.82; p = 0.004) and meningeal presentation (aOR = 7.0; 95% CI = 1.85–60.5; p= 0.04). Because clinical manifestations of non-neoformans cryptococcal infections are most often indistinguishable from Cryptococcus neoformans, a high index of suspicion remains important to facilitate early diagnosis and prompt treatment for such infections.


title: Gene therapy in surgery: Part II: Application to septic shock and to organ transplantation

text: Background: With the increasing body of knowledge in molecular biology, gene transfer respectively gene therapy becomes more and more a valid therapeutic option. Methods: This is a critical review of gene therapy protocols for treatment of different types of cancer. Furthermore, the pathophysiological mechanism, therapeutically strategies as well as experimental approaches toward gene transfer in septic shock and organ transplantation are critically elucidated. Results: Gene transfer as a therapeutic option was first successfully applied in children with severe combined immunodeficiency (SCID) in 1990. The majority of gene marking or gene therapy protocols approved for human clinical trials to date are related to the treatment of cancer. Besides viral vectors for brain tumors, non-viral vectors, liposomes particularly, with almost no side effects are increasingly used. Conclusions: Different approaches of gene transfer in cancer patients are under investigation. Experimental data of septic shock treatment and rejection therapy of the allograft in organ recipients with gene transfer are encouraging for future applications in clinical trials.


title: Atrial overexpression of angiotensin-converting enzyme 2 improves the canine rapid atrial pacing-induced structural and electrical remodeling: Fan, ACE2 improves atrial substrate remodeling

text: The purpose of this study was to investigate whether atrial overexpression of angiotensin-converting enzyme 2 (ACE2) by homogeneous transmural atrial gene transfer can reverse atrial remodeling and its mechanisms in a canine atrial-pacing model. Twenty-eight mongrel dogs were randomly divided into four groups: Sham-operated, AF-control, gene therapy with adenovirus-enhanced green fluorescent protein (Ad-EGFP) and gene therapy with Ad-ACE2 (Ad-ACE2) (n = 7 per subgroup). AF was induced in all dogs except the Sham-operated group by rapid atrial pacing at 450 beats/min for 2 weeks. Ad-EGFP and Ad-ACE2 group then received epicardial gene painting. Three weeks after gene transfer, all animals except the Sham group underwent rapid atrial pacing for another 3 weeks and then invasive electrophysiological, histological and molecular studies. The Ad-ACE2 group showed an increased ACE2 and Angiotensin-(1–7) expression, and decreased Angiotensin II expression in comparison with Ad-EGFP and AF-control group. ACE2 overexpression attenuated rapid atrial pacing-induced increase in activated extracellular signal-regulated kinases and mitogen-activated protein kinases (MAPKs) levels, and decrease in MAPK phosphatase 1(MKP-1) level, resulting in attenuation of atrial fibrosis collagen protein markers and transforming growth factor-β1. Additionally, ACE2 overexpression also modulated the tachypacing-induced up-regulation of connexin 40, down-regulation of connexin 43 and Kv4.2, and significantly decreased the inducibility and duration of AF. ACE2 overexpression could shift the renin–angiotensin system balance towards the protective axis, attenuate cardiac fibrosis remodeling associated with up-regulation of MKP-1 and reduction of MAPKs activities, modulate tachypacing-induced ion channels and connexin remodeling, and subsequently reduce the inducibility and duration of AF. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00395-015-0499-0) contains supplementary material, which is available to authorized users.


title: Surfactant replacement therapy for non-respiratory distress syndrome neonatal respiratory disease —research or clinical application?

text: Research studies have highlighted both physiological and pathological evidence to incriminate surfactant abnormality and/or deficiency in many neonatal respiratory diseases. Data from animal models and clinical studies support the concept that surfactant replacement therapy (SRT) may have a role to play in such problems. There is now, therefore, a need to perform further randomized controlled trials to assess the appropriate clinical application of SRT in non-respiratory distress syndrome neonatal respiratory disease.


title: Complement inhibition by soluble complement receptor type 1 fails to moderate cerulein-induced pancreatitis in the rat

text: CONCLUSION: Cerulein-induced pancreatitis in rats associated with remote liver and lung dysfunction. Soluble complement receptor 1 (sCR1) does not reduce the local or remote injury. Thus complement activation does not moderate cerulein-induced pancreatitis or the associated liver and lung injury. BACKGROUND: The local and remote injury of pancreatitis resembles other inflammatory events that are mediated by complement. This study examines the effect of complement inhibition with sCR1 in cerulein-induced pancreatitis in rats. METHODS: Thirteen Sprague-Dawley rats received five hourly subcutaneous doses of cerulein (100 μg initially, then 50 μg/kg). Six of these animals received hourly iv sCR1 (15 mg/kg, a proven complement-inhibiting dose in rats) and the other seven received iv saline. In parallel, 12 additional rats received hourly sc and iv saline. RESULTS: Compared to saline controls, rats receiving cerulein showed increased pancreatic wet-to-dry ratio (3.25∶8.52) hematocrit (40 to 47%), ascites volume (2.1 to 6.1 mL), serum amylase (1680 to 10,700 U/L), and ascites amylase (32,200 to 167,000 U/L) (allp<0.05). None of these parameters were modified by treatment with sCR1. Serum SGPT, which increased from 33.4 to 46.6 U/L in cerulein-infused rats, showed a trend toward reduction to 38.8 U/L in rats treated with sCR1. Cerulein-treated rats also had increased lung myeloperoxidase (0.069 to 0.097 U/g) and lung permeability, as assessed by alveolar lavage to serum ratio of labeled albumen (0.041∶0.121) (bothp<0.05). Neither were changed by sCR1 treatment.


title: Neuropathologische Befunde nach herzchirurgischen Operationen: Retrospektive über 6 Jahre

text: Neuropathological studies may contribute to the discovery of central nervous system complications after heart surgery and thus help to reduce the incidence of postoperative neurological or cognitive disturbances. We examined the brains of 262 such patients operated for coronary bypass, valve replacement, or heart transplantation. Circulatory disturbances (macro- and microhemorrhages, infarcts, subarachnoid hemorrhages, and hypoxemic brain damage) were present in 128 cases (49%), as the cause of death in 33 cases (12.6%). The infarcts were caused by local arteriosclerosis of brain arteries, arterial emboli originating from the operative sites or myocardial infarctions, or by fat emboli, foreign body emboli or megakaryocytic capillary emboli in rare cases. Inflammatory disturbances were present in 17 cases and consisted of fungal or bacterial septicopyemic changes (12) or of glial nodules (5) as the substrate of a viral or autoimmunencephalitis (Bickerstaff). An incidental finding was Alzheimer’s disease in 37 cases (14% of the material) of elderly patients, often associated with cerebral amyloid angiopathy but not as cause of death or cause of macroscopic brain hemorrhage. Since we have conducted an autopsy study, there is a limitation to transfer the documented changes to the total group of post-cardiac surgery patients with neurologic and cognitive deficits. Contrary to some previous reports, histologically overt microembolic phenomena do not seem to play a major role in our material. On the other hand, careful scrutiny revealed non-fatal white matter microhemorrhages of varying frequency in the different groups, especially after valve operations. These as well as the occasional glial nodules, after resorption and microscarring, could well be the cause of slight neurologic and cognitive impairments.


title: n−3 Polyunsaturated fatty acids and inflammation: From molecular biology to the clinic

text: The immune system is involved in host defense against infectious agents, tumor cells, and environmental insults. Inflammation is an important component of the early immunologic response. Inappropriate or dysfunctional immune responses underlie acute and chronic inflammatory diseases. The n−6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds that have important roles in inflammation and in the regulation of immunity. Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators, through several mechanisms, including decreased availability of AA, competition for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and decreased expression of COX-2 and 5-LOX. This alone is a potentially beneficial anti-inflammatory effect of n−3 FA. However, n−3 FA have a number of other effects that might occur down-stream of altered eicosanoid production or might be independent of this effect. For example, dietary fish oil results in suppressed production of proinflammatory cytokines and can modulate adhesion molecule expression. These effects occur at the level of altered gene expression. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease and to protect against the effects of endotoxin. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some asthmatics, supporting the idea that the n−3 FA in fish oil are anti-inflammatory. There are indications that the inclusion of fish oil in enteral and parenteral formulae is beneficial to patients.


title: Unusual manifestations of the antiphospholipid syndrome

text: The classical clinical picture of the antiphospholipid syndrome (APS) is characterized by venous and arterial thromboses, fetal losses and thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or antibodies to the protein “cofactor” b2 glycoprotein I. Single vessel involvement or multiple vascular occlusions may give rise to a wide variety of presentations. Any combination of vascular occlusive events may occur in the same individual and the time interval between them also varies considerably from weeks to months or even years. Deep vein thrombosis, sometimes accompanied by pulmonary embolism, is the most frequently reported manifestation in this syndrome. Cerebrovascular accidents—either stroke or transient ischemic attacks—are the most common arterial thrombotic manifestations. Early and late fetal losses, premature births and pre-eclampsia are the most frequent fetal and obstetric manifestations. Additionally, several other clinical features are relatively common in these patients, i.e., thrombocytopenia, livedo reticularis, heart valve lesions, hemolytic anemia, epilepsy, myocardial infarction, leg ulcers, and amaurosis fugax. However, a large variety of other clinical manifestations have been less frequently described in patients with the APS, with prevalences lower than 5%. These include, among others, large peripheral or aortic artery occlusions, Sneddon's syndrome, chorea, transverse myelopathy, intracardiac thrombus, adult respiratory distress syndrome, renal thrombotic microangiopathy, Addison's syndrome, Budd-Chiari syndrome, nodular regenerative hyperplasia of the liver, avascular necrosis of the bone, cutaneous necrosis or subungual splinter hemorrhages. In this article, some of these “unusual” manifestations are reviewed.


title: Obesity is Associated with Reduced Brain Tissue Oxygen Tension After Severe Brain Injury

text: BACKGROUND: Obesity has been associated with compromised tissue oxygenation and reduced organ perfusion. The brain is critically dependent on oxygen delivery, and reduced brain tissue oxygen tension (P(bt)O(2)) may result in poor outcome after brain injury. We tested the hypothesis that obesity is associated with compromised P(bt)O(2) after severe brain injury. METHODS: Patients with severe brain injury (GCS score ≤ 8) who underwent continuous P(bt)O(2) monitoring were retrospectively identified from a prospective single-center database. Patients, were classified by body mass index (BMI = weight (kg)/m(2)) and were included if they were obese (BMI ≥ 30) or non-obese (BMI = <30). RESULTS: Sixty-nine patients (mean age 46.4 ± 17.0 years) were included. Mean daily P(bt)O(2) was 25.8 (9.6) mmHg for the 28 obese and 31.8 (12.3) mmHg for the 41 non-obese patients (P = 0.03). Initial P(bt)O(2) and mean daily maximum P(bt)O(2) measurements also were significantly lower in obese patients than in non-obese patients. Univariate predictors of compromised P(bt)O(2) (defined as minutes P(bt)O(2) < 20 mmHg) included elevated BMI (P = 0.02), presence of ARDS (P < 0.01), mean PaO(2) (P < 0.01), maximum FiO(2) (P < 0.01), mean PaO(2):FiO(2) (P < 0.01), and mean CVP (P < 0.01). In multivariable analysis, BMI was significantly associated with compromised P(bt)O(2) (P = 0.02). Sex, age, and mean CVP were also identified as significant predictors of compromised P(bt)O(2); ARDS and PF ratio were not. CONCLUSIONS: In patients with severe brain injury, obesity was found to be an independent predictor of compromised P(bt)O(2). This effect may be mediated through obesity-related pulmonary dysfunction and inadequate compensatory mechanisms.


title: MicroRNA-34a Suppresses Autophagy in Alveolar Type II Epithelial Cells in Acute Lung Injury by Inhibiting FoxO3 Expression

text: Excessive autophagic activity of alveolar type II epithelial (AT-II) cells is one of the main causes of acute lung injury (ALI); however, the underlying molecular mechanism remains to be determined. The microRNAs (miRNAs) are involved with autophagy in many diseases. The objective of this study was therefore to investigate the relationship between the miRNA expression and the autophagic activity of the AT-II cells in the pathogenesis of ALI and its molecular mechanism. A mouse model of ALI and AT-II cell injury was induced using lipopolysaccharide (LPS) in vivo and in vitro, and the expression of miR-34a and the autophagy-related proteins LC3 II/I and p62 were determined. Moreover, the autophagic activity was investigated after miR-34a overexpression and inhibition. The effects of miR-34a on its target gene, FoxO3, in regulating autophagic activity in AT-II cells were also determined. LPS induced autophagic activity and increased the expression of miR-34a in lung tissues and in AT-II cells. The in vitro results showed that the upregulation of miR-34a suppressed, whereas the inhibition of miR-34a promoted, autophagy in AT-II cells. Moreover, miR-34a could directly bind to the 3′-untranslated region of the autophagy-related gene, FoxO3, to decrease its expression. In addition, the knockdown of FoxO3 expression inhibited the autophagic activity in AT-II cells. Together, this study suggested that miR-34a might suppress the excessive autophagic activity in AT-II cells via targeting FoxO3 to reduce the damage of LPS-induced ALI.


title: Acute liver failure

text: Acute liver failure in children is a rare but potentially fatal disease. Causes of ALF in neonatal period are different from those in early or late childhood. Despite the improvement in the paediatric intensive care, liver transplantation remains the only effective treatment. Use of newer treatment modalities (liver assist devices and hepatocyte transplantation) is still in experimental phase. Management requires early recognition, prompt diagnosis of treatable condition, supportive therapy and prevention of complications hence these children should ideally be treated in a specialist unit.