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We present the case of a young male patient who presented with paralysing muscle weakness due to severe hypokalaemia and hypophosphataemia. The initial patient history evaluations could not establish the aetiology. Only after we reviewed the patient’s history did he reveal that he had been following a severe calorie-restricted regime, the human chorionic gonadotropin diet, which had ended 2 days prior to developing symptoms. This information then allowed us to diagnose severe refeeding syndrome. As a further complication, the patient developed rhabdomyolysis. After correction of serum electrolytes, symptoms resolved completely. This case emphasises the potential harm of severely calorie-restricted diets, often recommended by online ‘experts’. Furthermore, we underline the importance of thorough history taking.

In a patient with a history of bariatric surgery, severe copper deficiency presenting with macrocytic hyperregenerative anaemia was diagnosed. Besides the impaired intestinal absorption due to a short bowel syndrome, the enteral zinc supplementation competitively decreased the intestinal copper uptake. Once the zinc supplementation was stopped, enteral copper replacement ensued and normalised haemoglobin levels with decreasing median corpuscular volume were observed during follow-up visits.

Un homme de 81 ans s’est presente a cause de troubles visuels de survenue nouvelle. Il a decrit des figures pentagonales a hexagonales reliees de facon reticulaire, qu’il percoit a differents endroits du champ visuel des yeux.

Summary Coronavirus disease 2019 (COVID-19) manifests with a range of severities, but immune signatures of mild and severe disease are still not fully understood. Here, we use mass cytometry and targeted proteomics to profile the innate immune response of patients with mild or severe COVID-19 and of healthy individuals. Sampling at different stages allows us to reconstruct a pseudo-temporal trajectory of the innate response. A surge of CD169+ monocytes associated with an IFN-γ+MCP-2+ signature rapidly follows symptom onset. At later stages, we observe a persistent inflammatory phenotype in patients with severe disease, dominated by high CCL3 and CCL4 abundance correlating with the re-appearance of CD16+ monocytes, whereas the response of mild COVID-19 patients normalizes. Our data provide insights into the dynamic nature of inflammatory responses in COVID-19 patients and identify sustained innate immune responses as a likely mechanism in severe patients, thus supporting the investigation of targeted interventions in severe COVID-19., Graphical Abstract, Highlights Systems analysis of the innate immune responses in COVID-19 up to 47 days after onset Surge of CD169+ and depletion of CD16+CD14− monocytes early after symptom onset High levels of inflammatory cytokines and immature neutrophils in severe COVID-19 Persistent inflammation in late severe cases, while normalization in mild cases, Chevrier et al. characterize the innate immune response in mild and severe COVID-19 patients and healthy individuals by mass cytometry and serum proteomics. They demonstrate profound phenotypic changes after SARS-CoV-2 infection and ongoing inflammation, with an innate signature switch in severe COVID-19 patients late in the disease course.

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a broad clinical presentation ranging from asymptomatic infection to fatal disease. Different features associated with the immune response to SARS-CoV-2, such as hyperinflammation and reduction of peripheral CD8+ T cell counts are strongly associated with severe disease. Here, we confirm the reduction in peripheral CD8+ T cells both in relative and absolute terms and identify T cell apoptosis and migration into inflamed tissues as possible mechanisms driving peripheral T cell lymphopenia. Furthermore, we find evidence of elevated serum interleukin-7, thus indicating systemic T cell paucity and signs of increased T cell proliferation in patients with severe lymphopenia. Following T cell lymphopenia in our pseudo-longitudinal time course, we observed expansion and recovery of poly-specific antiviral T cells, thus arguing for lymphopenia-induced T cell proliferation. In summary, this study suggests that extensive T cell loss and subsequent T cell proliferation are characteristic of severe COVID-19.

Background Whereas severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody tests are increasingly used to estimate the prevalence of SARS-CoV-2 infection, the determinants of these antibody responses remain unclear. Objectives To evaluate systemic and mucosal antibody responses toward SARS-CoV-2 in mild versus severe coronavirus disease 2019 (COVID-19) cases. Methods Using immunoassays specific for SARS-CoV-2 spike proteins, we determined SARS-CoV-2-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) in sera and mucosal fluids of two cohorts, including SARS-CoV-2 polymerase chain reaction (PCR)+ patients (n = 64) as well as PCR+ and PCR– healthcare workers (n = 109). Results SARS-CoV-2-specific serum IgA titers in mild COVID-19 cases were often transiently positive, whereas serum IgG titers remained negative or became positive 12–14 days after symptom onset. Conversely, patients with severe COVID-19 showed a highly significant increase of SARS-CoV-2-specific serum IgA and IgG titers after symptom onset. Very high titers of SARS-CoV-2-specific serum IgA correlated with severe acute respiratory distress syndrome (ARDS). Interestingly, some healthcare workers with negative SARS-CoV-2-specific serum antibody titers showed SARS-CoV-2-specific IgA in mucosal fluids with virus-neutralizing capacity in some cases. SARS-CoV-2-specific IgA titers in nasal fluids inversely correlated with age. Conclusions Systemic antibody production against SARS-CoV-2 develops mainly in severe COVID-19, with very high IgA titers seen in patients with severe ARDS, whereas mild disease may be associated with transient production of SARS-CoV-2-specific antibodies but stimulate mucosal SARS-CoV-2-specific IgA secretion., Graphical abstract, Our study suggests a model where the extent and duration of SARS-CoV-2-related clinical symptoms correlates with the systemic and mucosal virus-specific humoral immune responses, with implications for seroprevalence studies.

BackgroundInfection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes an acute illness termed coronavirus disease 2019 (COVID-19). Humoral immune responses likely play an important role in containing SARS-CoV-2, however, the determinants of SARS-CoV-2-specific antibody responses are unclear.MethodsUsing immunoassays specific for the SARS-CoV-2 spike protein, we determined SARS-CoV-2-specific immunoglobulin A (IgA) and immunoglobulin G (IgG) in sera and mucosal fluids of two cohorts, including patients with quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR)-confirmed SARS-CoV-2 infection (n = 56; median age 61 years) with mild versus severe COVID-19, and SARS-CoV-2-exposed healthcare workers (n = 109; median age 36 years) with or without symptoms and tested negative or positive by RT-qPCR.FindingsOn average, SARS-CoV-2-specific serum IgA titers in mild COVID-19 cases became positive eight days after symptom onset and were often transient, whereas serum IgG levels remained negative or reached positive values 9–10 days after symptom onset. Conversely, patients with severe COVID-19 showed a highly significant increase of SARS-CoV-2-specific serum IgA and IgG titers as a function of duration since symptom onset, independent of patient age and comorbidities. Very high levels of SARS-CoV-2-specific serum IgA correlated with severe acute respiratory distress syndrome (ARDS). Interestingly, some of the SARS-CoV-2-exposed healthcare workers with negative SARS-CoV-2-specific IgA and IgG serum titers had detectable SARS-CoV-2-specific IgA antibodies in their nasal fluids and tears. Moreover, SARS-CoV-2-specific IgA levels in nasal fluids of these healthcare workers were inversely correlated with patient age.InterpretationThese data show that systemic IgA and IgG production against SARS-CoV-2 develops mainly in severe COVID-19, with very high IgA levels seen in patients with severe ARDS, whereas mild disease may be associated with transient serum titers of SARS-CoV-2-specific antibodies but stimulate mucosal SARS-CoV-2-specific IgA secretion. The findings suggest four grades of antibody responses dependent on COVID-19 severity.

Background Inspired by the US Choosing Wisely®, in 2016 the Swiss Society of General Internal Medicine released a list of five treatments or diagnostic tests used in the hospital and considered unnecessary based on not improving patient care and adding to health care costs. These "Smarter Medicine" recommendations were implemented in the Department of Internal Medicine, Uster Hospital, in August 2016. They were supported by lectures and weekly email communications. We analyzed the number of blood draws before and after implementation of the recommendation aimed at reducing blood tests. Methods This retrospective analysis was conducted in the Department of Internal Medicine, Uster Hospital, Canton of Zurich, Switzerland. Patients hospitalized in the 3 months before and after implementation were analyzed. Results A total of 2023 hospitalizations were analyzed. There was a significant decrease in the number of blood draws after introduction of the recommendation: before implementation, the median number of blood draws per patient was 4 (interquartile range [IQR], 2-7); after implementation, the median was 4 (IQR, 2-6; P = 0.002). Indeed, since 46% of the patients in the first group had more than four blood tests, this ratio decreased to 39% after implementation. Discussion Inappropriate blood draws may lead to anemia, patient discomfort and false-positive results. The simple and low-cost interventions used to implement "Smarter Medicine" have changed physician behavior by reducing the number of blood orders. These results are promising. Whether such recommendations will impact patient and clinical outcomes remains unknown; hence, further studies are needed to clarify this issue.

BACKGROUND Despite the universal recognition that stroke is a major burden of public health in developed countries, little is known concerning its epidemiology and care outside of stroke centres. The objective of our study was to provide information concerning risk factors for stroke, stroke management and quality of care in a community hospital in Switzerland. METHODS Retrospective observational in-hospital study of adult stroke patients treated in a community hospital in Switzerland in collaboration with a nearby stroke centre. Patients were identified by the corresponding ICD-10 codes from July 2017 to December 2018. RESULTS We included 261 patients with a median age of 78 years (interquartile range [IQR] 68–85). Sixty-four percent (166) had ischaemic strokes, 18% (46) transient ischaemic attacks and 19% (49) intracranial bleeding. The most frequent risk factors were arterial hypertension in 195 (75%) patients, dyslipidaemia in 124 (48%) patients and overweight/obesity in 102 (39%). Dyslipidaemia and atrial fibrillation were undiagnosed at admission in 47 (38%) and 16 (27%) patients, respectively. Ninety-one (37%) patients with an out-of-hospital stroke presented within 4.5 hours after symptom onset. Intravenous thrombolysis was initiated in 27 patients (49% of the out-of-hospital ischaemic strokes presenting within 4.5 hours) and the median door-to-needle time was 55 minutes (IQR 40–67) and within 60 minutes in 16 (59%) patients. The most frequent poststroke complications were aspiration pneumonia in 22 (8%) followed by urinary tract infection in 14 (5%). The referral rate to a stroke centre or neurosurgical unit was 18%. CONCLUSION Our findings support further education of the population in recognition of stroke symptoms and assessment of cardiovascular risk factors according to guidelines. Telemedical cooperation with a local stroke centre can result in adequate quality of care in these patients.

Satisfactory therapeutic strategies for septic shock are still missing. Previously we found elevated levels of Wnt5A in patients with severe sepsis and septic shock. Wnt5A is released by activated macrophages but knowledge of its effects in the vascular system remains scant. Here we investigate the response of human coronary artery endothelial cells (HCAEC) to Wnt5A. We used a genome-wide differential expression approach to define novel targets regulated by Wnt5A. Gene ontology analysis of expression profiles revealed clusters of genes involved in actin cytoskeleton remodeling as the predominant targets of Wnt5A. Wnt5A targeted Rho-associated protein serine/threonine kinase (ROCK), leading to phosphorylation of LIM kinase-2 (LIMK2) and inactivation of the actin depolymerization factor cofilin-1 (CFL1). Functional experiments recording cytoskeletal rearrangements in living cells showed that Wnt5A enhanced stress fiber formation as a consequence of reduced actin depolymerization. The antagonist Wnt inhibitory factor 1 (WIF1) that specifically interferes with the WIF domain of Ryk receptors prevented actin polymerization. Wnt5A disrupted β-catenin and VE-cadherin adherens junctions forming inter-endothelial gaps. Functional experiments targeting the endothelial monolayer integrity and live recording of trans-endothelial resistance revealed enhanced permeability of Wnt5A-treated HCAEC. Ryk silencing completely prevented Wnt5A-induced endothelial hyperpermeability. Wnt5A decreased wound healing capacity of HCAEC monolayers; this was restored by the ROCK inhibitor Y-27632. Here we show that Wnt5A acts on the vascular endothelium causing enhanced permeability through Ryk interaction and downstream ROCK/LIMK2/CFL1 signaling. Wnt5A/Ryk signaling might provide novel therapeutic strategies to prevent capillary leakage in systemic inflammation and septic shock.

Modulation of proinflammatory responses induced by IL-1β in human vascular endothelial cells (VEC) to reduce tissue damage is an emerging therapeutic strategy to prevent loss of organ function during local or systemic inflammatory diseases. The pathways and signalling molecules involved in IL-1β-induced vascular endothelial inflammation that could be potential targets for therapeutic modulation remain still poorly addressed. Our study applies a genome-wide differential expression approach to identify candidate genes regulated by IL-1β in primary VEC derived from coronary artery (HCAEC). Genes regulated 2-fold were subjected to GO analysis for potential drug targets. We identified HGF as one of the genes upregulated by IL-1β in HCAEC. Gene ontology analysis mapped HGF to a highly significant barrier-injuring and repair pathway, and to an inflammatory disease biomarker network enriched in IL-1β transcriptome in VEC. Further, IL-1β upregulated the expression of BDKRB2, CTSS, and SERT which are also critically involved in regulating VEC monolayer barrier function and can be targeted by therapeutic drugs. To our knowledge, the expression of CTSS and HGF was not yet reported being regulated by IL-1β in human immunocompetent VEC. These findings stimulate further studies to evaluate the critical roles and benefits of therapeutic targeting of BDKRB2, CTSS, HGF, and SERT with known inhibitors to modulate VEC barrier function, and in consequence, vascular leakage in IL-1β-driven inflammatory diseases.

Background In 2013 the Swiss Diagnosis Related Groups ((Swiss)-DRG) was implemented in Intensive Care Units (ICU). Its impact on hospitalizations has not yet been examined. We compared the number of ICU admissions, according to clinical severity and referring institution, and screened whether implementation of Swiss-DRG affected admission policy, ICU length-of-stay (ICU-LOS) or ICU mortality. Methods Retrospective, single centre, cohort study conducted at the University Hospital Zurich, Switzerland between January 2009 and end of September 2013. Demographic and clinical data was retrieved from a quality assurance database. Results Admissions (n = 17,231) before the introduction of Swiss-DRG were used to model expected admissions after DRG, and then compared to the observed admissions. Forecasting matched observations in patients with a high clinical severity admitted from internal units and external hospitals (admitted / predicted: 709 / 703, [95% Confidence Interval (CI), 658–748] and 302 / 332, [95% CI, 269–365] respectively). In patients with low severity of disease, in-house admissions became more frequent than expected and external admission were less frequent (admitted / predicted: 1972 / 1910, [95% CI, 1898–1940] and 436 / 518, [95% CI, 482–554] respectively). Various mechanisms related to Swiss-DRG may have led to these changes. DRG could not be linked to significant changes in regard to ICU-LOS and ICU mortality. Conclusions DRG introduction had not affected ICU admissions policy, except for an increase of in-house patients with a low clinical severity of disease. DRG had neither affected ICU mortality nor ICU-LOS. Electronic supplementary material The online version of this article (10.1186/s12913-018-2869-4) contains supplementary material, which is available to authorized users.

Recently, we performed a contrast-enhanced thoracic 16-channel multi-slice computed tomography (CT) with intravenous (i.v.) administration of iodixanol [Visipaque, dose 0.5 g I/kg body weight (bw)] in a 73-year old patient, suffering from multiple myeloma and chronic renal failure (calculated creatinine clearance of 23ml/min). Three days later, an unenhanced CT of the upper abdomen was performed, showing a striking enhancement of the renal parenchyma of both kidneys [mean, 142 hounsfield units (HU)] (Figure 1). No contrast excretion within the collection system was noted. Eight days later there was still residual renal cortical attenuation of both kidneys (67HU). Unenhanced CT 17 days after the first examination revealed normal findings of both kidneys with complete vanishing of the parenchymal abnormality. The baseline serum creatinine was 2.3mg/dl (202 mmol/l) and rose to 2.6mg/dl (235 mmol/l) 4 days after the administration of the contrast media. Comment

Rectus sheath hematoma (RSH) is a rare bleeding site which can be life-threatening. Our aim was to analyze clinical features, diagnosis, treatment and outcome of these cases in a general hospital. Results: During a period of 24 months, 8 cases of RSH were diagnosed (0.1% of all inpatients). Mean age was 79.4 years (y, SD +/- 14.1). 75% were female. 7 patients (pts) were on therapy with oral anticoagulants (OAC), 2 had a history of additional therapy with aspirin (ASA), 4 had low molecular weight heparin (LMWH) for bridging of OAC therapy. 4 pts had INR values between 3.1 - 4.4. One pt with liver cirrhosis (Child A), mild thrombocytopenia had ASA and LMWH prophylactically. Five pts (63%) were coughing. Main symptom was localized pain in 7 pts. One pt was incidentally diagnosed on a CT scan performed for different reason. 7 pts had a palpable mass of the abdominal wall. 5 RSH were diagnosed with CT, 2 with ultrasound, 1 clinically. All pts were treated conservatively. In 7 pts vitamine K and Beriplex&#174 was substituted to reverse OAC. 4 pts received blood transfusions (1 - 4 units). The mean change of hemoglobin (Hb) was 37 g/l (SD +/- 22 g/l). The renal function was impaired in 7 pts (mean creatinine clearance 51 ml/min +/- 12.4) and declined further. 3 out of 8 pts died (38%, age 90 - 92 y, all female). In these patients, the observed change in Hb was 42 - 58 g/l. 2 pts had combination of VKA and LMWH. 1 pt had VKA only. Conclusion: Acute abdominal pain in pts with any form of OAC or therapy to inhibit platelet function should always raise suspicion about RSH. Extensive blood loss, shock and aggravation of renal failure can be fatal. In majority of cases, the hematoma is palpable and should prompt further examination of the abdominal wall. It is crucial to normalize coagulation parameters and to correct intravascular volume depletion to avoid shock and further decline of renal failure.

Human rabies is rare in Western Europe. It is not easily recognized in the absence of a history of exposure. We describe the clinical course, diagnosis and follow-up of an imported human rabies case in Switzerland. The patient, a U.S. citizen, presented at an outpatient clinic in Iraq with pain in his right shoulder on July 5, 2012. On July 8 he was transferred to a hospital in the United Arab Emirates, where he exhibited progressive encephalitis with coma. On July 29, he was transferred to a hospital in Switzerland, where he died on July 31, 2012. The autopsy showed severe encephalitis. Rabies was diagnosed by the rapid fluorescent focus inhibition test (RFFIT) and confirmed by fluorescence antibody testing (FAT) in brain smears and immunohistochemistry on paraffin-embedded brain sections. The viral strain was characterized by RT-PCR followed by sequencing and phylogenetic analysis as an American bat rabies strain associated with Tadarida brasiliensis. Close contacts and exposed health care workers received postexposure prophylaxis (PEP).

Microvascular leakage due to endothelial barrier dysfunction is a prominent feature of T helper 2 (Th2) cytokine mediated allergic inflammation. Interleukin-4 (IL-4) is a potent Th2 cytokine, known to impair the barrier function of endothelial cells. However, the effectors mediating IL-4 induced cytoskeleton remodeling and consequent endothelial barrier dysfunction remain poorly defined. Here we have used whole genome transcriptome profiling and gene ontology analyses to identify the genes and processes regulated by IL-4 signaling in human coronary artery endothelial cells (HCAEC). The study revealed Wnt5A as an effector that can mediate actin cytoskeleton remodeling in IL-4 activated HCAEC through the regulation of LIM kinase (LIMK) and Cofilin (CFL). Following IL-4 treatment, LIMK and CFL were phosphorylated, thereby indicating the possibility of actin stress fiber formation. Imaging of actin showed the formation of stress fibers in IL-4 treated live HCAEC. Stress fiber formation was notably decreased in the presence of Wnt inhibitory factor 1 (WIF1). Non-invasive impedance measurements demonstrated that IL-4 increased the permeability and impaired the barrier function of HCAEC monolayers. Silencing Wnt5A significantly reduced permeability and improved the barrier function of HCAEC monolayers upon IL-4 treatment. Our study identifies Wnt5A as a novel marker of IL-4 activated vascular endothelium and demonstrates a critical role for Wnt5A in mediating IL-4 induced endothelial barrier dysfunction. Wnt5A could be a potential therapeutic target for reducing microvascular leakage and edema formation in Th2 driven inflammatory diseases.

Background.The Molecular Adsorbent Recirculating System (MARS) has been shown to clear albumin-bound toxins from patients with liver failure but might cause bleeding complications potentially obscuring survival benefits. We hypothesized that monitoring clotting parameters and bed-side thromboelastography allows to reduce bleeding complications.Methods. Retrospective analysis of 25 MARS sessions during which clotting parameters were monitored by a standardized protocol.Results. During MARS therapy median INR increased significantly from 1.7 to 1.9 platelet count and fibrinogen content decreased significantly from 57 fL−1to 42 fL−1and 2.1 g/L to 1.5 g/L. Nine relevant complications occurred: the MARS system clotted 6 times 3 times we observed hemorrhages. Absent thrombocytopenia and elevated plasma fibrinogen predicted clotting of the MARS system (ROC 0.94 and 0.82). Fibrinolysis, detected by thromboelastography, uniquely predicted bleeding events.Conclusion. Bed-side thromboelastography and close monitoring of coagulation parameters can predict and, therefore, help prevent bleeding complications during MARS therapy.

Objective— Sepsis is a major cause of death for intensive care patients. High concentrations of inflammatory cytokines are characteristic of severe systemic inflammation and activated monocytes are their predominant cellular source. To identify targets for antiinflammatory intervention, we investigated the response of human macrophages to inflammatory and antiinflammatory mediators. Methods and Results— We profiled gene expression in human macrophages exposed to lipopolysaccharide (LPS) and interferon (IFN)-γ in the presence or absence of recombinant activated protein C (APC) or IL-10 and identified Wnt5A as one of the transcripts most highly induced by LPS/IFN-γ and suppressed by APC and IL-10. We confirmed regulation of Wnt5A protein in macrophages and detected it in sera and bone marrow macrophages of patients with severe sepsis. We established that a functional Wnt5A/frizzled-5/CaMKII signaling pathway was essential for macrophage inflammatory activation. To prove the essential contribution of Wnt5A we measured inflammatory cytokines after stimulation with Wnt5A, silenced Wnt5A by siRNA, and blocked receptor binding with soluble Frizzled–related peptide-1 (sFRP1). Conclusion— Wnt5A is critically involved in inflammatory macrophage signaling in sepsis and is a target for antiinflammatory mediators like APC or antagonists like sFRP1.

BACKGROUND: Numerous, mostly uncontrolled, observations suggest that artificial liver support with the Molecular Adsorbent Recirculating System (MARS) improves pathophysiologic sequelae and outcome of acute and acute-on-chronic liver failure. MARS is felt to be safe, but extracorporeal circuits may activate coagulation. OBJECTIVE: To assess the frequency of and risk factors for activation of coagulation during MARS treatment. PATIENTS/METHODS: Retrospective analysis of coagulopathy/bleeding complications observed during 83 consecutive MARS sessions in 21 patients (11 men; median age 46 years; median three sessions per patient; median duration of session 8 h). RESULTS: Nine clinically relevant episodes of coagulopathy/bleeding were observed in eight patients, forced to premature cessation of MARS in seven and ended lethal in four. Four complications occurred during the first, five during later (third to seventh) MARS sessions and two bleeders tolerated further sessions without complications. Coagulation parameters worsened significantly also during MARS sessions not associated with bleeding (P< or =0.004). In univariate analysis, patient's age, vasopressor therapy, pretreatment INR, fibrin D-dimer and fibrinogen concentrations, but not severity of underlying disease (MELD, Child-Pugh, SAPS II scores), were significantly associated with coagulopathy (P

The hemoglobin–haptoglobin (Hb–Hp) scavenger receptor CD163 is a monocyte/macrophage-restricted surface antigen, whose expression is strongly up-regulated by glucocorticoids. We have previously shown that CD163 is expressed by acute myeloid leukemia (AML) cells of monocytic lineage. Herein, we expand this finding by demonstrating constitutive and glucocorticoid-enhanced CD163 expression on French-American-British M4/M5 AML cells, and leukemic blasts of other AML subtypes and normal hematopoietic progenitor cells do not express CD163. We provide evidence that the functional characteristics of CD163 are preserved on malignant cells by showing the capability of types M4/M5 blast cells to internalize Hb–Hp by a CD163-mediated mechanism. Together, our results identify CD163 as a potential target for therapeutic intervention. It is important that CD163 does not appear to be released from leukemic blasts under noninflammatory conditions, thus reducing the probability of off-target side-effects as a result of competitive binding of potential therapeutic ligands to nonmembrane-bound CD163.

Pure red cell aplasia (PRCA) caused by neutralising anti-erythropoietin antibodies is a very rare disease. Since 1998, an increased incidence of PRCA in patients with kidney failure following treatment with recombinant human erythropoietin (rhEpo) has been reported, mostly in Europe. In most cases, PRCA was cured by immunosuppressive therapy, immunoglobulins, plasmapheresis or renal transplantation. We report an exceptionally prolonged course of PRCA over 68 months despite renal transplantation and different immunosuppressive regimens.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a platelet storage pool deficiency. Some patients also develop fatal pulmonary fibrosis and some have granulomatous colitis. Six human genes HPS1, ADB3A, HPS3, HPS4, HPS5, and HPS6 have been identified as cause of the six known subtypes of HPS. While there exist nearly 500 Puerto Rican and non-Puerto Rican HPS-1 patients, very few HPS-4 patients have been reported, and most of these have not been described in detail. We now delineate the clinical characteristics of an HPS-4 patient homozygous for a novel HPS-4 mutation, P685delC. The patient, the first individual with HPS reported from Sri Lanka, had severe pulmonary fibrosis, typical of HPS-1 disease, without granulomatous colitis. We conclude that pulmonary fibrosis occurs as part of HPS-4 and that HPS should be considered in all ethnic groups.

Introduction Salmonella is a typical cause of aortitis, which is associated with high morbidity and mortality. In infrarenal disease, besides open surgery, endovascular aortic repair as an alternative treatment has been reported. To the best of our knowledge, we report the first successful endovascular aortic repair documented by necropsy to date. Case presentation A 67-year-old Caucasian man presented with low back pain, fever and positive blood cultures for Salmonella Enteritidis. A computed tomography scan showed an enlargement and intramural hematoma of the infrarenal aortic wall; a Salmonella aortitis was suspected and antimicrobial therapy initiated. Because of substantial comorbidities, endovascular aortic repair was favored over open surgery; postoperatively the antibiotic treatment was continued for 12 months. Post-mortem there were neither macroscopic nor microscopic signs of aortitis or graft infection. Conclusions We could demonstrate by necropsy that endovascular aortic repair of infrarenal aortitis with prolonged pre- and postinterventional antibiotic therapy for 12 months was a minimally invasive alternative and should be considered in selected clinically stable patients with substantial co-morbidities.

QUESTIONS UNDER STUDY Community acquired pneumonia (CAP) and sepsis are leading causes of hospitalisation after admission to a medical emergency department (ED). Identifying these potentially life-threatening diseases is not always easy due to often unspecific or minimal symptoms. However, quick application of antibiotics is known to be crucial and is correlated with better outcome. The international guidelines of the joint commission suggest a 4 hour-rule for optimal quality of care in CAP and sepsis. In this study we assessed the door-to-needle time (DNT) in patients admitted to our ED with the diagnosis of CAP and/or sepsis. Furthermore we investigated the CRB-65 score, its clinical performance and its influence on DNT. METHODS Retrospective observational study of all patients admitted and hospitalised through the ED of a Swiss hospital with the diagnosis of sepsis or pneumonia from June 2009 to June 2010 (n = 139). RESULTS In 73% of the cases DNT was lower than the recommended 4 hours. In CAP, a correlation between the CRB-65 and DNT was not found (ρ = 0.13, p = 0.30). Further parameters, e.g. temperature or blood pressure did not improve DNT significantly. Analysis of the CRB-65 score was regularly impeded due to absent documented information on respiratory rate or confusion state. CONCLUSION In most cases it was feasible to fulfill the 4 hours DNT. The CRB-65 score is an easy bedside tool, which was not routinely assessed by our emergency room personnel but its assessment did not affect DNT in our hospital.

Hypersplenism can be defined by thrombocytopenia and/or neutropenia resulting from blood cell sequestration in an enlarged spleen. In multimorbid patients the differential diagnosis of cytopenia is challenging and currently there is no established test for diagnosing hypersplenism.The epinephrine stimulation test (EST) measures changes in platelets, neutrophil counts and spleen size following a subcutaneous epinephrine injection. We retrospectively analysed the results of EST in 228 patients.Increases in neutrophils and platelets after epinephrine injection were significantly greater in patients with enlarged than in patients with normal size spleens. Using cutoffs of low, intermediate and high confidence EST was positive in 69.8% vs. 41.3% (low confidence), 49.6% vs. 17.4% (intermediate confidence) and 38.8% vs. 10.9% (high confidence) in patients with enlarged vs. normal size spleens. Changes in platelet and neutrophil counts correlated with each other and with changes in spleen size, confirming cell release from the spleen during EST. When stratified according to the underlying diagnosis, patients with liver disease had the strongest response to EST, patients with malignant haematological diseases the weakest. In addition the response to EST was significantly related to changes in platelet and neutrophil counts after splenectomy, confirming the validity of our test. No serious side effects occurred during EST.When used in a large patient cohort, EST is a safe and simple diagnostic test. In this exploratory study EST is of value in evaluating patients with cytopenia and a positive EST argues strongly for hypersplenism. Future studies should prospectively evaluate EST for the management of patients with splenomegaly.

Progressive multi-focal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of John Cunningham virus. It is an opportunistic infection affecting patients who are severely immunocompromised due to an underlying disease or secondary to immunosuppressive therapy. To date, no effective antiviral therapy has been established, though several substances are being investigated. The authors present the case of a 39-year-old previously healthy patient who was diagnosed with PML and sarcoidosis stage III without having received prior immunosuppressive treatment. The patient did not respond to treatment with mirtazapine, which has been used empirically, and deceased shortly after diagnosis.

Iron deficiency is known to cause symptoms such as fatigue, depression and restless legs syndrome resulting in impaired quality of life and working capacity. We sought to examine the iron status of reportedly healthy individuals by a framed study design in 58 highly educated Swiss hospital employees and to compare the use of non invasive tests for assessing iron deficiency (ID). A structured interview was used to assess health status, nutritional intake and potential blood loss, blood counts as well as parameters proposed to diagnose iron deficiency were determined. All subjects felt well and were working at their maximum capacity. The male subjects were neither anaemic nor had decreased iron parameters however 50% (23/46) of the women had a serum ferritin of below 22 μg/L, still 33% (15/46) of the women had a ferritin value below the more stringent cut off value of 15 μg/L. In 15% (7/46) of the women we diagnosed iron deficient anaemia. Red meat consumption correlated with ferritin values as did the menstrual blood loss which was estimated by asking the amount of tampons used. Of the additionally analysed iron parameters only the percentage of hypochromic erythrocytes, soluble transferrin receptor and transferrin values were significantly correlated with ferritin and reached an AUCROC of ≥0.7 indicating good predictive tests. Nevertheless neither soluble transferrin receptor nor transferrin showed diagnostic advantages for the diagnosis of ID compared to ferritin alone or together with erythrocyte parameters. Working in a hospital environment and having access to health education does not seem to correlate with prevention of ID or ID anaemia in female hospital employees.

Background: Activated protein C (APC) has been introduced as a therapeutic agent for treatment of patients with severe sepsis due to its unique anticoagulant and anti-inflammatory properties in the vascular system. In this study we investigated novel targets for the anti-inflammatory action of APC in human macrophages. Methods: Using a genome-wide approach, effects of APC on the expression profile in inflammatory activated human macrophages were analyzed. Results: We identified, for the first time, genes that are specifically regulated by APC under inflammatory conditions, such as chromatin binding protein 4B (CHMP4B) and p300/CBP-associated factor (PCAF), thus indicating a role of APC in the epigenetic control of gene transcription. A functional assay showed the influence of APC in the acetyltransferase/ deacetylase activity of nuclear extracts from inflamed macrophages. Conclusion: Our data sheds new light on APC targets in inflammation and opens new lines of investigation that may be explored in order to further elucidate its unique molecule properties.

QUESTION Transient global amnesia (TGA) is characterised by the sudden occurrence of amnesia while lacking other neurological symptoms. Complete remission occurs within 24 hours. The pathogenesis remains unknown. The objective of this study was to evaluate the prevalence of TGA in a primary referral hospital in Uster, Switzerland and examine the accuracy of the diagnostic procedure and outcome. METHODS We conducted a retrospective review of patients with TGA admitted to the Uster hospital, Switzerland between 1/2005 and 10/2007. Of 8166 patients, 20 consecutive cases fulfilled the diagnostic criteria and were further analysed. We included presenting symptoms, diagnostic tests performed, treatment and outcome. A questionnaire to investigate the treating doctor's knowledge of TGA was conducted. A follow up was conducted in all patients at 19.1 +/- 7.1 months after presentation. RESULTS The incidence was 6.8/100 000/year. In all patients the symptoms resolved within 24 hours and all patients were seen by a consultant neurologist. Drug related causes were excluded. 25% episodes started after some form of exercise, 20% after emotional distress. All patients underwent cerebral imaging. 76% of the questionnaires sent to in-hospital physicians were returned. Diagnostic criteria of TGA were fully known in 75%. In 30% the diagnosis on admission was not TGA and had to be adjusted during the hospital stay. Follow up showed relapse in 10%. CONCLUSION TGA is a syndrome of which emergency physicians should be aware. The diagnosis is made clinically and the prognosis is good, although relapses may occur. Missed diagnoses may lead to uncertainty in patients and their relatives.

Wnt proteins are members of the highly conserved wingless family of proteins responsible for cell differentiation and development and for neoplastic and degenerative processes. Recently, Toll-like receptor-mediated Wnt signaling was found to be associated with innate immunity in Drosophila. Upregulation of Wnt5A in human macrophages upon microbial challenge indicated a similar mechanism. Toll-like receptor-mediated Wnt5A expression is a key process for sustained inflammatory macrophage activation through autocrine and paracrine signaling. Downregulation of Wnt5A expression and subsequent attenuation of inflammatory macrophage responses by activated protein C supports the link between inflammation and coagulation, another highly conserved biologic system. Direct evidence for the relevance of Wnt5A in severe systemic inflammation is provided by the finding of higher Wnt5A levels in patients with sepsis than in healthy individuals. The fact that Wnt5A signaling can be modulated by anti-inflammatory mediators makes this effector molecule an attractive target for therapeutic intervention in inflammatory diseases.

A 51-year-old man with known pheochromocytoma refused surgical treatment over several years and subsequently presented in catecholamine crisis with shock and multiple organ failure. Laboratory testing revealed liver failure with elevated liver enzymes and coagulation abnormalities, and imaging showed ischemia of extended parts of the right liver lobe. It also revealed a large thrombus in the right portal vein, which together with severe arterial vasoconstriction impaired the dual blood supply of the liver. The patient recovered after effective medical treatment and finally underwent surgical tumor resection. Thereafter, antihypertensive treatment could be stopped. We present this exceptional case of adrenal crisis and discuss the mechanisms leading to liver failure in general and portal vein thrombosis in particular.

QUESTION UNDER STUDY: To investigate the effectiveness of a single adjusted dose of oral vitamin K to temporarily reverse oral anticoagulation with phenprocoumon (Marcoumar) for heart catheterisation. METHODS: Patients under stable oral anticoagulation with phenprocoumon routinely scheduled for heart catheterizstion were given a single adjusted dose of oral vitamin K a day prior to the intervention. The customary anticoagulation scheme was kept unchanged with the exception of taking the double usual dose of phenprocoumon the evening after the intervention. The primary outcome was the achieved international normalised ratio (INR) immediately before the intervention. Secondary outcomes were the INR after one and four weeks, changes in phenprocoumon and coagulation factors II and VII and adverse events. RESULTS: 38 patients at a median age of 71 (63-74) years scheduled for heart catheterisation were included. The median INR changed from 2.2 (1.9-2.6) the day before to 1.5 (1.4-1.7) immediately before the intervention. An INR < or =1.5 respectively < or =1.8 was achieved in 61% and 95% of the patients. The INR values after one respectively four weeks were comparable to preintervention values. No thromboembolic or bleeding adverse events occurred during the study. CONCLUSION: A single adjusted oral dose of vitamin K given a day prior to heart catheterisation combined with a doubled phenprocoumon dose on the procedure day seems to be an easy applicable, safe and effective way to temporary reverse oral anticoagulation with phenprocoumon.

Background—During systemic inflammation, activation of vascular endothelium by proinflammatory cytokines leads to hypotension, microvascular thrombosis, and organ damage. Recent data suggest a link between coagulation and inflammation through the activated protein C (APC) pathway. We studied gene expression profiles in human coronary artery endothelial cells (HCAECs) exposed to proinflammatory stimuli and the influence of APC on expression of candidate genes regulated by these stimuli.Methods and Results—HCAECs were stimulated with interleukin-1β, interferon-γ, and tumor necrosis factor-α. In gene expression profiling, 400 of 8400 genes were regulated >2-fold. Verification of selected candidate genes was achieved by measuring expression of mRNA species by real-time polymerase chain reaction, cytokine secretion by ELISA, and metabolites of tetrahydrobiopterin (BH4) biosynthesis by high-performance liquid chromatography. BH4 synthesis, interleukin-6, interleukin-8, monocyte chemotactic protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) were downregulated by APC at the transcriptional and protein level. Endothelial nitric oxide synthase, endothelial adhesion molecule, and vascular cell adhesion molecule-1 were not affected by APC. Activities of transcription factors c-Fos, FosB, and c-Rel were inhibited by APC in inflamed HCAECs.Conclusions—Our study revealed a novel antiinflammatory mechanism of APC-dependent gene regulation in HCAECs since c-Fos–dependent induction of MCP-1 and ICAM-1 was suppressed. APC downregulates expression and activity of genes related to inflammation, most pronounced under intermediate or mild inflammatory conditions.

Background— Previous studies have provided evidence for the importance of platelet-derived nitric oxide (NO) for the regulation of hemostasis. Tetrahydrobiopterin (BH 4 ) is an essential cofactor and regulator of NO synthase activity in the vasculature; however, it is as yet unknown whether platelets dispose over a functional BH 4 synthesis. Methods and Results— We quantified mRNA expression of genes involved in BH 4 synthesis, measured enzymatic activities, and determined intraplatelet levels of pteridines in platelets from healthy volunteers and from patients treated for prolonged periods of time with glucocorticoids. Freshly isolated platelets from healthy volunteers show functional BH 4 synthesis, as evidenced by the presence of mRNA species and enzymatic activity of GTP cyclohydrolase I (GTPCH), 6-pyruvoyl tetrahydropterin synthase, and sepiapterin reductase. Biopterin was the major intraplatelet pteridine, whereas no neopterin was found. mRNA expression and enzymatic activity of GTPCH were undetectably low in platelets that had been stored for 5 days, and no pteridines were found in these platelets. Freshly isolated platelets from patients treated with glucocorticoids had decreased mRNA expression and activity of GTPCH compared with platelets from healthy volunteers. Conclusions— Human platelets dispose over a functional de novo BH 4 synthesis. Furthermore, our results indicate the potential of external factors, eg, prolonged storage or glucocorticoid therapy, to significantly affect BH 4 synthesis within platelets. Together, these findings offer new insights into the biology and pathobiology of platelet function in humans.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a platelet storage pool deficiency. Some patients also develop fatal pulmonary fibrosis and some have granulomatous colitis. Six human genes HPS1, ADB3A, HPS3, HPS4, HPS5, and HPS6 have been identified as cause of the six known subtypes of HPS. While there exist nearly 500 Puerto Rican and non-Puerto Rican HPS-1 patients, very few HPS-4 patients have been reported, and most of these have not been described in detail. We now delineate the clinical characteristics of an HPS-4 patient homozygous for a novel HPS-4 mutation, P685delC. The patient, the first individual with HPS reported from Sri Lanka, had severe pulmonary fibrosis, typical of HPS-1 disease, without granulomatous colitis. We conclude that pulmonary fibrosis occurs as part of HPS-4 and that HPS should be considered in all ethnic groups.

Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular neoplasm with unpredictable prognosis. We report on a patient suffering from a vascular neoplasm with primary manifestation in the skeleton and subsequent development of lesions of EHE in the spleen, liver and lung. Based on the assumption that involvement of visceral organs was due to metastatic spread, changes in clinical behavior, morphology, and proliferation index suggest malignant progression of the tumor. Analyzing the expression of genes known to be involved in the pathogenesis of vascular tumors, we found that the appearance of less differentiated tumor was paralleled by an accumulation of TP53 and murine double minute-2 (MDM-2) protein, decreased caveolin-1 (CAV-1) expression, and increased vascular endothelial growth factor (VEGF) expression. Mutations of the von-Hippel-Lindau-tumor-suppressor-gene (VHL) were excluded as mechanism of VEGF upregulation. Therefore, we propose that the expression of TP53, MDM-2, CAV-1 and VEGF as a marker of biologic behavior be verified in a larger case study of EHE.

wards normalization. Similarly, the extent of skin necrosis declined markedly, and in three patients full recovery was achieved. One patient lost three toes on both feet, but all other digits recovered fully. No complications that could be attributed to an adverse effect of drotrecogin alfa (activated) were noted. No bleeding events were observed under strict control of the platelet count and a limited dose of heparin. Patients 3 and 4 received 6 platelet concentrates to maintain platelet count above 30×103/μl. There was no need for freshfrozen plasma or red blood cell transfusions. The median ICU stay was 6 days (range 2–9 days) and hospital stay was 18 days (range 14–28 days). The excellent outcome in all cases despite septic shock with purpura fulminans and in two patients platelets counts below 30×103/μl on ICU admission underlines the potential advantage of drotrecogin alfa (activated) for the treatment of severe meningococcal infection. We suggest that a platelet count below 30×103/μl should not be an absolute exclusion criteria for treatment with drotrecogin alfa, provided that they can be kept above this limit during drotrecogin alfa (activated) substitution. References

Acute Epstein-Barr virus (EBV) infection commonly induces hematological abnormalities, most notably atypical lymphocytosis ("infectious mononucleosis"). In addition, mild decreases in platelet counts are commonly encountered in uncomplicated cases; however, severe thrombocytopenia is exceedingly rare. Here, we describe a 58-year-old white man who presented with cervical lymphadenopathy, thrombocytopenia, and a bleeding diathesis with minimal platelet counts of 0.5 x 10(9)/l. The diagnosis of acute EBV was serologically confirmed. Because of the bleeding diathesis and the prior ingestion of aspirin, treatment was started with intravenous methylprednisolone and immunoglobulins. Platelet counts normalized within 7 days, and the patient fully recovered. Although more common in children, adolescents, and young adults, acute EBV infection may also occur in older adults, and this differential diagnosis should be considered in every patient presenting with acute thrombocytopenia. In this report we also briefly summarize the literature on EBV-associated severe thrombocytopenia.

Introduction Hepatologists and internists often encounter patients with unexplained high serum ferritin concentration. After exclusion of hereditary hemochromatosis and hemosiderosis, rare disorders like hereditary hyperferritinemia cataract syndrome should be considered in the differential diagnosis. This autosomal dominant syndrome, that typically presents with juvenile bilateral cataracts, was first described in 1995 and has an increasing number of recognized molecular defects within a regulatory region of the L-ferritin gene (FTL). Case presentation Two patients (32 and 49-year-old Caucasian men) from our ambulatory clinic were suspected as having this syndrome and a genetic analysis was performed. In both patients, sequencing of the FTL 5' region showed previously described mutations within the iron responsive element (FTL c.33 C > A and FTL c.32G > C). Conclusion Hereditary hyperferritinemia cataract syndrome should be considered in all patients with unexplained hyperferritinemia without signs of iron overload, particularly those with juvenile bilateral cataracts. Liver biopsy and phlebotomy should be avoided in this disorder.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common hereditary enzymopathy, affecting an estimated 400 million people worldwide with some 140 known molecular G6PD defects.[1][1],[2][2] Adeficient variant from Switzerland, designated “G6PD Zurich,” was found to have an unusual