Prevalence and characterization of azole-resistant Aspergillus fumigatus in patients with cystic fibrosis: a prospective multicentre study in Germany.

Objectives: Aspergillus fumigatus is the most prevalent filamentous fungus in the respiratory tract of patients with cystic fibrosis (CF). The aim of this prospective multicentre study was to investigate the prevalence of azole-resistant A. fumigatus (ARAF) in respiratory secretions from CF patients across Germany and to characterize ARAF isolates by phenotypic and molecular methods. Methods: Twelve tertiary care centres from Germany participated in the study. In total, 2888 A. fumigatus isolates from 961 CF patients were screened for ARAF by using azole-containing agar plates. Antifungal susceptibility testing of isolates was performed by broth microdilution according to EUCAST guidelines. Analysis of mutations mediating resistance was performed using PCR and sequencing of the cyp51A gene. Furthermore, genotyping by microsatellite PCR was performed. Results: Of a total of 2888 A. fumigatus isolates, 101 isolates from 51 CF patients were found to be azole resistant (prevalence per patient 5.3%). The Essen centre had the highest prevalence (9.1%) followed by Munich (7.8%), Münster (6.0%) and Hannover (5.2%). Most ARAF isolates (n = 89) carried the TR34/L98H mutation followed by eight G54E/R, one TR46/Y121F/T289A and one F219S mutation. In two isolates no mutation was found. Genotyping results showed no major clustering. Forty-five percent of CF patients with ARAF had previously received azole therapy. Conclusions: This is the first multicentre study analysing the prevalence of ARAF isolates in German CF patients. Because of a resistance rate of up to 9%, susceptibility testing of A. fumigatus isolates from CF patients receiving antifungal treatment should be part of standard diagnostic work-up.

Investigación para el diagnóstico situacional local de la epidemia de ETM: Intervenciones preventivas para su contención: Área Programática del Hospital General de Agudos Juan A. Fernández 2015-2016 / Research for the local situational diagnosis of ETM epidemic: Preventive interventions for its containment: Acute General Hospital Juan A. Fernández Programmatic Area 2015-2016

El plan de Prevención y Control de Enfermedades Transmitidas por Mosquito (ETM): Dengue, Fiebre Chikungunya, Amarilla, y Zika de la CABA establece cuatro escenarios teóricos de riesgo que orientan la implementación de las acciones de prevención y control. En el presente informe se presentan los estudios de foco investigados en nuestra Área Programática (AP) y su georreferencia, a fin de obtener un diagnóstico situacional local que permita la ejecución de intervenciones oportunas y eficaces a fin de limitar la aparición de nuevos casos en el contexto epidémico 2015-2016. El objetivo general fue estudiar la epidemia de ETM para su comprensión y abordaje en el Área Programática del Hospital General de Agudos Juan A. Fernández, y el objetivo específico, prevenir y limitar la aparición de nuevos casos de ETM. (AU)

A point mutation in the extracellular domain of L1 blocks its capacity to confer metastasis in colon cancer cells via CD10.

The neural L1 transmembrane cell adhesion receptor of the immunoglobulin-like family is a target gene of Wnt-ß-catenin signaling in human colorectal cancer (CRC) cells and is expressed at the invasive edge of the tumor tissue. L1 overexpression in cultured CRC cells confers enhanced proliferation, motility and liver metastasis. We have analyzed the mechanisms of L1-mediated signaling in CRC cells by using various point mutations in the L1 ectodomain that are known to cause severe genetically inherited mental retardation disorders in patients. We found that all such L1 ectodomain mutations abolish the ability of L1 to confer metastatic properties in CRC cells. Using gene array analysis, we identified L1-mutation-specific gene expression signatures for the L1/H210Q and L1/D598N mutations. We identified CD10, a metalloprotease (neprilysin, neutral endopeptidase) and a gene that is specifically induced in CRC cells by L1 in an L1/H210Q mutation-specific manner. CD10 expression was required for the L1-mediated induction of cell proliferation, motility and metastasis, as suppression of CD10 levels in L1-expressing CRC cells abolished the L1 effects on CRC progression. The signaling from L1 to CD10 was mediated through the L1-ezrin-NF-κB pathway. In human CRC tissue L1 and CD10 were localized in partially overlapping regions in the more invasive areas of the tumor tissue. The results suggest that CD10 is a necessary component conferring the L1 effects in CRC cells. The identification of gene expression patterns of L1-domain-specific point mutations may provide novel markers and targets for interfering with L1-mediated CRC progression.

Induction of the intestinal stem cell signature gene SMOC-2 is required for L1-mediated colon cancer progression.

Overactivation of Wnt-ß-catenin signaling, including ß-catenin-TCF target gene expression, is a hallmark of colorectal cancer (CRC) development. We identified the immunoglobulin family of cell-adhesion receptors member L1 as a ß-catenin-TCF target gene preferentially expressed at the invasive edge of human CRC tissue. L1 can confer enhanced motility and liver metastasis when expressed in CRC cells. This ability of L1-mediated metastasis is exerted by a mechanism involving ezrin and the activation of NF-κB target genes. In this study, we identified the secreted modular calcium-binding matricellular protein-2 (SMOC-2) as a gene activated by L1-ezrin-NF-κB signaling. SMOC-2 is also known as an intestinal stem cell signature gene in mice expressing Lgr5 in cells at the bottom of intestinal crypts. The induction of SMOC-2 expression in L1-expressing CRC cells was necessary for the increase in cell motility, proliferation under stress and liver metastasis conferred by L1. SMOC-2 expression induced a more mesenchymal like phenotype in CRC cells, a decrease in E-cadherin and an increase in Snail by signaling that involves integrin-linked kinase (ILK). SMOC-2 was localized at the bottom of normal human colonic crypts and at increased levels in CRC tissue with preferential expression in invasive areas of the tumor. We found an increase in Lgr5 levels in CRC cells overexpressing L1, p65 or SMOC-2, suggesting that L1-mediated CRC progression involves the acquisition of a stem cell-like phenotype, and that SMOC-2 elevation is necessary for L1-mediated induction of more aggressive/invasive CRC properties.

Prevalence of Scedosporium species and Lomentospora prolificans in patients with cystic fibrosis in a multicenter trial by use of a selective medium.

OBJECTIVE: Detection of hyphomycetes of the Scedosporium apiospermum complex and Lomentospora prolificans (Sac-Lp) is not yet standardized. Prevalence rates in patients with cystic fibrosis (CF) and the resistance pattern of these pathogens in Germany are unknown. METHODS: In a one-year prospective study 11 laboratories used a selective medium for isolation of Sac-Lp, examining >11,600 respiratory samples from 2346 patients with CF. Isolates were identified by molecular methods and tested for susceptibility to antifungal drugs. RESULTS: The prevalence of Sac-Lp in patients with CF in Germany varied from 0.0 to 10.5% (mean: 3.1%) among the clinical centres. The benefit of the selective medium SceSel(+) compared to standard media for fungi was documented for >5000 samples. High antifungal resistance was detected in the S. apiospermum complex, and the multiresistance of L. prolificans was confirmed. CONCLUSION: Microbiology laboratories should be aware of these resistant species in patients with CF and consider using a selective medium.

Molecular weight and molar substitution are more important in HES-induced renal impairment than concentration after hemorrhagic and septic shock.

BACKGROUND: Clinical studies have raised concerns about the safety of 6% hydroxyethylstarch (HES) 130/0.42, but the pathomechanisms of this renal impairment remain unknown. To evaluate the effects of different HES concentrations, molar substitutions and molecular weights in HES-induced renal impairment, we used a porcine two-hit model that combined haemorrhagic and septic shock. METHODS: We conducted a prospective, randomised, double-blinded, controlled study in a university animal laboratory. Thirty anaesthetised and ventilated pigs were randomised to receive volume replacement therapy using 6% HES130/0.42, 6% HES200/0.5, 10% HES130/0.42 or 10% HES200/0.5, all dissolved in 0.9% NaCl rather than 0.9% NaCl alone. First, we bled the animals until they reached half of their baseline mean arterial pressure (MAP) for 45 minutes followed by fluid resuscitation. As a second hit, sepsis was induced using an Escherichia coli-laden clot 6 hours after haemorrhagic shock. Volume resuscitation started with a delay of two hours and a central venous pressure goal of 12 mmHg. RESULTS: At the end of the study, the groups showed no difference in cardiac output or MAP, but the volume balance (mL/kg BW) was significantly higher in the 0.9% NaCl group (346±90; P≤0.05) than in the other groups (6% HES130, 125±26; 6% HES200, 105±15; 10% HES130, 114±17; 10% HES200, 96±23). Creatinine clearance (mL/min) was significantly lower in the 6% HES200 (26±33) and 10% HES200 (15±18) groups compared to the 0.9% NaCl group (104±46; P≤0.05) but not in the HES 130 formulations (6% HES130: 64±51; 10% HES130: 58±38) at the end of the study. CONCLUSION: In this porcine two-hit shock model, treatment with 0.9% NaCl, HES 130/0.42 or HES 200/0.5 led to a similar maintenance of haemodynamic values. Despite this similar maintenance of the haemodynamic values, volume replacement with 6% and 10% HES 200/0.5 led to an accumulation of HES, higher colloid osmotic pressure and significantly reduced renal function after haemorrhagic and septic shock. These facts support the presumption that not the concentration but the degree of substitution and the molecular weight play a decisive role in HES-induced renal impairment.

Healthcare worker-related MRSA cluster in a German neonatology level III ICU: a true European story.

Here we investigated a cluster of eight newly Methicillin-resistant Staphylococcus aureus (MRSA)-colonized neonates at an ICU, and present data on molecular strain characterization as well as the source identification process in which we analyze the impact of MRSA-colonized HCWs. Molecular strain characterization revealed a unique pattern which was identified as spa-type t 127--an extremely rare strain type in Germany. Environmental sampling and screening of parents of colonized neonates proved negative. However, staff screening identified one healthcare worker (HCW; 1/134) belonging to a group of recently employed Romanian HCWs who was colonized with the spa 127 strain. Subsequent screening also detected MRSA in 9/51 Romanian HCWs (18%) and 7/9 (14% of all) isolates showed the same molecular pattern as the index case (spa/PFGE type). All carriers were successfully decolonized, after which no new patient cases occurred. As a result, we have now implemented a universal screening programme of all new employees as part of our infection control management strategy. MRSA-colonized HCWs can act as a source for in hospital transmission. Since HCWs from high endemic countries are particular prone to being colonized, they may pose a risk to patients.

[Fungal infections of the central nervous system in the immunocompetent host]. / Pilzinfektionen des Zentralnervensystems bei immunkompetentem Wirt.

The majority of mycoses which lead to mycotic tumors in patients without any predisposing underlying disease are either caused by Cryptococcus gattii and C. neoformans or by dematiaceous fungi which include Cladophialophora bantiana, Ramichloridium mackenziei, Exophiala and Fonsecaea species. The detection of hyphae in granuloma in the brain should lead to screening for pigmented fungi, which are recognized best in hematoxylin eosin (HE) or sometimes also in periodic acid-Schiff (PAS) stained sections. In patients who survive a near drowning accident and those who develop brain abscesses, scedosporiosis should always be considered as a possible infection.

Accelerating cardiac bidomain simulations using graphics processing units.

Anatomically realistic and biophysically detailed multiscale computer models of the heart are playing an increasingly important role in advancing our understanding of integrated cardiac function in health and disease. Such detailed simulations, however, are computationally vastly demanding, which is a limiting factor for a wider adoption of in-silico modeling. While current trends in high-performance computing (HPC) hardware promise to alleviate this problem, exploiting the potential of such architectures remains challenging since strongly scalable algorithms are necessitated to reduce execution times. Alternatively, acceleration technologies such as graphics processing units (GPUs) are being considered. While the potential of GPUs has been demonstrated in various applications, benefits in the context of bidomain simulations where large sparse linear systems have to be solved in parallel with advanced numerical techniques are less clear. In this study, the feasibility of multi-GPU bidomain simulations is demonstrated by running strong scalability benchmarks using a state-of-the-art model of rabbit ventricles. The model is spatially discretized using the finite element methods (FEM) on fully unstructured grids. The GPU code is directly derived from a large pre-existing code, the Cardiac Arrhythmia Research Package (CARP), with very minor perturbation of the code base. Overall, bidomain simulations were sped up by a factor of 11.8 to 16.3 in benchmarks running on 6-20 GPUs compared to the same number of CPU cores. To match the fastest GPU simulation which engaged 20 GPUs, 476 CPU cores were required on a national supercomputing facility.

Species and susceptibility distribution of 1062 clinical yeast isolates to azoles, echinocandins, flucytosine and amphotericin B from a multi-centre study.

Descriptive values were determined for eight antifungal agents within the course of a multi-centre study encompassing 1062 German and Austrian clinical yeast isolates. Candida albicans (54%) was the predominant species isolated followed by Candida glabrata (22%), Candida parapsilosis (6%), Candida tropicalis (5.7%), Candida krusei (4.3%), as well as eleven further candidal and four non-Candida yeast species. While 519 (48.9%) isolates were tested susceptible to all antifungals tested, no isolate was found to exhibit complete cross resistance. For C. albicans, the proportions of susceptible isolates were 93.2% (amphotericin B), 95.6% (flucytosine), 84.3% (fluconazole), 83.8% (posaconazole), 91.8% (voriconazole), 96.5% (anidulafungin), 96.2% (caspofungin) and 97.6% (micafungin). Patterns of complete parallel resistances were observed within azoles (8.8%) and echinocandins (1.7%). While a decreased susceptibility was found infrequently for echinocandins and flucytosine, it was more common for azoles with highest proportions for isolates of C. glabrata (fluconazole, 40.6%; posaconazole, 37.2%), Candida guilliermondii (fluconazole and posaconazole, each 25.0%), C. krusei (posaconazole, 28.3%; voriconazole, 60%), C. parapsilosis (fluconazole, 70.3%) and C. tropicalis (fluconazole, 62.3%). The descriptive values obtained in this study represent a valid basis for the comparison of recent and future epidemiological surveys to analyse the susceptibility of yeast isolates towards major antifungal substances.

External ventricular and lumbar drainage-associated meningoventriculitis: prospective analysis of time-dependent infection rates and risk factor analysis.

BACKGROUND: Data on time-dependency of external ventricular drainage (EVD)- and lumbar drainage (LD)-associated meningoventriculitis (MV) are scarce and discussions on the subject are controversial; no data exist for infection rates (IR) relative to drainage-days. For this reason, we conducted an observational study to determine time-dependent IRs and to perform a risk factor analysis. PATIENTS AND METHODS: All patients (n = 210) requiring an EVD or LD during an 18-month period in 2007 and 2008 were enrolled and characterized. Data on type and duration of drainage, ICP measurement, number of drainage manipulations, hospital stay and time point of MV were analysed statistically. RESULTS: A total of 34 MV cases were reported with 17 for each kind of drainage accounting for an IR of 7.5 and 24.7 MV/1000 EVD- and LD-days, respectively. Of these, 28/34 MV (82%) occurred within the first 12 days, and IRs were highest between days 4 and 9. Longer drainage duration (>5 and >9 days, respectively) was correlated with a significant lower risk of MV (p = 0.03; p < 0.001). In this study, significant risk factors for MV were LD [vs. EVD, OR: 2.3 (1.1-4.7); p = 0.01], a previous MV [OR: 7.0 (2.1-23.3); p = 0.002], and neoplasm [OR: 11.6 (3.4-39); p = 0.001]. Simultaneous drainage, ICP and a previous drainage showed no influence on infection. CONCLUSION: To the best of our knowledge, this study is the first to provide data on time dependency of EVD- and LD-associated MV-IR based on drainage-days. However, because of the limited scale of our study, it would be desirable to confirm these results in a more powerful larger study. In conclusion, we recommend that future efforts should be made to better identify preventable risk factors as well as to define time periods of higher risk for the difficult-to-diagnose MV infection as a first step in profiling high risk patients.

Prospective surveillance of drain associated meningitis/ventriculitis in a neurosurgery and neurological intensive care unit.

OBJECTIVES: There are currently no data available on drain associated infection occurrence related to the number of drainage days (DD), and thus drain associated infection rates. Therefore, a prospective surveillance study was conducted to determine drain associated infection rates and DD of hospital acquired external ventricular drain (EVD) and lumbar drain (LD) associated meningitis/ventriculitis in a neurosurgery and a neurological intensive care unit. METHODS: All patients admitted in 2005 and 2006 were documented. Data on age, admitting diagnosis, type and duration of drain, duration of hospital stay and occurrence of meningitis were recorded and analysed statistically. RESULTS: A total of 1333 patients were included, amounting to 3023 DD. After exclusion of 15 contaminations, a total of 26 cases of meningitis were reported accounting for an overall device associated meningitis rate of 8.6 infections/1000 DD. Infections associated with LD seemed to occur more frequently (19.9/1000 DD) compared with EVD (6.3/1000 DD). The presence of intraventricular blood and previous trauma were significant risk factors for infection (p = 0.003; p = 0.04). Finally, length of stay was significantly longer in meningitis patients (p = 0.0003). Coagulase negative staphylococci were the main pathogen (56%) causing meningitis, followed by Staphylococcus aureus (25%). CONCLUSIONS: To the best of the authors' knowledge, this study represents the first to provide data on EVD as well as LD associated meningitis rates calculated per 1000 DD; a parameter that is well established for other invasive devices such as central venous and urinary tract catheters. However, further prospective studies are needed to investigate the possible risk factors for meningitis.

Astrocytic protection of spinal motor neurons but not cortical neurons against loss of Als2/alsin function.

Three neurodegenerative diseases affecting upper and/or lower motor neurons have been associated with loss of ALS2/Alsin function: juvenile amyotrophic lateral sclerosis, primary lateral sclerosis and infantile-onset ascending hereditary spastic paralysis. The distinct neuronal vulnerability and the role of glia in these diseases remains, however, unclear. We here demonstrate that alsin-depleted spinal motor neurons can be rescued from defective survival and axon growth by co-cultured astrocytes. The astrocytic rescue is mediated by a soluble protective factor rather than by cellular contact. Cortical neurons are intrinsically as vulnerable to alsin depletion as spinal motor neurons but cannot be rescued by co-cultured astrocytes. To our knowledge, these data provide the first example of non-cell-autonomous glial effects in a recessive form of motor neuron disease and a potential rationale for the higher vulnerability of upper versus lower motor neurons in ALS2/Alsin-linked disorders.

Reforma del modelo de atención de la salud mental en la Ciudad Autónoma de Buenos Aires. Ejes conceptuales e instrumentos operativos / Supports for the reformulation of the model for the mental care at the city of buenos Aires

Se presentan las bases operativas del cambio de modelo de atención en salud mental, incluyendo su base de sustentación en la Ley 448, en los documentos nacionales e internacionales en la materia, los cambios programados en infraestructura, equipamiento, recursos humanos y gestión del ingreso a la red de complejidad ascendente.

The aim of this report was to present the supports for the reformulation of the model for the mental health care at the city of Buenos Aires, with conceptual guidelines and the operative instrumentation.

Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections.

OBJECTIVE: Physiological changes and local and systemic inflammation may affect plasma and tissue pharmacokinetics of antimicrobial agents in diabetics. The aim of the study was to investigate the penetration of linezolid into inflamed areas of infected diabetic foot wounds and the pharmacokinetics in the risk population of diabetics. METHODS: Pharmacokinetics and tissue penetration of linezolid into inflamed diabetic foot infection (DFI) tissue were determined at steady state in 15 patients with diabetes type 2 and DFI following administration of multiple oral doses of 600 mg given every 12 h. Second debridement was performed on days 4-6, 3 h after linezolid administration. Linezolid concentrations were determined in perinecrotic wound tissue of inflamed diabetic foot by high-performance liquid chromatography (HPLC). RESULTS: A mean maximum plasma concentration (C(max)) in plasma of 14.3 mg/L was attained at a median of 2.0 h [time to reach C(max) (T(max)) range 0.5-6.0 h). Area under the concentration time curve from zero to 12 h (AUC(0-12 h)) with a mean of 114.1 mgh/L and C(min) of 5.4 mg/L were achieved in patients with diabetes mellitus type 2. Penetration of linezolid into inflamed areas of DFI with tissue/plasma ratios of mean 101.7% [95% confidence interval (CI) 56; 148%] produced a mean concentration of 9.6 microg/g (95% CI 7.4; 11.8 microg/g) greater than those predicted to be effective against methicillin-resistant staphylococci [minimum concentration that inhibits 90% of organisms (MIC(90)) of 4 mg/L]. Tissue/plasma ratios correlated positive with systemic inflammation. CONCLUSION: Plasma pharmacokinetics of linezolid in diabetics and adequate levels in inflamed areas of diabetic foot wound suggest that an oral dose of 600 mg bd of linezolid provides effective concentrations for treating methicillin-resistant Staphylococcus aureus (MRSA) in DFI.

Mutant SOD1 detoxification mechanisms in intact single cells.

Mutant superoxide dismutase 1 (mtSOD1) causes dominantly inherited amyotrophic lateral sclerosis (ALS). The mechanism for mtSOD1 toxicity remains unknown. Two main hypotheses are the impairment of proteasomal function and chaperone depletion by misfolded mtSOD1. Here, we employed FRET/FLIM and biosensor imaging to quantitatively localize ubiquitination, as well as chaperone binding of mtSOD1, and to assess their effect on proteasomal and protein folding activities. We found large differences in ubiquitination and chaperone interaction levels for wild-type (wt) SOD1 versus mtSOD1 in intact single cells. Moreover, SOD1 ubiquitination levels differ between proteasomal structures and cytoplasmic material. Hsp70 binding and ubiquitination of wt and mtSOD1 species are highly correlated, demonstrating the coupled upregulation of both cellular detoxification mechanisms upon mtSOD1 expression. Biosensor imaging in single cells revealed that mtSOD1 expression alters cellular protein folding activity but not proteasomal function in the neuronal cell line examined. Our results provide the first cell-by-cell-analysis of SOD1 ubiquitination and chaperone interaction. Moreover, our study opens new methodological avenues for cell biological research on ALS.

[Septic shock with purpura fulminans after a dog bite]. / Sepsis mit Purpura Fulminans nach Hundebiss.

HISTORY AND CLINICAL FINDINGS: A 61-year-old man presented with a four-day history of back pain and nonspecific abdominal pain. His condition had significantly worsened since the day before admission with generalized weakness and dyspnea. His temperature was 39.1 C, he had tachycardia and was tachypneic. Peripheral cyanosis was noted. The abdomen was soft with mild epigastric tenderness. A diffuse skin rash developed with increasing petechial bleeding and central necrosis. It was revealed that he had been bitten by a dog several weeks before admission. INVESTIGATIONS: Laboratory data indicated an acute inflammatory process with a marked increase in white blood cells and C-reactive protein. An elevated procalcitonin level suggested a systemic bacterial infection. Chest X-ray and abdominal CT scan were unremarkable. Echocardiography revealed a globally hypokinetic heart with no evidence of valvular vegetations. One set of blood cultures grew micro-aerophilic, Gram-negative rods. Gene sequencing identified the slow growing, fastidious bacillus as CAPNOCYTOPHAGA CANIMORSUS. TREATMENT AND COURSE: The patient was admitted to the intensive care unit and initially treated with intravenous piperacillin/tazobactam and hydrocortisone for septic shock. Transfusions of platelets and blood products were given because of disseminated intravascular coagulation. The patient developed multi-organ failure requiring ventilation and hemodialysis; he died four days after admission. CONCLUSIONS: As a rare cause of septicemia, especially in immunocompromised patients, Capnocytophaga canimorsus infection should be considered after an animal bite. Given the slow growth of this bacterium in culture, Gram-staining of a peripheral blood smear may provide an early diagnosis and avoid delay before appropriate antibiotic therapy, which may favorably influence the potentially fatal course, is started.

Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL.

The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1(G93A) and SOD1(G85R), but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas/NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1(G93A) and SOD1(G85R) mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas/NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.

[Diagnostics and therapy for invasive fungal infections in an intensive care unit]. / Diagnostik und Therapie invasiver Pilzinfektionen auf der Intensivstation.

Invasive fungal infections are associated with a high mortality and have been increasing in incidence over the last few decades. Candidemia and, less commonly, invasive pulmonary aspergillosis are the most relevant fungal infections in critical care medicine. Risk factors for systemic Candida infections are the use of broad-spectrum antibiotics, a prolonged stay in an intensive care unit and gastrointestinal injury or surgery. Invasive aspergillosis usually occurs in immunocompromised patients. The diagnosis of invasive fungal infections remains challenging. The therapeutic spectrum includes fluconazol, conventional and liposomal amphotericin B, and the recently introduced agents caspofungin and voriconazol. For rational and cost-effective use, the clinician requires precise knowledge of the indications and limitations of these agents. This review focuses on the diagnostic and therapeutic options in severe Candida infections and invasive aspergillosis.