[Influenza]. / Influenza.

BACKGROUND: The influenza virus (IV)-associated mortality and morbidity remains high in Europe. OBJECTIVE: This article gives an overview of the pathogenesis, diagnostics and treatment optimization strategies according to the currently existing guidelines and clinical trials. MATERIAL AND METHODS: Literature search and analysis of national and international guidelines for the epidemiology, diagnostics, treatment and prevention of IV infections. RESULTS AND CONCLUSION: Although the incidence of IV infections remains underrecognized, it is the leading infectious disease-associated cause of mortality and morbidity in Europe. Viruses are mainly transmitted by aerosol inhalation and can cause a wide spectrum of symptoms, ranging from mild signs of a cold to severe respiratory failure requiring mechanical ventilation. The clinical diagnosis should be verified through a PCR-based test in patients with indications for treatment. Neuraminidase inhibitors are currently the treatment of choice for IV infections. Seasonal influenza vaccination is an efficient preventive method. It is therefore imperative to improve vaccination rates in Germany, which have been continuously declining since the pandemic of 2009/2010.

Efficacy of BRAF/MEK-inhibitor therapy for epithelioid glioblastoma with a novel BRAFV600 mutation.

Epithelioid glioblastoma (eGB), a very aggressive and rare brain tumour, is associated with a dismal median overall survival. Effective therapies for patients with eGB, particularly with leptomeningeal dissemination, are still lacking. Here, we describe a case of a 25-year-old male diagnosed with an intramedullary cervical tumour with subsequent leptomeningeal disease. Histopathology identified a highly necrotising, epithelioid-type tumour with high cell density, most compatible with the diagnosis of an eGB. DNA analysis revealed an unprecedented B-Raf protooncogene, serine/threonine kinase (BRAF) gene variant in exon 15 (ENST00000288602.6, c.1799_1810delinsATG, p.(V600_W604delinsDG)), triggering activation of the mitogen-activated protein kinase (MAPK) pathway. Consequently, we initiated MAPK inhibitor (MAPKi) therapy, utilizing a combination of BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors. Liquid chromatography-tandem mass spectrometry analysis confirmed the drugs' presence in the patient's cerebrospinal fluid, indicating their capacity to cross the blood-brain barrier. Remarkably, the patient responded very well to therapy and transitioned from a near-comatose state to significantly improved health, sustained for over three months. This study highlights that MAPKi, particularly targeted towards novel BRAFV600 mutations, might offer promising advancements in eGB treatment strategies.

CREB signalling regulates early survival, neuronal gene expression and morphological development in adult subventricular zone neurogenesis.

Neural stem cells in the subventricular zone (SVZ) of the lateral ventricles give rise to new interneurons of the olfactory bulb (OB) throughout life. SVZ/OB neurogenesis is influenced by olfactory network activity, which modulates the survival of new neurons during their integration into the OB network. Previous work suggested that such activity-dependent survival is regulated via the CREB signalling pathway. Curiously, CREB signalling is already active during the early developmental stages of adult SVZ/OB neurogenesis. To investigate the role of cell autonomous CREB signalling during early stages of adult SVZ/OB neurogenesis, we ablated CREB-pathway activity in the SVZ/OB neurogenic lineage using a retroviral strategy. Surprisingly, loss of CREB signalling resulted in increased cell death and loss of expression of the neurogenic transcription factor Pax 6, and of a subset of neuronal proteins in migrating neurons of the RMS. Moreover, post-migratory neurons in the OB displayed impaired dendritic development. These results demonstrate an essential role for CREB signalling in maturation of newborn neurons in the OB and uncover a novel role for CREB signalling in the survival and maintenance of neuronal gene expression during the early stages of SVZ/OB neurogenesis.

[Preoperative diagnostics and typing of abdominal soft tissue sarcomas]. / Präoperative Diagnostik und Typisierung abdomineller Weichteilsarkome.

BACKGROUND: Abdominal sarcomas are a heterogeneous group of rare soft tissue tumors and can be localized intraperitoneally or retroperitoneally. A pretherapeutic differentiated subtyping is essential for planning an individual, multimodal treatment concept in an interdisciplinary team of experts. OBJECTIVE: The central aspects of histology acquisition, imaging diagnostics and (molecular) pathological subtyping of abdominal soft tissue sarcomas are described in detail. MATERIAL AND METHODS: Imaging and pathological diagnostics are depicted based on the German S3 guidelines on adult soft tissue sarcomas, a current literature search and personal experiences at the Sarcoma Center at the National Center for Tumor Diseases in Dresden (NCT/UCC). RESULTS: Preoperative imaging and (molecular) pathological subtyping of abdominal soft tissue sarcomas place high demands on surgeons, radiologists and pathologists. Genome analyses of sarcomas have the potential to identify points of attack for individualized treatment options. The limitations of resectability can only be assessed by experienced sarcoma surgeons at specialized centers. CONCLUSION: The treatment of abdominal soft tissue sarcomas at an experienced center is associated with a better prognosis. Even at the first suspicion of an abdominal sarcoma, a referral to an experienced center should be made in order to guarantee optimal expertise in diagnostics and treatment.

Epidemic and endemic spread of Klebsiella pneumoniae producing SHV-5 beta-lactamase in Dubrava University Hospital, Zagreb, Croatia.

Plasmid-encoded resistance to broad-spectrum cephalosporins and aztreonam is becoming a widespread phenomenon in clinical medicine. These antibiotics are inactivated by an array of different extended-spectrum beta-lactamases (ESBLs) which have evolved by point mutations of parental TEM or SHV beta-lactamases. In a previous study conducted during 1994-1995, SHV-2, SHV-2a and SHV-5 beta-lactamases were found among Klebsiella pneumoniae isolates in Dubrava University Hospital. High prevalence of ESBLs among K. pneumoniae strains in this hospital (20%) required further investigation. In this investigation, beta-lactamases from 42 K. pneumoniae strains collected in 1997 and 15 in 2004 from Dubrava University Hospital, were characterized in order to study the evolution of plasmid-encoded resistance to extended-spectrum cephalosporins and aztreonam in that hospital over a prolonged study period. Susceptibility to antibiotics was determined by disk-diffusion and broth microdilution method. beta-lactamases were characterized by isoelectric focusing, determination of hydrolysis of beta-lactam substrates, polymerase chain reaction and sequencing of bla(SHV) genes. All K. pneumoniae strains and their Escherichia coli transconjugants produced beta-lactamase with an isoelectric point of 8.2. Based on sequencing of bla(SHV) genes enzymes of all transconjugants were identified as SHV-5 beta-lactamase which conferred on the producing isolates high level of ceftazidime and aztreonam resistance. In this study, an outbreak of nosocomial infections caused by SHV-5 producing K. pneumoniae was described in 1997 which evolved to endemic spread of SHV-5 producing K. pneumoniae due to multiple plasmid transfer in the Dubrava University Hospital. The strains from 1997 and 2004 were not clonally related. Hospital hygiene measures should be applied in order to control the spread of epidemic strains through the hospital wards and the consumption of the broad-spectrum cephalosporins needs to be restricted to reduce the selection pressure which enables the proliferation of ESBL producers in hospital.

Hydrogen clearance method for determining local cerebral blood flow. I. Spatial resolution.

To define the effective spatial resolution of the hydrogen clearance method, serial local CBF (LCBF) measurements were performed at different distances from the cortico-white matter junction of the cat brain. Twenty-five platinum-wire microelectrodes with a sensitive surface of 0.07 mm2 were inserted into the cerebral cortex of three cats through burr holes in the skull and advanced toward the ear-to-ear level in 1- or 0.1-mm steps. Most electrodes passed from high-perfusion regions into low-perfusion areas, indicating that the cortico-white matter junction had been traversed. Whereas within the gray and white matter the LCBF values were fairly constant, a striking decrease of CBF was registered at the cortico-white matter junction. Here the mean LCBF from 12 electrodes showed significant differences in flow between two locations 1 mm apart. On two occasions, a significant difference in CBF was found for locations only 0.1 mm apart. Despite this high spatial resolution, monoexponential clearance curves were detected only in the vicinity of the cortico-white matter junction. It is therefore assumed that factors other than flow might influence H2 clearance.

Hydrogen clearance method for determining local cerebral blood flow. II. Effect of heterogeneity in cerebral blood flow.

The time course of hydrogen uptake and washout was followed simultaneously in extracranial arterial blood, cortex, subcortical white matter, and caudate nucleus of the cat brain to study intercompartmental hydrogen concentration differences. A clear delay of 1-2 min was seen between the onsets of concentration increase in arterial blood and low-flow brain tissues. Equilibration time was dependent on local CBF and varied between 3 and 34 min. Hydrogen was not cleared simultaneously from the regions under detection. This led to considerable concentration differences within the cerebral tissue during washin and washout phases. Analysis of the clearance curves revealed that secondary equilibration occurs during washout. Hydrogen concentration in the external carotid artery was not a reliable reflection of tracer input in the brain tissues. The consequences of these observations for other techniques of CBF measurement using less diffusive gases and external detection are discussed.

Measurement of glucose utilisation with [18F]2-fluoro-2-deoxy-D-glucose: a comparison of different analytical methods.

A number of different analytical methods were applied to dynamic scans obtained with [18F]2-fluoro-2-deoxy-D-glucose and positron emission tomography. In particular, methods applying three, four, standard, or no rate constants were compared in four studies on three normal subjects. In addition, regional cerebral blood flow, oxygen utilisation, and blood volume were measured using the oxygen-15 steady-state inhalation technique. There was a large difference between values of glucose utilisation obtained with the various analytical methods, in particular between methods using three or four rate constants. This difference was not due to contamination of the tracer with [18F]2-fluoro-2-deoxy-D-mannose. For dynamic techniques, the separate measurement of regional cerebral blood volume was essential. Static techniques (single scans with standard or no rate constants) were best related to dynamic techniques utilising four rate constants. From the results, it followed, however, that these static techniques can only be applied clinically if relatively large disturbances of glucose metabolism and no changes in rate constants are anticipated. The lumped constant was assessed from the combined measurement of oxygen and glucose utilisation and was higher than previously reported.

Regional cerebral glucose transport in insulin-dependent diabetic patients studied using [11C]3-O-methyl-D-glucose and positron emission tomography.

Regional cerebral [11C]3-O-methyl-D-glucose ([11C]MeG) uptake kinetics have been measured in five insulin-dependent diabetic patients and four normal controls using positron emission tomography (PET). Concomitant measurement of regional cerebral blood volume and CBF enabled corrections for the presence of intravascular [11C]MeG signal in cerebral regions of interest to be carried out, and regional cerebral [11C]MeG unidirectional extraction fractions to be computed. Four of the five diabetic subjects were studied with their fasting plasma glucose level clamped at a normoglycaemic level (4 mM), and four were studied at hyperglycaemic plasma glucose levels (mean 13 mM). The four diabetic subjects whose fasting plasma glucose levels were clamped at a normoglycaemic level of 4 mM had mean fasting whole-brain, cortical, and white matter [11C]MeG extraction fractions of 15, 15, and 16%, respectively, values similar to those found for the four normal controls (whole brain, 14%; cortex, 13%; white matter, 17%). Mean regional cerebral [11C]MeG extraction fractions were significantly reduced in diabetic subjects during hyperglycaemia whether their plasma insulin levels were undetectable or whether they were raised by continuous intravenous insulin infusion. Such a reduction in [11C]MeG extraction under hyperglycaemic conditions can be explained entirely in terms of increased competition between [11C]MeG and D-glucose for the passive facilitated transport carrier system for hexoses across the blood-brain barrier (BBB). It is concluded that the number and affinity of D-glucose carriers present in the BBB are within normal limits in treated insulin-dependent diabetic subjects. In addition, insulin appears to have no effect on the transport of D-glucose across the BBB.

Glucose transport across the blood-brain barrier in normal human subjects and patients with cerebral tumours studied using [11C]3-O-methyl-D-glucose and positron emission tomography.

The kinetics of the regional cerebral uptake of [11C]3-O-methyl-D-glucose ([11C]MeG), a competitive inhibitor of D-glucose transport, have been studied in normal human subjects and patients with cerebral tumours using positron emission tomography (PET). Concomitant measurement of regional cerebral blood volume and blood flow enabled corrections for the contribution of intravascular tracer signal in PET scans to be carried out and regional unidirectional cerebral [11C]MeG extractions to be determined. A three-compartment model containing an arterial plasma and two cerebral compartments was required to produce satisfactory fits to experimental regional cerebral [11C]MeG uptake data. Under fasting, resting conditions, normal controls had mean unidirectional whole-brain, cortical, and white matter [11C]MeG extractions of 14, 13, and 17%, respectively. Mean values of k1 and k2, first-order rate constants describing forward and back transport, respectively, of tracer into the first cerebral compartment, were similar for [11C]MeG and [18F]2-fluoro-2-deoxy-D-glucose (18FDG), a second competitive inhibitor of D-glucose transport. k3, a rate constant describing FDG phosphorylation, was 20 times higher for cortical FDG uptake than the k3 fitted for [11C]MeG cortical uptake. Glioma [11C]MeG extractions ranged from normal levels of 12% to raised levels of 30%. Transport of [11C]MeG in and out of contralateral cortical tissue was significantly depressed in patients with gliomas. It is concluded that under fasting, resting conditions, regional cerebral glucose extraction remains relatively uniform throughout normal brain tissue. Gliomas, however, may have raised levels of glucose extraction. The nature of the second cerebral compartment required to describe [11C]MeG uptake is unclear, but it could represent either a useless phosphorylation-dephosphorylation cycle or nonspecific tracer uptake by a cerebral subcompartment.

Kinetic and spectroscopic characterization of an intermediate peroxynitrite complex in the nitrogen monoxide induced oxidation of oxyhemoglobin.

Stopped-flow spectroscopy studies of the nitrogen monoxide mediated oxidation of oxyhemoglobin in the pH range 5-10.5 show that an intermediate can be characterized at alkaline pH. The rate of decay of this species to methemoglobin increases significantly with decreasing pH such that it does not accumulate in quantities large enough to be observed under neutral or acidic conditions. Kinetic and spectroscopic properties of this intermediate support its assignment as a methemoglobin peroxynitrite complex.

Kinetic and spectroscopic characterization of an intermediate peroxynitrite complex in the nitrogen monoxide induced oxidation of oxyhemoglobin.

Stopped-flow spectroscopy studies of the nitrogen monoxide mediated oxidation of oxyhemoglobin in the pH range 5-10.5 show that an intermediate can be characterized at alkaline pH. The rate of decay of this species to methemoglobin increases significantly with decreasing pH such that it does not accumulate in quantities large enough to be observed under neutral or acidic conditions. Kinetic and spectroscopic properties of this intermediate support its assignment as a methemoglobin peroxynitrite complex.

Follow-up of spontaneous intracerebral haemorrhage by computed tomography.

The follow-up of 89 patients with spontaneous intracerebral haematomas was studied by computed tomography (CT). The aetiology of the haemorrhage was found to be hypertension in 52 cases, vascular malformation in 14 cases, and two haematomas were due to anticoagulant therapy. The lesion visible on CT consisted of an area of increased density surrounded by a rim of low attenuation. Most cases showed a progressive decrease in size of the total lesion. Exceptions to this pattern were observed, which may lead to the misdiagnosis of a tumour. The central area of increased density decreased in size much more quickly than the total lesion. Signs of a mass effect were observed up to the ninth week in the larger lesions. The resorption of blood, measured by the decrease in diameter of the central high attenuation area, was not dependent on the site or original size of the haematoma, but was slower in hypertensive haemorrhage than in haemorrhage due to vascular malformation. Contrast enhancement was observed up to the ninth week and was ring-like in most cases. Our data confirm the well-known finding that the bleeding cannot be demonstrated by examination of the CSF if the blood has not reached the ventricular system or the subarachnoid space.

A disease causing deletion of 29 base pairs in intron 15 in the MKS1 gene is highly associated with the campomelic variant of the Meckel-Gruber syndrome.

Meckel-Gruber syndrome (MKS) is an autosomal recessive disorder causing severe defects in the developing central nervous system and other organs. Recently, mutations in the MKS1 gene have been identified as disease causing in individuals of Finnish MKS families. The primary aim of the present study was to assess the frequency of the 'Finnish founder mutation' (29 bp IVS15-7_35) in the MKS1 gene in 20 aborted fetuses with a diagnosis of MKS. The secondary aim was to screen for novel mutations in the coding sequence of the MKS1 gene of MKS fetuses and to obtain genotype-phenotype correlations where possible. Furthermore, we evaluated the carrier rate of a deletion of 29 bp in intron 15 of the MKS1 gene in a German population. To identify and characterize mutations in the MKS1 gene, sequence analyses and quantitative real time polymerase chain reaction studies were performed. We could identify the same type of mutation, a deletion of 29 bp in intron 15 of the MKS1 gene, in 8 out of the 20 cases studied. Six out of the eight cases with such a mutation displayed the campomelic variant of MKS. The carrier frequency among 519 healthy German individuals was 1:260. This deletion in the MKS1 gene is highly associated with a distinct subtype of the MKS, namely the campomelic variant. In individuals of European origin suffering from the campomelic MKS variant, the described deletion is highly likely to be causative. Regarding the results of our study, the incidence of MKS in Germany can be estimated as 1:135,000. In families with a known mutation in the MKS1 gene, it is now possible to offer an early prenatal testing, for example with chorionic villus sampling and mutation analysis.

[Interdisciplinary training program for adults with psoriaisis: six months follow-up]. / Interdisziplinäre psoriasisschulung in blockform für erwachsene patienten: ein halbjahres-follow-up.

BACKGROUND: The aim of our pilot study was to evaluate effects of an interdisciplinary training program for adult psoriasis patients after six months follow-up. SUBJECTS AND METHODS: Eleven patients with psoriasis participated in an interdisciplinary training program over a weekend taught by dermatologists, psychologists/psychiatrists, and dieticians. Six months follow-up was performed with a questionnaire. RESULTS: The knowledge acquired improved the cooperation with the treating dermatologist (7 of 11), the patients' ability to cope with their disease (11 of 11), and their ability to improving their health status (8 of 11). Their general well-being was increased (9 of 11) and they could better care for their skin disease because they better understood the need for care (9 of 11), and could better judge the best approach for various levels of disease activity (8 of 11). CONCLUSION: These data show early benefits and suggest such a longer lasting effect of this type of psoriasis training and prevention program. Further studies with larger samples and control parameters will have to examine if these results can be confirmed.

Sleep disordered breathing in pediatric patients with tetralogy of Fallot.

Adverse effects on the pulmonary circulation in obstructive sleep disordered breathing (SDB) may place children with heart lesions affecting the right ventricle at increased risk for morbidity and mortality. We examined the distribution and effects of SDB in pediatric patients with tetralogy of Fallot (TOF). Families of 37 pediatric patients with TOF completed a survey of cardiac symptoms and school performance as well as a Pediatric Sleep Questionnaire (PSQ), a validated questionnaire for the screening of SDB in children 2-18 years of age. Medical records were reviewed for growth parameters, medical history, and most recent electrocardiogram (ECG) findings. Data from patients with SDB (PSQ score > or = 8, n = 14) were compared to data from patients without SDB (PSQ score < 8; n = 23). The prevalence of SDB in this population (38%) was significantly higher than the published prevalence of 5% in a healthy general pediatric population (p < 0.001). No significant difference was found in age, gender, or age and sex standardized body mass index between patients with or without SDB. No difference was seen in medication use or timing of surgical repair, whether primary or palliative. Patients with SDB had a significantly higher cardiac symptom score (p = 0.01) and increasing PSQ scores correlated with worsening cardiac symptom scores (p = 0.006). Increasing PSQ scores also correlated with worsening school performance (p = 0.001). No differences were seen in ECG data. The screened prevalence of SDB in the pediatric population with TOF is higher than in the general population; patients with TOF and SDB are more likely to have worse cardiac symptoms and poor school performance.