Idiopathic central diabetes insipidus in a large cohort of patients: the hypopituitarism ENEA rare observational (HEROS) study.

Central Diabetes Insipidus (CDI) is mainly associated with structural pathologies of the hypothalamic-pituitary area. Etiologies underlying CDI are identified in most patients, however idiopathic CDI is reported in 13-17% of cases after excluding other etiologies. The Hypopituitarism ENEA Rare Observational Study (HEROS study) retrospectively collected data of patients with idiopathic CDI from 14 pituitary centers in 9 countries. The cohort included 92 patients (59 females 64%), mean age at diagnosis was 35.4 ± 20.7 years, and a mean follow up of 19.1 ± 13.5 years following CDI diagnosis. In 6 women, diagnosis was related to pregnancy. Of 83 patients with available data on pituitary imaging, 40(48%) had normal sellar imaging, and 43(52%) had pathology of the posterior pituitary or the stalk, including loss of the bright spot, posterior pituitary atrophy or stalk enlargement. Anterior pituitary hormone deficiencies at presentation included hypogonadism in 6 (6.5%) patients (5 females), and hypocortisolism in one; during follow-up new anterior pituitary deficiencies developed in 6 patients. Replacement treatment with desmopressin was given to all patients except one, usually with an oral preparation. During follow up, no underlying disease causing CDI was identified in any patient. Patients with idiopathic CDI following investigation at baseline are stable with no specific etiology depicted during long-term follow-up.

Oxytocin and cortisol concentrations in adults with and without autism spectrum disorder in response to physical exercise.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, whose core symptoms consist of deficits in social interaction and communication as well as restricted and repetitive behavior. Brain oxytocin (OXT) has been associated with various prosocial behaviors, and might, therefore, be involved in the pathogenesis of disorders associated with socio-emotional dysfunctions such as ASD. However, significant associations between central and peripheral OXT levels may only be present in response to physiological or stressful stimuli but were not shown under baseline conditions. In this study, we, therefore, investigated salivary and plasma OXT in response to physical exercise in adults with ASD (n â€‹= â€‹33, mean age: 36.8 â€‹± â€‹10.7 years) without intellectual impairment (IQ â€‹> â€‹70) and neurotypical controls (n â€‹= â€‹31, mean age: 31.0 â€‹± â€‹11.7 years). To stimulate the OXT system, we used rapid cycling and measured cortisol (CORT) concentrations to monitor the physiological stress response. When controlling for age, neither salivary OXT (p â€‹= â€‹.469), plasma OXT (p â€‹= â€‹.297) nor CORT (p â€‹= â€‹.667) concentrations significantly differed between groups at baseline. In addition, neither OXT nor CORT concentrations significantly differed between groups after physical exercise. Social anxiety traits were negatively correlated with plasma, but not saliva OXT concentrations in neurotypicals at baseline, while empathetic traits were positively correlated with saliva, but not plasma concentrations in autistic patients at baseline. No significant correlations between salivary and plasma OXT concentrations were found at any time point. Future studies including adult participants should investigate the effect of age on CORT and OXT concentrations in response to stress.

Long term persistence of introduced Amblyomma geoemydae tick population under indoor conditions in Austria.

An indoor terrarium population of Amblyomma geoemydae was established subsequent to the import of a single yellow-marginated box turtle Cuora flavomarginata. This indoor tick population revealed an unexpected resistance against de-ticking trials, with persistence between 2010 and 2015, when the ticks were successfully eliminated. Ticks were collected from the bodies and shells of turtles, as well as from terraria soil. Species diagnosis of ticks was carried out according to distinguishable morphological characters and supported by molecular analysis using DNA-barcoding. Introduced exotic ticks are potential vectors of pathogens and can have an impact on wildlife, domestic animals and the human population. This case emphasizes the need for sharp surveillance and control measures on imported reptiles.

Peripapillary retinal nerve fibre layer thinning rate as a biomarker discriminating stable and progressing relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: Peripapillary retinal nerve fibre layer (pRNFL) thickness is a strong candidate as a biomarker of axonal degeneration in multiple sclerosis (MS). The aim was to determine a cut-off value of pRNFL thinning rates in relapsing-remitting MS (RRMS) to discriminate between stable and progressing patients. METHODS: In this 3-year prospective longitudinal study on 141 RRMS patients, annual pRNFL thinning rates (aLpRNFL) were determined by individual linear regression models. The best possible cut-off value discriminating clinically progressing (physical progression or cognitive decline) and stable patients was defined by receiver operating characteristic analysis. Cut-off values were validated using a multivariate logistic regression model. RESULTS: Average aLpRNFL in progressing patients (2.4 µm, SD 2.1) was significantly higher compared to stable patients (0.5 µm, SD 1.2, P < 0.001). At a predefined specificity of 90%, aLpRNFL >1.5 µm was able to distinguish between stable and progressing RRMS with a sensitivity of 76.1%. aLpRNFL >1.5 µm was associated with a 15-fold increased risk of clinically progressing MS (P < 0.001). CONCLUSIONS: A cut-off of aLpRNFL discriminating clinically progressing and stable RRMS was identified. After validation in independent cohorts, this cut-off could be used as a biomarker of axonal degeneration supporting disease monitoring in daily clinical routine.

Cerebrospinal fluid:serum glucose ratio in the ventricular and lumbar compartments: implications for clinical practice.

BACKGROUND AND PURPOSE: Calculation of the cerebrospinal fluid:serum glucose (CSF:SGlu ) ratio is part of the routine cerebrospinal fluid (CSF) work-up. Reference values have been defined for lumbar CSF, but are lacking for ventricular CSF. The objective of this study was to investigate whether the CSF:SGlu ratio is similar in lumbar and ventricular compartments, and to determine cut-off values for CSF:SGlu ratio in ventricular CSF. METHODS: We included CSF samples that were collected by either lumbar puncture or ventricular drainage, with a red blood cell count <500/µL, normal white blood cell count and age-related normal total protein content, with simultaneously withdrawn serum sample and time to laboratory processing of ≤2 h. This resulted in 1808 sample pairs. Glucose concentrations in CSF and serum were measured by enzymatic spectrophotometry. RESULTS: The CSF:SGlu ratio was similar in ventricular and lumbar compartments after controlling for age, sex, time between sample withdrawal and laboratory processing, CSF white blood cell and red blood cell count, CSF total protein and serum glucose concentration using a multiple linear regression model. Lower limits for CSF:SGlu ratio in the ventricular compartment, defined as 5th percentile, were 0.51 for patients with serum glucose concentration < 100 mg/dL, 0.45 for those with serum glucose concentration ≥ 100 mg/dL and <150 mg/dL, and 0.36 for those with serum glucose concentration ≥150 mg/dL. CONCLUSIONS: The CSF:SGlu ratio was similar in the ventricular and lumbar compartments, and depended mainly on time to laboratory processing and absolute serum glucose levels. Previously established lower limits for CSF:SGlu ratio in lumbar CSF can be also applied for ventricular CSF.

Combined evaluation of personality, risk and coping in MS patients: A step towards individualized treatment choice - The PeRiCoMS-Study I.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory neurological disease requiring disease-modifying treatment (DMT). To provide patients with the optimal individual therapeutic option, treatment recommendations should be based not only on individual disease course and DMT specific benefit-risk estimates, but also on patient's individual characteristics such as personality, risk attitude and coping strategies. However, these characteristics are difficult to objectify in clinical routine practice without the support of appropriate evaluation instruments. OBJECTIVE: To identify and to assemble an objective test battery measuring personality, risk attitude and coping strategies in MS patients. METHODS: A comprehensive literature search was performed to obtain all questionnaires assessing personality, risk attitude and coping strategies. Availability in German language, validation in a published normative collective and a reliability of >0.70 were required for our purposes. Based on these criteria, we chose the Big-Five-Personality Test, UPPS Impulsive Behaviour Scale, Domain-Specific Risk-Taking scale (DOSPERT), Brief-COPE and Stress & Coping Inventory (SCI). Results were compared to published normative controls of the respective questionnaires. RESULTS: Out of 22 MS patients (7 males, 15 females) participating in this study, 19 (86.4%) completed all questionnaires. The median completion time was 45min (min-max range: 25-60min). The median scores of the MS group were within the average range of published control samples in all questionnaires. CONCLUSIONS: We report that traits of personality, risk attitude and coping strategies can be effectively and feasibly tested in MS patients by the instruments used in our exploratory study. There were no differences between MS patients and healthy controls, thus enabling assessment without being influenced by the diagnosis of MS. After validation in a larger cohort the "PeRiCoMS"-battery will be useful as another step towards a more individualized shared-decision-making in every day routine practice.

Overexpression of human kynurenine-3-monooxygenase protects against 3-hydroxykynurenine-mediated apoptosis through bidirectional nonlinear feedback.

Kynurenine 3-monooxygenase (KMO) is a critical regulator of inflammation. The preferred KMO substrate, kynurenine, is converted to 3-hydroxykynurenine (3HK), and this product exhibits cytotoxicity through mechanisms that culminate in apoptosis. Here, we report that overexpression of human KMO with orthotopic localisation to mitochondria creates a metabolic environment during which the cell exhibits increased tolerance for exogenous 3HK-mediated cellular injury. Using the selective KMO inhibitor Ro61-8048, we show that KMO enzyme function is essential for cellular protection. Pan-caspase inhibition with Z-VAD-FMK confirmed apoptosis as the mode of cell death. By defining expression of pathway components upstream and downstream of KMO, we observed alterations in other key kynurenine pathway components, particularly tryptophan-2,3-dioxygenase upregulation, through bidirectional nonlinear feedback. KMO overexpression also increased expression of inducible nitric oxide synthase (iNOS). These changes in gene expression are functionally relevant, because siRNA knockdown of the pathway components kynureninase and quinolinate phosphoribosyl transferase caused cells to revert to a state of susceptibility to 3HK-mediated apoptosis. In summary, KMO overexpression, and importantly KMO activity, have metabolic repercussions that fundamentally affect resistance to cell stress.

Quantitation of intrathecal immunoglobulin synthesis - a new empirical formula.

BACKGROUND AND PURPOSE: Intrathecal immunoglobulin (Ig) synthesis occurs in various chronic inflammatory neurological diseases. Different formulae have been developed for quantitative determination of Ig synthesis within the cerebrospinal fluid (CSF) compartment. The hyperbolic formula of Reiber is frequently used which, however, returns a considerable number of false positive results in empirical observations. METHODS: A computerized database of more than 19 000 paired CSF and serum samples was screened for patients presumed negative for local Ig synthesis and a new formula characterizing this collective was calculated. The validity of this formula was confirmed by several validation steps. RESULTS: A cohort of 1173 patients with normal CSF findings was used for quantile regression. The 97.5th quantile of the formula Qlim(IgX)=a×Qalbb was considered as the cut-off curve for intrathecal Ig synthesis using different constants a and b for IgG, IgA and IgM. Compared to the Reiber formula, a lower level of false positive results was produced especially for IgM and IgA which was confirmed in a separate clinically well defined validation cohort. In 77 patients with discrepant findings between Reiber and our formula no specific diagnoses were found confirming the low diagnostic value of borderline Ig synthesis. CONCLUSIONS: A new approximation formula was developed for determination of intrathecal Ig synthesis which produces fewer false positive results without reducing diagnostic sensitivity.

Radioxenon standards used in laboratory inter-comparisons.

Preparation methods for (133)Xe standards of activity concentration and the results of the 2014 (133)Xe laboratory inter-comparison exercise are described. One element of the quality assurance/quality control (QA/QC) program for laboratories of the International Monitoring System (IMS) will be regular inter-comparison exercises. However, until recently, no activity concentration standards for benchmarking were available. Therefore, two (133)Xe activity concentration reference standards were produced independently by Idaho National Laboratory and Seibersdorf Laboratories and used for the 2014 laboratory inter-comparison exercise. The preparation of a complementary (127)Xe activity concentration standard as well as a (127)Xe laboratory inter-comparison exercise suggests (127)Xe as a suitable isotope for QA/QC of remote IMS noble gas stations.

Calibration of low-level beta-gamma coincidence detector systems for xenon isotope detection.

The beta-gamma coincidence detector systems used for the measurement of the CTBT-relevant xenon isotopes (Xe-131m, Xe-133m, Xe-133 and Xe-135) in the International Monitoring System network and in the On-Site Inspection are reviewed. These detectors typically consist of a well-type or bore-through NaI crystal into which a measurement cell, serving also as a sample container, is inserted. This work describes the current calibration procedure for energy, resolution and efficiency, implementation challenges, availability and uncertainties of the specific nuclear decay data and the path forward to full calibration validation using GEANT4.

Supratentorial white matter blurring associated with voltage-gated potassium channel-complex limbic encephalitis.

INTRODUCTION: Limbic encephalitis (LE) associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) is frequently non-paraneoplastic and associated with marked improvement following corticosteroid therapy. Mesial temporal lobe abnormalities are present in around 80 % of patients. If associated or preceded by faciobrachial dystonic seizures, basal ganglia signal changes may occur. In some patients, blurring of the supratentorial white matter on T2-weighted images (SWMB) may be seen. The purpose of this study was to evaluate the incidence of SWMB and whether it is specific for VGKC-LE. METHODS: Two experienced neuroradiologists independently evaluated signal abnormalities on FLAIR MRI in 79 patients with LE while unaware on the antibody type. RESULTS: SWMB was independently assessed as present in 10 of 36 (28 %) compared to 2 (5 %) of 43 non-VGKC patients (p = 0.009). It was not related to the presence of LGI1 or CASPR2 proteins of VGKC antibodies. MRI showed increased temporomesial FLAIR signal in 22 (61 %) VGKC compared to 14 (33 %) non-VGKC patients (p = 0.013), and extratemporomesial structures were affected in one VGKC (3 %) compared to 11 (26 %) non-VGKC patients (p = 0.005). CONCLUSION: SWMB is a newly described MRI sign rather specific for VGKC-LE.

IGF-I levels and depressive disorders: results from the Study of Health in Pomerania (SHIP).

In vitro and in vivo models revealed that the somatotropic system exerts central effects on the central nervous system. Disturbances to this system such as in the case of growth hormone deficiency or growth hormone excess, are associated with a wide range of psychiatric disorders. Nonetheless, there is no epidemiological data available regarding the influence of growth hormone and its mediator, insulin-like growth factor I (IGF-I), on depressive disorders. The objective of this study was to investigate whether endogenous IGF-I levels may predict depression in humans. We included 4079 adult subjects from the Study of Health in Pomerania (SHIP), a population-based study with a 5-year follow-up period. The main predictor was the baseline IGF-I value categorized in three levels as <10th percentile, between the 10th and the 90th percentile (the reference group) and >90th percentile. The outcome measure was the incidence of depressive disorders according to the Composite International Diagnostic-Screener (CID-S). After adjustment for potential confounding variables, females with IGF-I levels below the 10th percentile had a higher incidence of depressive disorders during follow-up (OR 2.70 95% CI 1.38-5.28, p=0.004) compared to females within the reference group (10th-90th percentile). Among males, those with IGF-I levels above the 90th percentile had a higher risk of depressive disorder (OR 3.26 95% CI 1.52-6.98, p=0.002) than those within the 10th-90th percentile. In conclusion we can demonstrate that low IGF-I levels in females and high IGF-I levels in males predict the development of depressive disorders in this general adult population sample.

Bacterial expression of human kynurenine 3-monooxygenase: solubility, activity, purification.

Kynurenine 3-monooxygenase (KMO) is an enzyme central to the kynurenine pathway of tryptophan metabolism. KMO has been implicated as a therapeutic target in several disease states, including Huntington's disease. Recombinant human KMO protein production is challenging due to the presence of transmembrane domains, which localise KMO to the outer mitochondrial membrane and render KMO insoluble in many in vitro expression systems. Efficient bacterial expression of human KMO would accelerate drug development of KMO inhibitors but until now this has not been achieved. Here we report the first successful bacterial (Escherichia coli) expression of active FLAG™-tagged human KMO enzyme expressed in the soluble fraction and progress towards its purification.

Radioxenon detections in the CTBT international monitoring system likely related to the announced nuclear test in North Korea on February 12, 2013.

Observations made in April 2013 of the radioxenon isotopes (133)Xe and (131m)Xe at measurement stations in Japan and Russia, belonging to the International Monitoring System for verification of the Comprehensive Nuclear-Test-Ban Treaty, are unique with respect to the measurement history of these stations. Comparison of measured data with calculated isotopic ratios as well as analysis using atmospheric transport modeling indicate that it is likely that the xenon measured was created in the underground nuclear test conducted by North Korea on February 12, 2013, and released 7-8 weeks later. More than one release is required to explain all observations. The (131m)Xe source terms for each release were calculated to 0.7 TBq, corresponding to about 1-10% of the total xenon inventory for a 10 kt explosion, depending on fractionation and release scenario. The observed ratios could not be used to obtain any information regarding the fissile material that was used in the test.

[Isolated gonadotropic deficiency after multiple concussions in a professional soccer player]. / Wie harmlos sind Kopfbälle? Hypogonadotroper Hypogonadismus nach leichten Schädel-Hirn-Traumata bei einem Profi-Fußballspieler.

HISTORY AND CLINICAL PRESENTATION: A 27-year-old man was admitted to our outpatient clinic with symptoms of loss at libido, erectile dysfunction and fatigue. He had been playing soccer from the age of 7, for the last 10 years as a high-level professional. During that time repeated mild head-trauma without loss of consciousness had occurred, mainly triggered by excessive header-training and occasional collisions. INVESTIGATIONS: Serum levels of testosterone and luteinizing hormone were low. A gonadotropin releasing hormone loading test revealed significant gonadotropin responses, therefore pituitary gonadotropic insufficiency was unlikely. Further pituitary insufficiency of any other axis was also excluded by insulin hypoglycemia test. Magnetic resonance imaging of the brain revealed no significant abnormalities of the hypothalamic-pituitary unit. TREATMENT AND COURSE: Testosterone substitution, at first applied transdermally, then intramuscularly, was initiated after approval by the National Anti Doping Agency. Four months later most of the symptoms had regressed. CONCLUSION: Pituitary deficiency in the course of craniocerebral trauma is frequent and may be transient or permanent, mostly affecting somatotropic or gonadotropic function. Hormonal imbalances may also be observed after mild but repeated trauma without loss of consciousness and should be considered in cases of isolated pituitary dysfunction, since such traumas may often occur in contacts sports such as boxing or intensive soccer play.

Rare missense P450c17 (CYP17A1) mutation in exon 1 as a cause of 46,XY disorder of sexual development: implications of breast tissue 'unresponsiveness' despite adequate estradiol substitution.

17-Alpha-hydroxylase/17,20-lyase deficiency (17OHD) is a rare autosomal recessive disorder resulting from mutations in the CYP17A1 gene, leading to impaired adrenal and gonadal steroidogenesis. We report for the first time a patient with a missense mutation at codon 96 (R96Q) of the CYP17A1 gene causing a 46,XY disorder of sexual development (DSD) that additionally showed lack of breast development despite highly dosed estradiol replacement treatment. This phenomenon could be attributed to irreversible breast tissue alterations following high serum progesterone levels.

Evidence for direct electron transfer by a gram-positive bacterium isolated from a microbial fuel cell.

Despite their importance in iron redox cycles and bioenergy production, the underlying physiological, genetic, and biochemical mechanisms of extracellular electron transfer by Gram-positive bacteria remain insufficiently understood. In this work, we investigated respiration by Thermincola potens strain JR, a Gram-positive isolate obtained from the anode surface of a microbial fuel cell, using insoluble electron acceptors. We found no evidence that soluble redox-active components were secreted into the surrounding medium on the basis of physiological experiments and cyclic voltammetry measurements. Confocal microscopy revealed highly stratified biofilms in which cells contacting the electrode surface were disproportionately viable relative to the rest of the biofilm. Furthermore, there was no correlation between biofilm thickness and power production, suggesting that cells in contact with the electrode were primarily responsible for current generation. These data, along with cryo-electron microscopy experiments, support contact-dependent electron transfer by T. potens strain JR from the cell membrane across the 37-nm cell envelope to the cell surface. Furthermore, we present physiological and genomic evidence that c-type cytochromes play a role in charge transfer across the Gram-positive bacterial cell envelope during metal reduction.

Generalized schemes for high-throughput manipulation of the Desulfovibrio vulgaris genome.

The ability to conduct advanced functional genomic studies of the thousands of sequenced bacteria has been hampered by the lack of available tools for making high-throughput chromosomal manipulations in a systematic manner that can be applied across diverse species. In this work, we highlight the use of synthetic biological tools to assemble custom suicide vectors with reusable and interchangeable DNA "parts" to facilitate chromosomal modification at designated loci. These constructs enable an array of downstream applications, including gene replacement and the creation of gene fusions with affinity purification or localization tags. We employed this approach to engineer chromosomal modifications in a bacterium that has previously proven difficult to manipulate genetically, Desulfovibrio vulgaris Hildenborough, to generate a library of over 700 strains. Furthermore, we demonstrate how these modifications can be used for examining metabolic pathways, protein-protein interactions, and protein localization. The ubiquity of suicide constructs in gene replacement throughout biology suggests that this approach can be applied to engineer a broad range of species for a diverse array of systems biological applications and is amenable to high-throughput implementation.

Inhibition of fibroblast growth factor receptor 1 endocytosis promotes axonal branching of adult sensory neurons.

Fibroblast growth factors (FGFs) promote axon growth during development and regeneration of the nervous system. Among the four types of FGF receptors (FGFRs), FGFR1 is expressed in adult sensory neurons of dorsal root ganglia (DRG), and overexpression of FGFR1 promotes FGF-2-induced elongative axon growth in vitro. Ligand-induced activation of FGFR1 is followed by endocytosis and lysosomal degradation, which leads to the termination of receptor signaling. We previously reported that the lysosomal inhibitor leupeptin enhances FGF-2-induced elongative axon growth of adult DRG neurons overexpressing FGFR1. To better understand the role of subcellular localization of FGFR1 in axon growth, we analyzed the effects of inhibition of endocytosis of FGFR1 on FGF-2-induced neurite outgrowth in PC12 pheochromocytoma cells and adult DRG neurons. The endocytosis inhibitors methyl-ß-cyclodextrin (MßCD) and chlorpromazine enhanced surface localization of FGFR1 in PC12 cells and DRG neurons. Furthermore, MßCD and chlorpromazine increased FGF-2-induced neurite outgrowth of PC12 cells and axonal branching of adult DRG neurons overexpressing FGFR1, whereas MßCD inhibited FGF-2-induced axonal elongation. Analysis of the signaling pathways involved in axon morphology revealed that FGF-2-induced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was increased by inhibition of FGFR1 endocytosis. Together, our results imply that inhibition of FGFR1 endocytosis by MßCD or chlorpromazine promotes FGF-2-induced axonal branching. The results of this study confirm that internalization of FGFR1 controls axon growth and morphology of adult sensory neurons via selective activation of intracellular signaling pathways.

Engineering strategies to recapitulate epithelial morphogenesis within synthetic three-dimensional extracellular matrix with tunable mechanical properties.

The mechanical properties (e.g. stiffness) of the extracellular matrix (ECM) influence cell fate and tissue morphogenesis and contribute to disease progression. Nevertheless, our understanding of the mechanisms by which ECM rigidity modulates cell behavior and fate remains rudimentary. To address this issue, a number of two and three-dimensional (3D) hydrogel systems have been used to explore the effects of the mechanical properties of the ECM on cell behavior. Unfortunately, many of these systems have limited application because fiber architecture, adhesiveness and/or pore size often change in parallel when gel elasticity is varied. Here we describe the use of ECM-adsorbed, synthetic, self-assembling peptide (SAP) gels that are able to recapitulate normal epithelial acini morphogenesis and gene expression in a 3D context. By exploiting the range of viscoelasticity attainable with these SAP gels, and their ability to recreate native-like ECM fibril topology with minimal variability in ligand density and pore size, we were able to reconstitute normal and tumor-like phenotypes and gene expression patterns in nonmalignant mammary epithelial cells. Accordingly, this SAP hydrogel system presents the first tunable system capable of independently assessing the interplay between ECM stiffness and multi-cellular epithelial phenotype in a 3D context.