Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations

Several genes with an essential role in the regulation of eating behavior and body weight are considered candidates involved in the etiology of eating disorders (ED), but no relevant susceptibility genes with a major effect on anorexia nervosa (AN) or bulimia nervosa (BN) have been identified. Brain-derived neurotrophic factor (BDNF) has been implicated in the regulation of food intake and body weight in rodents. We previously reported a strong association of the Met66 allele of the Val66Met BDNF variant with restricting AN (ANR) and low minimum body mass index in Spanish patients. Another single nucleotide polymorphism located in the promoter region of the BDNF gene (-270C>T) showed lack of association with any ED phenotype. In order to replicate these findings in a larger sample, we performed a case-control study in 1142 Caucasian patients with ED consecutively recruited in six different centers from five European countries (France, Germany, Italy, Spain and UK) participating in the 'Factors in Healthy Eating' project. We have found that the Met66 variant is strongly associated to all ED subtypes (AN, ANR, binge-eating/purging AN and BN), and that the -270C BDNF variant has an effect on BN and late age at onset of weight loss. These are the first two variants associated with the pathophysiology of ED in different populations and support a role for BDNF in the susceptibility to aberrant eating behaviors.     

Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany

The association between common variants in the FTO gene with weight, adiposity and body mass index (BMI) has now been widely replicated. Although the causal variant has yet to be identified, it most likely maps within a 47 kb region of intron 1 of FTO. We performed a genome-wide association study in the Sorbian population and evaluated the relationships between FTO variants and BMI and fat mass in this isolate of Slavonic origin resident in Germany. In a sample of 948 Sorbs, we could replicate the earlier reported associations of intron 1 SNPs with BMI (eg, P-value=0.003, β=0.02 for rs8050136). However, using genome-wide association data, we also detected a second independent signal mapping to a region in intron 2/3 about 40–60 kb away from the originally reported SNPs (eg, for rs17818902 association with BMI P-value=0.0006, β=−0.03 and with fat mass P-value=0.0018, β=−0.079). Both signals remain independently associated in the conditioned analyses. In conclusion, we extend the evidence that FTO variants are associated with BMI by putatively identifying a second susceptibility allele independent of that described earlier. Although further statistical analysis of these findings is hampered by the finite size of the Sorbian isolate, these findings should encourage other groups to seek alternative susceptibility variants within FTO (and other established susceptibility loci) using the opportunities afforded by analyses in populations with divergent mutational and/or demographic histories.     

Fragments of SLIT3 inhibit cellular migration

The repellent factor family of Slit molecules has been described as having a repulsive function in the developing nervous system on growing axons expressing the Roundabout (Robo) receptors. Recent studies determined the effects of Slit molecules on the migratory and invasive potential of several types of tumor cells but also on synovial fibroblasts (SFs) derived from rheumatoid arthritis (RA) patients. To optimize a potential therapeutic application we aimed at generatingfragments of Slit3 showing the same functional ability as the full-length molecule but having the advantage of a smaller size. Recombinant Slit3 proteins were expressed and analyzed by western blotting. Their activity was defined by functional assays such as migration assays with RASF and melanoma cells. Recombinant Slit3 containing only leucine rich repeat domain?2 (D2), the domain important for Robo binding and the minimal functional unit D2 dNC were both able to inhibit migration of RASFs as effectively as Slit3 with all 4?repeats. Collectively, our data showed that the ability of Slit3 to reduce the migratory activity of synovial cells from patients with RA and melanoma cells can be mimicked by small protein fragments derived from Slit3. Slit3 fragments may be helpful in therapeutic attempts; however, further studies are necessary in order to elucidate their activity in vivo.     

High thrombopoietin concentrations in the cerebrospinal fluid of neonates with sepsis and intraventricular hemorrhage may contribute to brain damage.

Thrombopoietin (TPO) and its receptor (TPOR) are expressed in the central nervous system (CNS). Although TPO shares significant homology with various neurotrophins, recent data indicate a proapoptotic function of TPO in the CNS. In this study, TPO concentrations were analyzed in the cerebrospinal fluid (CSF) of neonates. Human neuroblastoma-derived SH-SY5Y cells were established to elucidate the effects of inflammation and hypoxia on neuronal Tpo expression. TPO was detectable in the CSF of 6 of 15 neonates with bacterial infection/sepsis (median 140, range 2-613 pg/mL), 5 of 9 neonates with posthemorrhagic hydrocephalus (median 31, range 1.4-469 pg/mL), 3 of 4 neonates with posthemorrhagic hydrocephalus plus bacterial infection/sepsis or meningitis (median 97, range 6-397 pg/mL), but not in controls ( n = 3). Neither the presence of detectable TPO nor its level in the CSF significantly correlated with any clinical or laboratory parameter. In SH-SY5Y cells, TPO and TPOR expression was detected by RT-PCR and Western blot analysis. In vitro, interleukin-6 (IL-6) did not significantly change Tpo gene expression. In contrast, Tpo mRNA expression significantly decreased under hypoxia, whereas erythropoietin (EPO) mRNA expression increased. In conclusion, our data provide evidence that in neuronal cells, TPO production is regulated by different mechanisms than in hepatocytes.     

Hsp60-mediated T cell stimulation is independent of TLR4 and IL-12

Heat shock protein (Hsp) 60 is thought to function as endogenous danger signal by activating professional antigen-presenting cells (APC) through toll-like receptor (TLR) 4 and CD14, a mechanism that is also used by bacterial LPS. We recently showed that Hsp60 binds LPS and enhances LPS-induced immune stimulation. On the other hand, we also observed immune stimulation by Hsp60 independent of LPS which was partially mediated by Hsp60-induced IFN alpha. Here, we study the mechanisms involved in immune stimulation mediated by endotoxin-free Hsp60. We show that T cell co-stimulation induced by LPS-free Hsp60 was independent of TLR4 and the TLR-associated myeloide differentiation factor 88-signaling pathway. LPS-free Hsp60 did not induce IL-6, IL-12 or tumor necrosis factor alpha production in APC nor were these cytokines needed for Hsp60-mediated T cell co-stimulation in the absence of LPS. In contrast to endotoxin-free Hsp60, T cell co-stimulation induced by LPS or Hsp60/LPS complexes strictly depended on IL-12 and functional TLR-4. Furthermore, we show that LPS-free Hsp60 enhances IFN alpha expression in APC and that this cytokine represents one important mediator in immune stimulation by Hsp60 in the absence of LPS. Taken together, we provide evidence that endotoxin-free Hsp60 and LPS or Hsp60/LPS complexes employ different signaling mechanisms to transduce co-stimulatory signals.     

Posttraumatic growth in accident survivors: openness and optimism as predictors of its constructive or illusory sides

Posttraumatic growth (PTG), the phenomenon of self-reported positive outcomes of trauma, is assumed to consist of two sides: a constructive and an illusory side. This study investigates the relationship between PTG and its possible illusory and constructive predictors, as well as the moderating role of posttraumatic stress disorder (PTSD) severity. One-hundred two motor vehicle accident (MVA) survivors with full, subsyndromal, and without PTSD were assessed by multiple psychometric measures targeting PTSD severity, posttraumatic growth, optimism, and openness to experience. Hierarchical regression analysis yielded differential interaction effects between PTSD severity and optimism, as well as openness facets pointing to the moderating role of PTSD severity in the prediction of an illusory and a constructive factor in PTG.     

Comorbid painful physical symptoms and anxiety: prevalence, work loss and help-seeking

BACKGROUND: There is evidence that painful physical symptoms (PPS) are increased in patients with anxiety disorder (AD). This survey reports the 12-month prevalence and sociodemographic characteristics of PPS in subjects with and without AD, taking into account somatic comorbidity. In addition, the impact of PPS on work loss days (WLDs) and help-seeking was examined. METHODS: In a cross-sectional, population-based study, a representative random sample of non-institutionalised adults from Belgium, France, Germany, Italy, The Netherlands and Spain (N=21,425) was interviewed using the World Mental Health Composite Diagnostic Interview (CIDI 3.0 of the WHO). 8296 respondents provided data on the occurrence of PPS, from which 5489 respondents reported the number of work loss days. RESULTS: PPS were reported by 28% of respondents without AD and by 45% in those with AD. Female gender, higher age and lower educational level were predictive of PPS. No additive effect of AD and PPS was found on the WLD score, neither did the presence or not of a comorbid somatic disorder change the findings. Finally, respondents with both AD and PPS had numerically higher rates of help-seeking for emotional reasons (20.8% vs. 15.0% for respondents with AD but not PPS) and delayed their help-seeking for a numerically shorter period of time (289 vs. 413 days, respectively). LIMITATIONS: The most important limitation of this study was its reliance on self-reported data about somatic disorders. CONCLUSION: Approximately 45% of persons with anxiety disorder also reported the presence of PPS. No additive effect of AD and PPS was found on the WLD score, and the presence of PPS in AD does not delay help-seeking for emotional problems.     

Effect of Polymer Composition and Water Content on Proton Conductivity in Vinyl Benzyl Phosphonic Acid—4‐Vinyl Pyridine Copolymers

The proton conductivities of poly(vinylbenzyl phosphonic acid) (PVBPA) homopolymer and its statistical copolymers with 4‐vinyl pyridine [poly(VBPA‐stat‐4VP)s] are comprehensively studied in this work. Temperature and composition‐dependent “dry” proton conductivities of the copolymers have been determined and the self‐condensation of phosphonic acid groups has been quantified. The results show that the intrinsic proton conductivities of poly(VBPA‐stat‐4VP)s and PVBPA are quite low at 150 °C and exhibit time‐dependent changes due to anhydride formation at elevated temperatures. The effect of polymer composition on proton conduction shows a minimum at a 1:1 molar ratio of proton donor and acceptor groups and is discussed on the basis of the pK_a values of the electrolyte species. A trace amount of water significantly increases conductivity probably due to additional hydronium ion diffusion and water bridging effects. Water content and proton conductivities of poly(VBPA‐stat‐4VP)s are determined at different relative humidities. High amounts of water are absorbed at high humidities leading to high proton conductivities.

     

'Fat mass and obesity associated' gene (<Emphasis Type="Italic">FTO</Emphasis>): No significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolism markers in German obese children and adolescents

Background  

We have previously identified strong association of six single nucleotide polymorphisms (SNPs) in FTO (fat mass and obesity associated gene) to early onset extreme obesity within the first genome wide association study (GWA) for this phenotype. The aim of this study was to investigate whether the obesity risk allele of one of these SNPs (rs9939609) is associated with weight loss in a lifestyle intervention program. Additionally, we tested for association of rs9939609 alleles with fasting blood parameters indicative of glucose and lipid metabolism.     

NH4 + conductance in Xenopus laevis oocytes

 Superfusing Xenopus laevis oocytes with NH₄Cl (10 mmol/l, pH 7.5) resulted in an inward current at a clamp potential of –70 mV. In paired experiments (n=22), the NH₄Cl-induced peak current was –293±94 nA, under control conditions (osmolality: 240 mosmol/kg), and rose to –523±196 nA when osmolality was reduced to 144 mosmol/kg. In parallel with the rise in NH₄Cl-induced inward current, membrane conductance at –70 mV doubled and the zero-current potential changed from +3.3±9.4 mV to –22.0±8.0 mV (n=22) in the presence of NH₄Cl during exposure to a hypoosmolar solution. In the absence of NH₄Cl, oocytes responded to hypoosmolality with a shift in zero-current potential to more negative values and an increased conductance which became partially sensitive to isosorbiddinitrate (ISDN), suggesting the activation of a volume-sensitive K⁺ channel. Membrane conductance in the presence of NH₄Cl was decreased by ISDN to similar extents under isoosmolal and hypoosmolal conditions, indicating that NH₄ ⁺ enters the oocytes through a volume-sensitive conductance separate from the ISDN-sensitive K⁺ channel. Received: 20 July 1998 / Received after revision and accepted: 19 October 1998