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.     

C-KIT expression in ductal carcinoma in situ of the breast: co-expression with HER-2/neu

The proto-oncogene c-KIT (CD117) is highly expressed in normal breast epithelium and is decreased in invasive breast cancer. In this study, we analyzed the protein expression and the mutational status of c-KIT in ductal carcinoma in situ (DCIS) of the breast and correlated these findings with nuclear grade, architectural pattern, and expression of HER-2, estrogen receptor (ER)-alpha, and progesterone receptor (PR). C-KIT, HER-2, ER, and PR expression were analyzed immunohistochemically in 106 cases of paraffin-embedded DCIS (85 pure DCIS and 21 DCIS with concurrent carcinoma). Direct sequencing of exons 9 and 11 of the c-KIT gene was performed to analyze the hot spot mutational regions in representative cases. C-KIT expression was found in 55 (52.8%) of all DCIS, correlating with high nuclear grade (P < .0001), comedonecrosis (P < .0001), and solid growth pattern (P = .001). Furthermore, c-KIT expression was strongly associated with HER-2 positivity (P < .0001) and was significantly lower in ER- or PR-positive cases (P = .001 and P = .006, respectively). C-KIT expression alone or co-expression with HER-2 in pure DCIS did not differ significantly from DCIS with invasive component (P = .09). Mutational analysis in 6 c-KIT-positive DCIS revealed no activating mutations in exons 9 or 11. Our findings suggest that the expression of c-KIT protein might define a subset of poorly differentiated, HER-2-positive DCIS with decreased expression of steroid hormone receptors, comedonecrosis, and a solid growth pattern. The implications of c-KIT and HER-2 co-expression for breast carcinogenesis should be further evaluated.     

The influence of emotions on inhibitory functioning in borderline personality disorder

BACKGROUND: Borderline personality disorder (BPD) is characterized by an emotionally unstable and impulsive cognitive and behavioral style. Inhibitory dysfunction has been hypothesized as playing a crucial role in BPD psychopathology. This study aimed to systematically investigate differential inhibitory functions in patients with BPD as compared to healthy controls, and to investigate their expected impairment in the context of aversive emotions by comparing performances in neuropsychological tasks that present both neutral and emotional material. METHOD: Unmedicated female patients with BPD (n=28) were compared with age-matched healthy female controls (n=30) in the following tasks: the emotional Stroop test (inhibition of interference), directed forgetting (intentional, resource-dependent inhibition), and an emotional variant of the negative priming task (automatic, resource-independent inhibition). RESULTS: In comparison with the controls, the BPD patients showed reduced inhibition of negative material in the directed forgetting task and in the negative priming task. No effect was found in the emotional Stroop test. Significant correlations with current affect as well as trait anxiety and anger (but not impulsiveness) were found in the BPD group specifically for negative stimuli, while no such correlations were found in the control group. In addition to inhibitory deficiencies, BPD patients had difficulties remembering positive words in the directed forgetting task. CONCLUSIONS: Our data suggest that individuals with BPD have difficulties in actively suppressing irrelevant information when it is of an aversive nature. Inhibitory dysfunction appears to be closely related to state and trait variables of unstable affect, but not to self-reported impulsiveness.     

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Mutations in the ABCC6 gene, encoding the multidrug resistance-associated protein 6 (MRP6), cause pseudoxanthoma elasticum (PXE). This heritable disorder leads to pathological alterations in connective tissues. The implication of MRP6 deficiency in PXE is still unknown. Moreover, nothing is known about a possible compensatory expression of other ATP binding-cassette (ABC) transporter proteins in MRP6-deficient cells. We investigated the gene expression profile of 47 ABC transporters in human dermal fibroblasts of healthy controls (n=2) and PXE patients (n=4) by TaqMan low-density array. The analysis revealed the expression of 37 ABC transporter genes in dermal fibroblasts. ABCC6 gene expression was not quantifiable in fibroblasts derived from PXE patients. Seven genes (ABCA6, ABCA9, ABCA10, ABCB5, ABCC2, ABCC9 and ABCD2) were induced, whereas the gene expression of one gene (ABCA3) was decreased, comparing controls and PXE patients (with at least twofold changes). We reanalyzed the gene expression of selected ABC transporters in a larger set of dermal fibroblasts from controls and PXE patients (n=6, each). Reanalysis showed high interindividual variability between samples, but confirmed the results obtained in the array analysis. The gene expression of ABC transporter genes, as well as lineage markers of PXE, was further examined after inhibition of ABCC6 gene expression by using specific small-interfering RNA. These experiments corroborated the observed gene expression alterations, most notably in the ABCA subclass (up to fourfold, P<0.05). We therefore conclude that MRP6-deficient dermal fibroblasts exhibit a distinct gene expression profile of ABCA transporters, potentially to compensate for MRP6 deficiency. Moreover, our results point to a function for ABCC6/MRP6 in sterol transport, as sterols are preferential regulators of ABCA transporter activity and expression. Further studies are now required to uncover the role of ABCA transporters in PXE.     

Reduced Cbl phosphorylation and degradation of the zeta-chain of the T-cell receptor/CD3 complex in T cells with low Lck levels

T cells with short interfering RNA-mediated Lck-knockdown (kd) display paradoxical hyper-responsiveness upon TCR ligation. We have previously reported a possible mechanism for T-cell activation in cells with low levels of Lck depending on Grb2-SOS1 recruitment to the zeta-chain of TCR/CD3 (Methi et al., Eur. J. Immunol. 2007, 37: 2539-2548). Here, we show that short interfering RNA-mediated targeting of Lck caused a dramatic reduction in c-Cbl phosphorylation and a general reduction in protein ubiquitination after TCR stimulation. Specifically, this resulted in reduced ubiquitination of the zeta-chain, yet internalization of TCR/CD3 appeared to be normal after receptor engagement. However, zeta-chain levels were elevated in Lck-kd cells, and confocal microscopy revealed reduced colocalization of CD3-containing vesicles with endosomal and lysosomal compartments. We hypothesize that prolonged stability of internalized T-cell receptor complex may result in extended signaling in T cells with low Lck levels.     

Cognitive outcome in children and adolescents treated for acute lymphoblastic leukaemia with chemotherapy only

Objective: To examine cognitive outcome in children and adolescents with acute lymphoblastic leukaemia (ALL) in remission, treated with central nervous system prophylactic chemotherapy only.
Method: Thirty-five children and adolescents, age 8.4–15.3 years in long-term remission from ALL, 4.2–12.4 years post diagnosis, without relapse and no prediagnosis history of neurodevelopmental disorder were compared with 35 healthy controls matched for gender and age, on measures of intellectual functioning Wechsler Intelligence Scale for Children-Third Edition (WISC-III).
Results: All but two of the ALL survivors treated by chemotherapy only obtained WISC-III Total Intelligence Quotient (IQ) scores in the normal range (M = 95.3), but their scores were significantly below levels for their matched controls and below normative standards for WISC-III. The difference between patients and controls was significant at the p < 0.001 level for the following measures: Total IQ, Verbal IQ, Verbal Comprehension Index, Freedom from Distraction Index and three verbal subtest scores.
Conclusion: The results indicate long-term sequelae in global cognitive functions, and indicate that verbal function, processing speed, attention and complex visual-spatial problem solving may be affected in the chemotherapy only group.