Impairment of inhibitory control in response to food-associated cues and attentional bias of obese participants and normal-weight controls.

OBJECTIVE: Starting from a model of impaired response inhibition and salience attribution for addictive behaviour we investigated whether obese participants show a greater impairment of inhibitory control in response to food-associated cues compared with neutral stimuli and whether this is seen in normal-weight control subjects. In addition, we questioned whether an attentional bias towards food-associated cues can be observed in an early stage of information processing. DESIGN: Control-group study including the administration of behavioural tasks (that is, go/no-go task with food-associated and neutral words, visual dot probe task with food-associated and neutral pictures) and self-reported measures of eating behaviour and impulsivity. RESULTS: Although self-reported measures indicated disinhibition of eating behaviour of obese patients, we found that food-associated stimuli induced an impairment of inhibitory control in both obese participants as well as normal-weight controls. Results from the visual dot-probe task indicated that food-associated cues did not modulate attention allocation in a very early stage of information processing, which suggests that the incentive salience of food-associated stimuli might be lower than that of drug-associated cues. CONCLUSION: These findings are not in line with hypotheses derived from models of addictive behaviour and call into question that an impairment of inhibitory control in response to food-associated cues and salience attribution might be at the core of obesity. Future studies using larger sample sizes and refined experimental procedures are warranted to further investigate mechanisms controlling food intake in obesity.

How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure.

The serotonin transporter-linked promoter region (5-HTTLPR) polymorphism of the serotonin transporter gene is associated with amygdala response during negative emotion. The aim of this study was to investigate whether this genotype effect on amygdala function is mediated by current serotonin transporter (5-HTT) levels or rather by genetically induced influences during neurodevelopment, shaping brain structure. A total of 54 healthy subjects underwent functional and structural magnetic resonance imaging, [(11)C]DASB positron emission tomography and 5-HTTLPR genotyping to analyze the interrelationships between amygdala activation during processing of unpleasant stimuli, 5-HTTLPR genotype, amygdala volumes and 5-HTT levels in the midbrain and in other brain regions. In line with previous research, carriers of the short allele (S) showed increased amygdala activation. Path analysis demonstrated that this genotype effect was not procured by current 5-HTT availability but by amygdala structure, with smaller amygdala volumes in the S than in the LL genotype, as well as smaller volumes being associated with increased amygdala activation. Our findings stress the role of genetic effects during neurodevelopment.

Vaspin (SERPINA12) genotypes and risk of type 2 diabetes: Results from the MONICA/KORA studies.

Vaspin has recently been identified as novel adipokine with high expression in adipose tissue of obese and type 2 diabetic subjects and with potentially insulin-sensitising properties. However, the impact of vaspin gene variants on the risk of type 2 diabetes mellitus (T2DM) has not been determined yet. Therefore, the aim of our study was to investigate the association of vaspin single nucleotide polymorphisms (SNPs) with T2DM and obesity. We analysed the association between 25 vaspin SNPs and T2DM in initially healthy 35-84 year-old individuals of the population-based, cross-sectional German KORA F3 study and assessed the association with measures of obesity. Genotyping was carried out with matrix-assisted laser desorption/ionisation-time of flight mass spectrometry of allele-dependent primer extension products and associations with T2DM and obesity were analysed by logistic regression analysis. Our results demonstrate a significant association of vaspin SNP rs2236242 with T2DM in the KORA F3 study with the AA genotype bearing an increased risk (adjusted OR 2.35 [1.59; 3.46] versus AT/TT). This association appears to be independent of obesity. Our finding corroborates previous studies that suggested a link between the novel adipokine vaspin and glucose metabolism.

Significant association of a M129V independent polymorphism in the 5' UTR of the PRNP gene with sporadic Creutzfeldt-Jakob disease in a large German case-control study.

BACKGROUND: A single nucleotide polymorphism (SNP) in the coding region of the prion protein gene (PRNP) at codon 129 has been repeatedly shown to be an associated factor to sporadic Creutzfeldt-Jakob disease (sCJD), but additional major predisposing DNA variants for sCJD are still unknown. Several previous studies focused on the characterisation of polymorphisms in PRNP and the prion-like doppel gene (PRND), generating contradictory results on relatively small sample sets. Thus, extensive studies are required for validation of the polymorphisms in PRNP and PRND. METHODS: We evaluated a set of nine SNPs of PRNP and one SNP of PRND in 593 German sCJD patients and 748 German healthy controls. Genotyping was performed using MALDI-TOF mass spectrometry. RESULTS: In addition to PRNP 129, we detected a significant association between sCJD and allele frequencies of six further PRNP SNPs. No significant association of PRND T174M with sCJD was shown. We observed strong linkage disequilibrium within eight adjacent PRNP SNPs, including PRNP 129. However, the association of sCJD with PRNP 1368 and PRNP 34296 appeared to be independent on the genotype of PRNP 129. We additionally identified the most common haplotypes of PRNP to be over-represented or under-represented in our cohort of patients with sCJD. CONCLUSION: Our study evaluated previous findings of the association of SNPs in the PRNP and PRND genes in the largest cohorts for association study in sCJD to date, and extends previous findings by defining for the first time the haplotypes associated with sCJD in a large population of the German CJD surveillance study.

Genetics of type 2 diabetes: impact of interleukin-6 gene variants.

The KORA studies serve as a powerful tool for the genetic analysis of complex diseases like type 2 diabetes or the metabolic syndrome. These studies include more than 2,000 prevalent and incident type 2 diabetes cases. DNA of these patients is available to be used in genetic studies. Up to now the analyses have focussed on genes coding for proteins being involved in the inflammatory response. Interleukin-6 (IL-6) as the key mediator of the acute phase reaction is of interest. Elevated protein concentrations of IL-6 in the blood have been shown to predict type 2 diabetes. We investigated the association of the IL-6 single nucleotide polymorphism (SNP) C-174G with type 2 diabetes in a case-control study of 704 elderly participants of the KORA Survey S4 (1999/2001). When BMI, HDL cholesterol, physical activity, hypertension, hormone replacement therapy and smoking were considered as covariables the SNP C-174G showed a trend for association with type 2 diabetes (- 174G: OR 1.20, 95 % CI 0.90 - 1.59, p = 0.21).

Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys.

BACKGROUND: The melanocortin-4-receptor gene (MC4R) is part of the melanocortinergic pathway that controls energy homeostasis. In a recent meta-analysis, the MC4R V103I (rs2229616) polymorphism was shown to be associated with body weight regulation. Although no functional differences between the isoleucine comprising receptor and the wild type receptor have been detected as yet, this meta-analysis of 14 case-control studies reported a mild negative association with obesity (odds ratio (OR) 0.69, p = 0.03). However, evidence in a large population based study in a homogeneous population and a significant estimate of the change in quantitative measures of obesity is still lacking. METHODS: We analysed the data of two surveys of a white population with the same high quality study protocol, giving a total of 7937 participants. RESULTS: By linear regression, we found a significant decrease of 0.52 body mass index (BMI) units (95% confidence interval (CI) -0.02 to -1.03, p = 0.043) for carriers of the heterozygote rs2229616G/A genotype, which was observed in 3.7% of the participants. Logistic regression yielded a significantly negative association of the MC4R variant with "above average weight" (BMI > or = median BMI) yielding an OR of 0.75 (95% CI 0.59 to 0.95 p = 0.017). We obtained similar results comparing obese (BMI > or =30 kg/m2, World Health Organization results for 1997) with non-obese (BMI < 30 kg/m2) participants. The results were found for both sexes and each survey separately, and did not depend on the modelling of age, sex, or survey effects. CONCLUSIONS: Our study confirms previous findings of a meta-analysis that the relatively infrequent G/A genotype of the V103I MC4R polymorphism is negatively associated with above average weight and obesity in population based original data of 7937 participants, and extends previous findings by showing for the first time a significantly lower BMI in individuals carrying the infrequent allele of this MC4R variant.

Bactericidal activity of flucloxacillin against Staphylococcus aureus in primary keratinocyte cultures of lesional and unaffected skin of patients suffering from atopic dermatitis.

More than 90% of patients with atopic dermatitis (AD) are colonized by Staphylococcus aureus. Due to prevalent multi-resistant strains, it is highly difficult to eliminate S. aureus contamination of primary cell cultures of human AD skin by means of the antibiotics commonly used in cell culture. Therefore, an anti-staphylococcal treatment was investigated by which sterile proliferating keratinocyte cultures are attained from lesional and unaffected skin of AD patients by applying flucloxacillin, which in general is systemically used in vivo. The treatment with 1% flucloxacillin for 20 min included both colonized skin samples and contaminated primary cell cultures. In the case of persistent contamination, this step was repeated as often as required until complete decontamination without any cytotoxic indications was achieved. Antibacterial treatment with flucloxacillin permitted the cultivation of sterile, vital, and proliferating primary cultures of human skin keratinocytes from lesional and unaffected skin of AD patients with S. aureus colonization. The method increased the success rate of isolation of AD keratinocytes from 30 to 90%, representing on average 3 vs. 9 successfully isolated, sterile and proliferating cultures out of 10 contaminated skin biopsies, which is comparable to normal human keratinocyte isolation rates.

Significant association of the interleukin-6 gene polymorphisms C-174G and A-598G with type 2 diabetes.

Elevated blood concentrations of IL-6 have been shown to predict type 2 diabetes. Because the impact of IL-6 gene polymorphisms on diabetes status, parameters of the metabolic syndrome, and low-grade systemic inflammation has not been analyzed in a population-based study, we investigated the association of the IL-6 single nucleotide polymorphisms C-174G and A-598G on these parameters in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. Both -174G and -598G alleles were significantly associated with type 2 diabetes (-174G: odds ratio = 1.51, 95% confidence interval = 1.11-2.07, P = 0.0096; -598G: odds ratio = 1.56, 95% confidence interval = 1.13-2.15, P = 0.0069) but not with impaired glucose tolerance. In subgroup analyses, the association reached statistical significance in men and in leaner subjects (body mass index

[Depression and modern neuroimaging]. / Depression und moderne Bildgebung - Eine Ubersicht des aktuellen Forschungsstandes zur Anwendung bildgebender Verfahren bei depressiven Störungen -

Modern neuroimaging like PET, SPECT, MR-Volumetry, functional MRI and MR-Spectroscopy has effectively advanced research on aetiology, pathogenesis and therapy options of depressive disorders. This review highlights the status of current research on this topic. Consistent with morphological findings, which report alterations in regions of emotionally relevant networks of the brain in depressive disorders, findings of functional studies point to changes in the basal ganglia, the frontal cortex and the limbic system involving the hippocampus and the amygdala. During processing of emotional cues depressive patients show different activation patterns in the regions of the frontal lobe and the amygdala. In our study of a subgroup we were also able to show deficits in processing cues independently from the emotional quality of the stimulus - especially in posterior-parietal and prefrontal areas. In healthy subjects affective modulation correlates with an ordered interaction of ventral-limbic and dorsal-neocortical regions of the brain, which become unbalanced in depressive disorders. In the future, modern neuroimaging will open promising fields of research, which aim at the identification of valid neurofunctional subgroups of the heterogeneous affective disorders and the development of more adjusted and efficient therapy strategies.

Prion protein codon 129 polymorphism and risk of Alzheimer disease.

The authors investigated the PRNP Met129Val polymorphism in 1,393 subjects including 482 patients with Alzheimer disease (AD) and two independent control groups. In patients, PRNP Met homozygosity conferred increasing risk with decreasing age at onset (onset: 61 to 70 years, n = 151, p = 0.02, odds ratio [OR] = 1.72, 95% CI = 1.2 to 2.53; onset: < or =60 years, n = 138, p = 0.013, OR = 1.92, 95% CI = 1.31 to 2.87), whereas no association was obtained in patients with onset at older than 70 years. The results suggest involvement of the prion protein in the pathogenesis of early-onset AD.

Single nucleotide polymorphism screening and association analysis--exclusion of integrin beta 7 and vitamin D receptor (chromosome 12q) as candidate genes for asthma.

BACKGROUND: The human genes coding for integrin beta 7 (ITGB7) and vitamin D receptor (VDR) are two of the several candidate genes for asthma and related phenotypes found in a promising candidate region on chromosome 12q that has been identified in multiple genomewide screens and candidate gene approaches. METHODS: All exons, including parts of the neighbouring introns, and the predicted promoter region of the ITGB7 gene were screened for common polymorphisms in 32 independent asthmatic and healthy probands, resulting in the detection of two single nucleotide polymorphisms (SNPs) unknown so far. In addition to these SNPs, five already described SNPs of the ITGB7 and one in the human VDR gene were analysed in a Caucasian sib pair study of 176 families with at least two affected children, using matrix assisted laser desorption/ionization time of flight mass spectrometry. All confirmed SNPs were tested for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count and slope of the dose-response curve after bronchial challenge). RESULTS: Two new variations in the ITGB7 gene were identified. The coding SNP in exon 4 causes a substitution of the amino acid GLU by VAL, whereas the other variation is non-coding (intron 3). None of the eight analysed SNPs, of either the ITGB7 or the VDR genes, showed significant linkage/association with asthma or related phenotypes in the family study. CONCLUSIONS: These findings indicate that neither the human ITGB7 nor the VDR gene seem to be associated with the pathogenesis of asthma or the expression of related allergic phenotypes such as eosinophilia and changes in total IgE level.

Human natural immunoglobulin M antibodies induce apoptosis of human neuroblastoma cells by binding to a Mr 260,000 antigen.

Sera of healthy humans contain natural cytotoxic IgM antibodies that specifically recognize a Mr 260,000 antigen (NB-p260) on the surface of human neuroblastoma (NB) cells. Here we demonstrate that anti-NB IgM antibodies prepared from different healthy individuals induce, in all human NB cell lines analyzed thus far, typical morphological and biochemical features of apoptosis including nuclear fragmentation, chromatin condensation, and DNA fragmentation. Both the binding of human anti-NB IgM to NB cells and the induction of apoptosis could be inhibited by preincubation of NB cells with murine IgG raised against purified NB-p260. Furthermore, preincubation of human anti-NB IgM with purified NB-p260 immobilized onto a solid support abolished its ability to induce apoptosis in NB cells. Natural human anti-NB IgM failed to bind to and induce apoptosis in control tumor cell lines that lack expression of NB-p260. The anti-NB IgM-induced apoptotic response was also observed in vivo in xenografted human NB tumors. After a single i.v. injection of anti-NB IgM into nude rats bearing solid NB xenografts, many areas of pyknotic cells with fragmented nuclei were observed that stained positive using the terminal dUTP nick end labeling method. In conclusion, the data demonstrate that natural anti-NB IgM antibodies in the sera of healthy individuals are potent mediators of apoptotic cell death of NB cells both in vitro and in vivo. The NB-p260 antigen was identified as the apoptosis-inducing receptor for anti-NB IgM. Whereas natural anti-NB IgM and NB-p260 may be useful tools for immunotherapy of NB, their biological significance remains to be determined.

Mechanisms of in vivo anti-neuroblastoma activity of human natural IgM.

Normal human sera of healthy adults contain natural IgM antibodies which are cytotoxic for human neuroblastoma cells. In this study, we evaluated the anti-neuroblastoma activity of these natural IgM antibodies in nude rats bearing solid human neuroblastoma tumours. A single intravenous (i.v.) injection of purified cytotoxic IgM led to uptake of IgM in the tumours with massive perivascular complement activation and accumulation of neutrophil granulocytes after 24 h. Five consecutive i.v. injections of purified cytotoxic IgM into neuroblastoma-bearing animals resulted in complete growth arrest of even large established solid tumours which lasted for several weeks after discontinuation of the injections, whereas tumours of control animals continued to grow exponentially during the observation period. These studies suggest that natural anti-neuroblastoma IgM may have a potential as a novel therapeutic modality in the treatment of human neuroblastoma.

Growth arrest of solid human neuroblastoma xenografts in nude rats by natural IgM from healthy humans.

Neuroblastoma (NB) is the most common extracranial solid neoplasm of infancy and is associated with very poor prognosis in patients with advanced disease. Current therapeutic regimens of advanced NB which combine surgical resection with radiation therapy and/or chemotherapy brought some improvements, but in a significant number of patients, a cure remains elusive. Normal human serum of healthy adults contains natural IgM antibodies that are cytotoxic for human NB cells. In this study, we evaluated the anti-NB activity of these natural IgM antibodies in nude rats bearing solid human NB tumors. A single intravenous (i.v.) injection of purified cytotoxic IgM led to uptake of IgM into the tumors with massive perivascular complement activation and accumulation of neutrophil granulocytes after 24 hours. Five consecutive i.v. injections of purified cytotoxic IgM into NB-bearing animals resulted in complete growth arrest of even large and established solid tumors which lasted for several weeks after discontinuation of the injections, whereas tumors of control animals continued to grow exponentially during the observation period. These studies suggest that natural anti-NB IgM may have a potential as a novel therapeutic modality in the treatment of human NB.