The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children

<p>Abstract</p> <p>Background</p> <p>TMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.</p> <p>Methods</p> <p>The evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).</p> <p>Results</p> <p>TMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).</p> <p>Conclusion</p> <p>We conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.</p

FTO gene variation and measures of body mass in an African population

BACKGROUND: Variation in the fat mass and obesity associated (FTO) gene has been reproducibly associated with body mass index (BMI) and obesity in populations of White European origin. Data from Asians and African-Americans is less conclusive. METHODS: We assessed the effect of 16 FTO polymorphisms on body mass in a large population of predominantly lean Gambians (N(max) 2208) participating in a long-term surveillance program providing contemporary and early-life anthropometric measurements. RESULTS: Sixteen FTO tagSNPs screened here, including several associated with BMI in Europeans, were not associated with birth weight (BWT), early weight gain in 1-2 year olds, BMI in adults (> or = 18 y), or weight-for-height (WFH) z-score across all ages. No association was seen between genotype and WFH z-score or other measures of body mass. The confidence limits indicate that the effect size for WFH z-score never exceeded 0.17 units per allele copy for any SNP (excluding the three SNPs with allele < 15%). with much the lowest allele frequency. The confidence interval of the effect size for rs9939609 did not overlap that reported previously in Europeans. CONCLUSION: To our knowledge this is the first study of FTO gene variation in a well-characterised African population. Our results suggest that FTO gene variation does not influence measures of body mass in Gambians living a traditional lifestyle, or has a smaller effect than that detected in Europeans. These findings are not directly comparable to results from previous studies in African-Americans due to differences in study design and analysis. It is also possible that any effect of FTO genotype on body mass is of limited relevance in a lean population where little excess food is available, compared to similar ethnic populations where food supply is plentiful

Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer

Oral squamous-cell carcinoma (OSCC) is one of the most common types of human cancer. Typically OSCC cells show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. We previously identified Periostin as the gene demonstrating the highest fold change expression in the invasive clone by comparing the transcriptional profile of parent OSCC cell line and a highly invasive clone. Here, we demonstrated that Periostin overexpression enhanced invasiveness in oral cancer cell lines. To know the role of Periostin in invasion, angiogenesis and metastasis in OSCC cases, we first examined the expression of Periostin mRNA in 31 OSCC cases by RT–PCR and Periostin protein in 74 OSCC cases by immunohistochemistry. Then, we compared the Periostin expression with invasion pattern, metastasis and blood vessel density. Periostin mRNA and protein overexpression were frequently found in OSCC cases and Periostin expression was well correlated with the invasion pattern and metastasis. Moreover, blood vessel density of Periostin-positive cases was higher than those of Periostin-negative cases. Interestingly, recombinant Periostin enhanced capillary formation in vitro in a concentration-dependant manner. In summary, these findings suggest that Periostin may promote invasion and angiogenesis in OSCC, and that Periostin can be a strong marker for prediction of metastasis in oral cancer patients

Hypothalamic FTO is associated with the regulation of energy intake not feeding reward

<p>Abstract</p> <p>Background</p> <p>Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short- and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH) was utilized to study FTO signal in reward- and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal.</p> <p>Results</p> <p>Deprivation upregulated FTO mRNA, while leucine downregulated it. Consumption of palatable diets or macronutrient preference did not affect FTO expression. However, the propensity to ingest more energy without an effect on body weight was associated with lower FTO mRNA levels. We found that 4-fold higher number of FTO cells displayed c-Fos at meal termination as compared to initiation in the paraventricular and arcuate nuclei of re-fed mice. Moreover, ISH showed that FTO is present mainly in hunger-related sites and it shows a high degree of colocalization with anorexigenic oxytocin.</p> <p>Conclusion</p> <p>We conclude that FTO mRNA is present mainly in sites related to hunger/satiation control; changes in hypothalamic FTO expression are associated with cues related to energy intake rather than feeding reward. In line with that, neurons involved in feeding termination express FTO. Interestingly, baseline FTO expression appears linked not only with energy intake but also energy metabolism.</p

High Tumour Cannabinoid CB1 Receptor Immunoreactivity Negatively Impacts Disease-Specific Survival in Stage II Microsatellite Stable Colorectal Cancer

BACKGROUND: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome. METHODOLOGY/PRINCIPAL FINDINGS: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and ≥2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB(1)IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 85±5 and 66±8%; tumour interior, 86±4% and 63±8% for the CB(1)IR<2 and CB(1)IR≥2 groups, respectively. CONCLUSIONS/SIGNIFICANCE: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients

Early Infant Morbidity in the City of São Paulo, Brazil

BACKGROUND: Early infant morbidities may produce adverse outcomes in subsequent life. A low Apgar score is a convenient measure of early infant morbidity. We study determinants of early infant morbidity (sex, plurality, mode of delivery, prior losses, gestational age, prenatal care and birth weight, parity and maternal age, race, maternal education and community development) for the 1998-birth cohort, City of São Paulo, Brazil. METHODS: This study identified all deliveries that took place in the City of São Paulo during 1998. Information was extracted from 209,628 birth records. We used multivariate logistic regression to assess the effect of each independent variable on Apgar score less than seven at one minute and Apgar score less than seven at five minutes. RESULTS: Low birth weight, prematurity and community development were found to be strong predictors of morbidity. Maternal education showed strong negative correlation with both Apgar scores. The negative correlations between maternal schooling and Apgar scores were observed after prenatal care, parity and maternal age were included in the model. Unmeasured proximate factors may thus be the true source of disparity between educational groups. Children of very young adolescent mothers had lower Apgar scores at one minute (but not at five minutes) than those born to mothers 15 to 19. Parity one or higher was associated with decreased odds of low Apgar scores. Cesarean section and operative delivery were associated with higher odds of early infant morbidity. CONCLUSION: Education may allow mothers to have better care in the peripartum period. More educated mothers may be more likely to recognize certain morbidities through the pregnancy period and the monitoring of such morbidities yields better infant outcomes. Also, having less than seven prenatal care visits was found to predict early infant morbidity and one way to increase the use of such services is to focus on aspects of care that may lead to easier accessibility and continuity of prenatal care. Physicians should inform mothers about the risks associated with high number of children for a next infant and also about the risks for the infant associated with unnecessary cesarean sections. Special attention should be paid to adolescent mothers, since much of their increased risk is likely to be minimized by counseling

The importance of disease associations and concomitant therapy for the long-term management of psoriasis patients

It is well established that several inflammatory-type conditions, such as arthritis, diabetes, cardiovascular disease, and irritable bowel disease exist comorbidly and at an increased incidence in patients with psoriasis. Psoriasis and other associated diseases are thought to share common inflammatory pathways. Conditions such as these, with similar pathogenic mechanisms involving cytokine dysregulation, are referred to as immune-mediated inflammatory diseases (IMIDs). Considerable evidence for the genetic basis of cormobidities in psoriasis exists. The WHO has reported that the occurrence of chronic diseases, including IMIDs, are a rising global burden. In addition, conditions linked with psoriasis have been associated with increasing rates of considerable morbidity and mortality. The presence of comorbid conditions in psoriasis patients has important implications for clinical management. QoL, direct health care expenditures and pharmacokinetics of concomitant therapies are impacted by the presence of comorbid conditions. For example, methotrexate is contraindicated in hepatic impairment, while patients on ciclosporin should be monitored for kidney function. In addition, some agents, such as beta blockers, lithium, synthetic antimalarial drugs, NSAIDs and tetracycline antibiotics, have been implicated in the initiation or exacerbation of psoriasis. Consequently, collaboration between physicians in different specialties is essential to ensuring that psoriasis treatment benefits the patient without exacerbating associated conditions

Measurement of associated charm production induced by 400 GeV/c protons

An important input for the interpretation of the measurements of the SHiP ex- periment is a good knowledge of the differential charm production cross section, including cascade production. This is a proposal to measure the associated charm production cross section, employing the SPS 400 GeV/c proton beam and a replica of the first two interaction lengths of the SHiP target. The detection of the produc- tion and decay of charmed hadron in the target will be performed through nuclear emulsion films, employed in an Emulsion Cloud Chamber target structure. In order to measure charge and momentum of decay daughters, we intend to build a mag- netic spectrometer using silicon pixel, scintillating fibre and drift tube detectors. A muon tagger will be built using RPCs. An optimization run is scheduled in 2018, while the full measurement will be performed after the second LHC Long Shutdown