Impact sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes

Objective: Behavioral treatment of children suffering from hypothalamic obesity or uncomplicated obesity in combination with syndromes that aggravate this condition has proven to be ineffective. The combination of comorbidities and severe obesity lower the quality of these children's lives drastically. The present goal was to determine whether treatment with sibutramine has a beneficial effect on such children. Design and Subjects: A double-blind, placebo-controlled, cross-over study (20 ϩ 20 wk), followed by a 6-month open phase, was performed. The primary indicator of efficacy was the body mass index (BMI) SD score (SDS) value, which was analyzed using an ANOVA repeated-measures design [intention to treat (ITT)]. The 50 children (7-20 yr of age) involved included 22 with hypothalamic obesity and 28 with uncomplicated obesity plus aggravating syndromes. Forty-five patients completed the first phase, and 42 participated in the entire study. Results: The group that initially received the placebo demonstrated an insignificant decrease (Ϫ0.06) in BMI SDS during this treatment but a significant decrease (Ϫ0.68; P Ͻ 0.001) when treated with sibutramine. The other group demonstrated a reduction in their BMI SDS of Ϫ0.72 during administration of sibutramine and a rebound of ϩ0.43 when placed on the placebo (P Ͻ 0.001 in both cases). The response of children with hypothalamic obesity was also significant but was less pronounced than that of children with nonhypothalamic obesity. During the open phase, a continuous reduction in weight was observed. The treatment was tolerated well. Conclusion: The clinically and statistically significant weight reduction caused by sibutramine in this short-term study indicates that treatment of hypothalamic and syndromal obesity with this drug may be beneficial

c=1 Liouville Theory Perturbed by the Black-Hole Mass operator

We discuss the properties of the Liouville theory coupled to the c=1 matter when perturbed by an operator, the screening operator of the $SL(2;R)$ current algebra, which is supposed to generate the mass of the two-dimensional black hole. Mimicking the standard KPZ scaling theory of the Liouville system perturbed by the cosmological constant operator, we develop a scaling theory of correlation functions as functions of the mass of the black hole. Contrary to the case of KPZ, the present theory does not have the $c=1$ barrior and seems somewhat insensitive to the delatils of the matter content of the theory; the string succeptibility equals 1 independent of the matter central charge. It turns out that our scaling exponents agree with those of the deformed matrix model proposed recently by Jevicki and Yoneya.Comment: 10 pages,UT 65

Anomalous couplings for D-branes and O-planes

We study anomalous Wess-Zumino couplings of D-branes and O-planes in a general background and derive them from a direct string computation by factorizing in the RR channel various one-loop amplitudes. In particular, we find that Op-planes present gravitational anomalous couplings involving the Hirzebruch polynomial L, similarly to the roof genus A encoding Dp-brane anomalous couplings. We determine, in each case, the precise dependence of these couplings on the curvature of the tangent and normal bundles.Comment: 24 pages, LaTex, 5 figure

Renormalization of Supersymmetric Gauge Theories on Orbifolds: Brane Gauge Couplings and Higher Derivative Operators

We consider supersymmetric gauge theories coupled to hyper multiplets on five and six dimensional orbifolds and determine the bulk and local fixed point renormalizations of the gauge couplings. We infer from a component analysis that the hyper multiplet does not induce renormalization of the brane gauge couplings on the five dimensional orbifold S^1/Z_2. This is not due to supersymmetry, since the bosonic and fermionic contributions cancel separately. We extend this investigation to T^2/Z_N orbifolds using supergraph techniques in six dimensions. On general Z_N orbifolds the gauge couplings do renormalize at the fixed points, except for the Z_2 fixed points of an even ordered orbifold. To cancel the bulk one-loop divergences a dimension six higher derivative operator is needed, in addition to the standard bulk gauge kinetic term.Comment: 10 p

On the S-matrix of Type 0 String Theory

The recent discovery of non-perturbatively stable two-dimensional string backgrounds and their dual matrix models allows the study of complete scattering matrices in string theory. In this note we adapt work of Moore, Plesser, and Ramgoolam on the bosonic string to compute the exact S-matrices of 0A and 0B string theory in two dimensions. Unitarity of the 0B theory requires the inclusion of massless soliton sectors carrying RR scalar charge as asymptotic states. We propose a regularization of IR divergences and find transition probabilities that distinguish the otherwise energetically degenerate soliton sectors. Unstable D-branes can decay into distinct soliton sectors.Comment: 30 pages, 6 figures, harvma

Genetic Variance in the Adiponutrin Gene Family and Childhood Obesity

AIM: The adiponutrin gene family consists of five genes (PNPLA1-5) coding for proteins with both lipolytic and lipogenic properties. PNPLA3 has previously been associated with adult obesity. Here we investigated the possible association between genetic variants in these genes and childhood and adolescent obesity. METHODS/RESULTS: Polymorphisms in the five genes of the adiponutrin gene family were selected and genotyped using the Sequenom platform in a childhood and adolescent obesity case-control study. Six variants in PNPLA1 showed association with obesity (rs9380559, rs12212459, rs1467912, rs4713951, rs10947600, and rs12199580, p0.05). When analyzing these SNPs in relation to phenotypes, two SNPs in the PNPLA3 gene showed association with insulin sensitivity (rs12483959: beta = -0.053, p = 0.016, and rs2072907: beta = -0.049, p = 0.024). No associations were seen for PNPLA2, PNPLA4, and PNPLA5. CONCLUSIONS: Genetic variation in the adiponutrin gene family does not seem to contribute strongly to obesity in children and adolescents. PNPLA1 exhibited a modest effect on obesity and PNPLA3 on insulin sensitivity. These data, however, require confirmation in other cohorts and ethnic groups

Associations between severity of obesity in childhood and adolescence, obesity onset and parental BMI: a longitudinal cohort study

Objective: To explore the relationship between severity of obesity at age 7 and age 15, age at onset of obesity, and parental body mass index (BMI) in obese children and adolescents. Design: Longitudinal cohort study.Subjects:Obese children (n231) and their parents (n462) from the Swedish National Childhood Obesity Centre. Methods: Multivariate regression analyses were applied with severity of obesity (BMI standard deviation score (BMI SDS)) and onset of obesity as dependent variables. The effect of parental BMI was evaluated and in the final models adjusted for gender, parental education, age at onset of obesity, severity of obesity at age 7 and obesity treatment. Results: For severity of obesity at age 7, a positive correlation with maternal BMI was indicated (P<0.05). Severity of obesity at this age also showed a strong negative correlation with the age at onset of obesity. Severity of obesity at age 15 was significantly correlated with both maternal and paternal BMI (P≥0.01). In addition, BMI SDS at age 15 differed by gender (higher for boys) and was positively correlated with severity of obesity at age 7 and negatively correlated with treatment. Also, a negative correlation was indicated at this age for parental education. No correlation with age at onset was found at age 15. For age at onset of obesity there was no relevant correlation with parental BMI. Children within the highest tertile of the BMI SDS range were more likely to have two obese parents. Conclusion: The impact of parental BMI on the severity of obesity in children is strengthened as the child grows into adolescence, whereas the age at onset is probably of less importance than previously thought. The influence of parental relative weight primarily affects the severity of childhood obesity and not the timing. © 2011 Macmillan Publishers Limited All rights reserved.link_to_subscribed_fulltex

Genetic predisposition to mosaic Y chromosome loss in blood.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.This research has been conducted using the UK Biobank Resource under application 9905 and 19808. This work was supported by the Medical Research Council [Unit Programme number MC_UU_12015/2]. Full study-specific and individual acknowledgements can be found in the supplementary information

Immune cells lacking Y chromosome show dysregulation of autosomal gene expression

Funder: Kjell och Märta Beijers Stiftelse (SE)Funder: Hjärnfonden; doi: http://dx.doi.org/10.13039/501100003792Funder: Cancerfonden; doi: http://dx.doi.org/10.13039/501100002794Funder: Vetenskapsrådet; doi: http://dx.doi.org/10.13039/501100004359Funder: Alzheimerfonden; doi: http://dx.doi.org/10.13039/501100008599Funder: Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse (SE)Funder: Science for Life Laboratory (SE)Funder: Fundacja na rzecz Nauki Polskiej (PL)Funder: Uppsala UniversityAbstract: Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease