Human Obesity: A Heritable Neurobehavioral Disorder That Is Highly Sensitive to Environmental Conditions

The recent increase in the worldwide prevalenceof obesity has understandably focused attentionon the environmental determinants of this epi-demic. Whereas identifying the relative contribu-tions of the factors underlying this recent trend is critical, a comprehensive understanding of the causes of obesity will need to explain why, even in high-risk populations, many people remain lean. Contemporary studies indicate that the heritability of adiposity remains high, even in the face of a strongly obesogenic environment. Whereas the role of inheritance has long been appreciated, only re-cently have we begun to develop a genuine understanding of the critical role of specific molecules in sensing the state of nutrient storage and regulating food intake and energy expenditure. Notably, a number of single gene disorders resulting in human obesity have been uncovered and, strikingly, all of these defects impair the central control of food intake. Early indications are that commo

Malpractice awareness among surgeons at a teaching hospital in Pakistan

BACKGROUND: The duty of a doctor to take care presumes the person who offers medical advice and treatment to unequivocally possess the skills and knowledge to do so. However, a sense of responsibility cannot be guaranteed in the absence of accountability, which in turn requires a comprehensive medical law system to be in place. Such a system is almost non-existent in Pakistan. Keeping the above in mind, we designed this study to assess the knowledge, attitudes and practices of surgeons regarding malpractice at a tertiary care center in Pakistan. METHODS: This was an observational, cross-sectional, questionnaire-based study conducted during a three month period from 31st March, 2012 to 30th June, 2012 at Civil Hospital, Karachi. Surgeons who were available during the period of our study and had been working in the hospital for at least 6 months were included. Self-administered questionnaires were distributed after seeking informed, written consent. The specialties included were general surgery, cardiothoracic surgery, neurosurgery, ophthalmology, otolaryngology, plastic surgery, pediatric surgery, orthopedic surgery, oral and maxillofacial surgery and gynecology and obstetrics. The study questionnaire comprised of four sections. The first section was concerned with the demographics of the surgeons. The second section analyzed the knowledge of the respondents regarding professional negligence and malpractice. The third section assessed the attitudes surgeons with regard to malpractice. The last section dealt with the general and specific practices and experiences of surgeons regarding malpractice. RESULTS: Of the 319 surgeons interviewed, 68.7% were oblivious of the complete definition of malpractice. Leaving foreign objects inside the patient (79.6%) was the most commonly agreed upon form of malpractice, whereas failure to break news in entirety (43.9%) was most frequently disagreed. In the event of a medical error, majority (67.7%) were ready to disclose their error to the patient. The most common perceived reason for not disclosing the error was threat of a claim or assault (90.9%). Majority (68.3%) believed that malpractice had a negative effect on reputation. Only 13(4.1%) had received at least one legal claim for damages. Only about three-fourths (75.5%) had the habit of frequently obtaining informed consent from the patients. 83(26.0%) expressed reluctance in accepting a case that was deemed to be difficult. Financial gains and liabilities were responsible for biased approach in 8.5% and 12.2% of the respondents respectively. CONCLUSION: There is a dire need of programs aimed at increasing awareness among practicing surgeons in our setup. Proactive measures are required for the formulation of an efficient system of litigation. Physician accountability will not only arouse a greater sense of responsibility in them, but will also augment the confidence placed by patients on the healthcare system

Dopamine modulates the neural representation of subjective value of food in hungry subjects.

Although there is a rich literature on the role of dopamine in value learning, much less is known about its role in using established value estimations to shape decision-making. Here we investigated the effect of dopaminergic modulation on value-based decision-making for food items in fasted healthy human participants. The Becker-deGroot-Marschak auction, which assesses subjective value, was examined in conjunction with pharmacological fMRI using a dopaminergic agonist and an antagonist. We found that dopamine enhanced the neural response to value in the inferior parietal gyrus/intraparietal sulcus, and that this effect predominated toward the end of the valuation process when an action was needed to record the value. Our results suggest that dopamine is involved in acting upon the decision, providing additional insight to the mechanisms underlying impaired decision-making in healthy individuals and clinical populations with reduced dopamine levels.This is the author's accepted manuscript. The final version is available from the Society for Neuroscience in the Journal of Neuroscience at http://www.jneurosci.org/content/34/50/16856.abstract

Genetic Variance in the Spinocerebellar Ataxia Type 2 (ATXN2) Gene in Children with Severe Early Onset Obesity

Expansion of a CAG repeat in the coding region of exon 1 in the ATXN2 gene located in human chromosome 12q24.1 causes the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2). In contrast to other polyglutamine (polyQ) disorders, the SCA2 repeat is not highly polymorphic in central European (CEU) controls with Q22 representing 90% of alleles, and Q23 contributing between 5-7% of alleles. Recently, the ATXN2 CAG repeat has been identified as a target of adaptive selection in the CEU population. Mouse lines deficient for atxn2 develop marked hyperphagia and obesity raising the possibility that loss-of-function mutations in the ATXN2 gene may be related to energy balance in humans. Some linkage studies of obesity related phenotypes such as antipsychotic induced weight gain have reported significant lod scores on chromosome 12q24. We tested the hypothesis that rare loss-of-function ATXN2 variants cause obesity analogous to rare mutations in the leptin, leptin receptor and MC4R genes.We sequenced the coding region of ATXN2 including intron-exon boundaries in 92 severely obese children with a body mass index (BMI) >3.2 standard deviations above age- and gender-adjusted means. We confirmed five previously identified single nucleotide polymorphisms (SNPs) and three new SNPs resulting in two synonymous substitutions and one intronic polymorphism. Alleles encoding >Q22 were overrepresented in our sample of obese children and contributed 15% of alleles in children identified by their parents as white. SNP rs695872 closely flanking the CAG repeat showed a greatly increased frequency of C/C homozygotes and G/C heterozygotes compared with reported frequencies in the CEU population.Although we did not identify variants leading to novel amino acid substitutions, nonsense or frameshift mutations, this study warrants further examination of variation in the ATXN2 gene in obesity and related phenotypes in a larger case-control study with emphasis on rs695872 and CAG repeat structure

Obesity associated with increased brain age from midlife.

Common mechanisms in aging and obesity are hypothesized to increase susceptibility to neurodegeneration, however, direct evidence in support of this hypothesis is lacking. We therefore performed a cross-sectional analysis of magnetic resonance image-based brain structure on a population-based cohort of healthy adults. Study participants were originally part of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and included 527 individuals aged 20-87 years. Cortical reconstruction techniques were used to generate measures of whole-brain cerebral white-matter volume, cortical thickness, and surface area. Results indicated that cerebral white-matter volume in overweight and obese individuals was associated with a greater degree of atrophy, with maximal effects in middle-age corresponding to an estimated increase of brain age of 10 years. There were no similar body mass index-related changes in cortical parameters. This study suggests that at a population level, obesity may increase the risk of neurodegeneration.This work was supported by the Bernard Wolfe Health Neuroscience Fund and the Wellcome Trust (grant number RNAG/259). The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) research was supported by the Biotechnology and Biological Sciences Research Council (grant number BB/H008217/1).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neurobiolaging.2016.07.01

Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency.

Non-synonymous mutations affecting both alleles of PCSK1 (proprotein convertase 1/3) are associated with obesity and impaired prohormone processing. We report a proband who was compound heterozygous for a maternally inherited frameshift mutation and a paternally inherited 474kb deletion that encompasses PCSK1, representing a novel genetic mechanism underlying this phenotype. Although pro-vasopressin is not a known physiological substrate of PCSK1, the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation.ISF and SOR were supported by the Wellcome Trust, the MRC Centre for Obesity and Related Disorders and the UK NIHR Cambridge Biomedical Research Centre.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S1096719213001145#

Assessment of Eating Behavior Disturbance and Associated Neural Networks in Frontotemporal Dementia.

IMPORTANCE: Abnormal eating behaviors are common in patients with frontotemporal dementia (FTD), yet their exact prevalence, severity, and underlying biological mechanisms are not understood. OBJECTIVE: To define the severity of abnormal eating behavior and sucrose preference and their neural correlates in patients with behavioral variant FTD (bvFTD) and semantic dementia. DESIGN, SETTING, AND PARTICIPANTS: Forty-nine patients with dementia (19 with bvFTD, 15 with semantic dementia, and 15 with Alzheimer disease) were recruited, and their eating behavior was compared with that of 25 healthy controls. The study was conducted from November 1, 2013, through May 31, 2015, and data analyzed from June 1 to August 31, 2015. MAIN OUTCOMES AND MEASURES: Patients participated in an ad libitum breakfast test meal, and their total caloric intake and food preferences were measured. Changes in eating behavior were also measured using the Appetite and Eating Habits Questionnaire (APEHQ) and the Cambridge Behavioral Inventory (CBI). Sucrose preference was tested by measuring liking ratings of 3 desserts of varying sucrose content (A: 26%, B: 39%, C: 60%). Voxel-based morphometry analysis of whole-brain 3-T high-resolution brain magnetic resonance imaging was used to determine the gray matter density changes across groups and their relations to eating behaviors. RESULTS: Mean (SD) ages of patients in all 4 groups ranged from 62 (8.3) to 66 (8.4) years. At the ad libitum breakfast test meal, all patients with bvFTD had increased total caloric intake (mean, 1344 calories) compared with the Alzheimer disease (mean, 710 calories), semantic dementia (mean, 573 calories), and control groups (mean, 603 calories) (P < .001). Patients with bvFTD and semantic dementia had a strong sucrose preference compared with the other groups. Increased caloric intake correlated with atrophy in discrete neural networks that differed between patients with bvFTD and semantic dementia but included the cingulate cortices, thalami, and cerebellum in patients with bvFTD, with the addition of the orbitofrontal cortices and nucleus accumbens in patients with semantic dementia. A distributed network of neural correlates was associated with sucrose preference in patients with FTD. CONCLUSIONS AND RELEVANCE: Marked hyperphagia is restricted to bvFTD, present in all patients with this diagnosis, and supports its diagnostic value. Differing neural networks control eating behavior in patients with bvFTD and semantic dementia and are likely responsible for the differences seen, with a similar network controlling sucrose preference. These networks share structures that control cognitive-reward, autonomic, neuroendocrine, and visual modulation of eating behavior. Delineating the neural networks involved in mediating these changes in eating behavior may enable treatment of these features in patients with complex medical needs and aid in our understanding of structures that control eating behavior in patients with FTD and healthy individuals.This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) program grant (#1037746 to MK and JH) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021 to OP and JH) and other grants/sources (NHMRC project grant #1003139). We are grateful to the research participants involved with the ForeFront research studies. RA is a Royal Australasian College of Physicians PhD scholar and MND Australia PhD scholar. MI is an ARC Discovery Early Career Researcher Award Fellow Ahmed et al. (#DE130100463). OP is an NHMRC Career Development Research Fellow (#1022684). ISF is supported by the Wellcome Trust, Medical Research Council, European Research Council, NIHR Cambridge Biomedical Research Centre and The Bernard Wolfe Endowment.This is the author accepted manuscript. The final version is available from American Medical Association at http://dx.doi.org/10.1001/jamaneurol.2015.4478

ProxECAT: Proxy External Controls Association Test. A new case-control gene region association test using allele frequencies from public controls.

A primary goal of the recent investment in sequencing is to detect novel genetic associations in health and disease improving the development of treatments and playing a critical role in precision medicine. While this investment has resulted in an enormous total number of sequenced genomes, individual studies of complex traits and diseases are often smaller and underpowered to detect rare variant genetic associations. Existing genetic resources such as the Exome Aggregation Consortium (>60,000 exomes) and the Genome Aggregation Database (~140,000 sequenced samples) have the potential to be used as controls in these studies. Fully utilizing these and other existing sequencing resources may increase power and could be especially useful in studies where resources to sequence additional samples are limited. However, to date, these large, publicly available genetic resources remain underutilized, or even misused, in large part due to the lack of statistical methods that can appropriately use this summary level data. Here, we present a new method to incorporate external controls in case-control analysis called ProxECAT (Proxy External Controls Association Test). ProxECAT estimates enrichment of rare variants within a gene region using internally sequenced cases and external controls. We evaluated ProxECAT in simulations and empirical analyses of obesity cases using both low-depth of coverage (7x) whole-genome sequenced controls and ExAC as controls. We find that ProxECAT maintains the expected type I error rate with increased power as the number of external controls increases. With an accompanying R package, ProxECAT enables the use of publicly available allele frequencies as external controls in case-control analysis

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

Funder: NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation TrustFunder: NHS National Institute for Health Research Clinical Research NetworkFunder: Royal Society Darwin Trust Research ProfessorshipFunder: NIHR Senior Investigator AwardFunder: Health Data Research UKFunder: Higher Education Funding Council for England CatalystFunder: NIHR Cambridge Biomedical Research CentreFunder: Bernard Wolfe Health Neuroscience EndowmentFunder: The Botnar FondationThe discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action