Análisis de secuencias de accidente de pérdida de refrigerante en centrales nucleares de agua a presión mediante la metodología ISA

El accidente de pérdida de refrigerante (LOCA) en un reactor nuclear es uno de los accidentes Base de Diseño más preocupantes y estudiados desde el origen del uso de la tecnología de fisión en la industria productora de energía. El LOCA ocupa, desde el punto de vista de los análisis de seguridad, un lugar de vanguardia tanto en el análisis determinista (DSA) como probabilista (PSA), cuya diferenciada perspectiva ha ido evolucionando notablemente en lo que al crédito a la actuación de las salvaguardias y las acciones del operador se refiere. En la presente tesis se aborda el análisis sistemático de de las secuencias de LOCA por pequeña y mediana rotura en diferentes lugares de un reactor nuclear de agua a presión (PWR) con fallo total de Inyección de Seguridad de Alta Presión (HPSI). Tal análisis ha sido desarrollado en base a la metodología de Análisis Integrado de Seguridad (ISA), desarrollado por el Consejo de Seguridad Nuclear (CSN) y consistente en la aplicación de métodos avanzados de simulación y PSA para la obtención de Dominios de Daño, que cuantifican topológicamente las probabilidades de éxito y daño en función de determinados parámetros inciertos. Para la elaboración de la presente tesis, se ha hecho uso del código termohidráulico TRACE v5.0 (patch 2), avalado por la NRC de los EEUU como código de planta para la simulación y análisis de secuencias en reactores de agua ligera (LWR). Los objetivos del trabajo son, principalmente: (1) el análisis exhaustivo de las secuencias de LOCA por pequeña-mediana rotura en diferentes lugares de un PWR de tres lazos de diseño Westinghouse (CN Almaraz), con fallo de HPSI, en función de parámetros de gran importancia para los transitorios, tales como el tamaño de rotura y el tiempo de retraso en la respuesta del operador; (2) la obtención y análisis de los Dominios de Daño para transitorios de LOCA en PWRs, de acuerdo con la metodología ISA; y (3) la revisión de algunos de los resultados genéricos de los análisis de seguridad para secuencias de LOCA en las mencionadas condiciones. Los resultados de la tesis abarcan tres áreas bien diferenciadas a lo largo del trabajo: (a) la fenomenología física de las secuencias objeto de estudio; (b) las conclusiones de los análisis de seguridad practicados a los transitorios de LOCA; y (c) la relevancia de las consecuencias de las acciones humanas por parte del grupo de operación. Estos resultados, a su vez, son de dos tipos fundamentales: (1) de respaldo del conocimiento previo sobre el tipo de secuencias analizado, incluido en la extensa bibliografía examinada; y (2) hallazgos en cada una de las tres áreas mencionadas, no referidos en la bibliografía. En resumidas cuentas, los resultados de la tesis avalan el uso de la metodología ISA como método de análisis alternativo y sistemático para secuencias accidentales en LWRs. ABSTRACT The loss of coolant accident (LOCA) in nuclear reactors is one of the most concerning and analized accidents from the beginning of the use of fission technology for electric power production. From the point of view of safety analyses, LOCA holds a forefront place in both Deterministic (DSA) and Probabilistic Safety Analysis (PSA), which have significantly evolved from their original state in both safeguard performance credibility and human actuation. This thesis addresses a systematic analysis of small and medium LOCA sequences, in different places of a nuclear Pressurized Water Reactor (PWR) and with total failure of High Pressure Safety Injection (HPSI). Such an analysis has been grounded on the Integrated Safety Assessment (ISA) methodology, developed by the Spanish Nuclear Regulatory Body (CSN). ISA involves the application of advanced methods of simulation and PSA for obtaining Damage Domains that topologically quantify the likelihood of success and damage regarding certain uncertain parameters.TRACE v5.0 (patch 2) code has been used as the thermalhydraulic simulation tool for the elaboration of this work. Nowadays, TRACE is supported by the US NRC as a plant code for the simulation and analysis of sequences in light water reactors (LWR). The main objectives of the work are the following ones: (1) the in-depth analysis of small and medium LOCA sequences in different places of a Westinghouse three-loop PWR (Almaraz NPP), with failed HPSI, regarding important parameters, such as break size or delay in operator response; (2) obtainment and analysis of Damage Domains related to LOCA transients in PWRs, according to ISA methodology; and (3) review some of the results of generic safety analyses for LOCA sequences in those conditions. The results of the thesis cover three separated areas: (a) the physical phenomenology of the sequences under study; (b) the conclusions of LOCA safety analyses; and (c) the importance of consequences of human actions by the operating crew. These results, in turn, are of two main types: (1) endorsement of previous knowledge about this kind of sequences, which is included in the literature; and (2) findings in each of the three aforementioned areas, not reported in the reviewed literature. In short, the results of this thesis support the use of ISA-like methodology as an alternative method for systematic analysis of LWR accidental sequences.

Contribuições do direito norte-americano ao sistema de proteção do investidor no mercado de capitais brasileiro

O atual arcabouço normativo de proteção do investidor no mercado de capitais brasileiro teve suas linhas mestras cravadas pela reforma bancária introduzida pelas Leis 4.595, de 31 de dezembro de 1964, e 4.728, de 14 de julho de 1965, pela criação de um regulador especializado em mercado de capitais pela Lei 6.385, de 07 de dezembro de 1976, e pela reforma da legislação das sociedades anônimas introduzida pela Lei 6.404, de 15 de dezembro de 1976. Desde 1976, o arcabouço normativo de proteção do investidor no mercado de capitais brasileiro vem sendo desenvolvido a partir dessas linhas mestras iniciais, incorporando as lições aprendidas com as turbulências e euforias vividas pela economia nacional. Esse arcabouço normativo que aí está desde 1976 foi inspirado por contribuições do direito federal norte-americano, as quais foram conscientemente captadas no Brasil pelo legislador e pela comunidade jurídica nacional. Difundiram-se internacionalmente dos EUA para o Brasil os preceitos da proteção do investidor no mercado de capitais calcados na existência de um órgão regulador do mercado de capitais, na divulgação de informações relevantes para decisões de investimento (disclosure), na regulação funcional dos agentes do mercado de capitais e na vedação de fraudes com valores mobiliários.

Stakeholders' perceptions of Corporate Social Reporting (CSR) in Bangladesh

The paper addresses a significant gap in the CSR literature indicated by the lack of studies that examine non-managerial stakeholders’ perceptions of the practice. Recent calls in the CSR literature have emphasised the importance of giving voice to non-managerial stakeholders groups. The research examines the perceptions of a wide group of stakeholders in the context of a developing country, Bangladesh. A series of semi-structured interviews were conducted with various stakeholder groups including employees, consumers, pressure groups, regulatory body and accounting professionals. The current practice of CSR in Bangladesh is interpreted in terms of ‘largely cosmetic responses’, ‘marketing strategy’ and ‘response to pressures from international markets’. Additionally, while some of the interviewees sharply criticised the current process of imposing social accounting codes/standards on developing countries which fail to consider the important local socio-economic context, the findings suggest that there is overwhelming support for mandatory externally verified CSR reporting based on the principles of peoples’ right to know, full disclosure/completeness, and relevance, which are anchored in the broader principles of transparency and accountability.

The Barriers to the Integration of the Uterine Balloon Tamponade into South Africa and Ghana's Health Systems for the Management of Postpartum Hemorrhage

Background

Postpartum hemorrhage is the most significant contributor to maternal mortality globally, claiming 140,000 lives annually. Postpartum hemorrhage is a leading cause of maternal death in South Africa, with the literature indicating that 80 percent of the postpartum hemorrhage deaths in South Africa are avoidable. Ghana, as of 2010, witnesses 2700 maternal deaths annually, primarily because of poor quality of care in health facilities and services being difficult to access. As per WHO recommendations, uterotonics are integral to treating postpartum hemorrhage as soon as it is diagnosed. In case of persistent bleeding or limited availability of uterotonics, the uterine balloon tamponade (UBT) can be used as a second line of defense. If both these measures are unable to counter the bleeding, providers must perform surgical interventions. Literature on the UBT, as one tool in the protocol to address postpartum hemorrhage, has shown it to have success rates ranging from 60 to 100 percent. Despite the potential to lower the number of postpartum hemorrhage deaths in South Africa and Ghana, the UBT has not been incorporated widely in South Africa and Ghana. The aim of this study is to describe the barriers involved with integrating the UBT into South Africa and Ghana’s health systems to address postpartum hemorrhage.

Methods

The study took place in multiple sites in South Africa (Cape Town, Johannesburg, Durban and Mpumalanga) and in Accra, Ghana. South Africa and Ghana were selected because postpartum hemorrhage contributes greatly to their maternal mortality numbers and there is potential in both countries to lower those rates through greater use of the UBT. A total of 25 participants were interviewed through purposive sampling, snowball sampling and participant referrals, and included various categories of stakeholders integral to the integration process of a medical device. Individual in-depth interviews were used for data collection, with interview questions being tailored to each stakeholder category. The focus of the interviews was on the protocol used to counter postpartum hemorrhage, the frequency with which the UBT is used as part of the protocol, and the process of integrating it into the South Africa and Ghana’s health systems. The data collected were coded using NVivo and analyzed using content analysis.

Results

The barriers to integration of the uterine balloon tamponade to address postpartum hemorrhage in South Africa and Ghana were evident on the political, economic and health delivery levels. The results indicated that the barriers to integration in South Africa included the low recognition of postpartum hemorrhage as a problem, the lack of clarity surrounding the role of the Medicines Control Council as a regulatory body for medical devices, and low awareness of the UBT as an intervention to control postpartum hemorrhage. The barriers in Ghana were the cash constraints experienced by the Ghana Health Services to fund medical devices, a heavy reliance on donors for funding, and the lack of consistent knowledge on processes involving clinical trials for new medical devices in Ghana.

Conclusion

Existing literature on methods to counter postpartum hemorrhage to reduce maternal mortality has focused on and emphasized the efficacy of the UBT. Despite overwhelming evidence supporting the use of the UBT, many health systems across the world, particularly low-income countries, do not have access to the device owing to numerous barriers in integrating the device into obstetric care. This study illustrates the need to focus on incorporating the UBT into health systems for greater availability to health workers and its use as standard of care. Ultimately, this study can be used as a stepping-stone for more research on this subject, providing evidence to influence policymakers to integrate the UBT into their protocols for postpartum hemorrhage response.

Sex offender risk assessment and management in Ireland

This research examined sex offender risk assessment and management in Ireland. It focused on the statutory agencies with primary responsibility (Garda Síochána and the Probation Service). The goal was to document the historical, contextual and current systems, in addition to identifying areas of concern/improvements. The research was a mixed-methods approach. Eight studies were conducted. This incorporated documentary reviews of four Commission to Inquire Reports, qualitative interviews/focus groups with Garda staff, Probation Service staff, statutory agencies, community stakeholders, various Non-Governmental Organisations (NGOs) and sex offenders. Quantitative questionnaires were also administered to Garda staff. In all over 70 interviews were conducted and questionnaires were forwarded to 270 Garda members. The overall findings are: •Sex offender management in Ireland has become formal only since 2001. Knowledge, skills and expertise is in its infancy and is still evolving. •Mixed reviews and questions regarding fitness for purpose of currently used risk assessments tools were noted. •The Sex Offender Act 2001 requires additional elements to ensure safe sex offender monitoring and public protection. A judicial review of the Sex Offender Act 2001 was recommended by many respondents. •Interagency working under SORAM was hugely welcomed. The sharing of information has been welcomed by managing agencies as the key benefit to improving sex offender management. •Respondents reported that in practice, sex offender management in Ireland is fragmented and unevenly implemented. The research concluded that an independent National Sex Offender Authority should be established as an oversight and regulatory body for policy, strategy and direction in sex offender management. Further areas of research were also highlighted: ongoing evaluation and audits of the joint agency process and systems in place; recidivism studies tracking the risk assessment ratings and subsequent offending; and an evaluation of the current status of sex offender housing in Ireland.

Sustaining a Relationship : Insights from Canada on Linking the Government and Third Sector (Working Paper 1)

The embedding of third sector organisations in the policy world is fraught with tensions. Accountability and autonomy become oppositional forces causing an uneasy relationship. Government agencies are concerned that their equity and efficiency goals and objectives be met when they enter partnerships with the third sector for the delivery of programs and services. Third sector agencies question the impact of accountability mechanisms on their independence and identities. Even if the relationship between government and third sector agencies seems to be based on cooperation, concerns about cooptation (for nonprofits) and capturing (for governments) may linger calling the legitimacy of the partnership into question. Two means of improving the relationship between the governing and third sectors have been proposed recently in Canada by the Panel on Accountability and Governance in the Voluntary Sector (PAGVS) and the Joint Tables sponsored by the Voluntary Sector Task Force (VSTF). The two endeavours represent a historic undertaking in Canada aimed at improving and facilitating the relationship between the federal government and the nonprofit sector. The reports borrow on other country models but offer new insights into mediating the relationship, including new models for a regulatory body and a charity compact for Canada. Do these recommendations adequately address concerns of autonomy, accountability and cooptation or capturing? The Canadian reports do offer new insights into resolving the four tensions inherent in partnerships between the governing and third sector but also raise important questions about the nature of these relationships and the evolution of democracy within the Canadian political system.

Control de devolución de IVA a personas de la tercera edad

El presente trabajo de investigación lleva como título “CONTROL DE DEVOLUCIÓN DE IVA A PERSONAS DE LA TERCERA EDAD”, el cual realiza un análisis minucioso del proceso de devolución del Impuesto al Valor Agregado en la actualidad, y la manera en la que es factible mejorarlo. Lo que podemos observar en el desarrollo del presente trabajo de investigación, haciendo hincapié a como las personas de la Tercera Edad hacen uso de sus derechos, cual es el impacto que causa la devolución del IVA dentro de las Arcas Fiscales. El capítulo uno se enfoca principalmente a los aspectos generales de los Impuestos, como es: conceptos, elementos del impuesto, fines y efectos, clasificación y la trascendencia que ha tenido los impuestos desde la época colonial hasta la actualidad. El capítulo dos se orienta más a la entidad reguladora de los Impuestos en el Ecuador, el SRI, como es su misión, visión, facultades, objetivos, así como el detalle completo de la información necesaria acerca del Impuesto al Valor Agregado. En el capítulo tres encontraremos el análisis poblacional emitido por la INEC para el año 2015, dividido en sectores (Edades, Sexo, Provincia), el detalle completo del proceso de devolución de IVA para las personas de la Tercera Edad. Para concluir con el estudio, en el capítulo cuatro hacemos mención de las conclusiones y recomendaciones para el mejoramiento del proceso de devolución de IVA de las personas de la Tercera Edad.

Association of polymorphisms at the ADIPOR1 regulatory region with type 2 diabetes and body mass index in a Brazilian population with European or African ancestry

Association studies between ADIPOR1 genetic variants and predisposition to type 2 diabetes (DM2) have provided contradictory results. We determined if two single nucleotide polymorphisms (SNP c.-8503G>A and SNP c.10225C>G) in regulatory regions of ADIPOR1 in 567 Brazilian individuals of European (EA; N = 443) or African (AfA; N = 124) ancestry from rural (quilombo remnants; N = 439) and urban (N = 567) areas. We detected a significant effect of ethnicity on the distribution of the allelic frequencies of both SNPs in these populations (EA: -8503A = 0.27; AfA: -8503A = 0.16; P = 0.001 and EA: 10225G = 0.35; AfA: 10225G = 0.51; P < 0.001). Neither of the polymorphisms were associated with DM2 in the case-control study in EA (SNP c.-8503G>A: DM2 group -8503A = 0.26; control group -8503A = 0.30; P = 0.14/SNP 10225C>G: DM2 group 10225G = 0.37; control group 10225G = 0.32; P = 0.40) and AfA populations (SNP c.-8503G>A: DM2 group -8503A = 0.16; control group -8503A = 0.15; P = 0.34/SNP 10225C>G: DM2 group 10225G = 0.51; control group 10225G = 0.52; P = 0.50). Similarly, none of the polymorphisms were associated with metabolic/anthropometric risk factors for DM2 in any of the three populations, except for HDL cholesterol, which was significantly higher in AfA heterozygotes (GC = 53.75 ± 17.26 mg/dL) than in homozygotes. We conclude that ADIPOR1 polymorphisms are unlikely to be major risk factors for DM2 or for metabolic/anthropometric measurements that represent risk factors for DM2 in populations of European and African ancestries.

Fetal development of regulatory mechanisms for body fluid homeostasis

The balance of body fluids is critical to health and the development of diseases. Although quite a few review papers have shown that several mechanisms, including hormonal and behavioral regulation, play an important role in body fluid homeostasis in adults, there is limited information on the development of regulatory mechanisms for fetal body fluid balance. Hormonal, renal, and behavioral control of body fluids function to some extent in utero. Hormonal mechanisms including the renin-angiotensin system, aldosterone, and vasopressin are involved in modifying fetal renal excretion, reabsorption of sodium and water, and regulation of vascular volume. In utero behavioral changes, such as fetal swallowing, have been suggested to be early functional development in response to dipsogens. Since diseases, such as hypertension, can be traced to fetal origin, it is important to understand the development of fetal regulatory mechanisms for body fluid homeostasis in this early stage of life. This review focuses on fetal hormonal, behavioral, and renal development related to regulation of body fluids in utero.

Association of polymorphisms at the ADIPOR1 regulatory region with type 2 diabetes and body mass index in a Brazilian population with European or African ancestry

Association studies between ADIPOR1 genetic variants and predisposition to type 2 diabetes (DM2) have provided contradictory results. We determined if two single nucleotide polymorphisms (SNP c.-8503G>A and SNP c.10225C>G) in regulatory regions of ADIPOR1 in 567 Brazilian individuals of European (EA; N = 443) or African (AfA; N = 124) ancestry from rural (quilombo remnants; N = 439) and urban (N = 567) areas. We detected a significant effect of ethnicity on the distribution of the allelic frequencies of both SNPs in these populations (EA: -8503A = 0.27; AfA: -8503A = 0.16; P = 0.001 and EA: 10225G = 0.35; AfA: 10225G = 0.51; P < 0.001). Neither of the polymorphisms were associated with DM2 in the case-control study in EA (SNP c.-8503G>A: DM2 group -8503A = 0.26; control group -8503A = 0.30; P = 0.14/SNP 10225C>G: DM2 group 10225G = 0.37; control group 10225G = 0.32; P = 0.40) and AfA populations (SNP c.-8503G>A: DM2 group -8503A = 0.16; control group -8503A = 0.15; P = 0.34/SNP 10225C>G: DM2 group 10225G = 0.51; control group 10225G = 0.52; P = 0.50). Similarly, none of the polymorphisms were associated with metabolic/anthropometric risk factors for DM2 in any of the three populations, except for HDL cholesterol, which was significantly higher in AfA heterozygotes (GC = 53.75 ± 17.26 mg/dL) than in homozygotes. We conclude that ADIPOR1 polymorphisms are unlikely to be major risk factors for DM2 or for metabolic/anthropometric measurements that represent risk factors for DM2 in populations of European and African ancestries.

Expression of the iron regulatory peptide hepcidin is reduced in patients with chronic liver disease

Disturbances in iron metabolism often accompany liver disease in humans and hepatic iron deposition is a frequent finding. Since the peptide hepcidin, a major regulator of body iron homeostasis, is synthesised in the liver, alterations in hepcidin expression could be responsible for these effects. To investigate this possibility, we studied hepcidin expression in liver biopsies from patients with hepatitis C virus (HCV) infection, non-alcoholic fatty liver disease (NAFLD) and hemochromatosis (HC). Total RNA was extracted from the liver tissue of 24 HCV, 17 NASH and 5 HC patients, and 17 liver transplant donors (controls). The levels of mRNA for hepcidin and several other molecules involved in iron metabolism (DMT1, Dcytb, hephaestin, ferroportin, TfR1, TfR2, HFE and HJV) were examined by ribonuclease protection assay and expressed relative to the housekeeping gene GAPDH. The expression of hepcidin was significantly decreased in HCV and NASH patients relative to control liver (109±16 and 200±44 versus 325±26 respectively; P=0.008 and 0.02). We have previously reported similar findings in patients with HC, and this was confirmed in the current analysis (176±21; P=0.003). In both HCV and NAFLD patients the expression of the iron reductase Dcytb and the transferrin binding regulatory molecule TfR2 was also decreased, while the cellular iron exporter ferroportin showed a significant increase. Levels of the mRNA for the iron oxidase hephaestin were lower in HCV patients alone, while expression of the major transferrin binding molecule TfR1 was decreased only in NAFLD patients. Of particular interest was the finding that the expression of HJV (which is mutated in patients with juvenile HC) was significantly increased in NAFLD patients. No changes were seen in the expression of the iron importer DMT1 or the regulatory molecule HFE. Decreased expression of hepcidin in patients with HCV and NAFLD provides an explanation why iron homeostasis could be perturbed in these disorders. Reduced hepcidin levels would increase intestinal iron absorption and iron release from macrophages, which could contribute to hepatic iron accumulation. This in turn could lead to alterations in the expression of various proteins involved in iron transport and its regulation. Indeed most of the changes in the expression of such molecules observed in this study are consistent with this. However, the mechanisms leading to changes in the expression of hepcidin in these diseases remain to be elucidated.

Insulin-like peptide genes in honey bee fat body respond differently to manipulation of social behavioral physiology

Nutrient sensitive insulin-like peptides (ILPs) have profound effects on invertebrate metabolism, nutrient storage, fertility and aging. Many insects transcribe ILPs in specialized neurosecretory cells at changing levels correlated with life history. However, the major site of insect metabolism and nutrient storage is not the brain, but rather the fat body, where functions of ILP expression are rarely studied and poorly understood. Fat body is analogous to mammalian liver and adipose tissue, with nutrient stores that often correlate with behavior. We used the honey bee (Apis mellifera), an insect with complex behavior, to test whether ILP genes in fat body respond to experimentally induced changes of behavioral physiology. Honey bee fat body influences endocrine state and behavior by secreting the yolk protein precursor vitellogenin (Vg), which suppresses lipophilic juvenile hormone and social foraging behavior. In a two-factorial experiment, we used RNA interference (RNAi)-mediated vg gene knockdown and amino acid nutrient enrichment of hemolymph (blood) to perturb this regulatory module. We document factor-specific changes in fat body ilp1 and ilp2 mRNA, the bee`s ILP-encoding genes, and confirm that our protocol affects social behavior. We show that ilp1 and ilp2 are regulated independently and differently and diverge in their specific expression-localization between fat body oenocyte and trophocyte cells. Insect ilp functions may be better understood by broadening research to account for expression in fat body and not only brain.

Problems in the regulatory policy of the drug market

OBJECTIVE Analyze the implementation of drug price regulation policy by the Drug Market Regulation Chamber.METHODS This is an interview-based study, which was undertaken in 2012, using semi-structured questionnaires with social actors from the pharmaceutical market, the pharmaceuticals industry, consumers and the regulatory agency. In addition, drug prices were compiled based on surveys conducted in the state of Sao Paulo, at the point of sale, between February 2009 and May 2012.RESULTS The mean drug prices charged at the point of sale (pharmacies) were well below the maximum price to the consumer, compared with many drugs sold in Brazil. Between 2009 and 2012, 44 of the 129 prices, corresponding to 99 drugs listed in the database of compiled prices, showed a variation of more than 20.0% in the mean prices at the point of sale and the maximum price to the consumer. In addition, many laboratories have refused to apply the price adequacy coefficient in their sales to government agencies.CONCLUSIONS The regulation implemented by the pharmaceutical market regulator was unable to significantly control prices of marketed drugs, without succeeding to push them to levels lower than those determined by the pharmaceutical industry and failing, therefore, in its objective to promote pharmaceutical support for the public. It is necessary reconstruct the regulatory law to allow market prices to be reduced by the regulator as well as institutional strengthen this government body.

Effect of carbohydrate overfeeding on whole body macronutrient metabolism and expression of lipogenic enzymes in adipose tissue of lean and overweight humans

OBJECTIVE: Lipids stored in adipose tissue can originate from dietary lipids or from de novo lipogenesis (DNL) from carbohydrates. Whether DNL is abnormal in adipose tissue of overweight individuals remains unknown. The present study was undertaken to assess the effect of carbohydrate overfeeding on glucose-induced whole body DNL and adipose tissue lipogenic gene expression in lean and overweight humans. DESIGN: Prospective, cross-over study. SUBJECTS AND METHODS: A total of 11 lean (five male, six female, mean BMI 21.0+/-0.5 kg/m(2)) and eight overweight (four males, four females, mean BMI 30.1+/-0.6 kg/m(2)) volunteers were studied on two occasions. On one occasion, they received an isoenergetic diet containing 50% carbohydrate for 4 days prior to testing; on the other, they received a hyperenergetic diet (175% energy requirements) containing 71% carbohydrates. After each period of 4 days of controlled diet, they were studied over 6 h after having received 3.25 g glucose/kg fat free mass. Whole body glucose oxidation and net DNL were monitored by means of indirect calorimetry. An adipose tissue biopsy was obtained at the end of this 6-h period and the levels of SREBP-1c, acetyl CoA carboxylase, and fatty acid synthase mRNA were measured by real-time PCR. RESULTS: After isocaloric feeding, whole body net DNL amounted to 35+/-9 mg/kg fat free mass/5 h in lean subjects and to 49+/-3 mg/kg fat free mass/5 h in overweight subjects over the 5 h following glucose ingestion. These figures increased (P<0.001) to 156+/-21 mg/kg fat free mass/5 h in lean and 64+/-11 mg/kg fat free mass/5 h (P<0.05 vs lean) in overweight subjects after carbohydrate overfeeding. Whole body DNL after overfeeding was lower (P<0.001) and glycogen synthesis was higher (P<0.001) in overweight than in normal subjects. Adipose tissue SREBP-1c mRNA increased by 25% in overweight and by 43% in lean subjects (P<0.05) after carbohydrate overfeeding, whereas fatty acid synthase mRNA increased by 66 and 84% (P<0.05). CONCLUSION: Whole body net DNL is not increased during carbohydrate overfeeding in overweight individuals. Stimulation of adipose lipogenic enzymes is also not higher in overweight subjects. Carbohydrate overfeeding does not stimulate whole body net DNL nor expression of lipogenic enzymes in adipose tissue to a larger extent in overweight than lean subjects.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.