Serum Leptin Concentration, Body Mass Index and Incident Heart Failure: The Health, Aging, and Body Composition Study

Background: Leptin is produced primarily by adipocytes. Although originally associated with the central regulation of satiety and energy metabolism, increasing evidence indicates that leptin may be an important factor for congestive heart faire (CHF). In the study, we aimed to test the hypothesis that leptin may influence CHF pathophysiology via a pathway of increasing body mass index (BMI). Methods: We studied 2,389 elderly participants aged 70 and older (M; 1161, F: 1228) without CHF and with serum leptin measures at the Health Aging, and Body Composition study. We analyzed the association between serum leptin level and risk of incident CHF using Cox hazard proportional regression models. Elevated leptin level was defined as more than the highest quartile (Q4) of leptin distribution in the total sample for each gender. Adjusted-covariates included demographic, behavior, lipid and inflammation variables (partially-adjusted models), and further included BMI (fully-adjusted models). Results: In a mean 9-year follow-up, 316 participants (13.2%) developed CHF. The partially-adjusted models indicated that men and women with elevated serum leptin levels (>=9.89 ng/ml in men and >=25 ng/ml in women) had significantly higher risks of developing CHF than those with leptin level of less than Q4. The adjusted hazard ratios (95%CI) for incident CHF was 1.49 (1.04 -2.13) in men and 1.71 (1.12 -2.58) in women. However, these associations became non-significant after adjustment for including BMI for each gender. The fully-adjusted hazard ratios (95%CI) were 1.43 (0.94 -2.18) in men and 1.24 (0.77-1.99) in women. Conclusion: Subjects with elevated leptin levels have a higher risk of CHF. The study supports the hypothesis that the influence of leptin level on risk of CHF may be through a pathway related to increasing BMI.

Rapid high-performance liquid chromatographic determination with fluorescence detection of furosemide in human body fluids and its confirmation by gas chromatography-mass spectrometry.

Furosemide (FD: Lasix) is a loop diuretic which strongly increases both urine flow and electrolyte urinary excretion. Healthy volunteers were administered 40 mg orally (dissolved in water) and concentrations of FD were determined in serum and urine for up to 6 h for eight subjects, who absorbed water at a rate of 400 ml/h. Quantification was performed by HPLC with fluorescence detection (excitation at 233 nm, emission at 389 nm) with a limit of detection of 5 ng/ml for a 300-microliters sample. The elution of FD was completed within 4 min using a gradient of acetonitrile concentration rising from 30 to 50% in 0.08 M phosphoric acid. The delay to the peak serum concentration ranged from 60 to 120 min. FD was still easily measurable in the sera from all subjects 6 h after administration. In urine, the excretion rates reached their maximum between 1 and 3 h. The total amount of FD excreted in the urine averaged 11.2 mg (range 7.6-14.0 mg), with a mean urine volume of 3024 ml (range 2620-3596 ml). Moreover, the urine density was lower than 1.010 (recommended as an upper limit in doping analysis to screen diuretics) only for 2 h. An additional volunteer was administered 40 mg of FD and his urine was collected over a longer period. FD was still detectable 48 h after intake. Gas chromatography-mass spectrometry with different types of ionization was used to confirm the occurrence of FD after permethylation of the extract. Negative-ion chemical ionization, with ammonia as reactant gas, was found to be the most sensitive method of detection.

Absorbance enhancement in microplate wells for improved-sensitivity biosensors

A generic optical biosensing strategy was developed that relies on the absorbance enhancement phenomenon occurring in a multiple scattering matrix. Experimentally, inserts made of glass fiber membrane were placed into microplate wells in order to significantly lengthen the trajectory of the incident light through the sample and therefore increase the corresponding absorbance. Enhancement factor was calculated by comparing the absorbance values measured for a given amount of dye with and without the absorbance-enhancing inserts in the wells. Moreover, the dilution of dye in solutions with different refractive indices (RI) clearly revealed that the enhancement factor increased with the ΔRI between the membrane and the surrounding medium, reaching a maximum value (EF>25) when the membranes were dried. On this basis, two H2O2-biosensing systems were developed based on the biofunctionalization of the glass fiber inserts either with cytochrome c or horseradish peroxidase (HRP) and the analytical performances were systematically compared with the corresponding bioassay in solution. The efficiency of the absorbance-enhancement approach was particularly clear in the case of the cytochrome c-based biosensor with a sensitivity gain of 40 folds and wider dynamic range. Therefore, the developed strategy represents a promising way to convert standard colorimetric bioassays into optical biosensors with improved sensitivity.

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

A computable general equilibrium analysis of the relative price sensitivity required to induce rebound effects in response to an improvement in energy efficiency in the UK economy

In recent years there has been extensive debate in the energy economics and policy literature on the likely impacts of improvements in energy efficiency. This debate has focussed on the notion of rebound effects. Rebound effects occur when improvements in energy efficiency actually stimulate the direct and indirect demand for energy in production and/or consumption. This phenomenon occurs through the impact of the increased efficiency on the effective, or implicit, price of energy. If demand is stimulated in this way, the anticipated reduction in energy use, and the consequent environmental benefits, will be partially or possibly even more than wholly (in the case of ‘backfire’ effects) offset. A recent report published by the UK House of Lords identifies rebound effects as a plausible explanation as to why recent improvements in energy efficiency in the UK have not translated to reductions in energy demand at the macroeconomic level, but calls for empirical investigation of the factors that govern the extent of such effects. Undoubtedly the single most important conclusion of recent analysis in the UK, led by the UK Energy Research Centre (UKERC) is that the extent of rebound and backfire effects is always and everywhere an empirical issue. It is simply not possible to determine the degree of rebound and backfire from theoretical considerations alone, notwithstanding the claims of some contributors to the debate. In particular, theoretical analysis cannot rule out backfire. Nor, strictly, can theoretical considerations alone rule out the other limiting case, of zero rebound, that a narrow engineering approach would imply. In this paper we use a computable general equilibrium (CGE) framework to investigate the conditions under which rebound effects may occur in the Scottish regional and UK national economies. Previous work has suggested that rebound effects will occur even where key elasticities of substitution in production are set close to zero. Here, we carry out a systematic sensitivity analysis, where we gradually introduce relative price sensitivity into the system, focusing in particular on elasticities of substitution in production and trade parameters, in order to determine conditions under which rebound effects become a likely outcome. We find that, while there is positive pressure for rebound effects even where (direct and indirect) demand for energy is very price inelastic, this may be partially or wholly offset by negative income and disinvestment effects, which also occur in response to falling energy prices.

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.

Body mass index, cigarette smoking, and alcohol consumption and cancers of the oral cavity, pharynx, and larynx: modeling odds ratios in pooled case-control data.

Odds ratios for head and neck cancer increase with greater cigarette and alcohol use and lower body mass index (BMI; weight (kg)/height(2) (m(2))). Using data from the International Head and Neck Cancer Epidemiology Consortium, the authors conducted a formal analysis of BMI as a modifier of smoking- and alcohol-related effects. Analysis of never and current smokers included 6,333 cases, while analysis of never drinkers and consumers of < or =10 drinks/day included 8,452 cases. There were 8,000 or more controls, depending on the analysis. Odds ratios for all sites increased with lower BMI, greater smoking, and greater drinking. In polytomous regression, odds ratios for BMI (P = 0.65), smoking (P = 0.52), and drinking (P = 0.73) were homogeneous for oral cavity and pharyngeal cancers. Odds ratios for BMI and drinking were greater for oral cavity/pharyngeal cancer (P < 0.01), while smoking odds ratios were greater for laryngeal cancer (P < 0.01). Lower BMI enhanced smoking- and drinking-related odds ratios for oral cavity/pharyngeal cancer (P < 0.01), while BMI did not modify smoking and drinking odds ratios for laryngeal cancer. The increased odds ratios for all sites with low BMI may suggest related carcinogenic mechanisms; however, BMI modification of smoking and drinking odds ratios for cancer of the oral cavity/pharynx but not larynx cancer suggests additional factors specific to oral cavity/pharynx cancer.

Sex difference and the role of leptin in the association between high-sensitivity C-reactive protein and adiposity in two different populations.

Elevated high-sensitivity C-reactive protein (hs-CRP) concentration is associated with an increased risk of cardiovascular disease but this association seems to be largely mediated via conventional cardiovascular risk factors. In particular, the association between hs-CRP and obesity has been extensively demonstrated and correlations are stronger in women than men. We used fractional polynomials-a method that allows flexible modeling of non linear relations-to investigate the dose/response mathematical relationship between hs-CRP and several indicators of adiposity in Caucasians (Switzerland) and Africans (Seychelles) surveyed in two population-based studies. This relationship was non-linear exhibiting a steeper slope for low levels of hs-CRP and a higher level in women. The observed sex difference in the relationship between hs-CRP and adiposity almost disappeared upon adjustment for leptin, suggesting that these sex differences might be partially mediated, by leptin. All these relationship were similar in Caucasians and Africans. This is the first report on a non-linear relation, stratified by gender, between hs-CRP and adiposity.

Consequences of smoking for body weight, body fat distribution, and insulin resistance

Our aim was to critically evaluate the relations among smoking, body weight, body fat distribution, and insulin resistance as reported in the literature. In the short term, nicotine increases energy expenditure and could reduce appetite, which may explain why smokers tend to have lower body weight than do nonsmokers and why smoking cessation is frequently followed by weight gain. In contrast, heavy smokers tend to have greater body weight than do light smokers or nonsmokers, which likely reflects a clustering of risky behaviors (eg, low degree of physical activity, poor diet, and smoking) that is conducive to weight gain. Other factors, such as weight cycling, could also be involved. In addition, smoking increases insulin resistance and is associated with central fat accumulation. As a result, smoking increases the risk of metabolic syndrome and diabetes, and these factors increase risk of cardiovascular disease. In the context of the worldwide obesity epidemic and a high prevalence of smoking, the greater risk of (central) obesity and insulin resistance among smokers is a matter of major concern

Minu, Startu and all that:- Pitfalls in estimating the sensitivity of a worker’s wage to aggregate unemployment

In this paper we show that the inclusion of unemployment-tenure interaction variates in Mincer wage equations is subject to serious pitfalls. These variates were designed to test whether or not the sensitivity to the business cycle of a worker’s wage varies according to her tenure. We show that three canonical variates used in the literature - the minimum unemployment rate during a worker’s time at the firm(min u), the unemployment rate at the start of her tenure(Su) and the current unemployment rate interacted with a new hire dummy(δu) - can all be significant and "correctly" signed even when each worker in the firm receives the same wage, regardless of tenure (equal treatment). In matched data the problem can be resolved by the inclusion in the panel of firm-year interaction dummies. In unmatched data where this is not possible, we propose a solution for min u and Su based on Solon, Barsky and Parker’s(1994) two step method. This method is sub-optimal because it ignores a large amount of cross tenure variation in average wages and is only valid when the scaled covariances of firm wages and firm employment are acyclical. Unfortunately δu cannot be identified in unmatched data because a differential wage response to unemployment of new hires and incumbents will appear under both equal treatment and unequal treatment.

ADOS: an educational primary prevention programme for preventing excess body weight in adolescents.

OBJECTIVE: The prevalence of adolescent obesity has increased considerably over the past decade in Switzerland and has become a serious public health problem in Europe. Prevention of obesity using various comprehensive programmes appears to be very promising, although we must admit that several interventions had generally disappointing results compared with the objectives and target initially fixed. Holistic programmes including nutritional education combined with promotion of physical activity and behaviour modification constitute the key factors in the prevention of childhood and adolescent obesity. The purpose of this programme was to incorporate nutrition/physical education as well as psychological aspects in selected secondary schools (9th grade, 14-17 years). METHODS: The educational strategy was based on the development of a series of 13 practical workshops covering wide areas such as physical inactivity, body composition, sugar, energy density, invisible lipids, how to read food labels, is meal duration important? Do you eat with pleasure or not? Do you eat because you are hungry? Emotional eating. For teachers continuing education, a basic highly illustrated guide was developed as a companion booklet to the workshops. These materials were first validated by biology, physical education, dietician and psychologist teachers as well as school medical officers. RESULTS: Teachers considered the practical educational materials innovative and useful, motivational and easy to understand. Up to now (early 2008), the programme has been implemented in 50 classes or more from schools originating from three areas in the French part of Switzerland. Based on the 1-week pedometer value assessed before and after the 1 school-year programme, an initial evaluation indicated that overall physical placidity was significantly decreased as evidenced by a significant rise in the number of steps per day. CONCLUSION: Future evaluation will provide more information on the effectiveness of the ADOS programme.

Coloration signals the ability to cope with elevated stress hormones: effects of corticosterone on growth of barn owls are associated with melanism.

Stressful situations during development can shape the phenotype for life by provoking a trade-off between development and survival. Stress hormones, mainly glucocorticoids, play an important orchestrating role in this trade-off. Hence, how stress sensitive an animal is critically determines the phenotype and ultimately fitness. In several species, darker eumelanic individuals are less sensitive to stressful conditions than less eumelanic conspecifics, which may be due to the pleiotropic effects of genes affecting both coloration and physiological traits. We experimentally tested whether the degree of melanin-based coloration is associated with the sensitivity to an endocrine response to stressful situations in the barn owl. We artificially administered the mediator of a hormonal stress response, corticosterone, to nestlings to examine the prediction that corticosterone-induced reduction in growth rate is more pronounced in light eumelanic nestlings than in darker nest mates. To examine whether such an effect may be genetically determined, we swapped hatchlings between randomly chosen pairs of nests. We first showed that corticosterone affects growth and, thus, shapes the phenotype. Second, we found that under corticosterone administration, nestlings with large black spots grew better than nestlings with small black spots. As in the barn owl the expression of eumelanin-based coloration is heritable and not sensitive to environmental conditions, it is therefore a reliable, genetically based sign of the ability to cope with an increase in blood corticosterone level.

Introduced freshwater blenny influences the diet and body condition of the invasive dice snake in Lake Geneva

Non-indigenous species can have strong impacts on biodiversity by affecting trophic relationships in their new environments. The piscivorous dice snake (Natrix tessellata) has been introduced to Geneva Lake, western Switzerland, where the endangered viperine snake (Natrix maura) is native. Local, dramatic declines in the viperine snake population might be associated with the appearance of the dice snake through dietary overlap between these 2 species, which mainly feed on bullhead (Cottus gobio). In response to this decline, a control program for dice snake was implemented in 2007 to reduce numbers of this introduced snake. In 2010, a new species of fish, the freshwater blenny (Salaria fluviatilis), which shares the same habitat as the bullhead, was introduced into Lake Geneva and has since reached high densities. We determined the impact of freshwater blenny on diet composition and body condition of dice snakes. In addition, we tested for effects of the control program on the body condition of dice snakes and viperine snakes. We collected 294 dice snakes between 2007 and 2013. Based on morphology and a genetic marker (cytochrome b gene), we determined the ®sh species contained in these snakes' stomachs. We found a drastic switch in dice snake diet following the arrival of freshwater blenny, as consumption of bullhead declined by 68% and was replaced by the blenny. In addition, the body condition of dice snakes increased significantly after the arrival of freshwater blenny. The body condition of both snake species was positively correlated with the number of dice snakes removed from the study area. This finding has important implications concerning the conservation of the endangered viperine snake, and suggests that the control program of dice snakes should be continued.