Limited agreement between body mass index, waist and body fat in diagnosing obesity in the Swiss population

Objective: to assess the agreement between different anthropometric markers in defining obesity and the effect on the prevalence of obese subjects. Methods: population-based cross-sectional study including 3213 women and 2912 men aged 35-75 years. Body fat percentage (%BF) was assessed using electric bioimpedance. Obesity was defined using established cut-points for body mass index (BMI) and waist, and three population-defined cut-points for %BF. Between-criteria agreement was assessed by the kappa statistic. Results: in men, agreement between the %BF cut-points was significantly higher (kappa values in the range 0.78 - 0.86) than with BMI or waist (0.47 - 0.62), whereas no such differences were found in women (0.41 - 0.69). In both genders, prevalence of obesity varied considerably according to the criteria used: 17% and 24% according to BMI and waist in men, and 14% and 31%, respectively, in women. For %BF, the prevalence varied between 14% and 17% in men and between 19% and 36% in women according to the cut-point used. In the older age groups, a fourfold difference in the prevalence of obesity was found when different criteria were used. Among subjects with at least one criteria for obesity (increased BMI, waist or %BF), only one third fulfilled all three criteria and one quarter two criteria. Less than half of women and 64% of men were jointly classified as obese by the three population-defined cut-points for %BF. Conclusions: the different anthropometric criteria to define obesity show a relatively poor agreement between them, leading to considerable differences in the prevalence of obesity in the general population.

Changes in the risk of death after HIV seroconversion compared with mortality in the general population.

CONTEXT: Mortality among human immunodeficiency virus (HIV)-infected individuals has decreased dramatically in countries with good access to treatment and may now be close to mortality in the general uninfected population. OBJECTIVE: To evaluate changes in the mortality gap between HIV-infected individuals and the general uninfected population. DESIGN, SETTING, AND POPULATION: Mortality following HIV seroconversion in a large multinational collaboration of HIV seroconverter cohorts (CASCADE) was compared with expected mortality, calculated by applying general population death rates matched on demographic factors. A Poisson-based model adjusted for duration of infection was constructed to assess changes over calendar time in the excess mortality among HIV-infected individuals. Data pooled in September 2007 were analyzed in March 2008, covering years at risk 1981-2006. MAIN OUTCOME MEASURE: Excess mortality among HIV-infected individuals compared with that of the general uninfected population. RESULTS: Of 16,534 individuals with median duration of follow-up of 6.3 years (range, 1 day to 23.8 years), 2571 died, compared with 235 deaths expected in an equivalent general population cohort. The excess mortality rate (per 1000 person-years) decreased from 40.8 (95% confidence interval [CI], 38.5-43.0; 1275.9 excess deaths in 31,302 person-years) before the introduction of highly active antiretroviral therapy (pre-1996) to 6.1 (95% CI, 4.8-7.4; 89.6 excess deaths in 14,703 person-years) in 2004-2006 (adjusted excess hazard ratio, 0.05 [95% CI, 0.03-0.09] for 2004-2006 vs pre-1996). By 2004-2006, no excess mortality was observed in the first 5 years following HIV seroconversion among those infected sexually, though a cumulative excess probability of death remained over the longer term (4.8% [95% CI, 2.5%-8.6%] in the first 10 years among those aged 15-24 years). CONCLUSIONS: Mortality rates for HIV-infected persons have become much closer to general mortality rates since the introduction of highly active antiretroviral therapy. In industrialized countries, persons infected sexually with HIV now appear to experience mortality rates similar to those of the general population in the first 5 years following infection, though a mortality excess remains as duration of HIV infection lengthens.

Efficacy of Canakinumab (ACZ885), a Fully Human Anti-Interleukin (IL)-1beta Monoclonal Antibody, in the Prevention of Flares in Gout Patients Initiating Allopurinol Therapy

Background: Gout patients initiating urate lowering therapy have an increased risk of flares. Inflammation in gouty arthritis is induced by IL-1b. Canakinumab targets and inhibits IL-1b effectively in clinical studies. This study compared different doses of canakinumab vs colchicine in preventing flares in gout patients initiating allopurinol therapy.Methods: In this 24 week double blind study, gout patients (20-79 years) initiating allopurinol were randomized (1:1:1:1:1:1:2) to canakinumab s.c. single doses of 25, 50, 100, 200, 300 mg, or 150 mg divided in doses every 4 weeks (50+50+25+25 mg [q4wk]) or colchicine 0.5 mg p.o. daily for 16 weeks. Primary outcome was to determine the canakinumab dose giving comparable efficacy to colchicine with respect to the number of gout flares occurring during first 16 weeks. Secondary outcomes included number of patients with gout flares and C-reactive protein (CRP) levels during the first 16 weeks.Results: 432 patients were randomized and 391 (91%) completed the study. All canakinumab doses were better than colchicine in preventing flares and therefore, a canakinumab dose comparable to colchicine could not be determined. Based on a negative binomial model, all canakinumab groups, except 25 mg, reduced the flare rate ratio per patient significantly compared to colchicine group (rate ratio estimates 25 mg 0.60, 50 mg 0.34, 100 mg 0.28, 200 mg 0.37, 300 mg 0.29, q4wk 0.38; p<=0.05). The percentage of patients with flares was lower for all canakinumab groups (25 mg 27.3%, 50 mg 16.7%, 100 mg 14.8%, 200 mg 18.5%, 300 mg 15.1%, q4wk 16.7%) compared to colchicine group (44.4%). All patients taking canakinumab were significantly less likely to experience at least one gout flare than patients taking colchicine (odds ratio range [0.22 - 0.47]; p<=0.05 for all). The median baseline CRP levels were 2.86 mg/L for 25 mg, 3.42 mg/L for 50 mg, 1.76 mg/L for 100 mg, 3.66 mg/L for 200 mg, 3.21 mg/L for 300 mg, 3.23 mg/L for q4wk canakinumab groups and 2.69 mg/L for colchicine group. In all canakinumab groups with median CRP levels above the normal range at baseline, median levels declined within 15 days of treatment and were maintained at normal levels (ULN=3 mg/L) throughout the 16 week period. Adverse events (AEs) occurred in 52.7% (25 mg), 55.6% (50 mg), 51.9% (100 mg), 51.9% (200 mg), 54.7% (300 mg), and 58.5% (q4wk) of patients on canakinumab vs 53.7% of patients on colchicine. Serious AEs (SAE) were reported in 2 (3.6%; 25 mg), 2 (3.7%, 50 mg), 3 (5.6%, 100 mg), 3 (5.6%, 200 mg), 3 (5.7%, 300 mg) and 1 (1.9%, q4wk) patients on canakinumab and in 5 (4.6%) patients on colchicine. One fatal SAE (myocardial infarction, not related to study drug) occurred in colchicine group.Conclusion: In this large randomized, double-blind active controlled study of flare prevention in gout patients initiating allopurinol therapy, treatment with canakinumab led to a statistically significant reduction in flares compared with colchicine (standard of care), and was well tolerated.

Persistent unequal sex ratio in a population of grayling (salmonidae) and possible role of temperature increase.

In some fishes, water chemistry or temperature affects sex determination or creates sex-specific selection pressures. The resulting population sex ratios are hard to predict from laboratory studies if the environmental triggers interact with other factors, whereas in field studies, singular observations of unusual sex ratios may be particularly prone to selective reporting. Long-term monitoring largely avoids these problems. We studied a population of grayling (Thymallus thymallus) in Lake Thun, Switzerland, that has been monitored since 1948. Samples of spawning fish have been caught about 3 times/week around spawning season, and water temperature at the spawning site has been continuously recorded since 1970. We used scale samples collected in different years to determine the average age of spawners (for life-stage specific analyses) and to identify the cohort born in 2003 (an extraordinarily warm year). Recent tissue samples were genotyped on microsatellite markers to test for genetic bottlenecks in the past and to estimate the genetically effective population size (N(e) ). Operational sex ratios changed from approximately 65% males before 1993 to approximately 85% males from 1993 to 2011. Sex ratios correlated with the water temperatures the fish experienced in their first year of life. Sex ratios were best explained by the average temperature juvenile fish experienced during their first summer. Grayling abundance is declining, but we found no evidence of a strong genetic bottleneck that would explain the apparent lack of evolutionary response to the unequal sex ratio. Results of other studies show no evidence of endocrine disruptors in the study area. Our findings suggest temperature affects population sex ratio and thereby contributes to population decline. Persistencia de Proporción de Sexos Desigual en una Población de Tímalos (Salmonidae) y el Posible Papel del Incremento de la Temperatura.

Reduction in the use of diagnostic tests in infants with risk factors for early-onset neonatal sepsis does not delay antibiotic treatment.

Despite a low positive predictive value, diagnostic tests such as complete blood count (CBC) and C-reactive protein (CRP) are commonly used to evaluate whether infants with risk factors for early-onset neonatal sepsis (EOS) should be treated with antibiotics. We investigated the impact of implementing a protocol aiming at reducing the number of diagnostic tests in infants with risk factors for EOS in order to compare the diagnostic performance of repeated clinical examination with CBC and CRP measurement. The primary outcome was the time between birth and the first dose of antibiotics in infants treated for suspected EOS. Among the 11,503 infants born at ≥35 weeks during the study period, 222 were treated with antibiotics for suspected EOS. The proportion of infants receiving antibiotics for suspected EOS was 2.1% and 1.7% before and after the change of protocol (p = 0.09). Reduction of diagnostic tests was associated with earlier antibiotic treatment in infants treated for suspected EOS (hazard ratio 1.58; 95% confidence interval [CI] 1.20-2.07; p <0.001), and in infants with neonatal infection (hazard ratio 2.20; 95% CI 1.19-4.06; p = 0.01). There was no difference in the duration of hospital stay nor in the proportion of infants requiring respiratory or cardiovascular support before and after the change of protocol. Reduction of diagnostic tests such as CBC and CRP does not delay initiation of antibiotic treatment in infants with suspected EOS. The importance of clinical examination in infants with risk factors for EOS should be emphasised.

Residual venous obstruction, alone and in combination with D-dimer, as a risk factor for recurrence after anticoagulation withdrawal following a first idiopathic deep vein thrombosis in the prolong study.

OBJECTIVE: This study aims to assess the predictive value of residual venous obstruction (RVO) for recurrent venous thrombo-embolism (VTE) in a study using D-dimer to predict outcome. DESIGN: This is a multicentre randomised open-label study. METHODS: Patients with a first episode of idiopathic VTE were enrolled on the day of anticoagulation discontinuation when RVO was determined by compression ultrasonography in those with proximal deep vein thrombosis (DVT) of the lower limbs. D-dimer was measured after 1 month. Patients with normal D-dimer did not resume anticoagulation while patients with abnormal D-dimer were randomised to resume anticoagulation or not. The primary outcome measure was recurrent VTE over an 18-month follow-up. RESULTS: A total of 490 DVT patients were analysed (after excluding 19 for different reasons and 118 for isolated pulmonary embolism (PE)). Recurrent DVT occurred in 19% (19/99) of patients with abnormal D-dimer who did not resume anticoagulation and 10% (31/310) in subjects with normal D-dimer (adjusted hazard ratio: 2.1; p = 0.02). Recurrences were similar in subjects either with (11%, 17/151) or without RVO (13%, 32/246). Recurrent DVT rates were also similar for normal D-dimer, with or without RVO, and for abnormal D-dimer, with or without RVO. CONCLUSIONS: Elevated D-dimer at 1 month after anticoagulation withdrawal is a risk factor for recurrence, while RVO at the time of anticoagulation withdrawal is not.

Longer term clinical and virological outcome of sub-Saharan African participants on antiretroviral treatment in the Swiss HIV Cohort Study.

OBJECTIVES: Persons from sub-Saharan Africa (SSA) are increasingly enrolled in the Swiss HIV Cohort Study (SHCS). Cohorts from other European countries showed higher rates of viral failure among their SSA participants. We analyzed long-term outcomes of SSA versus North Western European participants. DESIGN: We analyzed data of the SHCS, a nation-wide prospective cohort study of HIV-infected adults at 7 sites in Switzerland. METHODS: SSA and North Western European participants were included if their first treatment combination consisted of at least 3 antiretroviral drugs (cART), if they had at least 1 follow-up visit, did not report active injecting drug use, and did not start cART with CD4 counts >200 cells per microliter during pregnancy. Early viral response, CD4 cell recovery, viral failure, adherence, discontinuation from SHCS, new AIDS-defining events, and survival were analyzed using linear regression and Cox proportional hazard models. RESULTS: The proportion of participants from SSA within the SHCS increased from 2.6% (<1995) to 20.8% (2005-2009). Of 4656 included participants, 808 (17.4%) were from SSA. Early viral response (6 months) and rate of viral failure in an intent-to-stay-on-cART approach were similar. However, SSA participants had a higher risk of viral failure on cART (adjusted hazard ratio: 2.03, 95% confidence interval: 1.50 to 2.75). Self-reported adherence was inferior for SSA. There was no increase of AIDS-defining events or mortality in SSA participants. CONCLUSIONS: Increased attention must be given to factors negatively influencing adherence to cART in participants from SSA to guarantee equal longer-term results on cART.

Predictors for the emergence of the 2 multi-nucleoside/nucleotide resistance mutations 69 insertion and Q151M and their impact on clinical outcome in the Swiss HIV cohort study.

The 69 insertion and Q151M mutations are multi-nucleoside/nucleotide resistance mutations (MNR). The prevalence among 4078 antiretroviral therapy (ART)-experienced individuals was <1.3%. Combined ART fully prevented MNR in subtype B infections. Case-control studies were performed to identify risk factors. Control subjects were patients with ≥ 3 thymidine-analogue mutations. The 69 insertion study (27 control subjects, 14 case patients) identified didanosine exposure as a risk (odds ratio, 5.0 per year; P = .019), whereas the Q151M study (which included 44 control subjects and 25 case patients) detected no associations. Following detection, individuals with Q151M tended to have lower suppression rates and higher mortality rates, relative to control subjects. Additional studies are needed to verify these findings in non-subtype B infections.

Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model.

Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 μM) and the more potent and specific P-gp inhibitor valspodar (5 μM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 μM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate.

Role of CD4+CD25+ regulatory T cells in the antigen specific induction of tolerance "via" the nasal route

ABSTRACT Asthma is a complex inflammatory syndrome caused by environmental factors in predisposed individuals (atopics). Its severity correlates with the presence of activated T lymphocytes and eosinophils in the bronchoalveolar lavage fluid (BALF). Induction of tolerance via the nasal route results in reduced recruitment of eosinophils into BALF upon challenge, inhibition of TH2 pro-inflammatory cytokine secretion and T cell hyporesponsiveness. Recently, CD4+CD25+ natural regulatory T cells (Treg) were proposed as key players in controlling the development of asthma and allergic disease. The objective of the present study is to investigate the role of CD4+CD25+ regulatory T cells in the mechanisms leading to tolerance in an established model of asthma. In this goal we depleted CD4+CD25+ T cells at different times during asthma and tolerance induction protocol in mice and looked at efficiency of tolerization (intranasal application of high dose of allergen) in the absence of natural Tregs. First, ovalbumin-sensitized mice were depleted of CD25+ T cells by intraperitoneal injection of anti-CD25 mAb (PC61) either for along-term (repeated injections of anti-CD25 from day 31 until the end of the protocol) or a short-term period (single injection of anti-CD25 before or after tolerance induction). We demonstrated that the long-term depletion of CD4+CD25+ T cells severely hampered tolerance induction (marked enhancement in eosinophil recruitment into BALF and a vigorous antigen specific T cell response to OVA upon allergen challenge) whereas transient depletions were not sufficient to do so. We then characterized T cell subsets by flow cytometry and observed that a large part of CD4+CD25+ T cells express Foxp3, an established marker of regulatory T cells. We also tested in-vitro suppressor activity of CD4+CD25+ T cells from tolerized mice by cell proliferation assay in coculture and observed a strong suppressive activity. Our data suggest that CD4+CD25+ T cells with regulatory properties play a crucial role in the induction of tolerance via the nasal route. The relationship between CD25+ natural Treg and inducible IL-10+ TRl-type Treg will have to be defined. RESUME L'asthme est un syndrome inflammatoire complexe provoqué par des facteurs environnementaux chez des individus génétiquement prédisposés (atopiques). Sa sévérité corrèle avec la présence des lymphocytes T activés et d'éosinophiles dans le lavage bronchoalvéolaire (BAL). L'induction de la tolérance par la voie nasale résulte en une diminution du recrutement des eosinophils dans le BAL, une inhibition de la sécrétion de cytokines pro-inflammatoires de type TH2 et de l'hypo-réponse des cellules T à l'allergène. Récemment, les cellules régulatrices «naturelles » de type CD4+CD25+ T (Tregs) ont été proposées comme acteurs essentiels dans le développement de l'asthme et de l'allergie. L'objectif de cette étude est d'étudier le rôle des cellules régulatrices CD4+CD25+ T dans les mécanismes menant à la tolérance dans un modèle établi d'asthme. Dans ce but nous avons déplété les cellules de CD4+CD25+ T à différents temps au cours du protocole d'induction d'asthme et de tolérance et nous avons regardé l'efficacité de l'induction de tolérance (application intranasale d'une dose importante d'allergène) en l'absence de Tregs. Dans un premier temps des souris sensibilisées à l'ovalbumine (OVA) ont été déplétées en cellules CD25+ T par l'injection intrapéritonéale d'anti-CD25 mAb (PC61) pour une longue période (injections répétées d'anti-CD25 du jour 31 jusqu'à la fin du protocole) ou pour une courte période (injection unique d'anti-CD25 avant ou après l'induction de tolérance). Nous avons démontré que la déplétion à long t erme des cellules de CD4+CD25+ T a empêché l'induction de tolérance (recrutement accru d'éosinophiles dans le BAL et une réponse vigoureuse des cellules T spécifiques de l'antigène après exposition à l'allergène) tandis des déplétions à court-terme n'ont pas cet effet. Nous avons ensuite caractérisé des sous-populations de cellules T par cytométrie de flux. Nous avons observé que la majorité des cellules CD4+CD25+ T expriment Foxp3, un marqueur établi des cellules régulatrices. Nous avons également examiné in vitro l'activité régulatrice des cellules T CD4+CD25+ issues de souris tolérisées. La prolifération de cellules T en coculture a démontré une forte activité suppressive des cellules CD4+CD25+. Nos données suggèrent que des cellules T CD4+CD25+ ayant des propriétés régulatrices jouent un rôle crucial dans l'induction de la tolérance par la voie nasale. Le rapport entre les cellules régulatrices naturelles CD4+CD25+ et les cellules régulatrices inductible de type TR1 I1-10+ devra être défini. RESUME DESTINE A UN LARGE PUBLIC L'asthme est une maladie inflammatoire des bronches, caractérisée par des crises de dyspnée (gêne respiratoire) témoignant d'une activation brutale des muscles bronchoconstricteurs, auxquelles s'associent un oedème et une hypersécrétion des muqueuses des voies aériennes ainsi qu'une importante production d'anticorps de l'allergie (IgE). Chez la plupart des enfants atteints et chez près de la moitié des adultes concernés par l'asthme, c'est une allergie à des substances présentes dans l'air environnant (acariens, pollens ou poils d'animaux) qui est à l'origine de la maladie. . Le traitement actuel de l'asthme repose d'une part sur le soulagement des symptômes grâce à des produits à base de stéroïdes ou des bronchodilatateurs. D'autre part, l'immunothérapie spécifique (aussi appelée désensibilisation) permet d'améliorer l'asthme et de «reprogrammer» le système immunitaire. C'est à ce jour, le seul moyen connu de faire régresser une allergie. Cependant l'immunothérapie prend beaucoup de temps (3 à 5 ans) et ne marche pas à tous les coups ni pour tous les antigènes. Il est donc important de mieux comprendre les mécanismes impliqués lors d'un tel traitement afin d'en améliorer l'efficacité. Af n de pouvoir investiguer en détail ces mécanismes des modèles d'immunothérapie ont été mis au point chez la souris. Notre étude se base sur un modèle d'asthme allergique chez la souris. Des souris sont rendues allergiques à l'ovalbumine (OVA) et présentent alors les caractéristiques majeures de l'asthme humain (recrutement de cellules inflammatoires dans les poumons, augmentation de la production d'IgE et de la résistance des bronches aux flux respiratoires). Ces souris asthmatiques une fois traitées par l'application nasale d'OVA (forme d'immunothérapie muqueuse) ne développent plus de réaction allergique lors d'une ré-exposition à l'allergène. Notre hypothèse est que cette «guérison» (tolérance) est liée à l'action de cellules (lymphocytes T CD4) dites «régulatrices» et caractérisées par le marqueur CD25. Pour le démontrer, nous avons éliminé ces cellules «régulatrices» CD25 de nos souris asthmatiques grâce à un anticorps monoclonal spécifique. Nous n'avons dès lors plus été en mesure d'induire une tolérance à l'allergène. Ceci suggère donc un rôle clé des cellules «régulatrices» T CD4+CD25+ dans la réussite de l'immunothérapie nasale dans notre modèle. Nos résultats n'excluent pas la participation d'autres cellules telles que les lymphocytes producteurs d'IL-10 (lymphocytes régulateurs induits). Le rôle respectif de ces sous-populations régulatrices devra être examiné dans les études à venir. Une meilleure maîtrise des mécanismes de régulation pourrait s'avérer cruciale pour améliorer les thérapies de l'asthme.

Carbon-isotope stratigraphy and ammonite faunal turnover for the Middle Jurassic in the Southern Iberian palaeomargin

Variations in the stable carbon-isotope ratio of marine and continental sediments can reflect changes in sink and flux modifications of the palaeocarbon cycle. Here we report carbon-isotope compositions of Middle Jurassic marine carbonates from the Betic Cordillera (southern Spain), which represents an ideal region to link the stable carbon-isotope curves directly to ammonite zones and subzones, and thereby for the first time achieve an accurate chronostratigraphic calibration. The five sections studied represent basin and high swell deposits of the Southern Iberian palaeomargin. We find a similar delta C-13 of carbonates between different oceanic areas, suggesting a homogeneous carbon-isotope oceanic reservoir through the Middle Jurassic. The Aalenian-Bajocian transition is a critical period in ammonite evolution; hence the Early Jurassic fauna are replaced by new ammonite families which become dominant throughout the Middle and Late Jurassic. For this reason, we compared the delta C-13 values of carbonates with ammonite diversity and extinction rates at different taxonomical levels in order to explore the possible relationship between the carbon cycle and ammonite evolution. The carbon-isotope values of carbonates are not exactly linearly correlated with the extinction rate and ammonite diversity, but the main faunal turnovers follow minimum delta C-13 values, where extinct taxa are replaced by new ones. Likewise, radiation episodes are associated with increasing delta C-13 values and with transgressive sea-level rise. All these data support the idea that perturbations in the global carbon cycle reflect rapid palaeoenvironmental changes. We made detailed analyses of these faunal turnovers, using them as a proxy to identify major palaeoenvironmental crises in their ecosystems forced by modification in the carbon cycle. (c) 2006 Elsevier B.V All rights reserved.

Prospective study of insulin-like growth factor-I, insulin-like growth factor-binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of coronary artery disease.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

Basin-internal derivation of hydrocarbons in the Witwatersrand Basin, South Africa: evidence from bulk and molecular δ13C data

Gold in the quartz-pebble conglomerates of the late Archean Witwatersrand Basin, South Africa, is often intimately associated with carbonaceous matter of organic/biogenic origin which occurs in the form of stratiform carbon seams and paragenetically late bitumen nodules. Both carbon forms are believed to be formed by solidification of migrating hydrocarbons. This paper presents bulk and molecular chemical and stable carbon isotope data for the carbonaceous matter, all of which are used to provide a clue to the source of the hydrocarbons. These data are compared with those from intra-basinal shales and overlying dolostone of the Transvaal Supergroup. The delta C-13 values of the extracts from the Witwatersrand carbonaceous material show small differences (up to 2.4 parts per thousand) compared to the associated insoluble organic matter. This suggests that the auriferous rocks were stained by mobile hydrocarbons produced by thermal and oxidative alteration of indigenous bitumens, a contribution from hydrocarbons derived from intra-basinal Witwatersrand shales cannot be excluded. Individual aliphatic hydrocarbons of the various carbonaceous materials were subjected to compound specific isotope analysis using on-line gas chromatography/combustion/stable isotope ratio mass spectrometry (GC/C/IRMS). The limited variability of the molecular parameters and uniform delta C-13 values of individual n-alkanes (-31.1 +/- 1.7 parts per thousand) and isoprenoids (-30.7 +/- 1.1 parts per thousand) in the Witwatersrand samples exclude the mixing of oils from different sources. Carbonaceous matter in the dolostones shows distinctly different bulk and molecular isotope characteristics and thus cannot have been the source of the hydrocarbons in the Witwatersrand deposits. All the various forms of Witwatersrand carbon appear indigenous to the Witwatersrand Basin, and the differences between them are explained by variable, in general probably short (centimeter- to meter-scale) hydrocarbon migration during diagenesis and subsequent hydrothermal infiltration. (C) 2001 Elsevier Science B.V. All rights reserved.

Vorapaxar in the secondary prevention of atherothrombotic events.

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).

Cigarette, cigar, and pipe smoking and the risk of head and neck cancers: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ≤ 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.