Contribution of modifiable risk factors to social inequalities in type 2 diabetes: prospective Whitehall II cohort study.

OBJECTIVE: To assess the contribution of modifiable risk factors to social inequalities in the incidence of type 2 diabetes when these factors are measured at study baseline or repeatedly over follow-up and when long term exposure is accounted for. DESIGN: Prospective cohort study with risk factors (health behaviours (smoking, alcohol consumption, diet, and physical activity), body mass index, and biological risk markers (systolic blood pressure, triglycerides and high density lipoprotein cholesterol)) measured four times and diabetes status assessed seven times between 1991-93 and 2007-09. SETTING: Civil service departments in London (Whitehall II study). PARTICIPANTS: 7237 adults without diabetes (mean age 49.4 years; 2196 women). MAIN OUTCOME MEASURES: Incidence of type 2 diabetes and contribution of risk factors to its association with socioeconomic status. RESULTS: Over a mean follow-up of 14.2 years, 818 incident cases of diabetes were identified. Participants in the lowest occupational category had a 1.86-fold (hazard ratio 1.86, 95% confidence interval 1.48 to 2.32) greater risk of developing diabetes relative to those in the highest occupational category. Health behaviours and body mass index explained 33% (-1% to 78%) of this socioeconomic differential when risk factors were assessed at study baseline (attenuation of hazard ratio from 1.86 to 1.51), 36% (22% to 66%) when they were assessed repeatedly over the follow-up (attenuated hazard ratio 1.48), and 45% (28% to 75%) when long term exposure over the follow-up was accounted for (attenuated hazard ratio 1.41). With additional adjustment for biological risk markers, a total of 53% (29% to 88%) of the socioeconomic differential was explained (attenuated hazard ratio 1.35, 1.05 to 1.72). CONCLUSIONS: Modifiable risk factors such as health behaviours and obesity, when measured repeatedly over time, explain almost half of the social inequalities in incidence of type 2 diabetes. This is more than was seen in previous studies based on single measurement of risk factors.

The evolution of social discounting in hierarchically clustered populations.

The expression of a social behaviour may affect the fitness of actors and recipients living in the present and in the future of the population. When there is a risk that a future reward will not be experienced in such a context, the value of that reward should be discounted; but by how much? Here, we evaluate social discount rates for delayed fitness rewards to group of recipients living at different positions in both space and time than the actor in a hierarchically clustered population. This is a population where individuals are grouped into families, families into villages, villages into clans, and so on, possibly ad infinitum. The group-wide fitness effects are assumed to either increase or decrease the fecundity or the survival of recipients and can be arbitrarily extended in space and time. We find that actions changing the survival of individuals living in the future are generally more strongly discounted than fecundity-changing actions for all future times and that the value of future rewards increases as individuals live longer. We also find that delayed fitness effects may not only be discounted by a constant factor per unit delay (exponential discounting), but that, as soon as there is localized dispersal in a population, discounting per unit delay is likely to fall rapidly for small delays and then slowly for longer delays (hyperbolic discounting). As dispersal tends to be localized in natural populations, our results suggest that evolution is likely to favour individuals that express present-biased behaviours and that may be time-inconsistent with respect to their group-wide effects.

A combined computational and functional approach identifies new residues involved in pH-dependent gating of ASIC1a.

Acid-sensing ion channels (ASICs) are key receptors for extracellular protons. These neuronal nonvoltage-gated Na(+) channels are involved in learning, the expression of fear, neurodegeneration after ischemia, and pain sensation. We have applied a systematic approach to identify potential pH sensors in ASIC1a and to elucidate the mechanisms by which pH variations govern ASIC gating. We first calculated the pK(a) value of all extracellular His, Glu, and Asp residues using a Poisson-Boltzmann continuum approach, based on the ASIC three-dimensional structure, to identify candidate pH-sensing residues. The role of these residues was then assessed by site-directed mutagenesis and chemical modification, combined with functional analysis. The localization of putative pH-sensing residues suggests that pH changes control ASIC gating by protonation/deprotonation of many residues per subunit in different channel domains. Analysis of the function of residues in the palm domain close to the central vertical axis of the channel allowed for prediction of conformational changes of this region during gating. Our study provides a basis for the intrinsic ASIC pH dependence and describes an approach that can also be applied to the investigation of the mechanisms of the pH dependence of other proteins.

Dinor-oxo-phytodienoic acid: a new hexadecanoid signal in the jasmonate family.

Jasmonic acid and its precursors are potent regulatory molecules in plants. We devised a method for the simultaneous extraction of these compounds from plant leaves to quantitate changes in the levels of jasmonate family members during health and on wounding. During our study, we identified a novel 16-carbon cyclopentenoic acid in leaf extracts from Arabidopsis and potato. The new compound, a member of the jasmonate family of signals, was named dinor-oxo-phytodienoic acid. Dinor-oxo-phytodienoic acid was not detected in the Arabidopsis mutant fad5, which is incapable of synthesizing 7Z,10Z, 13Z-hexadecatrienoic acid (16:3), suggesting that the metabolite is derived directly from plastid 16:3 rather than by beta-oxidation of the 18-carbon 12-oxo-phytodienoic acid. Simultaneous quantitation of jasmonate family members in healthy leaves of Arabidopsis and potato suggest that different plant species have different relative levels of jasmonic acid, oxo-phytodienoic acid, and dinor-oxo-phytodienoic acid. We term these profiles "oxylipin signatures." Dinor-oxo-phytodienoic acid levels increased dramatically in Arabidopsis and potato leaves on wounding, suggesting roles in wound signaling. Treatment of Arabidopsis with micromolar levels of dinor-oxo-phytodienoic acid increased the ability of leaf extracts to transform linoleic acid into the alpha-ketol 13-hydroxy-12-oxo-9(Z) octadecenoic acid indicating that the compound can regulate part of its own biosynthetic pathway. Tightly regulated changes in the relative levels of biologically active jasmonates may permit sensitive control over metabolic, developmental, and defensive processes in plants.

Streptozotocin induces a shift towards T regulatory cell responses in vivo

Objectives: Streptozotocin (STZ) induced diabetes is currently the most commonly used animalmodel for islet transplantation.However, STZtreatment and the ensuing hyperglycemia were both shown to affect the immune response, including an apparent induction of lymphopenia. The aim of this study was to evaluate the respective effect of STZ and hyperglycemia on the immune system in STZ induced diabetic C57BL/6 mice. Methods: Phenotypes and levels of T and B cells were analyzed by flow cytometry in blood and spleen over time. The effect of hyperglycemia was further characterized by insulin replacement, islet transplantation and by using Rip (rat insulin promoter) DTR (dipheteria tocin receptor) transgenic mice. Results: STZ but not hyperglycemia was toxic for splenocytes in vitro, whereas hyperglycemia correlated with diabetes associated blood and spleen lymphopenia in vivo. Moreover, independently of hyperglycemia, STZ lead to a relative increase of T regulatory cells which retained their suppressive capacity in vitro. Conclusion: These data suggest thatSTZand the ensuing acute hyperglycemia have major direct and indirect effects on immune homeostasis. Thus, high caution needs to be exercised in the interpretation of the results of tolerance induction and/or immunosuppressive protocols in STZ-induced diabetes and islet transplantation models.

A new clinical test in diagnosing quadriceps tendon rupture.

INTRODUCTION: Extensor mechanism ruptures might be easily overlooked and misdiagnosed, and delayed diagnosis of quadriceps tendon rupture is frequent. However, the literature recommends early surgical repair within 72 h. PATIENTS AND METHODS: This paper describes a new simple clinical diagnostic test that directly evaluates the integrity of the distal 5 cm of the quadriceps tendon itself. It consists of inserting a needle in the tendon, proximal to the suspected rupture and mobilising the knee joint. RESULTS: The suspected ruptured quadriceps tendons with a positive 'needle' diagnostic test were confirmed intra-operatively. CONCLUSIONS: This minimally invasive and easily available technique should be considered in the diagnostic work-up and treatment planning of patients with suspected tears of the quadriceps tendon.

Nouvelles armes thérapeutiques contre le mélanome de stade IV [New therapeutic weapons in stage IV melanoma].

The treatment of stage IV melanoma has been revolutionized over the last years with the development of immunotherapies that, for the first time, have shown a significant benefit in overall survival, as well as with extremely effective targeted therapies, that also led to improved survival. These results are the fruits of an important translational research effort that allowed a rational approach with a very fast clinical development. The treatment of metastatic melanoma is, therefore, an illustration of the new paradigms of modern molecular research in oncology. In this review, we will present the various agents that have made the proof of their clinical benefit, as well as the scientific discoveries that allowed their development. Some of the remaining questions will be touched upon with the ongoing clinical trials. Inclusion of patients in these studies remains the top priority to improve on the clinical care.