Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase

Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.     

Glycaemia (haemoglobin A1c) and incident ischaemic stroke: the Atherosclerosis Risk in Communities (ARIC) Study

BACKGROUND: Individuals with diabetes have a raised risk of stroke, but it is unclear whether sustained hyperglycaemia contributes to the development of cerebrovascular disease. Haemoglobin A1c (HbA(1c)), a measure of long-term glycaemia, is strongly related to retinopathy, nephropathy, and neuropathy in diabetes. We sought to assess the association between HbA(1c) and stroke in people with and without diabetes. METHODS: 10,886 participants without diabetes and 1635 participants with diabetes in the ARIC study, who did not have cardiovascular disease, were followed up for incident ischaemic stroke over 8-10 years. We assayed HbA(1c) for all 167 stroke cases and a sample of 680 non-cases in the adults without diabetes and for the full cohort of 1635 adults with diabetes (including 89 stroke cases). We assessed the relation between HbA(1c) concentrations (in tertiles specific for individuals with and without diabetes) and incident ischaemic stroke during follow-up using Cox proportional hazards models, controlling for risk factors for stroke. FINDINGS: The adjusted relative risks of stroke increased with increasing tertile of HbA1c in both adults without diabetes (p=0.02) and with diabetes (p<0.0001). Compared with adults without diabetes in the lowest tertile of HbA1c, the adjusted relative risks of stroke by HbA(1c) tertile were 1.18 (0.70-2.00) and 1.58 (0.94-2.66) in adults without diabetes and 1.75 (0.90-3.42), 2.29 (1.24-4.21), and 4.71 (2.69-8.25) in adults with diabetes. INTERPRETATION: Raised HbA(1c) could be an independent risk factor for stroke in people with and without diabetes, with relative risks similar to those previously reported for coronary heart disease.     

Gene immunization for allergic disorders

Conclusions For immunotherapy to regain a major role as a treatment for allergic disorders, improvements in current allergen immunotherapy are needed to decrease treatment-associated risks when compared to the risks involved in current pharmacological management protocols [1]. The recent findings described in this review suggest that there is potential for the development of a novel form of immunotherapy, i.e., allergen gene vaccination, which would be safe and effective. Gene vaccination does not result in inflammation when injected 11.d and has been shown to down-regulate antigen-specific IgE antibodies in mice and rats, and in the reduction of late phase allergic responses. The presence of ISS-containing DNA in the vaccine formulation, whether within the pDNA expression vectors, or co-injected, is important in the induction of IFN--mediated Th1 cell differentiation, IL-5 inhibition, and B cell isotype switching, which cumulatively may lead to the reduction of allergic responses (Fig. 4).To date, all the in vivo experiments showing IgE inhibition have been performed in mice and rats. However, based on the combined observations that pDNA is also taken up by human skin cells transplanted onto nude mice [25], and that ISS-containing DNA induces Th1-promoting cytokines from human PBMC, it is possible that the antiallergic responses observed in rodents will also occur in human. As for safety considerations, in vitro data indicate that the transfected cells secrete low levels of antigen which are unlikely to induce the anaphylactic reactions seen in vivo with classical immunotherapy. Furthermore, the allergens encoded by pDNA constructs can be designed to include a transmembrane domain and anchor, thereby preventing the secretion of allergen and possible induction of anaphylactic reactions.     

Study of the Breakup Under Shear of a New Thermally Reversible Water-in-Oil-in-Water (W/O/W) Multiple Emulsion

Purpose. Thickening of the external aqueous phase of W/O/W multiple emulsions is essential to increase the release under shear. However, it leads to globules bursting during fabrication. To reduce this problem, we have tested a novel thermally reversible hydrogel, EMP hydrogel. This way, the corresponding multiple emulsion (EMPME) would gel only at skin temperature, which may increase the active ingredient delivery when topically applied. Methods. Samples were sheared at different shear rates and temperatures (20, 30, and 35°C) with a controlled rheometer. A granulometric analysis was then performed with a laser diffraction granulometer, to assess the break up as a function of the shear rate at the three temperatures. Conductometric measurements (CDM 230 conductometer) provided the corresponding release curves. Results. As we expected, EMPME exhibited a thermally reversible behavior. Compared to a reference emulsion thickened by carbopol, this new thermo–sensitive multiple emulsion displayed higher break up and fraction released at 35°C. Conclusion. The first thermally reversible multiple emulsion has been developed in the present work. This one presents interesting advantages: (1) an easy fabrication process with a higher entrapment yield and (2) a higher fraction released at 35°C compared with the reference emulsion.     

Health of the elderly in a community in transition: a survey in Thiruvananthapuram City, Kerala, India

Results of a survey to assess the health and functional status of the elderly (defined as those who are 60 years or older) in Thiruvananthapuram city, the capital of Kerala state, India, are discussed. As the process of development results in longevity without concomitant economic success, traditional support systems break down. The differences in status of the elderly dependent on gender and socioeconomic class are highlighted. Women are poorer and generally suffer more morbidity than men in old age, even though their death rates are lower. The better-off among the elderly enjoy a quality of life much superior to their poor brethren. Thus, in transitional societies such as Kerala, socioeconomic status and gender play a significant role in determining the quality of life of the elderly, a finding which may have some policy implications.     

Pregnancy after bariatric surgery: a comprehensive review

Background Obesity continues to be a global epidemic, and strong evidence exists linking it with gestational complications such as macrosomia, hypertensive disorders of pregnancy, gestational diabetes, and cesarean section. Bariatric surgery, a highly effective treatment for obesity, may prevent such complications in subsequent pregnancies. Objective This review seeks to describe the risks and benefits of post-bariatric procedure pregnancies, in comparison to both community and obese cohorts. Results A thorough review of the literature suggests that post-surgery women are not at increased risk for poor perinatal outcomes, and moreover their risks for many obesity-related gestational complications are reduced after bariatric surgery. Data regarding fertility after bariatric surgery are quite ambiguous, however, and studies exist demonstrating both positive and negative associations between weight loss procedures and fertility. Conclusions Clinicians should be aware that data collected on this subject were often gathered from post-op pregnant women provided with good prenatal care and screening for nutritional deficiencies. Although pregnancy after bariatric surgery appears to be safe, providers should take extra care to properly monitor their post-op pregnant patients for appropriate weight gain and nourishment.