Relationship of physical activity vs body mass index with type 2 diabetes in women

CONTEXT: Physical inactivity and body mass index (BMI) are established independent risk factors in the development of type 2 diabetes; however, their comparative importance and joint relationship with diabetes are unclear. OBJECTIVE: To examine the relative contributions and joint association of physical activity and BMI with diabetes. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 37 878 women free of cardiovascular disease, cancer, and diabetes with 6.9 years of mean follow-up. Weight, height, and recreational activities were reported at study entry. Normal weight was defined as a BMI of less than 25; overweight, 25 to less than 30; and obese, 30 or higher. Active was defined as expending more than 1000 kcal on recreational activities per week. MAIN OUTCOME MEASURE: Incident type 2 diabetes, defined as a new self-reported diagnosis of diabetes. RESULTS: During the follow-up, 1361 cases of incident diabetes occurred. Individually, BMI and physical activity were significant predictors of incident diabetes. Compared with normal-weight individuals, the multivariate-adjusted hazard ratio (HR) was 3.22 (95% confidence interval [CI], 2.69-3.87) for overweight individuals and 9.09 (95% CI, 7.62-10.8) for obese individuals. For overall activity (kilocalories expended per week), compared with the least active first quartile, the multivariate-adjusted HRs were 0.91 (95% CI, 0.79-1.06) for the second quartile, 0.86 (95% CI, 0.74-1.01) for the third, and 0.82 (95% CI, 0.70-0.97) for the fourth (P for trend =.01). In the combined analyses, overweight and obese participants, whether active or inactive, had significantly elevated risks, compared with normal-weight active individuals. The multivariate-adjusted HRs were 1.15 (95% CI, 0.83-1.59) for normal-weight inactive, 3.68 (95% CI, 2.63-5.15) for overweight active, 4.16 (95% CI, 3.05-5.66) for overweight inactive, 11.5 (95% CI, 8.34-15.9) for obese active, and 11.8 (95% CI, 8.75-16.0) for obese inactive participants. CONCLUSIONS: Although BMI and physical inactivity are independent predictors of incident diabetes, the magnitude of the association with BMI was greater than with physical activity in combined analyses. These findings underscore the critical importance of adiposity as a determinant of diabetes.     

Desmin‐related myopathy

van Spaendonck‐Zwarts KY, van Hessem L, Jongbloed JDH, de Walle HEK, Capetanaki Y, van der Kooi AJ, van Langen IM, van den Berg MP, van Tintelen JP. Desmin‐related myopathy. Desmin‐related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES). We provide (i) a literature review on DRM, including clinical manifestations, inheritance, molecular genetics, myopathology and management and (ii) a meta‐analysis of reported DES mutation carriers, focusing on their clinical characteristics and potential genotype–phenotype correlations. Meta‐analysis: DES mutation carriers (n = 159) with 40 different mutations were included. Neurological signs were present in 74% and cardiological signs in 74% of carriers (both neurological and cardiological signs in 49%, isolated neurological signs in 22%, and isolated cardiological signs in 22%). More than 70% of carriers exhibited myopathy or muscular weakness, with normal creatine kinase levels present in one third of them. Up to 50% of carriers had cardiomyopathy and around 60% had cardiac conduction disease or arrhythmias, with atrioventricular block as an important hallmark. Symptoms generally started during the 30s; a quarter of carriers died at a mean age of 49 years. Sudden cardiac death occurred in two patients with a pacemaker, suggesting a ventricular tachyarrhythmia as cause of death. The majority of DES mutations were missense mutations, mostly located in the 2B domain. Mutations in the 2B domain were predominant in patients with an isolated neurological phenotype, whereas head and tail domain mutations were predominant in patients with an isolated cardiological phenotype.     

Synthesis and biological evaluation of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids as inhibitors of human protein kinase CK2

A novel series of substituted (thieno[2,3-d]pyrimidin-4-ylthio)carboxylic acids has been synthesized and tested in vitro towards human protein kinase CK2. It was revealed that the most active compounds inhibiting CK2 are 3-{[5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid and 3-{[5-(4-ethoxyphenyl)thieno[2,3-d]pyrimidin-4-yl]thio}propanoic acid (IC₅₀ values are 0.1 μM and 0.125 μM, respectively). Structure-activity relationships of 28 tested thienopyrimidine derivatives have been studied and binding mode of this chemical class has been predicted. Evaluation of the inhibitors on seven protein kinases revealed considerable selectivity towards CK2.     

Cyclohexanol analogues are positive modulators of GABA(A) receptor currents and act as general anaesthetics in vivo

GABA(A) receptors meet all the pharmacological criteria required to be considered important general anaesthetic targets. In the following study, the modulatory effects of various commercially available and novel cyclohexanols were investigated on recombinant human γ-aminobutyric acid (GABA(A), α(1)β(2)γ(2s)) receptors expressed in Xenopus oocytes, and compared to the modulatory effects on GABA currents observed with exposures to the intravenous anaesthetic agent, propofol. Submaximal EC(20) GABA currents were typically enhanced by co-applications of 3-300 μM cyclohexanols. For instance, at 30 μM 2,6-diisopropylcyclohexanol (a novel compound) GABA responses were increased ~3-fold (although similar enhancements were achieved at 3 μM propofol). As regards rank order for modulation by the cyclohexanol analogues at 30 μM, the % enhancements for 2,6-dimethylcyclohexanol~2,6-diethylcyclohexanol~2,6-diisopropylcyclohexanol~2,6-di-sec-butylcyclohexanol ?2,6-di-tert-butylcyclohexanol~4-tert-butylcyclohexanol>cyclohexanol~cyclopentanol~2-methylcyclohexanol. We further tested the potencies of the cyclohexanol analogues as general anaesthetics using a tadpole in vivo assay. Both 2,6-diisopropylcyclohexanol and 2,6-dimethylcyclohexanol were effective as anaesthetics with EC(50)s of 14.0 μM and 13.1 μM respectively, while other cyclohexanols with bulkier side chains were less potent. In conclusion, our data indicate that cyclohexanols are both positive modulators of GABA(A) receptors currents and anaesthetics. The positioning and size of the alkyl groups at the 2 and 6 positions on the cyclohexanol ring were critical determinants of activity.     

Pregnancy in patients with thalassemia major: a cohort study and conclusions for an adequate care management approach

An improvement in quality of life and survival occurred among thalassemia major (TM) patients: pregnancy in such patients has become a reality. Safe pregnancy and delivery require efforts to ensure the best outcomes. Between 2007 and 2016, 30 TM patients had 37 pregnancies. We analyzed the hematological parameters before, during, and after pregnancies and in 19 patients a cardiovascular magnetic resonance (CMR) T2* was performed. The mean age at first pregnancy was 30 ± 4 years; the current mean age is 35 ± 5 years. Twenty-four patients (80%) had a single pregnancy, five patients (17%) had two pregnancies, and one patient (3%) became pregnant three times. Seventeen pregnancies (46%) were spontaneous, 20 (64%) needed gonadotrophin-induced ovulation and/or reproductive technologies. All pregnancies resulted in live births. Seven were twin pregnancies (19%). The mean gestational hemoglobin was 9.2 ± 0.5 g/dl, lower than pre- and postpregnancy (9.8 ± 1 g/dl, p = ns and 9.6 ± 1 g/dl, p = 0.02, respectively). Median ferritin levels increased progressively (1071, range 409–5724 ng/ml, before pregnancy vs 2231, range 836–6918 ng/ml, after pregnancy, p < 0.0001). CMR before pregnancy showed a normal cardiac T2* (mean 35.34 ± 8.90 ms) and a mean liver iron concentration (LIC) of 3.37 ± 2.11 mg/g dry weight (dw). After pregnancy, the mean cardiac T2* was 31.06 ± 13.26 ms and the mean LIC was significantly increased (9.06 ± 5.75 mg/g dw, p = 0.0001). Pregnancy is possible and safe in thalassemia major. During pregnancy, iron accumulates, especially in the liver; a prompt resumption of chelation after delivery is mandatory.