log(TG)/HDL-C is related to both residual cardiometabolic risk and β-cell function loss in type 2 diabetes males

<p>Abstract</p> <p>Background</p> <p>T2DM is associated with atherogenic dyslipidemia (AD), defined as decreased HDL-C plus raised triglycerides (TG). AD confers increased risk for CAD, even when LDL-C is at target. AD is rarely assessed due to lack of screening methods consensus.</p> <p>Aim</p> <p>To establish the prevalence and severity of AD from <it>log</it>(TG)/HDL-C in T2DM males, and to determine how it relates to cardiometabolic phenotype, glucose homeostasis, micro- and macrovascular complications, and 10-year <it>UKPDS </it>CV risk.</p> <p>Methods</p> <p>585 T2DM males divided according to quintiles (Q) of <it>log</it>(TG)/HDL-C. AD prevalence defined as HDL-C <40 mg.dL^-1plus TG ≥150 mg.dL^-1. β-cell function assessed with HOMA.</p> <p>Results</p> <p>Mean HDL-C and TG were 44 (13) and 204 (155) mg.dL^-1. AD prevalence was 35%. AD correlated with lower β-cell function, with accelerated loss of insulin secretion, and with poorer HbA_1clevels. AD was related to a high prevalence of CAD, and also to 10-year absolute CAD risk.</p> <p>Conclusions</p> <p><it>log</it>(TG)/HDL-C is a simple means to estimate AD and the residual CV risk it confers in T2DM. AD closely associates with major cardiometabolic and glucose homeostasis determinants and poorer metabolic control. The ratio also relates to macroangiopathy prevalence and ranks future CAD risk, and is well-suited to capture non-LDL-related macrovascular residual risk and major glycemic determinants.</p

Distinct patterns of somatic alterations in a lymphoblastoid and a tumor genome derived from the same individual

Although patterns of somatic alterations have been reported for tumor genomes, little is known on how they compare with alterations present in non-tumor genomes. A comparison of the two would be crucial to better characterize the genetic alterations driving tumorigenesis. We sequenced the genomes of a lymphoblastoid (HCC1954BL) and a breast tumor (HCC1954) cell line derived from the same patient and compared the somatic alterations present in both. The lymphoblastoid genome presents a comparable number and similar spectrum of nucleotide substitutions to that found in the tumor genome. However, a significant difference in the ratio of non-synonymous to synonymous substitutions was observed between both genomes (P = 0.031). Protein–protein interaction analysis revealed that mutations in the tumor genome preferentially affect hub-genes (P = 0.0017) and are co-selected to present synergistic functions (P < 0.0001). KEGG analysis showed that in the tumor genome most mutated genes were organized into signaling pathways related to tumorigenesis. No such organization or synergy was observed in the lymphoblastoid genome. Our results indicate that endogenous mutagens and replication errors can generate the overall number of mutations required to drive tumorigenesis and that it is the combination rather than the frequency of mutations that is crucial to complete tumorigenic transformation

Distinct patterns of somatic alterations in a lymphoblastoid and a tumor genome derived from the same individual

Although patterns of somatic alterations have been reported for tumor genomes, little is known on how they compare with alterations present in non-tumor genomes. A comparison of the two would be crucial to better characterize the genetic alterations driving tumorigenesis. We sequenced the genomes of a lymphoblastoid (HCC1954BL) and a breast tumor (HCC1954) cell line derived from the same patient and compared the somatic alterations present in both. The lymphoblastoid genome presents a comparable number and similar spectrum of nucleotide substitutions to that found in the tumor genome. However, a significant difference in the ratio of non-synonymous to synonymous substitutions was observed between both genomes (P = 0.031). Protein–protein interaction analysis revealed that mutations in the tumor genome preferentially affect hub-genes (P = 0.0017) and are co-selected to present synergistic functions (P < 0.0001). KEGG analysis showed that in the tumor genome most mutated genes were organized into signaling pathways related to tumorigenesis. No such organization or synergy was observed in the lymphoblastoid genome. Our results indicate that endogenous mutagens and replication errors can generate the overall number of mutations required to drive tumorigenesis and that it is the combination rather than the frequency of mutations that is crucial to complete tumorigenic transformation

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Micro- and macrovascular risk and complications in T2DM males with obstructive sleep apnea

BACKGROUND : Obstructive sleep apnea syndrome (OSAS) is a comorbidity of obesity. OSAS is also an independent risk factor for type 2 diabetes (T2DM). OSAS promotes incident major adverse cardiovascular events (MACE). The prevalence of OSAS and its association with MACE are poorly documented in T2DM, a high-risk population. METHODS : We analyzed 580 consecutive male T2DM outpatients in whom OSAS was diagnosed through combined evaluation, including (hetero)anamnesis, Epworth's Sleepiness Scale (ESS), overnight oximetry, and confirmed by polysomnography. OSAS (+) (n=66) were compared to OSAS (–) (n=514) regarding cardiovascular (CV) risk factors, microvascular complications, MACE, and UKPDS 10-year absolute CVD risk. RESULTS : Mean (1 SD) age was 63 (11) years, diabetes duration 13 (9) years. Metabolic syndrome (MetS) prevalence was 77%, and HbA 7.5 (1.5)%. OSAS prevalence was 11.4%. There were no differences in age, diabetes duration, smoking, blood pressure (BP), and lipids (except for triglycerides) between OSAS (+) and (–). There were significant differences in the ESS score, BMI, waist, relative/absolute fat, skeletal muscle, conicity index, and visceral fat, all significantly higher in OSAS (+). Micro- and macrovascular complication prevalences were high, though not significantly different, in both groups, except for stroke prevalence, which was doubled in OSAS (+): 15 vs 7%; P=.05). Fasting triglycerides and cystatin-C levels were significantly higher in OSAS (+), the increase in the latter being unrelated to differences in eGFR between groups. UKPDS Risk Engine input variables and predicted risk were all similar in both groups, with a 10-year risk for CAD 20% and 22%, respectively in OSAS (–) and OSAS (+) patients (NS). CONCLUSIONS : OSAS is frequent in male T2DM patients who exhibit a high-risk cardiometabolic phenotype characterized by severe MetS score and prevalence, central fat accretion, insulin resistance, hypertriglyceridemia, and raised cystatin-C. The data indicate an association between OSAS and stroke prevalence. Using the T2DM-specific UKPDS Risk Engine, absolute 10-year CVD risk estimates were elevated, though not significantly different, between OSAS subgroups in primary CV prevention

Multiple biomarker strategy based on parathyroid hormone and natriuretic peptides testing for improved prognosis of chronic heart failure

Biomarkers offer new perspectives for a more personalized management of patients with heart failure (HF). Hyperparathyroidism is common in HF patients and parathyroid hormone (PTH) testing might provide added value for the prognostication of HF patients. Our objectives were therefore to determine the efficiency of multiple biomarker strategy based on PTH and natriuretic peptides measurement for the risk stratification of patients with HF. Circulating concentrations of bioactive PTH 1-84 and natriuretic peptides, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP), were measured with automated immunoassays in 45 healthy individuals and 137 HF patients with reduced left ventricular ejection fraction. Circulating levels of PTH 1-84 and natriuretic peptides were significantly increased in HF patients in comparison to HF patients. Over a long-term follow-up, baseline PTH 1-84 levels were related to the risk of cardiovascular death. Furthermore, in multiple biomarker approach, PTH measurement was additive to BNP and NT-proBNP testing for the cardiovascular risk assessment of HF patients. In conclusion, the combination of PTH 1-84 and natriuretic peptides testing improves the prognostication of HF patients and might allowed more personalized approach for risk stratification and treatment selection in HF patients