Sustained efficacy of dapagliflozin when added to metformin in type 2 diabetes inadequately controlled by metformin monotherapy

Background and aims: The selective SGLT2 inhibitor dapagliflozin (DAPA) reduces hyperglycaemia independently of insulin secretion or action by inhibiting renal glucose reabsorption. This study (MB102014) is a randomised double-blind, placebo (PBO)-controlled trial of DAPA added to metformin (MET) in T2DM (n=546) inadequately controlled with MET alone. Previously reported short-term data at week 24 showed significant mean reductions in the primary [HbA1c] and secondary [fasting plasma glucose (FPG) and weight] endpoints with DAPA compared to PBO. Here we report efficacy and safety results at week 102 of the long-term extension. Materials and methods: Patients aged 18-77 years with HbA1c 7-10% received DAPA 2.5 mg, 5 mg, 10 mg or PBO, plus open-label MET (≥1500mg/d). Exploratory endpoints at week 102 included changes from baseline in HbA1c, FPG and weight, and were analyzed by longitudinal repeated measures analysis. Results: Overall 71.2% of patients completed 102 weeks of the study; fewer on PBO (63.5%) than on DAPA 2.5 mg, 5 mg, and 10 mg (68.3%, 73.0%, 79.8%), due mainly to more patients on PBO discontinuing for lack of efficacy. At week 102, all DAPA groups showed greater mean reductions from baseline in HbA1c, FPG and weight compared to PBO (table), effects that were similar to those observed at week 24 and maintained throughout the trial. More patients at week 102 also achieved a therapeutic response of HbA1c<7% with DAPA 2.5 mg, 5 mg, and 10 mg (20.7%, 26.4%, 31.5%) than with PBO (15.4%). Adverse events (AEs), serious AEs and AEs leading to discontinuation were balanced across all groups. Signs and symptoms suggestive of genital infection (GenInf) were reported in 11.7%, 14.6%, 12.6% (DAPA 2.5 mg, 5 mg, 10 mg) and 5.1% (PBO) of patients, with 1 discontinuation due to GenInf. Signs and symptoms suggestive of urinary tract infection (UTI) were reported in 8.0%, 8.8%, 13.3% (DAPA 2.5 mg, 5 mg, 10 mg) and 8.0% (PBO), with 1 discontinuation due to UTI. No event of pyelonephritis was reported. Conclusion: In comparison to PBO, DAPA added to MET over 102 weeks demonstrated greater and sustained improvements in glycaemic control, clinically meaningful reduction in weight, and no increased risk of hypoglycaemia in patients with T2DM inadequately controlled with MET alone.

Selective Sonogashira Couplings in 1,2,4,5-tetrazine derivatives

1,2,4,5-Tetrazines are six-membered heterocyclic compounds in which the four nitrogen atoms are displayed in a symmetric fashion. Their reactivity is quite different from other heterocyclic aromatic systems due to its unique electron-withdrawing character, comparable to tetra-nitrobenzene. 1 In particular, 1,2,4,5- tetrazines are known to take part in [4+2] inverse-Diels–Alder cycloaddition processes which efficiently lead to the construction of substituted pyridazine systems that are important in drug development and biomarker applications. 2 However, the electronic character of 1,2,4,5-tetrazines hampered the development of 3- ethynyl- and 3,6-diethynyl-1,2,4,5-tetrazine derivatives for molecular electronic applications, proved by the scarcity of examples found in the literature. 3 Herein, we describe the synthesis and characterization of two novel ethynyl-based 1,2,4,5-tetrazine derivatives. Synthesis of 3,6-(4-bromophenyl)-1,2,4,5-tetrazine precursor (1) was achieved in good yield by Pinner’s method, starting from 4-bromobenzonitrile. Despite its low solubility in common organic solvents, this precursor was found to react smoothly under typical Sonogashira coupling conditions to selectively afford the 3-ethynyl (2) and 3,6-diethynyl (3) protected derivatives (Figure 1). Reaction conditions were evaluated in order to provide the best yields and to promote selectivity of the mono- or disubstituted ethynyl derivatives. Finally, deprotection was achieved affording, in the case of compound 3, an unprecedented 3,6- diethynyl-1,2,4,5-tetrazine compound. Time-Dependent Density Functional Theory (TDDFT) calculations for both deprotected ethynyl derivatives were used to simulate electronic spectra. A deep knowledge of the relevant electronic transitions involved and quantitatively satisfactory results of the calculated electronic excitations in comparison with experimental data were obtained.

Quantitative Proteomic Analysis Reveals Metabolic Alterations, Calcium Dysregulation, And Increased Expression Of Extracellular Matrix Proteins In Laminin α2 Chain-deficient Muscle.

Congenital muscular dystrophy with laminin α2 chain deficiency (MDC1A) is one of the most severe forms of muscular disease and is characterized by severe muscle weakness and delayed motor milestones. The genetic basis of MDC1A is well known, yet the secondary mechanisms ultimately leading to muscle degeneration and subsequent connective tissue infiltration are not fully understood. In order to obtain new insights into the molecular mechanisms underlying MDC1A, we performed a comparative proteomic analysis of affected muscles (diaphragm and gastrocnemius) from laminin α2 chain-deficient dy(3K)/dy(3K) mice, using multidimensional protein identification technology combined with tandem mass tags. Out of the approximately 700 identified proteins, 113 and 101 proteins, respectively, were differentially expressed in the diseased gastrocnemius and diaphragm muscles compared with normal muscles. A large portion of these proteins are involved in different metabolic processes, bind calcium, or are expressed in the extracellular matrix. Our findings suggest that metabolic alterations and calcium dysregulation could be novel mechanisms that underlie MDC1A and might be targets that should be explored for therapy. Also, detailed knowledge of the composition of fibrotic tissue, rich in extracellular matrix proteins, in laminin α2 chain-deficient muscle might help in the design of future anti-fibrotic treatments. All MS data have been deposited in the ProteomeXchange with identifier PXD000978 (http://proteomecentral.proteomexchange.org/dataset/PXD000978).

Epicardial And Pericardial Fat In Type 2 Diabetes: Favourable Effects Of Biliopancreatic Diversion.

Ectopic fat is often identified in obese subjects who are susceptible to the development of type 2 diabetes mellitus (T2DM). The ectopic fat favours the decrease in insulin sensitivity (IS) and adiponectin levels. We aimed to evaluate the effect of biliopancreatic diversion (BPD) on the accumulation of ectopic fat, adiponectin levels and IS in obese with T2DM. A nonrandomised controlled study was performed on sixty-eight women: 19 lean-control (23.0 ± 2.2 kg/m(2)) and 18 obese-control (35.0 ± 4.8 kg/m(2)) with normal glucose tolerance and 31 obese with T2DM (36.3 ± 3.7 kg/m(2)). Of the 31 diabetic women, 20 underwent BPD and were reassessed 1 month and 12 months after surgery. The subcutaneous adipose tissue, visceral adipose tissue, epicardial adipose tissue and pericardial adipose tissue were evaluated by ultrasonography. The IS was assessed by a hyperglycaemic clamp, applying the minimal model of glucose. One month after surgery, there was a reduction in visceral and subcutaneous adipose tissues, whereas epicardial and pericardial adipose tissues exhibited significant reduction at the 12-month assessment (p < 0.01). Adiponectin levels and IS were normalised 1 month after surgery, resembling lean-control values and elevated above the obese-control values (p < 0.01). After 12 months, the improvement in IS and adiponectin was maintained, and 17 of the 20 operated patients exhibited fasting glucose and glycated haemoglobin within the normal range. After BPD, positive physiological adaptations occurred in grade I and II obese patients with T2DM. These adaptations relate to the restoration of IS and decreased adiposopathy and explain the acute (1 month) and chronic (12 months) improvements in the glycaemic control.

Recovery Of The Incretin Effect In Type 2 Diabetic Patients After Biliopancreatic Diversion.

Context: Bariatric surgery often results in remission of the diabetic state in obese patients. Increased incretin effect seems to play an important role in the glycemic improvements after Roux-en-Y gastric bypass, but the impact of biliopancreatic diversion (BPD) remains unexplored. Objective: To elucidate the effect of BPD on the incretin effect and its interplay with beta-cell function and insulin sensitivity (IS) in obese subjects with type 2 diabetes (T2DM). Design, Setting and Patients: Twenty-three women were studied: a control group of 13 lean, normal glucose-tolerant women (lean NGT) studied once and 10 obese patients with T2DM studied before, 1 and 12 months after BPD. Intervention: The ObeseT2DM group underwent BPD. Main Outcome Measures: The change in incretin effect as measured by the isoglycemic intravenous glucose infusion test. Secondary outcomes encompassed IS and beta-cell function. Results: At baseline, the incretin effect was lower in obese T2DM compared to lean NGT (p<0.05). One month after BPD, the incretin effect was not changed, but at 12 months it reached the level of the lean NGT group (p>0.05). IS improved (p<0.05) 1 month after BPD and at 12 months it resembled the levels of the lean NGT group. Insulin secretory rate and beta-cell glucose sensitivity increased after BPD and achieved levels similar to lean NGT group 1 month after BPD and even higher levels at 12 months (p<0.05). Conclusions: BPD has no acute impact on the reduced incretin effect, but 12 months after surgery the incretin effect normalizes alongside normalization of glucose control, IS and beta-cell function.

Hypotheses, rationale, design, and methods for prognostic evaluation in type 2 diabetic patients with angiographically normal coronary arteries. The MASS IV-DM Trial

Background: The MASS IV-DM Trial is a large project from a single institution, the Heart Institute (InCor), University of Sao Paulo Medical School, Brazil to study ventricular function and coronary arteries in patients with type 2 diabetes mellitus. Methods/Design: The study will enroll 600 patients with type 2 diabetes who have angiographically normal ventricular function and coronary arteries. The goal of the MASS IV-DM Trial is to achieve a long-term evaluation of the development of coronary atherosclerosis by using angiograms and coronary-artery calcium scan by electron-beam computed tomography at baseline and after 5 years of follow-up. In addition, the incidence of major cardiovascular events, the dysfunction of various organs involved in this disease, particularly microalbuminuria and renal function, will be analyzed through clinical evaluation. In addition, an effort will be made to investigate in depth the presence of major cardiovascular risk factors, especially the biochemical profile, metabolic syndrome inflammatory activity, oxidative stress, endothelial function, prothrombotic factors, and profibrinolytic and platelet activity. An evaluation will be made of the polymorphism as a determinant of disease and its possible role in the genesis of micro- and macrovascular damage. Discussion: The MASS IV-DM trial is designed to include diabetic patients with clinically suspected myocardial ischemia in whom conventional angiography shows angiographically normal coronary arteries. The result of extensive investigation including angiographic follow-up by several methods, vascular reactivity, pro-thrombotic mechanisms, genetic and biochemical studies may facilitate the understanding of so-called micro- and macrovascular disease of DM.

Invasion of Ureaplasma diversum in Hep-2 cells

Background: Understanding mollicutes is challenging due to their variety and relationship with host cells. Invasion has explained issues related to their opportunistic role. Few studies have been done on the Ureaplasma diversum mollicute, which is detected in healthy or diseased bovine. The invasion in Hep-2 cells of four clinical isolates and two reference strains of their ureaplasma was studied by Confocal Laser Scanning Microscopy and gentamicin invasion assay. Results: The isolates and strains used were detected inside the cells after infection of one minute without difference in the arrangement for adhesion and invasion. The adhesion was scattered throughout the cells, and after three hours, the invasion of the ureaplasmas surrounded the nuclear region but were not observed inside the nuclei. The gentamicin invasion assay detected that 1% of the ATCC strains were inside the infected Hep-2 cells in contrast to 10% to the clinical isolates. A high level of phospholipase C activity was also detected in all studied ureaplasma. Conclusions: The results presented herein will help better understand U. diversum infections, aswell as cellular attachment and virulence.

Critical Properties at the Field-Induced Bose-Einstein Condensation in NiCl(2)-4SC(NH(2))(2)

We report new magnetization measurements on the spin-gap compound NiCl(2)-4SC(NH(2))(2) at the low-field boundary of the magnetic field-induced ordering. The critical density of the magnetization is analyzed in terms of a Bose-Einstein condensation of bosonic quasiparticles. The analysis of the magnetization at the transition leads to the conclusion for the preservation of the U(1) symmetry, as required for Bose-Einstein condensation. The experimental data are well described by quantum Monte Carlo simulations.

Flow boiling heat transfer of R134a and R245fa in a 2.3 mm tube

This paper presents new experimental flow boiling heat transfer results in micro-scale tubes. The experimental data were obtained in a horizontal 2.3 mm I.D stainless steel tube with heating length of 464 mm, R134a and R245fa as working fluids, mass velocities ranging from 50 to 700 kg m(-2) s(-1), heat flux from 5 to 55 kW m(-2), exit saturation temperatures of 22, 31 and 41 degrees C, and vapor qualities ranging from 0.05 to 0.99. Flow pattern characterization was also performed from images obtained by high-speed filming. Heat transfer coefficient results from 1 to 14 kW m(-2) K(-1) were measured. It was found that the heat transfer coefficient is a strong function of heat flux, mass velocity and vapor quality. The experimental data were compared against ten flow boiling predictive methods from the literature. Liu and Winterton [3], Zhang et al. [5] and Saitoh et al. [6] worked best for both fluids, capturing most of the experimental heat transfer trends. (C) 2010 Elsevier Ltd. All rights reserved.

Emissions of NO(x) and SO(2) from Coals of Various Ranks, Bagasse, and Coal-Bagasse Blends Burning in O(2)/N(2) and O(2)/CO(2) Environments

Oxy-coal combustion is a viable technology, for new and existing coal-fired power plants, as it facilitates carbon capture and, thereby, can mitigate climate change. Pulverized coals of various ranks, biomass, and their blends were burned to assess the evolution of combustion effluent gases, such as NO(x), SO(2), and CO, under a variety of background gas compositions. The fuels were burned in an electrically heated laboratory drop-tube furnace in O(2)/N(2) and O(2)/CO(2) environments with oxygen mole fractions of 20%, 40%, 60%, 80%, and 100%, at a furnace temperature of 1400 K. The fuel mass flow rate was kept constant in most cases, and combustion was fuel-lean. Results showed that in the case of four coals studied, NO(x) emissions in O(2)/CO(2) environments were lower than those in O(2)/N(2) environments by amounts that ranged from 19 to 43% at the same oxygen concentration. In the case of bagasse and coal/bagasse blends, the corresponding NO(x) reductions ranged from 22 to 39%. NO(x) emissions were found to increase with increasing oxygen mole fraction until similar to 50% O(2) was reached; thereafter, they monotonically decreased with increasing oxygen concentration. NO(x) emissions from the various fuels burned did not clearly reflect their nitrogen content (0.2-1.4%), except when large content differences were present. SO(2) emissions from all fuels remained largely unaffected by the replacement of the N(2) diluent gas with CO(2), whereas they typically increased with increasing sulfur content of the fuels (0.07-1.4%) and decreased with increasing calcium content of the fuels (0.28-2.7%). Under the conditions of this work, 20-50% of the fuel-nitrogen was converted to NO(x). The amount of fuel-sulfur converted to SO(2) varied widely, depending on the fuel and, in the case of the bituminous coal, also depending on the O(2) mole fraction. Blending the sub-bituminous coal with bagasse reduced its SO(2) yields, whereas blending the bituminous coal with bagasse reduced both its SO(2) and NO(x) yields. CO emissions were generally very low in all cases. The emission trends were interpreted on the basis of separate combustion observations.

The Protective Role of Lychnophora ericoides Mart. (Brazilian Arnica) in 1,2-Dimethylhydrazine-Induced Experimental Colon Carcinogenesis

Aberrant crypt foci (ACF) and colon rectal mucosal epithelial cell proliferation have been shown to be increased in patients with colon cancer and have been largely used for early detection of factors that influence colorectal carcinogenesis in rats. Fifty male Wistar rats were randomly divided into 5 groups. The groups G1 to G4 were given 4 injections of the carcinogen 1,2-dimethylhydrazine (DMH). The G2 group received Lychnophora ericoides (LE) extracts for 6 wk. The groups G3 and G4 received LE for 4 wk and 2 wk, respectively, at the postinitiation and initiation phases of colonic carcinogenesis. The group G5 was the control. Forty-two days after the first injections of DMH for the neoplasic induction, we observed a statistically significant decrease in the number of aberrant crypt foci (ACF) and an attenuation of the increase in cell proliferation induced by DMH in all the LE-treated groups. Thus, we concluded that Lychnophora ericoides extracts were effective against the development of cancer. These data suggest that LE has a protective influence on the process of colon carcinogenesis, suppressing both the initiation and the promotion of colonic carcinogenesis.

Two distinct regions in 2q24.2-q24.3 associated with idiopathic epilepsy

P>Approximately 50% of all carriers of 2q21-q31 deletions present epileptic seizures. The band 2q24 constitutes the smallest commonly deleted segment in these patients, and contains the voltage-gated sodium channel genes SCN1A and SCN2A, associated with Dravet syndrome and benign familial neonatal-infantile seizures, respectively. A further putative locus involving epilepsy in the region was previously identified through disruption of the SLC4A10 gene by translocation. In the course of performing high-resolution DNA copy number analyses on syndromic mentally impaired individuals, we encountered three patients with overlapping deletions in chromosome region 2q24. Two of these patients exhibited epileptic seizures in addition to mental deficiency. The deletion in one of the epileptic patients did not include the SCN cluster, demonstrating that a less severe form of epilepsy maps to an adjacent genomic region. This second region comprises about 3 Mb and contains the candidate gene SLC4A10, providing further support for the potential role of this gene in epilepsy.

Congenital intrahepatic arterioportal fistula presenting as severe undernutrition and chronic watery diarrhea in a 2-year-old girl

Intrahepatic arterioportal fistula (IAPF) is a rare cause of portal hypertension in young children. We report the case of a 2-year-old girl with severe undernutrition, chronic watery diarrhea, and gastrointestinal bleeding because of a congenital intrahepatic arterioportal fistula. Radiographic embolization and surgical ligation of the left hepatic artery were attempted, with no resolution of the symptoms. So, a left lobectomy was performed, with excellent results and prompt disappearance of the diarrhea. Hepatectomy should be considered as a definitive and reliable. therapy for congenital IAPF. (C) 2009 Elsevier Inc. All rights reserved.