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Aims To determine the impact of race and ethnicity on the efficacy, body weight and hypoglycaemia incidence with vildagliptin treatment in patients with type 2 diabetes mellitus using patient-level data from the vildagliptin clinical trial programme. Methods Data from 22 randomized, placebo-controlled global and local (Japan, China) registration studies of vildagliptin (50 mg once-daily or twice-daily) of ≥12-week duration were analysed by race (Caucasian [n = 2764] and Asian [n = 2232]) and by ethnicity (Japanese, Chinese, and Indian). The placebo-subtracted differences in the change in glycated haemoglobin (HbA1c) and body weight from baseline to week 12 or week 24 were evaluated by race or ethnicity using repeated measure analysis of unstructured covariance. Hypoglycaemia incidences were summarized using descriptive statistics. Results The HbA1c reduction from baseline with vildagliptin was similar across the racial/ethnic subgroups (−0.83% ± 0.02% to −1.01% ± 0.05%). Placebo-corrected HbA1c reduction was similar between Caucasian (−0.68% ± 0.03%) and Asian (−0.80% ± 0.03%) patients ( P value for interaction = .56); analysis by race and ethnicity showed better efficacy ( P < .02) in Japanese patients. Japanese patients were drug-naive and treated with a single oral anti-diabetes drug only; they showed no response to placebo. Weight neutrality of vildagliptin was demonstrated in all groups (0.47 ± 0.11 kg to −0.29 ± 0.08 kg). Hypoglycaemic events (≥1) were infrequent in all ethnic subgroups. Conclusions The glycaemic efficacy of vildagliptin was similar in Caucasian and Asian patients. The slightly better efficacy observed in Japanese patients was driven by the absence of placebo effect and might be explained by their earlier stage of diabetes compared to other subgroups.

Background The aim of the present study was to investigate the efficacy and safety of vildagliptin added onto insulin with or without metformin in an Asian, predominantly Chinese, population with type 2 diabetes mellitus (T2DM). Methods In this 24-week, multicenter, double-blind, placebo-controlled trial, patients with T2DM inadequately controlled (HbA1c 7.5%–11.0%) on stable therapy with long-acting, intermediate-acting, or premixed insulin, with or without concomitant metformin, were randomized to receive vildagliptin 50 mg b.i.d. or placebo. Results Of 293 patients randomized, 146 received vildagliptin and 147 received placebo treatment. At baseline, the overall mean age of patients was 58.1 years, mean T2DM duration was 11.3 years, and mean HbA1c was 8.7%. The adjusted mean (±SE) change in HbA1c at Week 24 in the vildagliptin and placebo groups was −1.08 ± 0.12% and −0.38 ± 0.12%, respectively (between-treatment difference −0.70 ± 0.16%; P

Aims To report the cardiovascular (CV) safety profile and heart failure (HF) risk of vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. Methods We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-vildagliptin treatments) was calculated using the Mantel–Haenszel (M–H) method. Results Of the 17 446 patients, 9599 received vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m2 (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61–1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M–H RR 1.08 (95% CI 0.68–1.70). Conclusions This large meta-analysis indicates that vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in vildagliptin-treated patients.

Summary Passive acoustic monitoring is frequently used for marine mammals, and more recently it has also become popular for terrestrial species. Key advantages are the monitoring of (1) elusive species, (2) different taxa simultaneously, (3) large temporal and spatial scales, (4) with reduced human presence and (5) with considerable time saving for data processing. However, terrestrial sound environments can be highly complex; they are very challenging when trying to automatically detect and classify vocalizations because of low signal-to-noise ratios. Therefore, most studies have used manual preselection of high-quality sounds to achieve better classification rates. Consequently, most systems have never been validated under realistic field conditions. In this study, we evaluated the performance of a passive acoustic monitoring system for four primate species in the highly noisy rain forest environment of the Tai National Park, Cote d'Ivoire. We collected 12 851 h of recordings with 20 autonomous recording units and did not preselect high-quality sounds manually. To automatically detect and classify the sounds of interest, we used an automated system built on speaker segmentation, support vector machines and Gaussian mixture models. One hundred and seventy-nine hours of recordings were used for validating the system. The system performed well in detecting the loud calls of Cercopithecus diana and Colobus polykomos with a recall of 50% and 42%, respectively. Recall rates were lower for Pan troglodytes and Procolobus badius. To determine the presence of Cercopithecus diana and Colobus polykomos with a certainty of P > 0·999, 2 and 7 h of recordings were needed, respectively. For these two species, our automated approach reflected the spatio-temporal distribution of vocalization events well. Despite the seemingly low precision, time investment for the manual removal of false positives in the system's output was only 3·5% compared to a human collecting and processing the primate vocalization data. The proposed monitoring system is already fully applicable for Cercopithecus diana and Colobus polykomos, whereas it needs further improvement for the other species tested. In principle, it can be applied to any distinctive animal sound and can be implemented for the collection of acoustic data for behavioural, ecological and conservation studies.

Objective The aim of the present study was to assess the efficacy and safety of vildagliptin as add-on to sulfonylurea therapy in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy. Methods The 24-week randomized double-blind placebo-controlled study compared vildagliptin 50 mg, q.d., with placebo as add-on to glimepiride in T2DM patients who were inadequately controlled (HbA1c 7.5%–11.0% [58–97 mmol/mol]) on a stable dose of sulfonylurea for ≥12 weeks before study entry. Results In all, 279 patients were randomized to receive either vildagliptin (n = 143) or placebo (n = 136). At baseline, overall mean age was 58.5 years, body weight 68.1 kg, duration of diabetes 6.9 years and daily glimepiride dose 3.3 mg. After 24 weeks, the adjusted mean change (AMΔ) in HbA1c was −0.7% (−8 mmol/mol; baseline 8.6%, 70 mmol/mol) in the vildagliptin group and −0.2% (−2 mmol/mol; baseline 8.7%, 72 mmol/mol) in the placebo group, with a treatment difference of −0.5% (−5 mmol/mol; P

Aim The aim of this study is to assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in type 2 diabetes mellitus (T2DM). Methods This is a multicentre, double-blind, placebo-controlled, parallel group, clinical trial in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. Patients received treatment with vildagliptin 50 mg bid or placebo for 24 weeks. Results In all, 449 patients were randomized to vildagliptin (n = 228) or placebo (n = 221). After 24 weeks, the difference in adjusted mean change in haemoglobin A1c (HbA1c) between vildagliptin and placebo was −0.7 ± 0.1% (p

The impact of bulky carcinogen-DNA adducts positioned at or near recognition sites (CpG) of eukaryotic DNA methyltransferases on their catalytic activities is poorly understood. In the present study, we employed site-specifically modified 30-mer oligodeoxyribonucleotides containing stereoisomeric benzo[a]pyrene diol epoxide (B[a]PDE)-derived guanine (B[a]PDE-N(2)-dG) or adenine (B[a]PDE-N(6)-dA) adducts of different conformations as substrates of the catalytic domain of murine Dnmt3a (Dnmt3a-CD). The fluorescence of these lesions was used to examine interactions between Dnmt3a-CD and DNA. In B[a]PDE-DNA•Dnmt3a-CD complexes, the intensity of fluorescence of the covalently bound B[a]PDE residues is enhanced relative to the protein-free value when the B[a]PDE is positioned in the minor groove [(+)- and (-)-trans-B[a]PDE-N(2)-dG adducts in the CpG site] and when it is intercalated on the 5'-side of the CpG site [(+)-trans-B[a]PDE-N(6)-dA adduct]. The fluorescence of B[a]PDE-modified DNA•Dnmt3a-CD complexes exhibits only small changes when the B[a]PDE is intercalated with base displacement in (+)- and (-)-cis-B[a]PDE-N(2)-dG adducts and without base displacement in the (-)-trans-B[a]PDE-N(6)-dA adduct. The initial rates of methylation were significantly reduced by the minor groove trans-B[a]PDE-N(2)-dG adducts, regardless of their position in the substrate and by the intercalated cis-B[a]PDE-N(2)-dG adducts within the CpG site. The observed changes in fluorescence and methylation rates are consistent with the flipping of the target cytosine and a catalytic loop motion within the DNA•Dnmt3a-CD complexes. In the presence of the regulatory factor Dnmt3L, an enhancement of both methylation rates and fluorescence was observed, which is consistent with a Dnmt3L-mediated displacement of the catalytic loop towards the CpG site.

Aim Assess long-term safety and efficacy of the dipeptidlyl peptidase-4 (DPP-4) inhibitor vildagliptin in 369 patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment (RI). Methods Double-blind, randomized, parallel-group, 52-week clinical trial comparing safety and efficacy of vildagliptin (50 mg qd, n = 216) and placebo (n = 153) added to ongoing stable antihyperglycaemic treatment, in patients with T2DM and moderate or severe (glomerular filtration rate [GFR] ≥30 to

Aliskiren is the first direct renin inhibitor approved for the treatment of hypertension. Blood pressure (BP) control in stage 2 hypertension with aliskiren monotherapy has not been reported. This was a post hoc analysis of the subgroup of patients with stage 2 systolic hypertension (baseline mean sitting systolic BP [msSBP]≥160 mmHg) who completed the 12-week monotherapy phase of a 6-month, double-blind, randomized study. A total of 175 patients were randomized to aliskiren 150 mg (n = 88) or ramipril 5 mg (n = 87) with optional up-titration to aliskiren 300 mg or ramipril 10 mg, respectively, at weeks 6 and 12. In the subgroup of patients with stage 2 systolic hypertension, aliskiren lowered msSBP and mean sitting diastolic BP (msDBP) by 22.3/12.7 mmHg from baseline to week 12; compared with a reduction of 18.1/10.2 mmHg with ramipril. The maximum BP reductions achieved with aliskiren were 60.0/34.0 mmHg (from a baseline of 172.7/107.3 mmHg). Aliskiren was noninferior (P < 0.0001) to ramipril for SBP reduction with nonsignificant superiority (P = 0.052), and superior (P = 0.043) to ramipril for DBP reduction. The proportion of patients who achieved BP control (

Electronic properties and magnetoresistance of polyimide (PI) films implanted by 40 keV Co + ions with high fluences at various ion current densities are studied. Insulator-to-metal transition (IMT) is found for the highest implantation fluence (1.25 x 10 17 cm -2 ) at ion current densities of 8 and 12 μA/cm 2 . The IMT is caused by the radiation-induced alteration of the implanted PI and agglomeration of the Co nanoparticles (NPs) providing an efficient percolation way for the charge carriers. Impedance spectroscopy shows the increase in capacitance with fluence for the samples on the dielectric side of the IMT, which is caused by formation of the conductive metal NPs and carbonised clusters separated by insulating polymer media. The percolation of the conductive phase for the samples on the metallic side of the IMT results in an inductive character of the impedance. The magnotoresistive effect is found to be positive for the samples on the dielectric side of the IMT and negative for the samples on the metallic side.

A system identification (SI) and Prony's model based algorithm for modelling and prediction of a time-domain transient response is introduced and applied to time-domain transmission line matrix (TLM) transient responses in order to extrapolate parameters of microwave circuits and accelerate the simulation process. Application of moment matching model order reduction (MOR) techniques to the TLM method is presented with emphasis placed on Krylov subspace methods based on the Lanczos process and its modifications. The Krylov subspace methods are attractive for MOR in the TLM framework because the construction of orthonormal and biorthogonal bases for correspondent Krylov subspaces can be carried out through a direct application of the implicit TLM solver. MOR applied to TLM allows one to generate a compact macromodel of a TLM-system and significantly reduce the computational time. The efficiency and advantages of the SI and MOR techniques are demonstrated through their applications to the full-wave analysis of different electromagnetic structures. In addition, a brief comparison of SI and MOR involved for modelling of a planar patch antenna is provided. Copyright © 2006 John Wiley & Sons, Ltd.

Cells of the mononuclear and endothelial lineages are targets for viruses which cause hemorrhagic fevers (HF) such as the filoviruses Marburg and Ebola, and the arenaviruses Lassa and Junin. A recent model of Marburg HF pathogenesis proposes that virus directly causes endothelial cell damage and macrophage release of TNF-alpha which increases the permeability of endothelial monolayers [Feldmann et al. , 1996]. We show that Lassa virus replicates in human monocytes/macrophages and endothelial cells without damaging them. Human endothelial cells (HUVEC) are highly susceptible to infection by both Lassa and Mopeia (a non-pathogenic Lassa-related arenavirus). Whereas monocytes must differentiate into macrophages before supporting even low level production of these viruses, the virus yields in the culture medium of infected HUVEC cells reach more than 7 log10 PFU/ml without cellular damage. In contrast to filovirus, Lassa virus replication in monocytes/macrophages fails to stimulate TNF-alpha gene expression and even down-regulates LPS-stimulated TNF-alpha mRNA synthesis. The expression of IL-8, a prototypic proinflammatory CXC chemokine, was also suppressed in Lassa virus infected monocytes/macrophages and HUVEC on both the protein and mRNA levels. This contrasts with Mopeia virus infection of HUVEC in which neither IL-8 mRNA nor protein are reduced. The cumulative down-regulation of TNF-alpha and IL-8 expression could explain the absence of inflammatory and effective immune responses in severe cases of Lassa HF.

The dependences of magnetoresistance and Hall coefficient on magnetic and electric fields are investigated in epitaxial n-GaAs layers with shallow donor concentration Nd ⪅ 1014 cm−3. Measurements are carried out at 4.5 K in magnetic fields up to 3 T. The investigated samples have S-shaped (current controlled) current-voltage characteristics due to impact ionization of shallow impurities. The relative magnetoresistance scales as ΔQ ∝ exp Bα at weak electric fields, where α = 2.06 ± 0.04 and 0.54 ± 0.02 for weak and strong magnetic fields, respectively, and ΔQ ∝ Bβ close to the breakdown field Ebr, where β = 1.09 ± 0.02. In electric fields above breakdown (E > Ebr) the magnetoresistance is found to be proportional to Bγ with γ = 1.96 ± 0.08. The Hall coefficient decreases for E Ebr with increasing magnetic field strength.

The effect of electric fields on the magnetoresistance of intermediately doped crystals (4 × 1015 ≦ ≦ ne ≦ 3 × 1016 cm−3) of n-type epitaxial gallium arsenide a t T = 4.2 K is studied. It is established that negative magnetoresistance is observed only in weak electric fields. Positive magnetoresistance is observed in an electric field higher than the impurity breakdown field. A transition from negative magnetoresistance to positive magnetoresistance is found to occur in an electric field less than the breakdown field. A model is suggested to explain magnetoresistance changes in electric fields, which takes into account the decrease of the negative component of magnetoresistance due to a decrease in the concentration of magnetic centres and the increase of the positive component due to the appearance of nonequilibrium carriers in the conduction band. [Russian Text Ignored].

Changes in the Hall coefficient and Fermi level (EF) at T = 300 K as a function of the flux (Tirr ≦ 50°C) of 60Co and stopping spectrum (Emax = 100 MeV) γ-rays, electrons (2.5 to 10 MeV), protons (640 MeV), and fast reactor neutrons in float-zone and pulled n- and p-type Si are studied. It is found that for all kinds of irradiation, the floated zone n-type Si changes the type of its conductivity and a Fermi level stabilization takes place within some range of particle fluxes at Ev + 0.48 eV (proton and neutron irradiation) or at Ev + 0.39 eV (60Co γ-rays, electrons). The Fermi level stabilization at Ev + 0.48 eV is concluded to be determined by the accumulation at dominant concentrations of divacancies having donor, (Ev + 0.28 eV), and acceptor, (Ec −0.40 eV), levels in the forbidden gap and the Fermi level stabilization at Ev + 0.39 eV the accumulation of multicharge complexes involving primary radiation defects and residual impurities (possibly, carbon). The Fermi level position near the middle of the forbidden gap at Ev + (0.54 ± 0.03) eV, which is achieved during prolonged irradiation, is due to the accumulation of vacancy and interstitial types of intrinsic structural damages, being annealed at T = 80 to 150°C. [Russian Text Ignored].

The change of charge-carrier concentration is studied when irradiating floated zone n- and p-type Si with ϱ = (1 to 5) × 102 and (1 to 60) × 103 ω cm by high fluxes of 60Co γ-rays (Φe = 1 × 1017 to 2 × 1019 cm−2) and electrons with energy Ee = 4 to 10 MeV (Φe = 1 × 1015 to 5 × 1016 cm−2). The temperature dependences of the Hall coefficient are measured. The analysis of the results on the accumulation under irradiation and annealing of radiation defects allows one to conclude that various trends of the dose dependences of hole concentration with the kinds of bombarding particles used are due to the difference in the production efficiencies of radiation defects under electron and γ-ray irradiation. The possibility of formation of phosphorus-two vacancy complexes by adding vacancies to E-centres during prolonged γ-irradiation is shown while electrons produce preferentially divacancies. Phosphorus-two vacancy complexes are stable up to T = 400 to 500 °C and introduce a deep acceptor level at Ev + 0.35 eV into the forbidden gap of Si. It is found that the annealing character of radiation defects in heavily irradiated Si does not depend on the kind of irradiation and is due to the rearrangements of intrinsic structural defects. [Russian Text Ignored].

Mossbauer spectroscopy was used to study the temperature dependence (4.2 to 77 K) of the hyperfine structure (hfs) in jarosites H3OFe3[(OH)6(SO4)2], Pb{Fe3[(OH)6(SO4)2]}2, and K(Fe2.5Al0.5)[(OH)6(SO4)2]. For the two first compounds the magnetic hfs collapsed above the Neel temperatures, 17.5 and 50 K, respectively, to a paramagnetic quadrupole doublet. In the third compound, at all temperatures in the range from TN=54 K down to 4.2 K the coexistence of the magnetic hfs and paramagnetic quadrupole doublet appeared. In this paper, a qualitative explanation of the newly observed phenomenon is given. Mit Mosbauerspektroskopie wurde die Temperaturabhangigkeit (4,2 bis 77 K) der Hyperfeinstruktur (hfs) in den Jarositen H3OFe3[(OH)6(SO4)2], Pb{Fe3[(OH)6(SO4)2]}2 und K(Fe2,5Al0,5) [(OH)6(SO4)2] untersucht. Fur die beiden ersten Verbindungen fallt die magnetische hfs oberhalb der Neel-Temperatur, 17,5 bzw. 50 K, zu einem paramagnetischen Quadrupol-Dublett zusammen. In der dritten Verbindung tritt im gesamten Temperatur-bereich von TN=54 K bis herunter zu 4,2 K die Koexistenz der magnetischen hfs und des paramagnetischen Quadrupol-Dubletts auf. Es wird eine qualitative Erklarung des beobachteten Phanomens gegeben.