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The high-precision X-ray diffraction setup for work with diamond anvil cells (DACs) in interaction chamber 2 (IC2) of the High Energy Density instrument of the European X-ray Free-Electron Laser is described. This includes beamline optics, sample positioning and detector systems located in the multipurpose vacuum chamber. Concepts for pump-probe X-ray diffraction experiments in the DAC are described and their implementation demonstrated during the First User Community Assisted Commissioning experiment. X-ray heating and diffraction of Bi under pressure, obtained using 20 fs X-ray pulses at 17.8 keV and 2.2 MHz repetition, is illustrated through splitting of diffraction peaks, and interpreted employing finite element modeling of the sample chamber in the DAC.

In the current study, the metabolism of two novel psychoactive substances (NPSs), mephedrone and methoxetamine (MXE), was studied in vitro in pig liver microsomes to determine potential metabolites by liquid chromatography-mass spectrometry (LC-MS). Later, in vitro studies were performed using HepaRG™ cells to determine the human metabolites of these drugs using gas chromatography-mass spectrometry (GC-MS). The aim of the study was to detect metabolites from the metabolic mixture in the human cell lines using GC-MS, since this is a more readily available technique within forensic laboratories. Microsomes were prepared through a conventional ultracentrifugation method and incubated under optimized conditions with the drugs for 3 h. Subsequently, the samples were investigated using LC-MS. A similar methodology was then applied in the HepaRG™ cells, and the GC-MS conditions were optimized using N,O-bis(trimethylsilyl)trifluoroacetamide as a derivatization agent. The analysis showed two molecules from a successful in vitro metabolism, namely, hydroxytoly-mephedrone and nor-dihydro mephedrone. For MXE, two metabolites are presented produced by the O-demethylation and reduction of the ketone moiety to the corresponding alcohol, respectively. Using the human HepaRG™ cells, only nor-dihydro mephedrone could be identified by GC-MS. Since hydroxytoly-mephedrone and the MXE metabolites are more polar, it is suggested that GC-MS even with derivatization may not be suitable. In addition, cytotoxicity was studied utilizing HepaRG™ cell lines. The drugs show cytotoxic effects causing in vitro cell death, within the specified range of EC50 0.3211 mM (79 μg/mL) and 0.6297 mM (111 μg/mL) for mephedrone and MXE, respectively. These drugs were able to cause 73–84% cell death.

The identification of the fuel found in a crime scene and establishing its source is important for forensic investigations. In this study petrol and diesel samples were analysed in order to identify chemical composition and additives with the aim of obtaining a set of markers or compounds that will allow forensic scientists to identify fuel sources. The study was performed using petrol and diesel sold in the city of Lincoln (UK) during four seasons (winter, spring, summer, autumn).Diesel samples, representing eight different brands were analyzed by gas chromatography−mass spectrometry (GC−MS) and principal component analysis (PCA). From the GC–MS analytical results, MTBE and ETBE were identified as the additive more preferably added in super unleaded petrol samples that can be used to aid in separation and identification. In diesel, the distribution of FAME contents showed the effect of seasonal variation as these were found in all spring, summer and autumn samples, but not found in all winter ones. The selection of a reduced number of key fuel compounds and additives was also shown to be sufficient to achieve a high level of classification among the different fuel samples. Leave–one–out cross–validation was applied in order to validate the results.

OBJECTIVE: To compare the efficacy and tolerability of vildagliptin and rosiglitazone during a 24-week treatment in drug-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, active-controlled, parallel-group, multicenter study of 24-week treatment with vildagliptin (100 mg daily, given as equally divided doses; n = 519) or rosiglitazone (8 mg daily, given as a once-daily dose; n = 267). RESULTS: Monotherapy with vildagliptin and rosiglitazone decreased A1C (baseline = 8.7%) to a similar extent during the 24-week treatment, with most of the A1C reduction achieved by weeks 12 and 16, respectively. At end point, vildagliptin was as effective as rosiglitazone, improving A1C by -1.1 +/- 0.1% (P < 0.001) and -1.3 +/- 0.1% (P < 0.001), respectively, meeting the statistical criterion for noninferiority (upper-limit 95% CI for between-treatment difference

Objective: To compare long-term efficacy and safety of initial combination therapy with nateglinide/metformin versus glyburide/metformin.Research Design and Methods: We conducted a randomized, multicenter, double-masked, 2-year study of 428 drug-naïve patients with type 2 diabetes. Patients received 120 mg a.c. nateglinide or 1.25 mg q.d. glyburide plus 500 mg q.d. open-label metformin for the initial 4 weeks. During a subsequent 12-week titration period, glyburide and metformin were increased by 1.25- and 500-mg increments to maximum daily doses of 10 and 2,000 mg, respectively, if biweekly fasting plasma glucose (FPG) > or = 6.7 mmol/l. Nateglinide was not titrated. Blinding was maintained by use of matching placebo for nateglinide and glyburide. An 88-week monitoring period followed, during which HbA1c (A1C), FPG, and postprandial glucose excursions (PPGEs) during an oral glucose tolerance test were measured.Results: In nateglinide/metformin-treated patients, mean A1C was 8.4% at baseline and 6.9% at week 104. In glyburide/metformin-treated patients, mean A1C was 8.3% at baseline and 6.8% at week 104 (P < 0.0001 vs. baseline for both treatments, NS between treatments). The deltaPPGE averaged -96 +/- 19 (P < 0.0001) and -57 +/- 22 mmol.l(-1).min(-1) (P < 0.05) in patients receiving nateglinide/metformin and glyburide/metformin, respectively, whereas deltaFPG was -1.6 +/- 0.2 (P < 0.0001) and -2.4 +/- 0.2 mmol/l (P < 0.0001) in patients receiving nateglinide/metformin and glyburide/metformin, respectively (P < 0.01 between groups). Thus, the two treatments achieved similar efficacy with differential effects on FPG versus PPGE. Hypoglycemia occurred in 8.2 and 17.7% of patients receiving nateglinide/metformin and glyburide/metformin, respectively.Conclusions: Similar good glycemic control can be maintained for 2 years with either treatment regimen, but nateglinide/metformin may represent a safer approach to initial combination therapy. [ABSTRACT FROM AUTHOR]

In the municipalities Ventaquemada and Turmequé (Boyacá- Colombia), we identified 20 small agricultures by their production systems including the following Andean tubers: Ullucus tuberosus Caldas (ulluco), Oxalis tuberosa Molina (oca), and Tropaeolum tuberosum R. & P. (Mashua), which were important in their family meals and culture, however, their use has declined and the area has not seen research and development processes that provide alternatives for handling, conservation, use and marketing, and now are at the risk of disappearing. This research conducted participatory assessment processes for the characterization of production systems and initiated reassessment processes of territorial heritage, identifying common sub-farm agrobiodiversity and projects for these traditional Andean tuber crops in order to enhance the special and knowhow knowledge surrounding the production.

Resumen: Condiciones de vida deficientes, contaminación fecal de agua, de alimentos y del suelo favorecen la transmisión de parásitos intestinales. Para establecer asociación entre pobreza e infestación parasitaria se evaluaron aspectos socio-sanitarios (composición familiar, estrato social, vivienda), ambientales (agua, excretas) y coproparasitológicos (examen directo y kato) en 257 sujetos (2 a 18 años), de Valencia Estado Carabobo. Se encontró: Predominio de escolares en estrato IV, de estructura monofamiliar y de 5 personas por grupo; 48,2% de infestación, alta prevalencia en escolares (mono (57,3%) y poliparasitismo (52,6%). Los protozoarios fueron más prevalentes en el estrato IV (63,9%) y los helmintos en el estrato V (64,3%). No se encontró asociación estadísticamente significativa entre estrato socioeconómico por el método de Graffar- Méndez Castellano y parasitosis, pero sí entre parasitosis y ausencia de cloacas, agua no tratada, baño intradomiciliario, ausencia de piso y número de personas por familia. Predominio de protozoarios en familias de hasta 5 personas (56,6%) y helmintos en familias con más de cinco personas (78,6%). Asociación significativa entre Blastocystis hominis, Entamoeba coli y Ascaris lumbricoides y familias de más de 5 personas. Hubo estrecha asociación entre parasitosis y condiciones socio-sanitarias, ambientales y conductuales, lo que favorece la morbilidad en este grupo poblacional, perpetuando el ciclo de pobreza e infestación parasitaria. Abstract: Poor living conditions, fecal contamination of food, water and soil are factors that contribute to intestinal parasites transmission. In order to stablish association between poverty and parasite infestation, socio-sanitary (family structure, social stratum, housing), environmental (water and excreta disposition) and coproparasitological (direct and kato examination) aspects were evaluated, in 257 subjects (2-18 years old), from Valencia, Carabobo State. Findings were: High prevalence of school children, of stratum IV, of monofamiliar structure, with five persons per group. Parasite infestation was found in 48.2% of children, more prevalent in school children, with mono (53.7%) and polyparasitism (52.6%). Protozoa forms were more prevalent in stratum IV (63.9%) and helminths forms in stratum V (64.3%). There was not statistically significant association between socioeconomic strata assessed by Graffar-Méndez Castellano method and parasitic infestation, but between parasitic infestation and sociosanitary conditions (absence of sewers, non-treated water, intradomicile bath, absence of floor and number of people by family), statistically significant association was present. Predominance of protozoa in subjects from small families groups (less than five persons) was 56.6% while in children from large families groups (higher than five persons), prevalence of helminths was 78.6%. Significant association was found between Blastocystis hominis, Entamoeba coli and Ascaris lumbricoides and large families groups. It is concluded that a strong and significant association was found between parasite infestations and socio-sanitary, environmental and cultural conditions, situation that favours a high morbidity rate, which perpetuates the interactions cycle of poverty and parasite infestations.

El presente artículo trata de exponer cómo incide en la organización de fondos y servicios un contexto bilíngüe, alemán-español, en una biblioteca en el exterior, orientada fundamentalmente al usuario y especializada en cultura hispánica.

The use of spherical wave expansion of the solution of the wave equation to predict Far-Field values from data measured in the Near-Field region is a well known technique, typically used to perform antenna measurements in compact anechoic chambers. However, when designing the computing algorithm it is fundamental to validate the results and to quantify the numerical error of the method. In this regard, a computer application that samples the electric Near-Field and calculates the values of the electric Far-Field region using spherical wave expansion was developed to measure antenna radiation patterns in the Fresnel zone inside a fully anechoic chamber. In order to validate the code, this paper describes three validation methods: firstly, using the theoretical electric Near-Field values of an infinitesimal dipole as the input to the algorithm to compare the output with the response analytically expected; secondly, using a Far-Field electric field data of a calibrated half wavelength dipole measured in an anechoic chamber and finally, using an electric Near-Field data of a calibrated half wavelength dipole measured in the same chamber. These methods provide simple procedures to calculate the error introduced by the code in different scenarios that should be considered to estimate the measurement uncertainty.

El uso de la expansión de la solución de la ecuación de onda en coordenadas esféricas es una técnica bien conocida para la caracterización de antenas dentro de cámaras anecoicas compactas. Sin embargo, al diseñar el algoritmo de cómputo, es fundamental validar los resultados y cuantificar el error numérico del método. Para ello, se desarrolló un código que calcula el campo eléctrico radiado a partir de las muestras de campo eléctrico en la zona de Fresnel utilizando expansión de ondas en coordenadas esféricas, permitiendo estimar el patrón de radiación. La validación del código se realiza de tres maneras: primeramente, se utilizan los valores de campo eléctrico cercano generado por un dipolo infinitesimal calculados analíticamente, para compararse luego los resultados de dicho algoritmo con los valores de campo lejano de la antena obtenidos por su expresión analítica; en segundo lugar, se mide el campo eléctrico en zona lejana de un dipolo de media onda calibrado, se utilizan dichos valores como entrada al programa y la salida se compara con la entrada utilizada; y, finalmente, se mide el campo eléctrico en zona cercana de un dipolo de media onda calibrado, se determina el campo lejano con el algoritmo y los valores resultantes se comparan con las mediciones de la misma antena en campo lejano. Estas pruebas permitieron calcular el error introducido por el código en escenarios diferentes, los cuales ayudan a estimar la incertidumbre de la medición.

Levothyroxine (LT4) is the standard of care for treating hypothyroidism. Despite the established efficacy of LT4, 50% of treated patients fail to achieve normal thyrotropin levels. Oral formulations of LT4 that bypass the gastric phase of dissolution may offset some of the therapeutic shortcomings observed with tablets. An oral solution of LT4 can be administered to patients who are unable to swallow tablets; allows flexibility to individualize dosing; and may mitigate interference with LT4 absorption caused by food, coffee, increased gastric pH from atrophic gastritis, and malabsorption from bariatric surgery. The bioavailability of a novel LT4 oral solution and a reference LT4 tablet were compared in a randomized, laboratory-blinded, single-dose, 2-period, 2-sequence, crossover study in healthy euthyroid subjects. A single 600-μg oral dose of LT4 solution (30 mL × 100 μg/5 mL) or tablet (2 × 300-μg tablet) was administered under fasting conditions in each study period, and total thyroxine concentrations were measured for 72 hours after administration. The ratio of geometric least-squares means and 90% confidence intervals for area under the concentration-time curve from time 0 to 72 hours and maximum plasma concentration were calculated. Among 42 subjects in the pharmacokinetic population, the geometric least-squares mean ratio of area under the concentration-time curve from time 0 to 72 hours and maximum plasma concentration for baseline-adjusted thyroxine was 109.1% and 107.9%, respectively, meeting Food and Drug Administration bioequivalence criteria. Adverse events (AEs) were similar between treatment groups with no serious AEs or discontinuations for AEs. Comparable bioavailability was observed between the LT4 oral solution and reference tablet after a single oral 600-μg dose under fasting conditions., (© 2023, The American College of Clinical Pharmacology.)

The search for new materials is intimately linked to the development of synthesis methods. In the current urge for the sustainable synthesis of materials, taking inspiration from Nature's ways to process matter appears as a virtuous approach. In this review, we address the concept of geoinspiration for the design of new materials and the exploration of new synthesis pathways. In geoinspiration, materials scientists take inspiration from the key features of various geological systems and processes occurring in nature, to trigger the formation of artificial materials and nanomaterials. We discuss several case studies of materials and nanomaterials to highlight the basic geoinspiration concepts underlying some synthesis methods: syntheses in water and supercritical water, thermal shock syntheses, molten salt synthesis and high pressure synthesis. We show that the materials emerging from geoinspiration exhibit properties differing from materials obtained by other pathways, thus demonstrating that the field opens up avenues to new families of materials and nanomaterials. This review focuses on synthesis methodologies, by drawing connections between geosciences and materials chemistry, nanosciences, green chemistry, and environmental sciences.

Chronic Chagas disease (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis compared to other cardiomyopathies. We show the expression and activity of Matrix Metalloproteinases (MMP) and of their inhibitors TIMP (tissue inhibitor of metalloproteinases) in myocardial samples of end stage CCC, idiopathic dilated cardiomyopathy (DCM) patients, and from organ donors. Our results showed significantly increased mRNA expression of several MMPs, several TIMPs and EMMPRIN in CCC and DCM samples. MMP-2 and TIMP-2 protein levels were significantly elevated in both sample groups, while MMP-9 protein level was exclusively increased in CCC. MMPs 2 and 9 activities were also exclusively increased in CCC. Results suggest that the balance between proteins that inhibit the MMP-2 and 9 is shifted toward their activation. Inflammation-induced increases in MMP-2 and 9 activity and expression associated with imbalanced TIMP regulation could be related to a more extensive heart remodeling and poorer prognosis in CCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Baron, Ferreira, Teixeira, Moretti, Santos, Frade, Kuramoto, Debbas, Benvenuti, Gaiotto, Bacal, Pomerantzeff, Chevillard, Kalil and Cunha-Neto.)

Mercury's metallic core is expected to have formed under highly reducing conditions, resulting in the presence of significant quantities of silicon alloyed to iron. Here we present the phase diagram of the Fe-FeSi system, reconstructed from in situ X-ray diffraction measurements at pressure and temperature conditions spanning over those expected for Mercury's core, and ex situ chemical analysis of recovered samples. Under high pressure, we do not observe a miscibility gap between the cubic fcc and B2 structures, but rather the formation of a re-entrant bcc phase at temperatures close to melting. Upon melting, the investigated alloys are observed to evolve towards two distinct Fe-rich and Fe-poor liquid compositions at pressures below 35-38 GPa. The evolution of the phase diagram with pressure and temperature prescribes a range of possible core crystallization regimes, with strong dependence on the Si abundance of the core., (© 2022. The Author(s).)

The ultrafast synthesis of ε-Fe 3 N 1+ x in a diamond-anvil cell (DAC) from Fe and N 2 under pressure was observed using serial exposures of an X-ray free electron laser (XFEL). When the sample at 5 GPa was irradiated by a pulse train separated by 443 ns, the estimated sample temperature at the delay time was above 1400 K, confirmed by in situ transformation of α- to γ-iron. Ultimately, the Fe and N 2 reacted uniformly throughout the beam path to form Fe 3 N 1.33 , as deduced from its established equation of state (EOS). We thus demonstrate that the activation energy provided by intense X-ray exposures in an XFEL can be coupled with the source time structure to enable exploration of the time-dependence of reactions under high-pressure conditions.

Properties of liquid silicates under high-pressure and high-temperature conditions are critical for modeling the dynamics and solidification mechanisms of the magma ocean in the early Earth, as well as for constraining entrainment of melts in the mantle and in the present-day core-mantle boundary. Here we present in situ structural measurements by X-ray diffraction of selected amorphous silicates compressed statically in diamond anvil cells (up to 157 GPa at room temperature) or dynamically by laser-generated shock compression (up to 130 GPa and 6,000 K along the MgSiO 3 glass Hugoniot). The X-ray diffraction patterns of silicate glasses and liquids reveal similar characteristics over a wide pressure and temperature range. Beyond the increase in Si coordination observed at 20 GPa, we find no evidence for major structural changes occurring in the silicate melts studied up to pressures and temperatures exceeding Earth's core mantle boundary conditions. This result is supported by molecular dynamics calculations. Our findings reinforce the widely used assumption that the silicate glasses studies are appropriate structural analogs for understanding the atomic arrangement of silicate liquids at these high pressures., Competing Interests: The authors declare no competing interest.

In this article, the specification and application of the new double-sided YAG laser-heating system built on beamline I15 at Diamond Light Source are presented. This system, combined with diamond anvil cell and X-ray diffraction techniques, allows in situ and ex situ characterization of material properties at extremes of pressure and temperature. In order to demonstrate the reliability and stability of this experimental setup over a wide range of pressure and temperature, a case study was performed and the phase diagram of lead was investigated up to 80 GPa and 3300 K. The obtained results agree with previously published experimental and theoretical data, underlining the quality and reliability of the installed setup., (open access.)

Objective: ITCA 650 is a subdermal osmotic mini-pump that continuously delivers exenatide subcutaneously for 3-6 months. The efficacy, safety, and tolerability of ITCA 650 added to diet and exercise alone or combined with metformin, sulfonylurea, or thiazolidinedione monotherapy or a combination of these drugs was evaluated in poorly controlled patients with type 2 diabetes (T2D) who were ineligible for participation in a placebo-controlled study (FREEDOM-1) because of severe hyperglycemia (HbA 1c >10% [86 mmol/mol])., Research Design and Methods: This 39-week, open-label, phase 3 trial enrolled patients aged 18-80 years with HbA 1c >10% to ≤12% (86-108 mmol/mol) and BMI 25-45 kg/m 2 . Patients received ITCA 650 20 μg/day for 13 weeks, then 60 μg/day for 26 weeks. The primary end point was change in HbA 1c at week 39., Results: Sixty patients were enrolled. At baseline, mean HbA 1c was 10.8% (94.7 mmol/mol) and mean (± SD) duration of diabetes was 8.6 (± 5.3) years. At week 39, there was a mean reduction in HbA 1c of -2.8% (-30.3 mmol/mol; P < 0.001 vs. baseline) and in body weight of -1.2 kg ( P = 0.105), and 25% of patients achieved HbA 1c <7% (53 mmol/mol). A reduction in HbA 1c of ≥1% (≥10.9 mmol/mol) occurred in 90% of patients. The most common adverse events were nausea, vomiting, diarrhea, and headache. Gastrointestinal adverse events were generally transient and subsided over time; only 4 patients (6.7%) discontinued for gastrointestinal events., Conclusions: Treatment with ITCA 650, the first injection-free glucagon-like peptide 1 receptor agonist, resulted in significant improvements in glycemic control in poorly controlled long-standing T2D patients with a high baseline HbA 1c >10%., (© 2018 by the American Diabetes Association.)

Objective: ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes., Research Design and Methods: This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA 1c ) 7.5-10% [58-86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 μg/day, or ITCA 650 60 μg/day. Primary end point was change in HbA 1c at 39 weeks., Results: Least squares (LS) mean change from baseline HbA 1c was -1.1% [-12.2 mmol/mol] and -1.2% [-13.2 mmol/mol] for ITCA 650 40 and 60 μg/day, respectively ( P < 0.001 vs. placebo -0.1% [-1.3 mmol/mol]). In a prespecified analysis, greater HbA 1c reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (-1.7% vs. -1.2% [-18.6 and -13.1 mmol/mol]). At week 39, HbA 1c <7% [53 mmol/mol] was attained in 37%, 44%, and 9% of ITCA 650 40 μg/day, ITCA 650 60 μg/day, and placebo groups, respectively ( P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was -2.3 kg and -3.0 kg for ITCA 650 40 and 60 μg/day, respectively ( P ≤ 0.015 vs. placebo -1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient., Conclusions: ITCA 650 significantly reduced HbA 1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications., (© 2017 by the American Diabetes Association.)

Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America and affects 10 million people worldwide. Approximately 12000 deaths attributable to Chagas disease occur annually due to chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy presenting with heart failure and arrythmia; 30% of infected subjects develop CCC years after infection. Genetic mechanisms play a role in differential progression to CCC, but little is known about the role of epigenetic modifications in pathological gene expression patterns in CCC patients' myocardium. DNA methylation is the most common modification in the mammalian genome., Methods: We investigated the impact of genome-wide cardiac DNA methylation on global gene expression in myocardial samples from end-stage CCC patients, compared to control samples from organ donors., Results: In total, 4720 genes were differentially methylated between CCC patients and controls, of which 399 were also differentially expressed. Several of them were related to heart function or to the immune response and had methylation sites in their promoter region. Reporter gene and in silico transcription factor binding analyses indicated promoter methylation modified expression of key genes. Among those, we found potassium channel genes KCNA4 and KCNIP4, involved in electrical conduction and arrythmia, SMOC2, involved in matrix remodeling, as well as enkephalin and RUNX3, potentially involved in the increased T-helper 1 cytokine-mediated inflammatory damage in heart., Conclusions: Results support that DNA methylation plays a role in the regulation of expression of pathogenically relevant genes in CCC myocardium, and identify novel potential disease pathways and therapeutic targets in CCC.

The identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing Trypanosoma cruzi -induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by T. cruzi . Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after T. cruzi infection, the mechanisms underlying its effects on T. cruzi -induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of T. cruzi Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during T. cruzi infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that T. cruzi -induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-γ-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of T. cruzi -infected animals. Furthermore, in vivo IFN-γ blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively, we describe a novel regulatory mechanism where Ebi3 dampens cardiac inflammation by modulating the overproduction of IFN-γ, the bona fide culprit of Chagas disease cardiomyopathy.

Long noncoding RNAs (lncRNAs) modulate gene expression at the epigenetic, transcriptional, and posttranscriptional levels. Dysregulation of the lncRNA known as myocardial infarction-associated transcript (MIAT) has been associated with myocardial infarction. Chagas disease causes a severe inflammatory dilated chronic cardiomyopathy (CCC). We investigated the role of MIAT in CCC. A whole-transcriptome analysis of heart biopsy specimens and formalin-fixed, paraffin-embedded samples revealed that MIAT was overexpressed in patients with CCC, compared with subjects with noninflammatory dilated cardiomyopathy and controls. These results were confirmed in a mouse model. Results suggest that MIAT is a specific biomarker of CCC., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

The β1i, β2i and β5i immunoproteasome subunits have an important role in defining the repertoire of MHC class I-restricted epitopes. However, the impact of combined deficiency of the three immunoproteasome subunits in the development of protective immunity to intracellular pathogens has not been investigated. Here, we demonstrate that immunoproteasomes play a key role in host resistance and genetic vaccination-induced protection against the human pathogen Trypanosoma cruzi (the causative agent of Chagas disease), immunity to which is dependent on CD8+ T cells and IFN-γ (the classical immunoproteasome inducer). We observed that infection with T. cruzi triggers the transcription of immunoproteasome genes, both in mice and humans. Importantly, genetically vaccinated or T. cruzi-infected β1i, β2i and β5i triple knockout (TKO) mice presented significantly lower frequencies and numbers of splenic CD8+ effector T cells (CD8+CD44highCD62Llow) specific for the previously characterized immunodominant (VNHRFTLV) H-2Kb-restricted T. cruzi epitope. Not only the quantity, but also the quality of parasite-specific CD8+ T cell responses was altered in TKO mice. Hence, the frequency of double-positive (IFN-γ+/TNF+) or single-positive (IFN-γ+) cells specific for the H-2Kb-restricted immunodominant as well as subdominant T. cruzi epitopes were higher in WT mice, whereas TNF single-positive cells prevailed among CD8+ T cells from TKO mice. Contrasting with their WT counterparts, TKO animals were also lethally susceptible to T. cruzi challenge, even after an otherwise protective vaccination with DNA and adenoviral vectors. We conclude that the immunoproteasome subunits are key determinants in host resistance to T. cruzi infection by influencing both the magnitude and quality of CD8+ T cell responses.

Chagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.

Objective: to verify the effectiveness of the rubber elastic band in the treatment of large wounds of the body wall of rabbits by means of traction of its edges., Methods: we studied 30 New Zealand rabbits, divided into three groups (n=10): Group 1- healing by secondary intention; Group 2- removal and eutopic repositioning of skin as full thickness skin graft; Group 3- Approximation of wound edges with elastic rubber band. In all animals, we removed a segment of the back skin and subcutaneous tissue down to the fascia, in accordance with an acrylic mold of 8 cm long by 12 cm wide. All animals were observed for 21 days., Results: two animals of groups 1 and 2 had wound abscess. In Group 2, there was partial or total graft loss in 90% of animals. The complete closure of the wounds was observed in four animals of Group 1, six of Group 2 and eight of Group 3. There was no difference between the scar resistance values of groups 2 and 3, which were higher than those in Group 1. The scars of the three groups were characterized by the presence of mature connective tissue mixed with blood vessels and inflammatory infiltration, predominantly polymorphonuclear., Conclusion: the tensile strength of the wound edges with rubber elastic band is as efficient as the skin graft to treat rabbits' large body wounds.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) could provide valuable findings for tendon regeneration. A non-invasive image method that can effectively evaluate the quality of the scar tissue has not yet been employed., Methods: Thirteen New Zealand rabbits were divided into two groups: group 1--non-treated control (n = 4); group 2--surgical intervention (n = 9). The central portion of the Achilles tendon was resected, and after 30 days, DCE-MRI was performed. Contrast enhancement methods were applied using the region of interest (ROI) technique. In the medium third of the Achilles tendon, the intra-substantial signal intensity and the presence of hyper-intense intra-tendon focus points and of signal heterogeneity were evaluated. Antero-posterior and transversal diameters of the tendon were measured. The Achilles tendon was removed and dissected free from other tissues. Sections from the central part of the tendon were stained for histological analysis., Results: The difference between the contrast enhancement curves of the control and surgical groups (p < 0.0001) was observed. The surgical group had an intense contrast enhancement in the contrast sequences, enlargement of the diameter and intra-substantial signal intensity alteration, with hyper-signal focus points and widening of the tendon sheath, which presented irregular contours and intense contrast enhancement. On histology, the Achilles tendon presented diffuse widening of the tendon sheath and wedge-shaped areas with scarring tissue rich in disordered collagen fibres. These findings were related to alteration in the intra-substantial signal intensity, with hyper-signal focus points in the DCE-MRI., Conclusions: MRI with perfusion could be a useful technique for evaluating tissue and fibrous scarring in tendons.

Chagas disease cardiomyopathy (CCC), the main consequence of Trypanosoma cruzi (T.cruzi) infection, is an inflammatory cardiomyopathy that develops in up to 30% of infected individuals. The heart inflammation in CCC patients is characterized by a Th1 T cell-rich myocarditis with increased production of interferon (IFN)-γ, produced by the CCC myocardial infiltrate and detected at high levels in the periphery. IFN-γ has a central role in the cardiomyocyte signaling during both acute and chronic phases of T.cruzi infection. In this review, we have chosen to focus in its pleiotropic mode of action during CCC, which may ultimately be the strongest driver towards pathological remodeling and heart failure. We describe here the antiparasitic protective and pathogenic dual role of IFN-γ in Chagas disease.

Background/methods: Chagas disease is caused by an intracellular parasite, Trypanosoma cruzi, and it is a leading cause of heart failure in Latin America. The main clinical consequence of the infection is the development of a Chronic Chagas disease Cardiomyopathy (CCC), which is characterized by myocarditis, hypertrophy and fibrosis and affects about 30% of infected patients. CCC has a worse prognosis than other cardiomyopathies, like idiopathic dilated cardiomyopathy (DCM). It is well established that myocardial gene expression patterns are altered in CCC, but the molecular mechanisms underlying these differences are not clear. MicroRNAs are recently discovered regulators of gene expression, and are recognized as important factors in heart development and cardiovascular disorders (CD). We analyzed the expression of nine different miRNAs in myocardial tissue samples of CCC patients in comparison to DCM patients and samples from heart transplant donors. Using the results of a cDNA microarray database on CCC and DCM myocardium, signaling networks were built and nodal molecules were identified., Results: We observed that five miRNAs were significantly altered in CCC and three in DCM; importantly, three miRNAs were significantly reduced in CCC as compared to DCM. We observed that multiple gene targets of the differentially expressed miRNAs showed a concordant inverse expression in CCC. Significantly, most gene targets and involved networks belong to crucial disease-related signaling pathways., Conclusion: These results suggest that miRNAs may play a major role in the regulation of gene expression in CCC pathogenesis, with potential implication as diagnostic and prognostic tools., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Optimizing glycemic control in patients with type 2 diabetes mellitus (T2DM) not controlled with ≥ 1 oral antidiabetes drugs (OADs) is challenging. Many therapeutic options exist; however, data comparing the effectiveness of different strategies are lacking for the management of patients with T2DM. Our study aim was to provide comparative data on efficacy and hypoglycemia when initiating insulin glargine (glargine) versus alternative treatment options (not including the newest antidiabetes agents, glucagon-like peptide [GLP]-1 receptor agonists, dipeptidyl peptidase [DPP]-4 inhibitors or sodium-glucose linked transporter [SGLT]-2 inhibitors) in insulin-naive patients with T2DM who remained uncontrolled with OADs., Methods: Patient-level data were pooled from 9 randomized controlled trials of ≥ 24 weeks duration with comparable patient populations. The effect of adding glargine was compared with intensification of lifestyle interventions or OADs, addition of neutral protamine Hagedorn (NPH) insulin, insulin lispro, premixed insulin, or all comparators pooled, on patient glycated hemoglobin (HbA1c) level, fasting plasma glucose level, weight, and hypoglycemia., Results: A greater proportion of patients achieved a target HbA1c level ≤ 7.0% with glargine treatment than with pooled comparators, intensification of OADs, or lifestyle interventions; there was no difference when compared with NPH, premixed, or insulin lispro use. The rate for reported hypoglycemic events was lower for glargine use than for pooled comparators or other insulins, but higher compared with intensification of lifestyle interventions or OADs. When stratified by baseline HbA1c level, efficacy/target attainment with glargine use was better than for pooled comparators across all HbA1c strata; OAD intensification, when baseline HbA1c level was ≥ 8.0%; and premixed insulin if baseline HbA1c level was < 8.0%; but similar to other insulins for all other categories. The incidence of reported hypoglycemia was less frequent with glargine use than other insulins, but more frequent than intensification of lifestyle interventions or OADs., Conclusion: When adequate glycemic control is not achieved using OADs in patients with T2DM, initiating insulin glargine is generally less likely to elicit hypoglycemia than initiating NPH, premixed, or prandial insulins, and the benefit-risk balance supports initiating insulin rather than intensification of OAD therapy when baseline HbA1c level is ≥ 8.0%.

Background: Cardiovascular risk factors (CVRFs) may complicate optimization of therapy in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with oral antidiabetes drugs (OADs). We assessed the influence of patient baseline CVRFs on efficacy and rate of hypoglycemia with use of insulin glargine (glargine) added to ongoing OAD treatment compared with alternative therapeutic options; namely, intensification of lifestyle interventions or adding OADs, neutral protamine Hagedorn (NPH), lispro, or premixed insulin in patients failing OADs., Methods: Patient-level data were pooled from 9 randomized controlled trials of glargine and comparators for 24 weeks in insulin-naive patients with T2DM inadequately controlled on OADs. Efficacy (goal attainment-glycated hemoglobin (HbA1c) level ≤ 7.0% or decrease ≥ 1.0% change from baseline) and hypoglycemia rates (symptomatic, confirmed, nocturnal, or severe) were compared for patients treated with glargine (n = 1462) and pooled (n = 1476) and individual comparators, overall; and in patients with hypertension (~69%), dyslipidemia (~58%), history of cardiovascular disease (~25%), or any CVRF (~83%) at baseline., Results: The patient groups were well-balanced at baseline (HbA1c level 8.7%; diabetes duration, 8.6 years). Use of glargine was associated with greater patient goal attainment (57.7% vs 51.4% for HbA1c level ≤ 7.0%; P < 0.001), modestly larger reductions in HbA1c level (-1.68% vs -1.51%; P < 0.001), and less symptomatic hypoglycemia than occurred with pooled comparators, regardless of patient CVRFs (5.04 vs 7.01 events/patient-year of exposure, respectively; P < 0.001). Reductions in HbA1c level and hypoglycemia rates were significantly greater with glargine use than with intensification of OADs or lifestyle modifications, overall, and in patients with any CVRF. Reductions in HbA1c level were greater and hypoglycemia rates lower with use of glargine compared with premixed insulin, overall, and in patients with any CVRF. Reductions in HbA1c level were similar and hypoglycemia rates lower with use of glargine, NPH, and lispro insulin, regardless of patient CVRFs., Conclusion: The glycemic benefits of glargine use compared with alternative therapeutic options are maintained without excess hypoglycemia in patients with CVRFs.

Aims: Evaluate the efficacy and tolerability of ITCA 650 in subjects with type 2 diabetes treated for up to 48 weeks., Methods: This was a 24-week extension to a randomized, 24-week, open-label, phase 2 study in subjects with type 2 diabetes inadequately controlled with metformin. Subjects received ITCA 650 mg (20, 40, 60 or 80 μg/day). Mean changes for HbA1c, weight, and fasting plasma glucose (FPG) were evaluated., Results: Mean changes in HbA1c from baseline to week 48 ranged from -0.85% to -1.51%. At week 48, ≥64% of subjects with an HbA1c ≤7% at week 24 maintained an HbA1c ≤7%. The incidence of adverse events (AEs) was dose-related and ranged from 13.3% with 20 μg/day to 37.5% with 80 μg/day. Most AEs were mild and transient; the incidence of nausea declined from 12.9% to 9.5% over the 24-week extension. One subject on ITCA 650 80 μg/day experienced mild intermittent vomiting. Three (3.5%) subjects experienced severe AEs, but none were considered related to study drug., Conclusion: Significant changes in HbA1c, body weight, and FPG attained with ITCA 650 were maintained to 48 weeks. The incidence of AEs was lower in the 24-week extension than in the initial 24-week treatment phase., (Published by Elsevier Inc.)

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is characterized by immunopathology driven by IFN-γ secreting Th1-like T cells. T. cruzi has a thick coat of mucin-like glycoproteins covering its surface, which plays an important role in parasite invasion and host immunomodulation. It has been extensively described that T. cruzi or its products-like GPI anchors isolated from GPI-anchored mucins from the trypomastigote life cycle stage (tGPI-mucins)-are potent inducers of proinflammatory responses (i.e., cytokines and NO production) by IFN-γ primed murine macrophages. However, little is known about whether T. cruzi or GPI-mucins exert a similar action in human cells. We therefore decided to further investigate the in vitro cytokine production profile from human mononuclear cells from uninfected donors exposed to T. cruzi as well as tGPI-mucins. We observed that both living T. cruzi trypomastigotes and tGPI-mucins are potent inducers of IL-12 by human peripheral blood monocytes and this effect depends on CD40-CD40L interaction and IFN-γ. Our findings suggest that the polarized T1-type cytokine profile seen in T. cruzi infected patients might be a long-term effect of IL-12 production induced by lifelong exposure to T. cruzi tGPI-mucins.

Objective: To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes., Research Design and Methods: We conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 μg/day of ITCA 650 or Ex-BID 5 → 10 μg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 μg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24., Results: HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9-8.0% was -0.98, -0.95, and -0.72% for the 20 and 40 μg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤ 7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (≈ 1.4% from baseline) were achieved with 60 and 80 μg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤ 7% at 24 weeks; respectively. Weight was reduced by 2.8-3.7 kg (P < 0.05) at 24 weeks in all except the 20 → 20 μg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 μg/day relative to Ex-BID; and 60 μg/day had the best profile of tolerability and HbA1c lowering., Conclusions: ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20 → 60 μg/day regimen was considered the best dose for further examination in phase 3.

Background: Exenatide, a glucagon-like peptide-1 receptor agonist administered by self-injection, decreases plasma glucose, glycosylated hemoglobin (HbA1c), and weight in patients with type 2 diabetes. ITCA 650 is an investigational new drug that provides continuous subcutaneous delivery of exenatide., Objective: This randomized, open-label, multicenter, 28-day study evaluated the tolerability, pharmacodynamics, and pharmacokinetics of ITCA 650 in patients with type 2 diabetes., Methods: The study enrolled patients with type 2 diabetes who were receiving a stable regimen of diet and exercise alone or a stable dose of metformin monotherapy, thiazolidinedione monotherapy, or metformin plus thiazolidinedione combination therapy. Patients were randomized to receive 10, 20, 40, or 80 μg/d of ITCA 650 placed subcutaneously for 28 days. Plasma glucose, HbA1c, insulin, and weight were measured at regular intervals throughout the study. Exenatide levels and anti-exenatide antibodies were also assessed., Results: Forty-four patients were randomized to treatment. From baseline to end point, significant (P < 0.05) decreases in fasting plasma glucose levels, 2-hour postprandial glucose levels, and glucose AUC curve were seen in all treatment groups. HbA1c levels also decreased significantly (P < 0.001) in all 4 treatment groups. Weight was significantly (P < 0.05) lowered in the 40- and 80-μg/d groups. Detectable levels of exenatide were noted within 12 to 24 hours of ITCA 650 placement, reached steady state by 24 hours, and then remained relatively steady during a plateau period until device removal on day 29. Exenatide levels declined to undetectable levels within 24 hours after removal of the ITCA 650. The most common adverse events were nausea, decreased appetite, and vomiting; these were transient and mostly mild or moderate in severity. Mild local adverse events related to the healing process were common at the placement site but abated after 1 week. Twelve patients developed anti-exenatide antibodies; however, the pharmacokinetics of ITCA 650 were not altered compared with those who did not develop antibodies., Conclusions: ITCA 650 provided continuous and controlled subcutaneous delivery of exenatide for 28 days that was generally well tolerated and produced significant reductions in plasma glucose, HbA1c, and weight. Further studies are warranted to characterize the long-term tolerability and efficacy of ITCA 650 for the treatment of patients with type 2 diabetes. ClinicalTrials.gov identifier: NCT01798264., (Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.)

Aim: To compare the efficacy and tolerability of vildagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) who are inadequately controlled [haemoglobin A(1c) (HbA(1c)) 7.5 to 11%] with prior sulphonylurea (SU) monotherapy., Methods: This 24-week, multicentre, randomized, double-blind, placebo-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (50 mg given once or twice daily) vs. placebo added to glimepiride (4 mg once daily) in 515 patients with T2DM. Adjusted mean changes from baseline to end-point (AMDelta) in HbA(1c), fasting plasma glucose, fasting lipids and body weight were compared by analysis of covariance., Results: The between-group difference (vildagliptin - placebo) in AMDelta HbA(1c) was -0.6 +/- 0.1% in patients receiving vildagliptin 50 mg daily and -0.7 +/- 0.1% in those receiving 100 mg daily (p < 0.001 vs. placebo for both). Greater efficacy was seen in patients > or =65 years of age (-0.7 +/- 0.1% and -0.8 +/- 0.2% for 50 and 100 mg daily respectively) and in patients with baseline HbA(1c) > 9% (Delta = -1.0 +/- 0.2% and -0.9 +/- 0.2% for 50 and 100 mg daily respectively). Relative to placebo, patients receiving vildagliptin also had improvements in beta-cell function and postprandial glucose, with small changes in fasting lipids and body weight. The incidences of adverse events (AEs) (67.1, 66.3 and 64.2%) and serious AEs (2.9, 2.4 and 5.1%) were similar in patients receiving 50 mg vildagliptin, 100 mg vildagliptin or placebo respectively. The incidence of hypoglycaemic events was low but slightly higher in the group receiving vildagliptin 100 mg (3.6%) than in the group receiving vildagliptin 50 mg (1.2%) or placebo (0.6%)., Conclusions: In patients with T2DM inadequately controlled with prior SU monotherapy, addition of vildagliptin (50 or 100 mg daily) to glimepiride (4 mg once daily) improves glycaemic control and is well tolerated. Addition of vildagliptin 50 mg daily to SU monotherapy may be a particularly attractive therapy in elderly patients.

Aim: The aim of this work was to assess the efficacy and tolerability of nateglinide alone or in combination with metformin in elderly patients with type 2 diabetes (T2DM)., Methods: Study 1 was a 12-week, multicentre, randomized, double blind and placebo-controlled study of nateglinide monotherapy (120 mg, before meals) in 66 drug-naïve patients with T2DM aged >or=65 years. Study 2 was a 104-week, multicentre, randomized, double blind and active-controlled study of nateglinide (120 mg, before meals) or glyburide (up to 5 mg bid) in combination with metformin (up to 1000 mg bid) in 69 treatment-naïve patients with T2DM aged >or=65 years. HbA(1c), fasting and postprandial glucose levels, and safety assessments were made., Results: In Study 1, nateglinide significantly reduced HbA(1c) from baseline (7.6 +/- 0.1% to 6.9 +/- 0.1%; Delta = -0.7 +/- 0.1%, p < 0.001) and compared with placebo (between-group difference = -0.5%, p = 0.004 vs. nateglinide). No hypoglycaemia was reported. In Study 2, combination therapy with nateglinide/metformin significantly reduced HbA(1c) from baseline (7.8 +/- 0.2% to 6.6 +/- 0.1%; Delta = -1.2 +/- 0.2%, p < 0.001), as did glyburide/metformin (7.7 +/- 0.1% to 6.5 +/- 0.1%; Delta = -1.2 +/- 0.1%, p < 0.001). There was no difference between treatments (p = 0.310). One nateglinide/metformin-treated patient experienced a mild hypoglycaemic episode compared with eight episodes in eight patients on glyburide/metformin; one severe episode led to discontinuation. Target HbA(1c) (<7.0%) was achieved by 60% of patients receiving nateglinide (Study 1) and 70% of nateglinide/metformin-treated patients (Study 2)., Conclusion: Initial drug treatment with nateglinide, alone or in combination with metformin, is well tolerated and produces clinically meaningful improvements in glycaemic control in elderly patients with T2DM.

Objective: Cardiovascular disease may be increased in patients with systemic vasculitides (SV). The Ankle-Brachial Pressure Index (ABPI) is a non-invasive tool for the assessment of cardiovascular risk (CV). Our aim was to determine the prevalence of an abnormal ABPI in patients with SV and healthy controls and to correlate with clinical and serological parameters., Methods: We studied 54 consecutive vasculitis patients (20 males) attending the vasculitis clinic and 49 healthy subjects. Patients were classified according to the ACR 1990 criteria and the Chapel Hill Consensus definitions. There were 18 patients with Wegener's granulomatosis, eight with Behcet's disease, seven with Churg-Strauss Syndrome, three with Henoch-Schonlein purpura, three with polyarteritis nodosa, three with Takayasu's disease, three with p-ANCA associated vasculitis, three with urticarial vasculitis, two with cutaneous leucocytoclastic angiitis, one with microscopic polyangiitis, one with primary central nervous system angiitis, one giant cell arteritis and one with cutaneous vasculitis secondary to Sjogren's syndrome. Traditional risk factors as well as glucose, lipid profile, CRP, hsCRP, ANCA and aPL were assessed. ABPI was measured according to a consensus statement on the methodology., Results: The ABPI was abnormal in 11/54 (20.4%) of SV patients and 2/49 (4%) of the control group (chi(2) with Yates correction = 4.8, P

Objective: This study was conducted to determine the effects of vildagliptin on incretin hormone levels, islet function, and postprandial glucose control in subjects with impaired glucose tolerance (IGT)., Research Design and Methods: A 12-week, double-blind, randomized, parallel-group study comparing vildagliptin (50 mg q.d.) and placebo was conducted in 179 subjects with IGT (2-h glucose 9.1 mmol/l, A1C 5.9%). Plasma levels of intact glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), glucose, insulin, C-peptide, and glucagon were measured during standard meal tests performed at baseline and at week 12. Insulin secretory rate (ISR) was estimated by C-peptide deconvolution. The between-group differences (vildagliptin - placebo) in the adjusted mean changes from baseline to end point in the total and incremental (Delta) area under the curve (AUC)(0-2 h) for these analytes were assessed by ANCOVA; glucose AUC(0-2 h) was the primary outcome variable., Results: Relative to placebo, vildagliptin increased GLP-1 (DeltaAUC, +6.0 +/- 1.2 pmol x l(-1) x h(-1), P < 0.001) and GIP (DeltaAUC, +46.8 +/- 5.4 pmol . l(-1) x h(-1), P < 0.001) and decreased glucagon (DeltaAUC, -3.0 +/- 1.0 pmol x l(-1) x h(-1), P = 0.003). Although postprandial insulin levels were unaffected (DeltaAUC, +20.8 +/- 35.7 pmol x l(-1) x h(-1), P = 0.561), prandial glucose excursions were reduced (DeltaAUC, -1.0 +/- 0.3 mmol x l(-1) x h(-1), P < 0.001), representing an approximately 30% decrease relative to placebo. Beta-cell function as assessed by the ISR AUC(0-2 h)/glucose AUC(0-2 h) was significantly increased (+6.4 +/- 2.0 pmol x min(-1) x m(-2) x mmol x l(-1), P = 0.002). Adverse event profiles were similar in the two treatment groups, and no hypoglycemia was reported., Conclusions: The known effects of vildagliptin on incretin levels and islet function in type 2 diabetes were reproduced in subjects with IGT, with a 32% reduction in postprandial glucose excursions and no evidence of hypoglycemia or weight gain.

Aims/hypothesis: Type 2 diabetes is difficult to manage in patients with a long history of disease requiring insulin therapy. Moreover, addition of most currently available oral antidiabetic agents increases the risk of hypoglycaemia. Vildagliptin is a dipeptidyl peptidase-IV inhibitor, which improves glycaemic control by increasing pancreatic beta cell responsiveness to glucose and suppressing inappropriate glucagon secretion. This study assessed the efficacy and tolerability of vildagliptin added to insulin therapy in patients with type 2 diabetes., Materials and Methods: This was a multicentre, 24-week, double-blind, randomised, placebo-controlled, parallel-group study in patients with type 2 diabetes that was inadequately controlled (HbA(1c) = 7.5-11%) by insulin. Patients received vildagliptin (n = 144; 50 mg twice daily) or placebo (n = 152) while continuing insulin therapy., Results: Baseline HbA(1c) averaged 8.4 +/- 0.1% in both groups. The adjusted mean change from baseline to endpoint (AMDelta) in HbA(1c) was -0.5 +/- 0.1% and -0.2 +/- 0.1% in patients receiving vildagliptin or placebo, respectively, with a significant between-treatment difference (p = 0.01). In patients aged >/=65 years, the AMDelta HbA(1c) was -0.7 +/- 0.1% in the vildagliptin group vs -0.1 +/- 0.1% in the placebo group (p < 0.001). The incidence of adverse events was similar in the vildagliptin (81.3%) and placebo (82.9%) groups. However, hypoglycaemic events were less common (p < 0.001) and less severe (p < 0.05) in patients receiving vildagliptin than in those receiving placebo., Conclusions/interpretation: Vildagliptin decreases HbA(1c) in patients whose type 2 diabetes is poorly controlled with high doses of insulin. Addition of vildagliptin to insulin therapy is also associated with reduced confirmed and severe hypoglycaemia. ClinicalTrials.gov ID no.: NCT 00099931.

Aim: The aim of this study was to compare efficacy and tolerability of initial combination therapy with vildagliptin/pioglitazone to component monotherapy., Methods: This 24-week, multicentre, randomized, double-blind, active-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (100 mg q.d.), pioglitazone (30 mg q.d.) and vildagliptin combined with pioglitazone (100/30 mg q.d. or 50/15 mg q.d.) in 607 drug-naive patients with type 2 diabetes (T2DM). The primary outcome measure was change from baseline in HbA(1c) in patients receiving initial combination therapy compared with pioglitazone monotherapy., Results: After 24-week treatment, adjusted mean changes in HbA(1c) from baseline (approximately 8.7%) in patients receiving pioglitazone monotherapy, 50/15 mg combination, 100/30 mg combination and vildagliptin monotherapy were -1.4 +/- 0.1%, -1.7 +/- 0.1%, -1.9 +/- 0.1% and -1.1 +/- 0.1% respectively. Both low-dose and high-dose combinations were significantly more efficacious than pioglitazone alone (p = 0.039 and p < 0.001 respectively). Adjusted mean changes in fasting plasma glucose were -1.9 +/- 0.2, -2.4 +/- 0.2, -2.8 +/- 0.2 and -1.3 +/- 0.2 mmol/l respectively, and both combination groups were significantly more effective than pioglitazone monotherapy (p = 0.022 and p < 0.001 respectively). The overall incidence of adverse events ranged from 45.8% in the low-dose combination to 51.6% in the pioglitazone monotherapy group. The incidence of peripheral oedema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%). One mild hypoglycaemic event was reported by one patient receiving high-dose combination and one patient receiving vildagliptin monotherapy., Conclusions: First-line treatment with vildagliptin/pioglitazone combination in patients with T2DM provides better glycaemic control than either monotherapy component yet has minimal risk of hypoglycaemia and a tolerability profile comparable with component monotherapy.

Aim: The purpose of this study was to assess the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor vildagliptin in combination with the thiazolidinedione (TZD) pioglitazone in patients with type 2 diabetes (T2DM)., Methods: This was a 24-week, multicentre, double-blind, randomized, parallel-group study comparing the effects of vildagliptin (50 or 100 mg daily) with placebo as an add-on therapy to pioglitazone (45 mg daily) in 463 patients with T2DM inadequately controlled by prior TZD monotherapy. Between-treatment comparisons of efficacy parameters were made by analysis of covariance model., Results: The adjusted mean change (AM Delta) in haemoglobin A(1c) from baseline to endpoint was -0.8 +/- 0.1% (p = 0.001 vs. placebo) and -1.0 +/- 0.1% (p < 0.001 vs. placebo), respectively, in patients receiving vildagliptin 50 or 100 mg daily. Relative to baseline, vildagliptin added to pioglitazone also reduced fasting plasma glucose (FPG) (AM Delta FPG =-0.8 +/- 0.2 mmol/l and -1.1 +/- 0.2 mmol/l; not significant (NS) vs. placebo) and postprandial glucose (PPG) [AM Delta PPG =-1.9 +/- 0.6 mmol/l and -2.6 +/- 0.6 mmol/l (p = 0.008 vs. placebo)] for 50 and 100 mg daily respectively. Relative to placebo, both doses of vildagliptin significantly increased the insulin secretory rate/glucose by more than threefold. The overall incidence of adverse events (AEs) was 55.5, 50.0 and 48.7% in patients receiving vildagliptin 50 mg, 100 mg daily or placebo respectively. Serious AEs were experienced by 6.8, 1.3 and 5.7% of patients receiving vildagliptin 50 mg, 100 mg daily or placebo respectively. Mild hypoglycaemia was reported by 0, 0.6 and 1.9% of patients, respectively, receiving vildagliptin 50 mg, 100 mg daily or placebo., Conclusion: Vildagliptin is effective and well tolerated when added to a maximum dose of pioglitazone, without increasing the risk of hypoglycaemia.

The anatomical and physiological changes of aging make elderly people a vulnerable group to malnutrition and specific deficiencies of nutrients such as vitamin B12 and folate. This study was aimed to establish relationships among serum vitamin B12, folate, homocysteine concentrations and dietary intake and adequacy. Fifty five male and female elderly (60 and more years), free-living, were assessed. Measurements were: serum vitamin B12 and folate by radioimmunoanalysis (RIA), homocysteine by polarized fluorescence immunoassay, nutrient intake by three 24 hours recalls and food frequency questionnaire. Nutritional status was determined by Body Mass Index (BMI). Serum vitamin B12 and folate were at normal range (423,3+/-227,6 pmol/l and 6,4 +/- 4,5 mg/ml), but 17,5% of elderly had B12 deficiency and 12% had folate deficiency. Serum homocysteine was higher than reference values (15,8+/-4,4 mmol/l), but 47,5% showed concentrations above 15 mmol/L, male population showed higher mean value (p: 0,01). Nutrient intake was inadequate by deficiency. BMI indicated 11,8% of undernutrition, 29,4% of overweight and 20,6% of obesity A negative and inverse correlation between homocysteine and serum folate was found. Results suggest a biochemical deficiency of B12 and folate that is expressed as elevated homocysteine levels. These finding represent a high cardiovascular risk factor for this elderly group.

Antidiabetic agents that augment insulin secretion can cause hypoglycemia. With the current trend toward early and aggressive treatment of patients with type 2 diabetes, the hypoglycemic potential of insulinotropic agents is of concern. This study aimed to compare the propensity of the "glinide," nateglinide, and the sulfonylurea (SU), glyburide, to elicit hypoglycemia in type 2 diabetic patients with moderately elevated fasting plasma glucose (FPG). Hyperglycemic clamps (target plasma glucose = 11.1 mmol/L) were initiated, and 30 minutes later patients received a single oral dose of nateglinide (120 mg, n = 15) or glyburide (10 mg, n = 12) in a double-blind fashion. At the end of the 2-hour clamp when the glucose infusion was terminated, plasma glucose and insulin levels were measured for 4 additional hours. The minimum plasma glucose level achieved after terminating the glucose infusion (glucose nadir) was used as an index of hypoglycemic potential. The mean (+/-SEM) glucose nadir was significantly lower in patients given glyburide (3.3 +/- 0.2 mmol/L) versus nateglinide (4.4 +/- 0.3 mmol/L, P = .025). Confirmed hypoglycemia (plasma glucose < or = 2.8 mmol/L) occurred in 2 of 12 patients given glyburide and in none of those given nateglinide. Plasma insulin levels were significantly higher from 100 to 240 minutes after clamp termination in patients given glyburide versus nateglinide. Nateglinide has less hypoglycemic potential than glyburide, suggesting that nateglinide may be a more appropriate insulinotropic agent for patients with moderate fasting hyperglycemia, such as elderly patients and those with comorbid cardiac ischemia.

Objective: To assess the efficacy and tolerability of the combination of nateglinide (120 mg, ac) and metformin (500 mg, tid) as initial treatment in drug-naïve patients with type 2 diabetes mellitus (T2DM)., Research Design and Methods: This study reports data from the treatment-naïve (TN) subgroup of patients in a previously published, randomized, multicenter, placebo-controlled, 24- week trial that compared nateglinide, metformin, and the combination therapy (CT) in 701 patients with T2DM with baseline HbA(1c) between 6.8% and 11.0%. Of the 401 TN patients, 104, 104, 89, and 104 patients received nateglinide (120 mg, ac), metformin (500 mg, tid), CT, and placebo, respectively. The baseline characteristics of each group were similar, with mean age, BMI, duration of diabetes, HbA(1c), and fasting plasma glucose (FPG) levels of approximately 58 years, 30 kg/m(2), 4 Gastrointestinal side effects occurred in 27% of years, 8.2%, and 10.2 mmol/L, respectively., Results: In patients receiving initial CT, HbA(1c) decreased substantially (Delta = -1.6 +/- 0.1%, p < 0.0001 vs. baseline or placebo) from a mean baseline of 8.2 +/- 0.1%, an effect significantly greater than the 0.8% reduction observed with both monotherapies (p < 0.001); whereas, in placebo-treated patients, HbA(1c) increased modestly (Delta = +0.3 +/- 0.1%, p < 0.05) from an identical baseline value. Seventy percent of CT-treated patients achieved a target HbA(1c) of < 7.0%. Both fasting plasma glucose (FPG) and the 2-hour postprandial glucose excursion (PPGE) after a liquid meal challenge decreased by 2.3 mmol/L in patients receiving CT, while the changes from baseline values in FPG and PPGE were +0.2 +/- 0.3 mmol/L and -0.5 +/- 0.2 mmol/L, respectively, in placebo-treated patients. The incremental 30-minute post-load insulin levels increased by 88 +/- 32 pmol/L (p = 0.006) in patients receiving CT and did not change significantly in placebo-treated patients. patients receiving CT (vs. 27.9% in the metformin monotherapy, and 14.4% in the placebo groups). Confirmed hypoglycemia (glucose