Role of arginase 2 in systemic metabolic activity and adipose tissue fatty acid metabolism in diet-induced obese mice

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction

Impact of a catch-up strategy of DT-IPV vaccination during hospitalization on vaccination coverage among people over 65 years of age in france: The HOSPIVAC study (Vaccination during hospitalization)

In France, diphtheria tetanus and inactivated polio vaccine (DT-IPV) coverage and immunization are insufficient in the elderly and decrease with age. The principal objective of this study was to assess the impact of a strategy of catch-up DT-IPV vaccination during hospitalization in people over the age of 65 years in central France (the Sarthe region). We performed a prospective, single-center, cluster-randomized study (four hospital wards). We included patients aged ≥65 years, without mental impairment, contraindication and who accepted to participate, hospitalized in the internal medicine wards in Le Mans Hospital from 28 May 2018 to 27 May 2019. The DT-IPV vaccination status of the patients was determined at inclusion and the wards were randomized (intervention and control). In the intervention group, vaccination was up-dated during hospitalization. In case of temporary contraindication, vaccination was prescribed at hospital discharge. Patients hospitalized in the control wards received oral information only. Final immunization status was determined by calling the patient’s general practitioner two months after hospital discharge. One hundred and fifty seven patients were included: 73 in the intervention and 84 in the control arm. Baseline immunization coverage was 46.5%. Vaccination coverage increased from 56.2% to 80.8% in the intervention group and from 38.1% to 40.5% in the control group (p < 0.001). Having received sufficient information from the general practitioner was the only factor associated with vaccination being up-to-date in uni- and multivariate analysis: OR = 5.07 [2.45–10.51]. In a setting of low vaccination coverage DT-IPV vaccination during hospitalization is an effective catch-up strategy

Sustainability of European winter wheat- and maize-based cropping systems: Economic, environmental and social ex-post assessment of conventional and IPM-based systems

In order to ensure higher sustainability of winter wheat and maize production in Europe, cropping systems featuring different levels of Integrated Pest Management (IPM) need to be tested in the field and validated for their sustainability before being adopted by farmers. However, the sustainability evaluation of cropping systems is difficult to perform effectively due to the complex economic, social and environmental dimensions of sustainability. Within the EU research project PURE, nine long-term experiments were conducted in various European regions from 2011 to 2014, comparing two IPM levels against the conventional system (CS) in winter wheat- and maize-based cropping systems. IPM1 encompassed some pesticide use in semi-diverse crop rotations while IPM2 favoured reduced- and non-chemical methods in diverse rotations. The modified DEXiPM (DEXi Pest Management) model for arable cropping systems was used for ex-post assessments to compare the economic, environmental and social sustainability of these systems. The assessments showed that in six out of nine trials the CS was overall unsustainable because of low evaluation of the environmental sustainability that was mainly due to high pesticide use and simplified crop rotations where the choice of crops is primarily market-driven. In contrast, six IPM1 and five IPM2 systems could be classified as sustainable, achieving ‘medium’ or ‘high’ scores for all three sustainability dimensions. Differences in the socio-economic conditions across countries and/or climatic and soil conditions across experimental trials highlighted that IPM is based on general principles that must be adapted to address specific local conditions. Overall, IPM systems included more diverse crop rotations and practices compared to the CS, promoting IPM-based strategies with less pesticide use but also a reduced reliance on pesticides that could partially compensate for any yield reductions by the savings on pesticide and application costs. It is recommended that the results of the study should be disseminated to policy-makers, advisors and farmers and that their implementation should be considered on a regional level. Regional policies to encourage the adoption of more sustainable systems based on IPM principles, as well as better support by more closely involving the regional advisory services for the general implementation of IPM is further recommended. Ex-post analysis with DEXiPM also identified the constraints of the IPM1 and IPM2 systems evaluated as not sustainable. These were related to i) environmental issues for those IPM1 systems that still relied mainly on pesticide use and had less diverse crop rotations, and ii) economic issues for IPM2 systems, mainly due to the choice of less profitable crops in the rotation, as well as to yield penalties caused by the very low pesticide use or replacing pesticides with less effective non-chemical methods. The identification of these constraints is a valuable input to the local and regional discussion on how to adopt IPM and develop more sustainable cropping systems

Evaluation of vardenafil for the treatment of subjective tinnitus: a controlled pilot study

<p>Abstract</p> <p>Background</p> <p>Vardenafil (Levitra^®) represents a potent and highly selective phosphodiesterase type 5 (PDE5) inhibitor, which is established for treatment of various diseases. There are several unpublished reports from patients stating that vardenafil has a considerable therapeutic effect on their concomitant tinnitus. This pilot study was conducted to specifically assess the effect of vardenafil in patients with chronic tinnitus.</p> <p>Methods</p> <p>This trial was based on a prospective, randomized, double-blind, placebo-controlled, parallel group design. Fourty-two consecutive subjects with mon- or binaural chronic tinnitus received 10 mg vardenafil (N = 21) or matching placebo tablets (N = 21) administered orally twice a day over a period of 12 weeks. Clinical examination and data acquisition took place at each visit: at baseline, after 4 weeks, after 12 weeks (end of treatment with study medication), and at non-medicated follow-up after 16 weeks. Assessment of clinical effectiveness was based on a standardized tinnitus questionnaire (TQ), the Short Form 36 health survey (SF-36), audiometric measurements (mode, pitch and loudness of tinnitus; auditory thresholds) and biomarkers of oxidative stress in patients' blood (malondialdehyde, protein carbonyl, homocysteine and total antioxidative status). Therapeutic efficacy was evaluated by comparison of subjective and objective parameters with baseline data between both treatment groups (ANCOVA).</p> <p>Results</p> <p>Vardenafil had no superior efficacy over placebo in the treatment of chronic tinnitus during this study. The primary efficacy criterion 'TQ total score' failed to demonstrate significant improvement compared to placebo. Subjective reports of TQ subscales and general quality of life areas (SF-36), objective audiometric examinations as well as investigated biomarkers for oxidative stress did not reveal any significant treatment effects. The safety profile was favorable and consistent with that in other vardenafil studies.</p> <p>Conclusion</p> <p>Although hypoxia and ischemia play a special role in the pathogenesis of tinnitus, the PDE5-inhibitor-induced increase of nitric oxide-mediated vasodilatation exerted no specific influence on tinnitus symptomatology. Considering the unclear risk of rarely associated hearing impairment, systemic application of vardenafil or other PDE5 inhibitors prove to be not appropriate for therapy of chronic tinnitus.</p

A review of analytical methods for the determination of four new phosphodiesterase type 5 inhibitors in biological samples and pharmaceutical preparations

The introduction of oral phosphodiesterase type 5 inhibitor therapy in 1998 revolutionized the treatment of erectile dysfunction. Erectile dysfunction is the most common sexual problem in men. It often has a profound effect on intimate relationships and quality of life. The analysis of pharmaceuticals is an important part of the drug development process as well as for routine analysis and quality control of commercial formulations. Whereas the determination of sildenafil citrate, vardenafil and tadalafil are well documented by a variety of methods, there are few publications about the determination of udenafil, lodenafil carbonate, mirodenafil and avanafil. The paper presents a brief review of the action mechanism, adverse effects, pharmacokinetics and the most recent analytical methods that can determine drug concentration in biological matrices and pharmaceutical formulations of these four drugs.A introdução da terapia oral com inibidores da fosfodiesterase tipo 5, em 1998, revolucionou o tratamento da disfunção erétil. A disfunção erétil é o problema sexual mais comum em homens. Muitas vezes tem um efeito profundo nas relações íntimas e na qualidade de vida. A análise de produtos farmacêuticos é uma parte importante do processo de desenvolvimento de fármacos, bem como para a análise de rotina e controle de qualidade das formulações comerciais. Enquanto a determinação do citrato de sildenafila, vardenafila e tadalafila está bem documentada por uma variedade de métodos, existem poucas publicações sobre a determinação de udenafila, carbonato de lodenafila, mirodenafila e avanafila. O artigo apresenta uma breve revisão do mecanismo de ação, efeitos adversos, farmacocinética e os mais recentes métodos analíticos, que podem determinar a concentração do fármaco em matrizes biológicas e formulações farmacêuticas destes quatro fármacos