BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes.

RATIONALE: In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS (nitric oxide synthase) cofactor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype. OBJECTIVE: Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes. METHODS AND RESULTS: In contrast to the vascular endothelium, BH4 levels, superoxide production, and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca2+]i (intracellular calcium) decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild-type mice 12 weeks post-diabetes induction (streptozotocin, 42-45 mg/kg) was prevented in mGCH1-Tg (mice with elevated myocardial BH4 content secondary to trangenic overexpression of GTP-cyclohydrolase 1) and reversed in wild-type mice receiving oral BH4 supplementation from the 12th to the 18th week after diabetes induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of nNOS (the neuronal NOS isoform) in mGCH1-Tg. In HEK (human embryonic kidney) cells, S-nitrosoglutathione led to a PKG (protein kinase G)-dependent increase in plasmalemmal density of the insulin-independent glucose transporter GLUT-1 (glucose transporter-1). In cardiomyocytes, mGCH1 overexpression induced a NO/sGC (soluble guanylate cyclase)/PKG-dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by 31phosphorous magnetic resonance spectroscopy), and myocardial function. CONCLUSIONS: We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via an nNOS-mediated increase in insulin-independent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4-based therapeutics in human diabetic cardiomyopathy. Graphic Abstract: A graphic abstract is available for this article.

Is adherence to the Mediterranean diet associated with good sleep duration in primary-school children?

Objective: The Mediterranean diet (MD) contributes to preventing numerous chronic diseases and has benefits on cognitive development. Adherence to the MD is associated with sleep quality and duration in adults and adolescents, but this association seems to have been little investigated in primary-school children. The aim of this cross-sectional study was to verify whether good sleep duration was associated with adherence to the MD. Design: The study enrolled a sample of Italian primary school children. Their mothers were asked to answer an anonymous, self-administered questionnaire investigating the children's adherence to the MD (using the KidMed score) and variables related to their lifestyles, behavioral traits and socio-economic factors. Logistic regression models were developed to analyze the association between adherence to the MD, entered as the dependent variable, and adequacy of sleep duration. Setting: Primary schools in Padova, Italy. Subjects: 267 Italian 6-year-olds in their first year of primary school. Results: The multivariate analysis showed an association between adherence to the MD and hours of sleep: for children with a good sleep duration, the odds ratio of a poor-to-moderate adherence to the MD was 0.282 (95% CI, 0.109-0.681, p < 0.05). Conclusion: Ensuring an adequate sleep duration may be an important strategy for enhancing adherence to the MD. Sleep and dietary education should be included in future health promotion programs.

Health care service use and costs for a cohort of high-needs elderly diabetic patients.

AIMS: To describe the impact of diabetes comorbidities on the health care services use and costs of a cohort of elderly patients with diabetes and high health care needs (HHCN), based on real-world data. METHODS: We focused on a cohort of diabetic patients with HHCN belonging to Resource Utilization Bands 4 and 5 according to the Adjusted Clinical Group (ACG) system. Their comorbidities were assessed using the clinical diagnoses that the ACG system assigns to single patients by combining different information flows. Regression models were applied to analyze the associations between comorbidities and health care service use or costs, adjusting for age and sex. RESULTS: Our analyses showed that all health care service usage measures (e.g. access to emergency care; number of outpatient visits) and the total annual costs and pharmacy costs are associated significantly with comorbidity class. Instead, no differences in hospitalization rates by comorbidity class were revealed. CONCLUSION: The association between a larger number of comorbidities and higher total health care service usage and costs was seen mainly for primary care services. This underscores the need to strengthen primary care for today's aging and multimorbid population.

Adherence to Therapy, Physical and Mental Quality of Life in Patients with Multiple Sclerosis.

Ensuring multiple sclerosis (MS) patients' adherence to therapy is often challenging, but it is crucial to their survival and health-related quality of life (HRQoL). The aim of the present study was to outline connections between adherence, physical and mental HRQoL, levels of psychological readiness to engage in a treatment, levels of social support, anthropometric, socio-demographic and clinical factors in patients suffering from MS. This cross-sectional study involved a sample of 237 Italian MS patients. A survey was conducted with a structured self-administered online questionnaire using validated measures of quality of life, adherence to therapy and anthropometric, socio-demographic, psychological and clinical variables. A path analysis was used to test the overall structure of the associations between the variables. The pathway indicates a positive association between mental health index and a stronger degree of engagement and being or having been in a long-term relationship. Physical health index was positively associated with age, having an occupation, and having a specific form of MS. Having had relapses in the previous year raised the odds of better adherence to therapy, while an increase in Body Mass Index (BMI) reduced them. Our findings could help in the management of MS patients, promoting behavioral interventions that take the psychological and socio-demographic peculiarities of each patient into account with a view to improving their adherence to therapy.

Healthcare Service Usage and Costs for Elderly Patients with Obstructive Lung Disease.

Background: The worldwide prevalence of obstructive lung disease (OLD) is increasing, especially among people >65 years old, and nearly three in four adults with OLD have two or more comorbid conditions. This study describes the impact of such comorbidities on the healthcare service usage and related costs in a country with universal health coverage, basing on a large cohort of elderly patients with OLD and employing real-world data. Methods: We carried out a retrospective cohort study on a large population of elderly (age >64 years) patients with OLD served by a Local Health Unit in northern Italy. Their comorbidities were assessed using the clinical diagnoses assigned by the Adjusted Clinical Group (ACG) system to individual patients by combining different information flows. Correlations between number of comorbidities and total annual healthcare service usage and costs were examined with Spearman's test. Regression models were applied to analyze the associations between the above-mentioned variables, adjusting for age and sex. Results: All types of healthcare service usage (access to emergency care; number of outpatient visits; number of hospital admissions) and pharmacy costs increased significantly with the number of comorbidities. Average total annual costs increased steadily with the number of comorbidities, ranging from € 1158.84 with no comorbidities up to € 9666.60 with 6 comorbidities or more. Poisson regression analyses showed an independent association between the number of comorbidities and the use of every type of healthcare service. Conclusion: These results based on real-world data provide evidence that the burden of care for OLD patients related to their comorbidities is independent of and in addition to the burden related to OLD alone and is strongly dependent on the number of comorbidities, suggesting a holistic approach to multimorbid patients with OLD is the most sound public health strategy.

Low dose of acetylsalicylic acid and oxidative stress-mediated endothelial dysfunction in diabetes: a short-term evaluation.

Current guidelines suggest the use of low doses of acetylsalicylic acid (ASA) for patients with diabetes mellitus (DM) in primary prevention. However, the evidences demonstrating the beneficial effect of ASA in primary prevention are conflicting. In this pilot study, we evaluated in a group of diabetic patients, in primary prevention, the impact of ASA treatment on oxidative stress and vascular function. We enrolled 22 newly diagnosed diabetic patients, without any previous clinical evidence of cardiovascular disease, to receive, in primary prevention, ASA (100 mg/daily). We tested, in basal condition, after 4 weeks of ASA administration and after 4 weeks of pharmacological washout, the impact of ASA treatment on endothelial function, assessed by a semipletysmographic method, measuring the main oxidative stress parameters related to it. As expected, after 4 weeks of treatment, ASA induced a significant reduction of plasma thromboxane-A2, as a consequence of cyclooxygenase-1 inhibition. By contrast, ASA significantly increased the plasma and urine 8-iso-PGF2α, a well-known prothrombotic molecule, parallel to an increase of plasma NOX2 levels. The enhancement of this oxidative pathway is associated with a significant impairment of endothelial vasodilation, assessed by reactive hyperemia index (RHI). The pharmacological washout reverted all parameters to basal condition. Our findings suggest that ASA utilization for primary prevention in diabetic patients causes a significant increase of oxidative stress burden impairing the vascular function. Present data, if confirmed on a larger population, could permanently discourage the use of the ASA for the primary prevention in patients with DM.