1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice

1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is an immune modulator that prevents experimental autoimmune diseases. Receptors for 1,25-(OH)(2)D(3) are present in pancreatic beta-cells, the target of an autoimmune assault in nonobese diabetic (NOD) mice. The aim of this study was to investigate the in vivo and in vitro effects of 1,25-(OH)(2)D(3) on beta-cell gene expression and death and correlate these findings to in vivo diabetes development in NOD mice. When female NOD mice were treated with 1,25-(OH)(2)D(3) (5 microg/kg per 2 d), there was a decrease in islet cytokine and chemokine expression, which was accompanied by less insulitis. Complementing these findings, we observed that exposure to 1,25-(OH)(2)D(3) in three cell systems INS-1(E) cell line, fluorescence-activated cell sorting purified rat beta-cells, and NOD-severe combined immunodeficient islets) suppressed IP-10 and IL-15 expression in the beta-cell itself but did not prevent cytokine-induced beta-cell death. This 1,25-(OH)(2)D(3)-induced inhibition of chemokine expression in beta-cells was associated with a decreased diabetes incidence in some treatment windows targeting early insulitis. Thus, although a short and early intervention with 1,25-(OH)(2)D(3) (3-14 wk of age) reduced diabetes incidence (35 vs. 58%, P < or = 0.05), a late intervention (from 14 wk of age, when insulitis is present) failed to prevent disease. Of note, only early and long-term treatment (3-28 wk of age) prevented disease to a major extent (more than 30% decrease in diabetes incidence). We conclude that 1,25-(OH)(2)D(3) monotherapy is most effective in preventing diabetes in NOD mice when applied early. This beneficial effect of 1,25-(OH)(2)D(3) is associated with decreased chemokine and cytokine expression by the pancreatic islets.     

Left egocentric neglect in early subacute right-stroke patients is related to damage of the superior longitudinal fasciculus

Brain Imaging and Behavior - A typical consequence of stroke in the right hemisphere is unilateral spatial neglect. Distinct forms of neglect have been described, such as space-based (egocentric)...     

Larvicidal activity of 94 extracts from ten plant species of northeastern of Brazil against Aedes aegypti L. (Diptera: Culicidae)

In an effort to find effective and affordable ways to control of Aedes aegypti L. (Diptera: Culicidae), the larvicidal activities of 94 extracts from ten plant species belonging to eight families [Guettarda grazielae and Spermacoce verticillata (Rubiaceae), Coccoloba mollis and Triplaris americana (Polygonaceae), Eschweilera ovata (Lecytidaceae), Merremia aegyptia (Convolvulaceae), Ouratea nitida (Ochnnaceae), Protium heptaphyllum (Burseraceae), Rourea doniana (Connaraceae), and Tovomita brevistaminea (Guttiferae)], widely found in the northeast of Brazil, were initially screened at 250 μg/mL. Nineteen of the 94 extracts from six plant species (C. mollis, G. grazielae, M. aegyptia, R. doniana, S. verticillata, and T. americana) showed significant activity (>75% mortality) against the fourth instar larvae. Some of these extracts showed 100% mosquito larvae mortality, with LD₅₀ values lower 200 μg/mL. When compared to synthetic insecticide Temephos (LD₅₀ 8.7 μg/mL), two of them, hexane (LD₅₀ 12.1 μg/mL) and ethyl acetate (LD₅₀ 51.6 μg/mL) extracts from stems of R. doniana and G. grazielae, respectively, were the most effective. The isolation and purification of these extracts are in progress and evaluation of these compounds will be needed to identify the active component.     

Prevalence of "high-riding" superior pericardial recesses on thin-section 16-MDCT scans

OBJECTIVE: The aim of this study was to evaluate the prevalence of "high-riding" superior pericardial recess (HRSPR) on thin-section (1 mm) 16-multidetector computed tomography (MDCT) scans. MATERIALS AND METHODS: Three hundred and fourteen consecutive chest CT scans obtained with a thin-section 16 MDCT were retrospectively evaluated. The prevalence and characteristic of HRSPR were analyzed. RESULTS: HRSPR was depicted in 21 patients (11 men and 10 women) (6.6%) who ranged in age from 28 to 72 years (mean age, 57 years). The extended recesses were rounded/oval shaped in five patients and triangular, spindle, half moon or irregular shaped in the other 16 patients. CONCLUSION: Our data suggest as HRSPRs are more frequently and better depicted on thinsection MDCT scans, and this improves the capability to distinguish this superior extension of the superior aortic recess from abnormal findings such as lymphadenopathy, cystic lesions, and aortic dissection.     

Computational analysis of the mutations in BAP1, PBRM1 and SETD2 genes reveals the impaired molecular processes in renal cell carcinoma

Clear cell Renal Cell Carcinoma (ccRCC) is due to loss of von Hippel–Lindau (VHL) gene and at least one out of three chromatin regulating genes BRCA1-associated protein-1 (BAP1), Polybromo-1 (PBRM1) and Set domain-containing 2 (SETD2). More than 350, 700 and 500 mutations are known respectively for BAP1, PBRM1 and SETD2 genes. Each variation damages these genes with different severity levels. Unfortunately for most of these mutations the molecular effect is unknown, so precluding a severity classification. Moreover, the huge number of these gene mutations does not allow to perform experimental assays for each of them. By bioinformatic tools, we performed predictions of the molecular effects of all mutations lying in BAP1, PBRM1 and SETD2 genes. Our results allow to distinguish whether a mutation alters protein function directly or by splicing pattern destruction and how much severely. This classification could be useful to reveal correlation with patients’ outcome, to guide experiments, to select the variations that are worth to be included in translational/association studies, and to direct gene therapies.     

Alzheimer,s Disease Risk and Progression: The Role of Nutritional Supplements and their Effect on Drug Therapy Outcome

Alzheimer''s disease (AD) is the most common neurodegenerative disease in the elderly population. Despite significant advancements in understanding the genetic and molecular basis of AD, the pathology still lacks treatments that can slow down or reverse the progression of cognitive deterioration. Recently, the relationship between nutrient deficiency and dementia onset has been highlighted. AD is in fact a multifactorial pathology, so that a multi-target approach using combinations of micronutrients and drugs could have beneficial effects on cognitive function in neurodegenerative brain disorders leading to synaptic degeneration. Primarily, this review examines the most recent literature regarding the effects of nutrition on the risk/progression of the disease, focusing attention mostly on antioxidants agents, polyunsaturated fatty acids and metals. Secondly, it aims to figure out if nutritional supplements might have beneficial effects on drug therapy outcome. Even if nutritional supplements showed contrasting evidence of a likely effect of decreasing the risk of AD onset that could be studied more deeply in other clinical trials, no convincing data are present about their usefulness in combination with drug therapies and their effectiveness in slowing down the disease progression.     

Renin-Angiotensin System Blockers and Statins Are Associated With Lower In-Hospital Mortality in Very Elderly Hypertensives

Objectives

Cardiovascular diseases are mainly related to hypertension and dyslipidemia and increase with aging because of the larger time span for these risk factors to damage arterial blood vessels. The impact of cardiovascular drug therapy on outcomes in the very elderly hospitalized is still not well established. The aim of our study was to evaluate the associations between cardiovascular therapy and in-hospital mortality in very elderly hypertensives.

Vitamin D and diabetes

Vitamin D deficiency predisposes individuals to type 1 and type 2 diabetes, and receptors for its activated form—1,25-dihydroxyvitamin D₃—have been identified in both beta cells and immune cells. Vitamin D deficiency has been shown to impair insulin synthesis and secretion in humans and in animal models of diabetes, suggesting a role in the development of type 2 diabetes. Furthermore, epidemiological studies suggest a link between vitamin D deficiency in early life and the later onset of type 1 diabetes. In some populations, type 1 diabetes is associated with certain polymorphisms within the vitamin D receptor gene. In studies in nonobese diabetic mice, pharmacological doses of 1,25-dihydroxyvitamin D₃, or its structural analogues, have been shown to delay the onset of diabetes, mainly through immune modulation. Vitamin D deficiency may, therefore, be involved in the pathogenesis of both forms of diabetes, and a better understanding of the mechanisms involved could lead to the development of preventive strategies.     

Acute Exacerbation of Chronic Obstructive Pulmonary Disease in Oldest Adults: Predictors of In-Hospital Mortality and Need for Post-acute Care

ObjectivesOlder age is associated with higher risk of death during acute exacerbations of chronic obstructive pulmonary disease (AE-COPD). Older patients hospitalized for AE-COPD often require post-acute care after acute phase. The aim of this study was to evaluate components of a comprehensive geriatric assessment and clinical/laboratory parameters, in order to find predictors of in-hospital mortality and need for post-acute care in patients aged 80 and older hospitalized for AE-COPD.DesignProspective observational study.SettingHospital assessment.Participants121 patients consecutively admitted to an internal medicine and geriatrics department for AE-COPD.MeasuresActivities of Daily Living (ADL) Hierarchy scale, Geriatric Index of Comorbidity, cognitive impairment, and clinical and laboratory parameters were collected.ResultsMean age: 87.0 ± 4.9 years; male: 54.5%. In-hospital mortality (18.2% of patients) was significantly associated with functional disability, high comorbidity, cognitive impairment, anemia, older age, lower albumin, higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and white blood cell levels, oral corticosteroids taken before admission, and no angiotensin-converting enzyme inhibitors or angiotensin receptor blockers taken before admission. In a stepwise logistic regression, functional dependence (P = .006), cognitive impairment (P = .038), and oral corticosteroids therapy before hospitalization (P = .035) were independently associated with a higher risk of in-hospital mortality. Among laboratory parameters, only NT-proBNP remained significantly associated with in-hospital mortality (P = .026). The need for post-acute care (18.2% of survivors) was associated with older age, higher admission Pco₂, greater comorbidity, and cognitive impairment. In a stepwise logistic regression, only cognitive impairment (P = .016) and ln_Pco₂ (P = .056) confirmed their association with the need for post-acute care.Conclusions/implicationsPreadmission functional dependence, cognitive impairment, and corticosteroid use, plus elevated NT-proBNP at admission are risk factors for mortality during an AE-COPD in the oldest old. Therefore, medical providers should consider these, as well as the patient's advance directives, in planning hospital care. Furthermore, providers should arrange especially careful posthospitalization monitoring and frequent follow-up of individuals with cognitive impairment and baseline hypercapnia.