Association of autoantibodies anti-OxLDL and markers of inflammation with stage of HIV infection

Univ São Paulo, Dept Pathol, Sch Dent, BR-05508900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, Sect Lipids Atherosclerosis & Vasc Biol, São Paulo, BrazilUniv São Paulo, Dept Immunol, Inst Biomed Sci 4, BR-05508900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Med, Sect Lipids Atherosclerosis & Vasc Biol, São Paulo, BrazilWeb of Scienc

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Study of risk factors for atherosclerosis in HIV positive patients who use HAART with periodontal disease

A aterosclerose e suas doenças associadas constituem a principal causa de morte no Brasil. Aterosclerose é uma doença inflamatória crônica que atinge a parede das artérias causando bloqueio das mesmas o que eventualmente pode produzir infarto do miocárdio ou acidente vascular cerebral (AVC). A periodontite é uma enfermidade inflamatória causada pelos subprodutos tóxicos que as bactérias produzem quando se colonizam na placa bacteriana. Essa doença é comum em pacientes HIV positivos e o uso de terapia anti-retroviral altamente ativa (HAART) utilizada nesses pacientes ocasiona efeitos adversos, como a lipodistrofia, fato este que pode apressar o ciclo da aterogênese. Assim, existe uma relação entre a presença da aterosclerose e da doença periodontal em pacientes HIV positivos. No entanto, essa relação é pouco estudada na literatura e é o objetivo desse estudo que avaliou 31 pacientes portadores do HIV com diagnóstico de periodontite crônica e 38 pacientes HIV positivos sem periodontite. Ambos os grupos utilizavam a HAART. Nesses pacientes foi avaliado o perfil lipídico (colesterol total, HDL-C, triglicérides, LDL-C), a expressão de anticorpos anti-oxLDL, as concentrações de citocinas séricas (TNF-, IL-1, IL-6 e IL-10) e os dados do hemograma completo, antes e 12 meses após o tratamento periodontal. Os resultados indicaram que os indivíduos com periodontite crônica quando comparados com o grupo controle apresentam níveis plasmáticos aumentados de leucócitos e neutrófilos; e após o tratamento periodontal, as concentrações plasmáticas de TNF-, IL-1 e IgG diminuíram. Assim, vimos que alguns dos marcadores de risco para doenças cardiovasculares diminuem após um plano de reabilitação oral visando o tratamento da doença periodontal em pacientes HIV positivos. Conseqüentemente, sugerimos que a periodontite pode ser um fator de risco para o desenvolvimento da aterosclerose nesses pacientes.Atherosclerosis and its associated diseases are the leading cause of death in Brazil. Atherosclerosis is a chronic inflammatory disease that affects the wall of the arteries causing blockage that eventually leads to myocardial infarction or stroke. Periodontitis is an inflammatory disease caused by toxic byproducts produced by bacteria that colonize the oral plaque. HIV positive patients commonly present periodontal diseases and the highly active anti-retroviral therapy (HAART) used in these patients lead to side effects such as lipodystrophy which in turn, can speed up the cycle of atherogenesis. Therefore, there is an occult association between the presence of atherosclerosis and periodontal diseases in these patients. However, this correlation is rarely investigated in the literature and was the objective of this study that analysed 30 HIV positive patients with and 39 HIV positive patients without periodontal disease. All the participants were under HAART. Herein we analysed the lipid profile (total cholesterol, HDL-C, triglycerides, LDL-C), the expression of antioxLDL, concentrations of serum cytokines (TNF-, IL-1, IL-6 and IL-10) and full blood test before and 12 months after periodontal treatment. The results showed that individuals with chronic periodontitis presented increased plasmatic levels of leukocytes and neutrophils and after the periodontal treatment, plasmatic levels of TNF-, IL-1 and IgG decreased. Thus, we showed that some of the risk markers for cardiovascular diseases decrease after oral rehabilitation aiming treatment of periodontal disease in HIV positive patients. Therefore, we suggest that periodontites can be a risk factor for the development of atherosclerosis in these patients

Evaluation of the mechanical properties of the cured acetic silicone added with magnesium silicate

Os silicones requerem várias caraterísticas e requisitos para seu uso na confecção de próteses faciais, principalmente, referente a textura da pele; para alcançar essa meta devem ser adicionados outros materiais. O objetivo deste trabalho foi avaliar as propriedades mecânicas de um silicone nacional RTV. de cura acética, disponível no mercado, adicionando silicato de magnésio (talco). O material foi estudado em seu estado original e com acréscimo de 10% e 20% de silicato de magnésio. Foi submetido a testes de alongamento de ruptura, resistência à tração ou tensão de ruptura e de resistência ao rasgamento. Após a avaliação individual dos corpos de prova, obteve-se uma média total de cada grupo e submeteu-se a estudo comparativo frente aos resultados obtidos por meio de análise de variância (ANOVA) e teste de Tukey. O silicone em estado original mostrou-se mais resistente ao alongamento. O silicone com adição de 10 % de silicato de magnésio modificou suas propriedades mecânicas e obteve maior resistencia à tração. O silicone com adição de 20 % de silicato magnésio obteve maior resistência ao rasgamento. O silicone em que foi adicionado 10 % de silicato de magnésio de maneira geral obteve os valores mais significativos nas três propriedades testadas, o que indica que adicionando mais de 10 % diminui as propriedades mecânicas gradualmente, tornando-se inversamente proporcionais.The silicones request many characteristics and requirements for the use in the making of facial prostheses. To reach that objective other materials should be added. The aim of this work was to evaluate the mechanical properties of a national acetic cure silicone RTV, available in the market, adding silicate of magnesium (talc). The material was studied in your natural state and with increment of 10% and 20% of silicate of magnesium. It was submitted to tests of elongation and break, tensile strength and tear strength. After the individual evaluation of the specimens, it was obtained measured total of the each group and submitted to study comparative front to the results obtained through variance analysis (ANOVA) and Tukey test. The silicone in been original it showed to be more resistant to the elongation. The silicone with addition of 10% of silicate of magnesium modified your mechanical properties and obtained larger tear resistance. The silicone with addition of 20% of silicate magnesium obtained larger resistance to the tear strength. The silicone in witch it added 10% of silicate of magnesium in general obtained the more significant values in the three tested properties; that means that the increment of more than 10% lesses the properties gradually, becoming inversely proportional

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (<60, 60-69, and >_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 & PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and >_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele