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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Imbalanced Matrix Metalloproteinases in Cardiovascular Complications of End-Stage Kidney Disease: A Potential Pharmacological Target

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)End-stage kidney disease (ESKD) is a major health problem associated with very high morbidity and mortality secondary to cardiovascular complications, especially in ESKD patients on dialysis. Therefore, exploring key mechanisms underlying cardiovascular alterations associated with ESKD may offer reasonable pharmacological targets that may benefit these patients. Imbalanced matrix metalloproteinases (MMP) activities have been implicated in many cardiovascular diseases, and growing evidence now indicates that excessive MMP activities contribute to cardiovascular complications in ESKD patients. However, there is no study on the effects of MMP inhibitors (MMPIs) in such patients. MMPIs may prevent against the vascular and cardiac changes associated with ESKD. In this MiniReview, we aimed at reviewing current evidence supporting the idea that pharmacological inhibition of imbalanced MMP activities in ESKD may decrease the morbidity and mortality associated with cardiovascular complications in ESKD patients. However, MMPs have variable effects during different phases of kidney disease, and therefore optimal timing for MMP inhibition during a disease process may vary significantly and is largely undetermined. While current research shows that MMPs play a role in the pathogenesis of the cardiovascular alterations found in ESKD patients, clinical studies are required to validate the idea of using MMPIs in ESKD.1105409415Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Imbalanced matrix metalloproteinases in cardiovascular complications of end‐stage kidney disease: a potential pharmacological target

End-stage kidney disease (ESKD) is a major health problem associated with very high morbidity and mortality secondary to cardiovascular complications, especially in ESKD patients on dialysis. Therefore, exploring key mechanisms underlying cardiovascular alterations associated with ESKD may offer reasonable pharmacological targets that may benefit these patients. Imbalanced matrix metalloproteinases (MMP) activities have been implicated in many cardiovascular diseases, and growing evidence now indicates that excessive MMP activities contribute to cardiovascular complications in ESKD patients. However, there is no study on the effects of MMP inhibitors (MMPIs) in such patients. MMPIs may prevent against the vascular and cardiac changes associated with ESKD. In this MiniReview, we aimed at reviewing current evidence supporting the idea that pharmacological inhibition of imbalanced MMP activities in ESKD may decrease the morbidity and mortality associated with cardiovascular complications in ESKD patients. However, MMPs have variable effects during different phases of kidney disease, and therefore optimal timing for MMP inhibition during a disease process may vary significantly and is largely undetermined. While current research shows that MMPs play a role in the pathogenesis of the cardiovascular alterations found in ESKD patients, clinical studies are required to validate the idea of using MMPIs in ESKD1105409415CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPES

Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels

Altered levels of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in cardiovascular alterations associated with end stage kidney disease (ESKD). Genetic polymorphisms in MMP-9 gene affect MMP-9 levels. We examined how MMP-9 polymorphisms and haplotypes affect the changes in plasma MMP-9 and TIMP-1 levels found in patients with ESKD undergoing hemodialysis.We studied 94 ESKD patients undergoing hemodialysis for at least 3 months. MMP-9 and TIMP-1 were measured by ELISA in plasma from blood samples collected before and after a session of hemodialysis. Genotypes for three MMP-9 polymorphisms (C− 1562T, rs3918242; − 90 (CA)14–24, rs2234681; and Q279R, rs17576) were determined by Taqman® Allele Discrimination Assay and real-time polymerase chain reaction. Haplotype frequencies were determined with the software program PHASE 2.1. Hemodialysis increased MMP-9 and TIMP-1 levels (P 0.05). Hemodialysis increased MMP-9 and TIMP-1 levels in subjects with the CC (but not CT or TT) genotype for the C− 1562T polymorphism (P 0.05), hemodialysis increased MMP-9 levels and MMP-9/TIMP-1 ratios in subjects carrying the CLQ haplotype (P = 0.0012 and P = 0.0045, respectively). ESKD patients with the QQ genotype for the Q279R polymorphism or with the CLQ haplotype are exposed to more severe increases in MMP-9 levels after hemodialysis. Such patients may benefit from the use of MMP inhibitors4144651FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPNão te

Matrix Metalloproteinase (MMP)-2 Genetic Variants Modify the Circulating MMP-2 Levels in End-Stage Kidney Disease

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of renal diseases, and imbalanced MMP-2 and its endogenous inhibitor (the tissue inhibitor of metalloproteinases-2; TIMP-2) are implicated in the vascular alterations of end-stage kidney disease (ESKD) patients. We have examined whether MMP-2 gene polymorphisms and haplotypes modify MMP-2 and TIMP-2 levels in ESKD patients as well as the effects of hemodialysis on the concentrations of these biomarkers. Methods: We determined MMP-2 and TIMP-2 plasma levels by gelatin zymography and ELISA, respectively, in 98 ESKD patients and in 38 healthy controls. Genotypes for two relevant MMP-2 polymorphisms (C-T-1306 and C-T-735 in the promoter region) were determined by TaqMan (R) allele discrimination assay and real-time polymerase chain reaction. The software program PHASE 2.1 was used to estimate the haplotype frequencies. Results: We found increased plasma MMP-2 and TIMP-2 levels in ESKD patients compared to controls (p<0.05), and hemodialysis decreased MMP-2 (but not TIMP-2) levels (p<0.05). The T allele for the C-T-735 polymorphism and the C-T haplotype were associated with higher MMP-2 (but not TIMP-2) levels (p<0.05), whereas the C-T-1306 had no effects. Hemodialysis decreased MMP-2 (but not TIMP-2) levels independently of MMP-2 genotypes or haplotypes (p<0.05). Conclusions: MMP-2 genotypes or haplotypes modify MMP-2 levels in ESKD patients, and may help to identify patients with increased MMP-2 activity in plasma. Hemodialysis reduces MMP-2 levels independently of MMP-2 genetic variants. Copyright (C) 2012 S. Karger AG, Basel353209215Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Matrix metalloproteinase (MMP)-2 genetic variants modify the circulating MMP-2 levels in end-stage kidney disease

Matrix metalloproteinases (MMPs) play important roles in the pathophysiology of renal diseases, and imbalanced MMP-2 and its endogenous inhibitor (the tissue inhibitor of metalloproteinases-2; TIMP-2) are implicated in the vascular alterations of end-stage kidney disease (ESKD) patients. We have examined whether MMP-2 gene polymorphisms and haplotypes modify MMP-2 and TIMP-2 levels in ESKD patients as well as the effects of hemodialysis on the concentrations of these biomarkers. We determined MMP-2 and TIMP-2 plasma levels by gelatin zymography and ELISA, respectively, in 98 ESKD patients and in 38 healthy controls. Genotypes for two relevant MMP-2 polymorphisms (C–1306T and C–735T in the promoter region) were determined by TaqMan® allele discrimination assay and real-time polymerase chain reaction. The software program PHASE 2.1 was used to estimate the haplotype frequencies. We found increased plasma MMP-2 and TIMP-2 levels in ESKD patients compared to controls (p < 0.05), and hemodialysis decreased MMP-2 (but not TIMP-2) levels (p < 0.05). The T allele for the C–735T polymorphism and the C-T haplotype were associated with higher MMP-2 (but not TIMP-2) levels (p < 0.05), whereas the C–1306T had no effects. Hemodialysis decreased MMP-2 (but not TIMP-2) levels independently of MMP-2 genotypes or haplotypes (p < 0.05). MMP-2 genotypes or haplotypes modify MMP-2 levels in ESKD patients, and may help to identify patients with increased MMP-2 activity in plasma. Hemodialysis reduces MMP-2 levels independently of MMP-2 genetic variants3532092015CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPnão temnão te

Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background: Altered levels of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in cardiovascular alterations associated with end stage kidney disease (ESKD). Genetic polymorphisms in MMP-9 gene affect MMP-9 levels. We examined how MMP-9 polymorphisms and haplotypes affect the changes in plasma MMP-9 and TIMP-1 levels found in patients with ESKD undergoing hemodialysis. Methods: We studied 94 ESKD patients undergoing hemodialysis for at least 3 months. MMP-9 and TIMP-1 were measured by ELISA in plasma from blood samples collected before and after a session of hemodialysis. Genotypes for three MMP-9 polymorphisms (C-1562T, rs3918242; -90 (CA)(14-24), rs2234681; and Q279R, rs17576) were determined by Taqman (R) Allele Discrimination Assay and real-time polymerase chain reaction. Haplotype frequencies were determined with the software program PHASE 2.1. Results: Hemodialysis increased MMP-9 and TIMP-1 levels (P0.05). Hemodialysis increased MMP-9 and TIMP-1 levels in subjects with the CC (but not CT or TT) genotype for the C-1562T polymorphism (P0.05), hemodialysis increased MMP-9 levels and MMP-9/TIMP-1 ratios in subjects carrying the CLQ haplotype (P = 0.0012 and P = 0.0045, respectively). Conclusion: ESKD patients with the QQ genotype for the Q279R polymorphism or with the CLQ haplotype are exposed to more severe increases in MMP-9 levels after hemodialysis. Such patients may benefit from the use of MMP inhibitors. (C) 2012 Elsevier B.V. All rights reserved.4144651Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Functional matrix metalloproteinase (MMP)-9 genetic variants modify the effects of hemodialysis on circulating MMP-9 levels

Background: Altered levels of matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in cardiovascular alterations associated with end stage kidney disease (ESKD). Genetic polymorphisms in MMP-9 gene affect MMP-9 levels. We examined how MMP-9 polymorphisms and haplotypes affect the changes in plasma MMP-9 and TIMP-1 levels found in patients with ESKD undergoing hemodialysis. Methods: We studied 94 ESKD patients undergoing hemodialysis for at least 3 months. MMP-9 and TIMP-1 were measured by ELISA in plasma from blood samples collected before and after a session of hemodialysis. Genotypes for three MMP-9 polymorphisms (C-1562T, rs3918242; -90 (CA)(14-24), rs2234681; and Q279R, rs17576) were determined by Taqman (R) Allele Discrimination Assay and real-time polymerase chain reaction. Haplotype frequencies were determined with the software program PHASE 2.1. Results: Hemodialysis increased MMP-9 and TIMP-1 levels (P&lt;0.05). Genotypes had no effects on baseline MMP-9 and TIMP-1 levels (P&gt;0.05). Hemodialysis increased MMP-9 and TIMP-1 levels in subjects with the CC (but not CT or TT) genotype for the C-1562T polymorphism (P&lt;0.05), and increased MMP-9 levels in subjects with the QQ (but not QR or RR) genotype for the Q279R polymorphism (P&lt;0.05), whereas the CA(n)(14-24) polymorphism had no major effects. While MMP-9 haplotypes had no effects on baseline MMP-9 levels (P&gt;0.05), hemodialysis increased MMP-9 levels and MMP-9/TIMP-1 ratios in subjects carrying the CLQ haplotype (P = 0.0012 and P = 0.0045, respectively). Conclusion: ESKD patients with the QQ genotype for the Q279R polymorphism or with the CLQ haplotype are exposed to more severe increases in MMP-9 levels after hemodialysis. Such patients may benefit from the use of MMP inhibitors. (C) 2012 Elsevier B.V. All rights reserved.Fundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao PauloConselho Nacional de Desenvolvimento Cientifico e TecnologicoConselho Nacional de Desenvolvimento Cientifico e Tecnologic

Endothelial Nitric Oxide Genotypes and Haplotypes Are Not Associated with End-Stage Renal Disease

The identification of genetic markers associated with chronic kidney disease (CKD) may help to predict its development. Because reduced nitric oxide (NO) bioavailability and endothelial dysfunction are involved in CKD, genetic polymorphisms in the gene encoding the enzyme involved in NO synthesis (endothelial NO synthase [eNos]) may affect the susceptibility to CKD and the development of end-stage renal disease (ESRD). We compared genotype and haplotype distributions of three relevant eNOS polymorphisms (T(-786) C in the promoter region, Glu298Asp in exon 7, and 4b/4a in intron 4) in 110 healthy control subjects and 127 ESRD patients. Genotypes for the T(-786) C and Glu298Asp polymorphisms were determined by TaqMan (R) Allele Discrimination assay and real-time polymerase chain reaction. Genotypes for the intron 4 polymorphism were determined by polymerase chain reaction and fragment separation by electrophoresis. The software program PHASE 2.1 was used to estimate the haplotypes frequencies. We considered significant a probability value of p < 0.05/number of haplotypes (p < 0.05/8 = 0.0063). We found no significant differences between groups with respect to age, ethnicity, and gender. CKD patients had higher blood pressure, total cholesterol, and creatinine levels than healthy control subjects (all p < 0.05). Genotype and allele distributions for the three eNOS polymorphisms were similar in both groups (p > 0.05). We found no significant differences in haplotype distribution between groups (p > 0.05). The lack of significant associations between eNOS polymorphisms and ESRD suggests that eNOS polymorphisms may not be relevant to the genetic component of CKD that leads to ESRD.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP-Brazil)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil)Centro Nefrologico de Taquar