37 research outputs found
Plasma redox status is impaired in the portacaval shunted rat – the risk of the reduced antioxidant ability
Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci
Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project
Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series
Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study.
PURPOSE: As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19-free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS: This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19-free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS: Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19-free surgical pathways. Patients who underwent surgery within COVID-19-free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19-free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score-matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19-free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION: Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks
Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study
PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks
Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease
Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues
Ultrastructure of invertebrate muscle cell types
The muscular cells of invertebrates can be
divided into three major classes on the basis of their
striation pattem: transversely striated, obliquely striated,
or smooth muscle. Transversely striated muscles have
either continuous or discontinuous Z lines and, thus, can
be subdivided into two types respectively. Of al1
invertebrate muscles, the transversely striated muscle
with continuos Z lines is the most similar to the
vertebrate skeletal muscle and is present in arthropods,
whose musculature (including the visceral muscles) only
consists of this cell type. These muscles are multinucleate
cells that contain myofibrils showing welldefined
sarcomeres. Transversely striated muscles with
discontinuous Z lines, consisting of multiple small
electrondense patches, are found in the translucent
portions of adductor muscles of some bivalves and in the
heart muscle of the gastropods. This muscle is formed by
mononucleated cells with centrally-located nuclei and a
single myofibril. The obliquely striated muscle appears
in nematodes, annelids, molluscs, brachiopods and
chaetognathes and consists of mononucleated cells with
both thick and thin myofilaments which form
sarcomeres delimited by Z lines. Myofilaments are not
perpendicular but oblique to the Z lines, so that both A
and 1 bands may be seen together in each of the three
spatial planes of view. Smooth muscle has been reported
in coelenterates, annelids, molluscs, brachiopods and
echinoderms, but is lacking in arthropods. These muscle
cells have a centrally-located nucleus and abundant thin
and thick myofilaments without apparent sarcomeres.
The most relevant characteristics of invertebrate muscle
cells are the following. The thick (myosin) myofilarnents
show a variable length (from 2.2 pm up to 6 pm) and width (from 14 nm up to 231 nm) and contain a central
core of paramyosin, which is absent in vertebrate
muscles. Thick filaments are homogenous in
transversely striated muscles and either homogeneous or
fusiform in the obliquely striated and smooth muscles.
Thin filaments measure 6 nm in diameter. They contain
tropomyosin and, only in striated muscles, also troponin. The thinlthick filament ratio varies from 311 to 611, even
in smooth muscles. The plaques for filament anchorage
(Z lines in striated muscles or electrondense bodies in
smooth muscles) contain a-actinin. The striated
(transversely or obliquely) muscles show long
sarcomeres (up to 9 pm) and the number of thin
filaments around each thick filament varies from 3 to 12,
so that each thin filament is shared by two thick
filaments. Z lines in the striated muscles show a variety
of structures that differ from one species to another
(filament bundles in nematodes, bars in annelids, small
patches in molluscs, etc). Many striated muscles contain
titin (connectin) and intermediate filaments and display a
sarcotubular system consisting of T tubules and
sarcoplasmic reticulum tubules. Both structures form
dyads and, more rarely, triads. The location of T tubules
as well as the configuration and distribution of
sarcoplasmic reticulum vary among muscles and species.
Invertebrate smooth muscle differs from that of
vertebrates principally in the higher proportion and
larger diameter of thick myofilaments. These may be
fusiform and their size and number may vary widely
among cells. These muscle cells may be classified by the
characteristics of both the thick filaments and the
electrondense bodies for filament anchorage
Comparison of point of care and clinical laboratory analysis of cystatin-C levels in patients with renal nephropathy
This study utilized the descriptive-comparative research design. Two methods were applied, point of care test and clinical laboratory testing, both employing the Latex-particle Enhanced Immunoturbidimetric Assays (PETIA) principle to be able to measure and analyze the levels of Cystatin-C for each of the participants of the study in order to rectify whether POCT results were comparable with the standard laboratory results. Purposive sampling was used as a sampling technique. The preferrred sample size was a total of 32 patients in De La Salle University Medical Center (DLSUMC) following the important inclusion criteria of those with renal disease (nephropathy) either undergoing dialysis or not, male or female with ages ranging from 18 to 65 years old to determine the Cystatin C level results in POCT and standardized clinical laboratory. Exclusion cirteria include those respondents that had taken corticosteroids, and those characteristics that disqualify prospective subjects from inclusion in the study. The sample collection were taken from each patients. One sample was tested for Cystatin-C POCT using capillary blood and the other sample for teh actual Cystatin-C laboratory analysis using venous blood. Samples from capillary blood were collected by a registered medical technologist while the venous blood was collected from the IV line of the dialysis patients by their assigned nurse. The samples were sent immediately and without delay for the Cystatin-C analysis in the National Kidney and Transplant Institute (NKTI). Data was recorded as the laboratory results were released (standardized clinical laboratory testing). For the results in Cystatin-C POCT, an immediate reading within 10 minutes was made. Results were recorded on the original data collection sheet and were secured for data analysis. Data was analyzed through mean, standard deviation, t-test and f-score. The study concluded that the results of the POCT used in determining Cystatin-C levels were proven to be unvarying and strongly comparable to the results of clinical laboratory test. Therefore, point of care testing using capillary blood sample, which can deliver immediate result an at approximately 10 minutes, can be excellent alternative method in detecting Cystatin-C levels especially in emergency cases