Influence of sex on cerebrospinal fluid density in adults

The extent of sensory block during spinal anaesthesia is unpredictable and is influenced by many factors, mainly patient position, site of injection, baricity and the dose of drug injected. Among other factors, cerebrospinal fluid (CSF) density has been advocated to affect subarachnoid distribution of local anaesthetics. In this study, we have investigated the influence of patient characteristics such as sex, age, weight and height on variations in the density of CSF in more than 46 consecutive patients undergoing spinal anaesthesia. CSF 2 ml was obtained after spinal puncture and before injection of local anaesthetic. Mean CSF density measured at 37°C was mean 1.00054 (SD 0.00017) g ml−1, with significantly lower CSF densities in women (1.00049 (0.00011) g ml−1) than in men (1.00058 (0.00011) g ml−1) (P = 0.024). In contrast, there was no correlation between age, weight or height, and CSF density. These results suggest that sex significantly influenced CSF density and may therefore modify subarachnoid distribution of local anaesthetic

Epinephrine and clonidine do not improve intrathecal sufentanil analgesia after total hip replacement†

Background. We compared analgesia after intrathecal sufentanil alone, sufentanil with epinephrine 200µg and sufentanil with clonidine 30 µg in patients after total hip replacement, the endpoints being onset and duration of action. Methods. We performed a randomized double‐blind study of 45 patients for elective total hip arthroplasty using continuous spinal anaesthesia. As soon as a pain score higher than 3 on a 10 cm visual analogue scale was reported, sufentanil 7.5 µg alone, sufentanil 7.5 µg + epinephrine 200 µg or sufentanil 7.5 µg + clonidine 30 µg in 2 ml normal saline was given intrathecally. Pain scores, rescue analgesia (diclofenac and morphine) and adverse effects (respiratory depression, postoperative nausea and vomiting, itching) were observed for 24h after surgery. Results. Time to a pain score of 3 [281 (36) vs 288 (23) vs 305 (30) min] were similar in all three groups. Adverse effects and analgesic requirements during the first 24h were also similar. Conclusion. After total hip replacement, all three analgesic regimens gave good analgesia with comparable onset and duration of action, and minor adverse effects. Br J Anaesth 2002; 89: 562-

PREOPERATIVE SEDATION BEFORE REGIONAL ANAESTHESIA: COMPARISON BETWEEN ZOLPIDEM, MIDAZOLAM AND PLACEBO

The quality of premedication induced by oral midazolam and zolpidem, a new imidazopyridine hypnotic, was assessed in a controlled, double-blind study in 93 patients undergoing elective surgery under spinal or extradural anaesthesia. The patients were allocated randomly to three groups. Each group received the same treatment twice at two different doses. The night before operation, patients received zolpidem 10 mg, midazolam 7.5 mg or placebo and, 1 h before operation, zolpidem 20 mg, midazolam 15 mg or placebo. The sleep inducing effects of the drugs were comparable. Zolpidem and midazolam were significantly more effective sedatives than placebo 45 min after administration, but no difference was noted between the drugs. There was a comparable incidence of anterograde amnesia with zolpidem and midazolam, but the onset was shorter after zolpidem. Side effects were comparable in the three groups. Zolpidem is an effective hypnotic with a rapid onset and short duration of action which may be an alternative to midazolam for premedicatio

Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in over 140,000 European Descendants

Genome-wide association study–identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10−6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10−6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes

Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for Cp

Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention