Single nucleotide polymorphisms and post-operative complications following major gastrointestinal surgery: A systematic review and meta-analysis

Background: The human genome is an under-researched area of pre-operative risk stratification. Studies of genetic polymorphisms and their associations with acute post-operative complications in gastrointestinal surgery have reported statistically significant results, but have varied in methodology, genetic variations studied, and conclusions reached. To provide clarity, we conducted a systematic review and meta-analysis of single nucleotide polymorphisms and their association with post-operative complications after major gastro-8 intestinal surgery. Methods: We performed a literature search using Ovid MEDLINE and Web of Science databases. Studies were included if they investigated genetic polymorphisms and their associations with post-operative complications after major gastrointestinal surgery. We extracted clinical and genetic data from each paper and assessed for quality against the STrengthening the REporting of Genetic Association Studies (STREGA) guidelines. Odds ratios were presented, with 95% confidence intervals, to assess strengths of association. We conducted a meta-analysis on TNF-alpha-308, which had been assessed in three papers. Results: Our search returned 68 papers, of which 5 were included after screening and full-text review. Twenty-two different single nucleotide polymorphisms (SNPs) were investigated in these studies. We found that all papers were genetic association studies, and had selected SNPs related to inflammation. The outcome investigated was most commonly post-operative infection, but also anastomotic leak and other non-infectious complications. Statistically significant associations were found for: TNF-alpha-308, IL-10-819, PTGS2-765 and IFN-gamma-874. There was significant variability in study quality and methodology. We conducted a meta-analysis on associations between the TNF-alpha-308 polymorphism and post-operative infection and report an OR of 1.18 (CI 0.27 – 5.21). Conclusions: We found biologically plausible associations between SNPs involved in inflammation and post-operative infection, but the available data were too limited and of insufficient quality to reach definitive conclusions. Further work is needed, including genome-wide association studies (GWAS)

Gianturco Z-stent placement for the treatment of chronic central venous occlusive disease: implantation of 208 stents in 137 symptomatic patients

PURPOSETo report the technical successes, adverse events, and long-term stent patency rates of Gianturco Z-stents for management of chronic central venous occlusive disease.METHODSOverall, 137 patients, with mean age 48.6±16.1 years (range, 16-89 years), underwent placement of Gianturco Z-stents for chronic central venous occlusions. Presenting symptoms included lower extremity edema (n=66, 48.2%), superior vena cava syndrome (n=30, 21.9%), unilateral upper extremity swelling (n=20, 14.6%), hemodialysis fistula or catheter dysfunction (n=11, 8.0%), ascites (n=8, 5.8%), and both ascites and lower extremity edema (n=2, 1.5%). Most common etiologies of central venous occlusion were prior central venous access placement (n=58, 42.3%), extrinsic compression (n=29, 21.2%), and post-surgical anastomotic stenosis (n=27, 19.7%). Number of stents placed, stent implantation location, stent sizes, technical successes, adverse events, need for re-intervention, follow-up evaluation, stent patencies, and mortality were recorded. Technical success was defined as recanalization and stent reconstruction with restoration of in-line venous flow. Adverse events were defined by the Society of Interventional Radiology Adverse Event Classification criteria. Primary and primary-assisted stent patencies were analyzed using Kaplan-Meier analysis.RESULTSIn total, 208 Z-stents were placed. The three most common placement sites were the inferior vena cava (n=124, 59.6%), superior vena cava (n=44, 21.2%), and brachiocephalic veins (n=27, 13.0%). Technical success was achieved in 133 patients (97.1%). There were two (1.5%) severe adverse events (two cases of stent migration to the right atrium), one (0.7%) moderate adverse event, and one (0.7%) mild adverse event. Mean follow-up was 43.6±52.7 months. Estimated 1-, 3-, and 5-year primary stent patency was 84.2%, 84.2%, and 82.1%, respectively. Estimated 1-, 3-, and 5-year primary-assisted patency was 92.3%, 89.6%, and 89.6%, respectively. The 30- and 60- day mortality rates were 2.9% (n=4) and 5.1% (n=7), none of which were directly attributable to Z-stent placement.CONCLUSIONGianturco Z-stent placement is safe and effective for the treatment for chronic central venous occlusive disease with durable short- and long-term patencies

Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease

INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations

Prone transradial catheterization for combined single-session endovascular and percutaneous interventions: approach, technical success, safety, and outcomes in 15 patients

PURPOSE:We aimed to report approach, safety, technical success, and clinical outcomes of prone trans- radial access (PTRA) and demonstrate feasibility for procedures requiring simultaneous arterial intervention and prone percutaneous access. METHODS:Fifteen patients underwent PTRA, seven females (47%) and eight males (53%), mean age of 55 years (range, 19–78 years). All patients underwent PTRA for combined transarterial and posterior-approach percutaneous interventions. Variables included sheath size (French, F), type of anesthesia, arterial intervention technical success, posterior-approach percutaneous intervention technical success, estimated blood loss (mL), fluoroscopy and procedure time, complications, and follow-up.RESULTS:Mean sheath size was 4 F (range, 4–6 F; SD = 0.5). Arterial interventions included transarterial embolization of renal (n=6), hepatic (n=2), and pelvic vessels (n=2), diagnostic arteriography (n=4), and embolization of an arteriovenous malformation (n=1). Posterior-approach intervention technical success was 100% (15/15). PTRA technical success was 100% (15/15). Posterior-approach percutaneous interventions included retroperitoneal (n=5) and pelvic (n=1) mass biopsies, nephrostomy tube placement (n=2), cryoablation of pelvic (n=2) and renal (n=1) masses, sclerotherapy of arteriovenous malformations (n=2), foreign body removal from the renal collecting system (n=2), ablation of a renal tumor (n=1), intracavitary injection of pulmonary mycetoma (n=1), and ablation and cementoplasty of a vertebral body tumor (n=1). The biopsies were diagnostic (6/6). There were no minor or major access-site complications.CONCLUSION:PTRA is a safe and feasible method for performing combined arterial and posterior approach percutaneous interventions without the need for repositioning

Dementia Revealed: Novel Chromosome 6 Locus for Late-Onset Alzheimer Disease Provides Genetic Evidence for Folate-Pathway Abnormalities

Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold () were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, ). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (; Bonferroni-corrected P = 0.022). Subsequent genotyping of SNPs in high linkage disequilibrium () with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P = 0.016; rs2073067, P = 0.03; rs2072064, P = 0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P = 0.002 ( in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P = 0.005; rs803422, P = 0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development

FE65 Binds Teashirt, Inhibiting Expression of the Primate-Specific Caspase-4

The Alzheimer disease (AD) amyloid protein precursor (APP) can bind the FE65 adaptor protein and this complex can regulate gene expression. We carried out yeast two-hybrid studies with a PTB domain of FE65, focusing on those genes that might be involved in nuclear signaling, and identified and validated Teashirt proteins as FE65 interacting proteins in neurons. Using reporter systems, we observed that FE65 could simultaneously recruit SET, a component of the inhibitor of acetyl transferase, and Teashirt, which in turn recruited histone deacetylases, to produce a powerful gene-silencing complex. We screened stable cell lines with a macroarray focusing on AD-related genes and identified CASP4, encoding caspase-4, as a target of this silencing complex. Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. Expression studies in postmortem samples demonstrated decreasing expression of Teashirt and increasing expression of caspase-4 with progressive cognitive decline. Importantly, there were significant increases in caspase-4 expression associated with even the earliest neuritic plaque changes in AD. We evaluated a case-control cohort and observed evidence for a genetic association between the Teashirt genes TSHZ1 and TSHZ3 and AD, with the TSHZ3 SNP genotype correlating with expression of Teashirt3. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD. Thus the cell biological, gene expression and genetic data support a role for Teashirt/caspase-4 in AD biology. As caspase-4 shows evidence of being a primate-specific gene, current models of AD and other neurodegenerative conditions may be incomplete because of the absence of this gene in the murine genome

Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias

The sources, impact and management of car park runoff pollution: a review

Traffic emissions contribute significantly to the build-up of diffuse pollution loads on urban surfaces with their subsequent mobilisation and direct discharge posing problems for receiving water quality. This review focuses on the impact and mitigation of solids, metals, nutrients and organic pollutants in the runoff deriving from car parks. Variabilities in the discharged pollutant levels and in the potentials for pollutant mitigation complicate an impact assessment of car park runoff. The different available stormwater best management practices and proprietary devices are reported to be capable of reductions of between 20% and almost 100% for both suspended solids and a range of metals. This review contributes to prioritising the treatment options which can achieve the appropriate pollutant reductions whilst conforming to the site requirements of a typical car park. By applying different treatment scenarios to the runoff from a hypothetical car park, it is shown that optimal performance, in terms of ecological benefits for the receiving water, can be achieved using a treatment train incorporating permeable paving and bioretention systems. The review identifies existing research gaps and emphasises the pertinent management practices as well as design issues which are relevant to the mitigation of car park pollution

REPORT Whole-Exome Sequencing Links a Variant in DHDDS to Retinitis Pigmentosa

Increasingly, mutations in genes causing Mendelian disease will be supported by individual and small families only; however, exome sequencing studies have thus far focused on syndromic phenotypes characterized by low locus heterogeneity. In contrast, retinitis pigmentosa (RP) is caused by >50 known genes, which still explain only half of the clinical cases. In a single, one-generation, nonsyndromic RP family, we have identified a gene, dehydrodolichol diphosphate synthase (DHDDS), demonstrating the power of combining whole-exome sequencing with rapid in vivo studies. DHDDS is a highly conserved essential enzyme for dolichol synthesis, permitting global N-linked glycosylation. Zebrafish studies showed virtually identical photoreceptor defects as observed with N-linked glycosylation-interfering mutations in the light-sensing protein rhodopsin. The identified Lys42Glu variant likely arose from an ancestral founder, because eight of the nine identified alleles in 27,174 control chromosomes were of confirmed Ashkenazi Jewish ethnicity. These findings demonstrate the power of exome sequencing linked to functional studies when faced with challenging study designs and, importantly, link RP to the pathways of N-linked glycosylation, which promise new avenues for therapeutic interventions. Retinitis pigmentosa (RP) refers to a large group of genetically heterogeneous retinal degenerative disorders characterized by early rod photoreceptor dysfunction followed by progressive rod and cone photoreceptor dysfunction and photoreceptor death (MIM 268000). Impaired night vision followed by impaired peripheral vision generally starts in adolescence to young adulthood, with subsequent impaired central vision in later life. We studied a family of Ashkenazi Jewish (AJ) origin in which three out of four siblings (two females and one male) were diagnosed with RP in their teenage years ( To identify the genetic cause of this likely recessive subtype of RP, we screened all genes known to harbor RP mutations and found that they were negative for mutations. Classic linkage approaches were not applicable because of the size of the nonconsanguineous family, so we performed whole-exome sequencing in the three affected siblings and one unaffected sibling (Whole Human Exome Capture kit, Roche). We produced approximately 10 gigabases (Gb) of paired-end 75 bp sequence reads per individual on the Illumina GAII platform. To test the overall quality of the sequence data, we compared the genotypes of variants found in the sequence data to variants derived from genotyping via a genome-wide SN