Cardiorespiratory effects of venous lipid micro embolization in an experimental model of mediastinal shed blood reinfusion

<p>Abstract</p> <p>Background</p> <p>Retransfusion of the patient's own blood during surgery is used to reduce the need for allogenic blood transfusion. It has however been found that this blood contains lipid particles, which form emboli in different organs if the blood is retransfused on the arterial side. In this study, we tested whether retransfusion of blood containing lipid micro-particles on the venous side in a porcine model will give hemodynamic effects.</p> <p>Methods</p> <p>Seven adult pigs were used. A shed blood surrogate containing 400 ml diluted blood and 5 ml radioactive triolein was produced to generate a lipid embolic load. The shed blood surrogate was rapidly (<2 minutes) retransfused from a transfusion bag to the right atrium under general anesthesia. The animals' arterial, pulmonary, right and left atrial pressure were monitored, together with cardiac output and deadspace. At the end of the experiment, an increase in cardiac output and pulmonary pressure was pharmacologically induced to try to flush out lipid particles from the lungs.</p> <p>Results</p> <p>A more than 30-fold increase in pulmonary vascular resistance was observed, with subsequent increase in pulmonary artery pressure, and decrease in cardiac output and arterial pressure. This response was transient, but was followed by a smaller, persistent increase in pulmonary vascular resistance. Only a small portion of the infused triolein passed the lungs, and only a small fraction could be recirculated by increasing cardiac output and pulmonary pressure.</p> <p>Conclusion</p> <p>Infusion of blood containing lipid micro-emboli on the venous side leads to acute, severe hemodynamic responses that can be life threatening. Lipid particles will be trapped in the lungs, leading to persistent effects on the pulmonary vascular resistance.</p

Effects of the neurogranin variant rs12807809 on thalamocortical morphology in schizophrenia

10.1371/journal.pone.0085603PLoS ONE812-POLN

Genetic correction of PSA values using sequence variants associated with PSA levels

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldMeasuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.info:eu-repo/grantAgreement/EC/FP7/202059/ 218071 Urological Research Foundation P50 CA90386-05S2 Robert H. Lurie Comprehensive Cancer Center p30 CA60553 Health Technology Assessment Programme 96/20/06 96/20/99 Department of Health, England Cancer Research UK C522/A8649 Medical Research Council of England G0500966 ID 75466 National Cancer Research Institute (NCRI), UK Southwest National Health Service Research and Development NCRI National Institute for Health Resear

Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility.

Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.Support for the Netherlands Twin Register was obtained from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193,480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB; European Research Council (ERC-230374 and ERC-284167); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1). Part of the genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951). We acknowledge support from VU Amsterdam and the Institute for Health and Care Research (EMGO+). The Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). Dale R. Nyholt was supported by the Australian Research Council (ARC) Future Fellowship (FT0991022), NHMRC Research Fellowship (APP0613674) Schemes and by the Visiting Professors Programme (VPP) of the Royal Netherlands Academy of Arts and Sciences (KNAW). Allan F. McRae was supported by an NRMRC Career Development Fellowship (APP1083656). Grant W. Montgomery was supported by NIH grant (HD042157, a collaborative study of the genetics of DZ twinning) and NHMRC Fellowship (GNT1078399). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886), and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). We would like to thank also 23andMe's consented research participants for contributing data on age at menarche for the FSHB gene locus and the Twinning Gwas Consortium (TGC). Co-authors from: Finland (Anu Loukola, Juho Wedenoja, Emmi Tikkanen, Beenish Qaiser), Sweden (Nancy Pedersen, Andrea Ganna), United kingdom King's College London (Department of Twin Research & Genetic Epidemiology: Pirro Hysi, Massimo Mangino), Institute of Psychiatry, Psychology & Neuroscience, Medical Research Council Social, Genetic and Developmental Psychiatry Centre (Eva Krapohl, Andrew McMillan).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ajhg.2016.03.00

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinnIL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (β = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.Netherlands Asthma Foundation University Medical Center Groningen Ministry of Health and Environmental Hygiene of Netherlands Netherlands Asthma Stichting Astma Bestrijding BBMRI European Respiratory Society private and public research funds AstraZeneca ALK-Abello, Denmar

Sequence variants associating with urinary biomarkers

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms