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Background: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk., Methods: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci., Results: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals., Conclusions: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Previous research in animal models suggests that brain-derived neurotrophic factor (BDNF) is involved in stress-modulated alcohol consumption. However, relatively few studies have investigated this issue in humans, and results of existing studies have been heterogeneous. The primary aim of the current study was to examine the within-subjects effect of acute stress (timed math plus cold pressor) on serum BDNF levels (ΔBDNF: post- minus pre-stress) in healthy social drinkers (N=68, 20 male). A secondary aim was to explore which heritable and environmental factors in our limited sample might exert the greatest influences on ΔBDNF. Importantly, presence versus absence of the BDNF Val 66 Met polymorphism (rs6265), which has often been discounted in studies of human serum BDNF, was included as a between-subjects control variable in all statistical analyses. Our results indicated that acute stress decreased serum BDNF. Further, multiple regression analyses revealed that quantitative family history of alcohol use disorder (qFH) and age at first alcohol use together accounted for 15% of the variance in ΔBDNF. Thus, the influences of qFH and age at first alcohol use may explain some of the heterogeneity that exists in previous studies of human serum BDNF. These results parallel findings in animal models and suggest that stress-related changes in serum BDNF are influenced by both heritable (qFH) and environmental (early alcohol consumption) factors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The addition of dextran with a molecular weight of 40,000 Dalton in pulmonary preservation solutions has proved to be beneficial. However, dextrans of other size have not yet been investigated. Therefore, it is unclear whether dextran 40,000 represents the optimal additive for lung preservation solutions., Method: In a working rat heart-lung model, lung were preserved with regular Euro-Collins solution or with Euro-Collins solution containing 5% dextran of different sizes: 40,000 Dalton molecular weight; 70,000 Dalton molecular weight; 160,000 Dalton molecular weight. After 2 hours of ischemia functional (oxygenation; pulmonary vascular resistance) and structural (wet/dry-ratio, light microscopy) data were assessed and the amount of dextran in the lung tissue was measured., Results: Lungs preserved with Euro-Collins solution 70,000 Dalton molecular weight or Euro-Collins solution 160,000 Dalton molecular weight exhibited superior functional and structural results when compared with Euro-Collins solution and Euro-Collins solution 40,000 Dalton molecular weight. Additionally, the least amount of dextran in the lung tissue was found in organs preserved with Euro-Collins solution 160,000 Dalton molecular weight after ischemia and reperfusion., Conclusions: Dextrans are useful additives for lung preservation solutions. However, the size of the molecules is important because dextrans of 160,000 Dalton molecular weight were superior to dextrans of lower molecular weight in our study.

In the present report the prevalence, severity, and risk factors of tricuspid valve regurgitation (TR) in 251 heart transplant recipients have been analyzed retrospectively. Tricuspid valve function was studied by color-flow Doppler echocardiogram and annual heart catheterization. The presence or severity of TR was graded on a scale from 0 (no TR) to 4 (severe). Additional postoperative data included rate of rejection, number of endomyocardial biopsies, incidence of transplant vasculopathy, and preoperative and postoperative hemodynamics. The incidence of grade 3 TR increases from 5% at 1 year to 50% at 4 years after transplantation. Multivariate analysis showed rate of rejection and donor heart weight to be significant risk factors. The ischemic intervals as well as the preoperative and postoperative pulmonary hemodynamics did not affect the severity or prevalence of TR. These results indicate that various factors appear to have an impact on the development of TR and that the prevalence might be lowered by a reduction of the number of biopsies performed and when possible, oversizing of donor hearts.

The present study assessed the extent to which remission of nephrotic-range proteinuria occurred in patients with Type I diabetes enrolled in the Captopril Study, a placebo controlled multicenter clinical trial of captopril therapy in diabetic nephropathy. Of the 409 patients recruited into the Captopril Study, 108 had nephrotic-range proteinuria (> 3.5 g/24 hr) at entry in the Study (baseline). This group was the subject of the present study. Remission of nephrotic-range proteinuria was defined as follows: (1) Onset of the remission was taken as the date when proteinuria was first noted to be < or = 1.0 g/24 hr. (2) The reduction in proteinuria had to be sustained for a minimum of six months and until the end of the Captopril Study. (3) During the remission, the average of all 24 hour proteinuria measurements could not exceed 1.5 g. (4) Decline in renal function could not explain the reduced proteinuria. That is, the patient's serum creatinine during the entire period of observation in the Captopril Study had to remain at less than a doubling of the baseline serum creatinine. Remission of nephrotic-range proteinuria occurred in 7 of 42 patients assigned to captopril (16.7%, mean follow-up 3.4 +/- 0.8 years) and in 1 of 66 patients assigned to placebo (1.5%, mean follow-up 2.3 +/- 1.1 years; P = 0.005, comparing remission rate in captopril vs. placebo-treated patients).(ABSTRACT TRUNCATED AT 250 WORDS)

The toxicity of long-term immunosuppressive therapy has become a major concern in long-term follow-up of heart transplant recipients. In this respect the quality of renal function is undoubtedly linked to cyclosporin A (CsA) drug levels. In cardiac transplantation, specific CsA trough levels have historically been maintained between 250 and 350 micrograms/L in many centers without direct evidence for the necessity of such high levels while using triple-drug immunosuppression. This retrospective analysis compares the incidence of acute and chronic graft rejection as well as overall mortality between groups of patients with high (250 to 350 micrograms/L) and low (150 to 250 micrograms/L) specific CsA trough levels. A total of 332 patients who underwent heart transplantation between October 1985 and October 1992 with a minimum follow-up of 30 days were included in this study (46 women and 276 men; aged, 44 +/- 12 years; mean follow-up, 1,122 +/- 777 days). Standard triple-drug immunosuppression included first-year specific CsA target trough levels of 250 to 300 micrograms/L. Patients were grouped according to their average creatinine level in the first postoperative year (group I, < 130 mumol/L, n = 234; group II, > or = 130 mumol/L, n = 98). The overall 5-year survival excluding the early 30-day mortality was 92% (group I, 216/232) and 91% (group II, 89/98) with 75% of the mortality due to chronic rejection. The rate of rejection for the entire follow-up period was similar in both groups (first year: group I, 3.2 +/- 2.6 rejection/patient/year; group II, 3.6 +/- 2.7 rejection/patient/year; p = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Refixation of dissected aortic layers with gelatin-resorcin-formaldehyde/glutaraldehyde (GRFG) adhesive represents a new option in the surgical treatment of aortic dissection. Because of its ability to reinforce the delicate structures of the acutely dissected aortic wall, GRFG has been used increasingly in recent years. However, the biomechanical properties of the adhesive are still unclear, and little is known regarding the optimal mode of its application. In an ex vivo study, aortic specimens from sheep were glued with warm (45 degrees C) adhesive under wet and dry conditions and submitted to defined degrees of compression (5 Newtons [N], 20 N). Bonded specimens were retracted to assess tensile strength and elasticity compared with two reference adhesives: cyanoacrylate gel and fibrin glue. Gelatin-resorcin-formaldehyde/glutaraldehyde and cyanoacrylate gel showed similar results at 5 N. Both provided better adhesion when applied under dry conditions (GRFG 5 N: dry, 3.5 +/- 1.6 N/cm2; wet, 1.4 +/- 1.0 N/cm2; cyanoacrylate gel 5 N: dry, 4.8 +/- 1.8 N/cm2; wet, 3.2 +/- 1.3 N/cm2). At 20 N, GRFG tensile strength was significantly increased for either condition compared with values at 5 N (GRFG 20 N: dry, 17.1 +/- 4.2 N/cm2; wet, 4.8 +/- 1.8 N/cm2). Fibrin glue demonstrated only weak adhesive properties even under dry conditions (fibrin glue 5 N: dry, 0.8 +/- 0.3 N/cm2). Gelatin-resorcin-formaldehyde/glutaraldehyde has good adhesive properties both in wet and dry tissue. Bonding capacity can be substantially increased when applied on dry surfaces and at increased pressures.

In a canine model, the quality of lung preservation was assessed using pulmonary artery flush after prostacyclin administration with either modified Euro-Collins solution or University of Wisconsin solution. Twelve combined heterotopic heart and orthotopic left lung allotransplantations were performed after 6 hours of cold ischemia. Myocardial preservation was achieved using St. Thomas Hospital solution. Donor organs were anastomosed parallel to the recipient's heart and right lung, and the superior vena cava inflow was directed into the transplanted heart-left lung block after ligation of the recipient's superior vena cava proximal to the caval anastomosis. Postoperatively, cardiorespiratory function was evaluated separately for donor and recipient organs at an inspired oxygen fraction of 0.4 for a maximum of 12 hours. Significantly improved oxygenation and lower pulmonary vascular resistance index of the donor lung was observed in the University of Wisconsin + prostacyclin group, whereas pulmonary artery pressures showed no significant differences in between both groups. It is concluded that superior results in lung preservation can be achieved with pulmonary artery flush perfusion using University of Wisconsin solution and prostacyclin when compared with Euro-Collins solution and prostacyclin.