Genetic contributors to variation in alcohol consumption vary by race/ethnicity in a large multi-ethnic genome-wide association study.

Alcohol consumption is a complex trait determined by both genetic and environmental factors, and is correlated with the risk of alcohol use disorders. Although a small number of genetic loci have been reported to be associated with variation in alcohol consumption, genetic factors are estimated to explain about half of the variance in alcohol consumption, suggesting that additional loci remain to be discovered. We conducted a genome-wide association study (GWAS) of alcohol consumption in the large Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort, in four race/ethnicity groups: non-Hispanic whites, Hispanic/Latinos, East Asians and African Americans. We examined two statistically independent phenotypes reflecting subjects' alcohol consumption during the past year, based on self-reported information: any alcohol intake (drinker/non-drinker status) and the regular quantity of drinks consumed per week (drinks/week) among drinkers. We assessed these two alcohol consumption phenotypes in each race/ethnicity group, and in a combined trans-ethnic meta-analysis comprising a total of 86 627 individuals. We observed the strongest association between the previously reported single nucleotide polymorphism (SNP) rs671 in ALDH2 and alcohol drinker status (odd ratio (OR)=0.40, P=2.28 × 10-72) in East Asians, and also an effect on drinks/week (beta=-0.17, P=5.42 × 10-4) in the same group. We also observed a genome-wide significant association in non-Hispanic whites between the previously reported SNP rs1229984 in ADH1B and both alcohol consumption phenotypes (OR=0.79, P=2.47 × 10-20 for drinker status and beta=-0.19, P=1.91 × 10-35 for drinks/week), which replicated in Hispanic/Latinos (OR=0.72, P=4.35 × 10-7 and beta=-0.21, P=2.58 × 10-6, respectively). Although prior studies reported effects of ADH1B and ALDH2 on lifetime measures, such as risk of alcohol dependence, our study adds further evidence of the effect of the same genes on a cross-sectional measure of average drinking. Our trans-ethnic meta-analysis confirmed recent findings implicating the KLB and GCKR loci in alcohol consumption, with strongest associations observed for rs7686419 (beta=-0.04, P=3.41 × 10-10 for drinks/week and OR=0.96, P=4.08 × 10-5 for drinker status), and rs4665985 (beta=0.04, P=2.26 × 10-8 for drinks/week and OR=1.04, P=5 × 10-4 for drinker status), respectively. Finally, we also obtained confirmatory results extending previous findings implicating AUTS2, SGOL1 and SERPINC1 genes in alcohol consumption traits in non-Hispanic whites.

Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response.

The first-line treatment of hyperuricemia, which causes gout, is allopurinol. The allopurinol response is highly variable, with many users failing to achieve target serum uric acid (SUA) levels. No genome-wide association study (GWAS) has examined the genetic factors affecting allopurinol effectiveness. Using 2,027 subjects in Kaiser Permanente's Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort, we conducted a GWAS of allopurinol-related SUA reduction, first in the largest ethnic group, non-Hispanic white (NHW) subjects, and then in a stratified transethnic meta-analysis. ABCG2, encoding the efflux pump BCRP, was associated with SUA reduction in NHW subjects (P = 2 × 10(-8) ), and a missense allele (rs2231142) was associated with a reduced response (P = 3 × 10(-7) ) in the meta-analysis. Isotopic uptake studies in cells demonstrated that BCRP transports allopurinol and genetic variants in ABCG2 affect this transport. Collectively, this first GWAS of allopurinol response demonstrates that ABCG2 is a key determinant of response to the drug.

Association between the oxytocin receptor (OXTR) gene and children's social cognition at 18 months.

At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation and self-recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social-cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, this study hypothesized that variability in the oxytocin receptor gene (OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socio-emotional functioning. At 18 months, social cognition was measured using previously validated and developmentally sensitive tasks assessing children's joint attention, empathy, cooperation and self-recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897 and rs237899. A family-based association design was used to control for population admixture and stratification, and additional non-genomic covariates were controlled. Results showed that variability in rs11131149 was significantly associated with social cognition (P=0.009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149-rs2254298 was also associated with social cognition (P=0.020). Implications for normative and pathological development are discussed, and key areas for future research are proposed.

Effect of spinal cord stimulation in a rodent model of post-operative ileus.

Post-operative ileus (POI) is a transient impairment of gastrointestinal (GI) transit that develops after abdominal surgery. The goal of this study was to investigate the effect of spinal cord stimulation (SCS) on gastric emptying and upper GI transit in a rat model of POI. All rats had an electrode placed on the dorsal surface of the spinal cord between the T(5) and T(8) segments. After recovery, gastric emptying and upper GI transit (geometric centre and head of meal) were assessed using a radiolabelled meal fed to each rat via oral gavage. In unanaesthetized rats, SCS (15, 25, 50, 100, 200 Hz, 0.2 ms at 90% motor threshold for 15 min) was performed immediately after the meal. The sham control group had no current applied. The naïve group was without POI or SCS. Gastric emptying was significantly delayed in sham-stimulated rats with POI compared with naïve controls (39.8 +/- 6.2%vs 76.5 +/- 4.9%, P < 0.001). In rats with POI that underwent SCS, there was a significant acceleration of gastric emptying to levels that resembled those of naïve controls (65.1 +/- 7.4%, P < 0.05). However, while SCS did not normalize the geometric centre and head of the meal when compared with the naïve group, it did significantly improve both parameters compared with the sham stimulation group. In summary, SCS normalizes gastric emptying and improves upper GI transit in a rodent model of POI. Further experiments are required to address the mechanism(s) by which SCS exhibits prokinetic activity.

The Xylum Clot Signature Analyzer: a dynamic flow system that simulates vascular injury.

The Xylum Clot Signature Analyzer (CSA) is an automated, user-friendly, benchtop analyzer that assesses platelet function and coagulation in non-anticoagulated whole blood under physiological flow and temperature conditions. From blood drawn in a single venipuncture, the CSA measures: a) the time for platelets to occlude holes "punched" in a blood conduit (platelet hemostasis time or PHT); b) collagen-induced thrombus formation (CITF) as blood flows in a channel containing a collagen fiber; and c) clotting time (CT). Micrographs show platelet-rich thrombi in the punched holes and on the collagen surface after a run. PHT and CITF increased at lower shear rate, suggesting that shear activation of platelets is involved in hole closure and in collagen-induced thrombus formation. In blood mixed with anti-von Willebrand's factor (vWF) antibodies, anti-GPIb antibodies, aurin tricarboxylic acid (ATA), or anti-GPIIb-IIIa, PHT and CITF were prolonged, further supporting the reflection of platelet function by those parameters. At low shear rate (<1000 sec(-1)), native blood and blood treated with anti-vWF did not have significantly different PHTs or CITFs. At high shear rate (>6000 sec(-1)), the PHT and CITF of the anti-vWF-treated sample were significantly greater than those of the untreated sample. This supports the inhibition of shear-induced activation of platelets by anti-vWF in the CSA. Heparin-treated blood showed significantly longer CT, indicating that coagulation of blood under flow is inhibited by heparin. The CSA thus assess multiple aspects of hemostasis under near-physiological conditions.

U.S. Food and Drug Administration pesticide program: incidence/level monitoring of domestic and imported pears and tomatoes.

In 1992-1993, the U.S. Food and Drug Administration (FDA) conducted a statistically based study of pesticide residues in domestic and imported pears and tomatoes. For pears, 710 domestic and 949 imported samples were collected and analyzed; 79% of the domestic and 72% of the imported samples had detectable residues. Thiabendazole, a fungicide with postharvest uses, was found with greatest frequency in both groups of pears. Four domestic and 12 imported samples contained violative residues, mainly of pesticides for which there are no U.S. tolerances on pears. The statistically weighted (by shipment size) violation rates for domestic and imported pears were 1.0 and 0.9%, respectively. For tomatoes, 1219 domestic and 144 imported samples were collected and analyzed; 84% of the domestic and 91% of the imported samples had detectable residues. Methamidophos, an insecticide, had the greatest frequency of occurrence in both groups of tomatoes. Thirty-three domestic and 5 imported samples were violative, nearly all the result of acephate use, for which there is no U.S. tolerance on tomatoes. The statistically weighted violation rates for domestic and imported tomatoes were 1.9 and 7.0%, respectively. The statistically weighted violation rates calculated for domestic and imported pears and domestic tomatoes in this study were lower than those observed under FDA's regulatory monitoring in recent years. The violation rate for imported tomatoes was somewhat higher under statistical monitoring than under regulatory monitoring. The results of the statistically based study show that, as in regulatory monitoring, the levels of pesticide residues found are generally well below U.S. tolerances.

Pseudocyst of the auricle.

BACKGROUND: Pseudocyst of the auricle is a benign swelling of the ear characterized by collection of fluid within an unlined intracartilaginous cavity. The etiology and pathogenesis of this disorder remain unknown. Various forms of management have been described in several case reports and small series. OBJECTIVE: Description of a surgical procedure for successful management of pseudocyst of the auricle. METHODS: Case report of a patient who declined nonsurgical treatment options following failed management with aspiration. RESULTS: The described procedure resulted in cure of the pseudocyst with good cosmetic outcome. CONCLUSION: Pseudocyst of the auricle can be successfully managed by surgical excision of the anterior wall of the cyst.

Minimizing Corns and Calluses.

In brief: Calluses can be advantageous to some athletes but painful to others, while corns are characteristically painful. Corns and calluses, which may be confused with plantar warts, can be differentiated by gentle paring with a scalpel. This will reveal soft, granular, elongated mounds of dermis projecting up into the epidermis if the abnormality is a wart. Treatment of corns and calluses includes relieving the cause of pressure or friction. Properly fitting shoes and corn/callus pads can help prevent or minimize these common skin disorders.

Acute acral pustulosis.

We report a patient with a pustular eruption in an acral distribution that developed abruptly 4 days after a streptococcal pharyngitis. The histology showed an intraepidermal vesicle filled with neutrophils with an underlying lymphocytic vasculitis. Direct immunofluorescence demonstrated heavy deposition of C3 within the vessel walls. In addition, circulating immune complexes were found.

Vibrio vulnificus septicemia.

We report a case of Vibrio vulnificus infection in a middle-aged alcoholic man with Laennec's cirrhosis. The patient had recently received a puncture wound from the shell of a shrimp while fishing in the Gulf of Mexico. He presented with acrally distributed urticarial plaques, purpura, and bullae, as well as signs and symptoms of septic shock. Vibrio vulnificus was isolated from the blood, and histologic examination of the skin biopsy specimen demonstrated a devitalized, inflammatory, cell-poor superficial dermis and an acute cellulitis of the subcutis, with extensive tissue destruction. In addition, a necrotizing vasculitis, with a relative paucity of inflammatory cells but numerous bacilli around dermal vessels, was noted.

Determination of coumarin as an adulterant in vanilla flavoring products by high-performance liquid chromatography.

A high-performance liquid chromatographic procedure was developed for the isolation and quantitation of coumarin from vanilla-based liquid flavorings of Mexican origin. Forty products representing fourteen different Mexican brands were assayed for coumarin, vanillin, and ethyl vanillin by the proposed method. The procedure has been adapted to the analysis of other products including domestic vanilla extracts and imitation vanilla flavorings for vanillin, ethyl vanillin, 4-hydroxybenzaldehyde and piperonal. Chromatographic retention data for thirty-seven compounds associated with vanillin and vanilla products employing two mobile phase systems are presented.

Determination of mercury-containing pharmaceuticals by vapor phase atomic absorption spectroscopy.

A procedure was developed for the determination of mercurials of pharmaceutical interest. Protic acid cleavage of the compound was followed by reduction of the resulting mercuric ion and vapor phase atomic absorption spectroscopy. This procedure was applied to 11 different mercurial compounds in various pharmaceutical preparations and offers excellent sensitivity with respect to presently used compendial assays. Comparative analytical data between this procedure and compendial methodology are presented.

Determination of methadone hydrochloride in a maintenance dosage formulation.

A colorimetric method for direct quantitative assay of methadone hydrochloride in liquid oral dosage forms is presented. The procedure involves the formation of a dye complex with bromothymol blue buffer solution. The resultant complex is extracted with benzene and measured spectrophotometrically. Duplicate tests on the formulation showed 99.2% of the labeled amount of methadone.