An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry.

Fast beta (20-28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10-8. The most significantly associated SNP, rs11720469 (ß: -0.124; P<4.5 × 10-9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Genome-wide polygenic scores for age at onset of alcohol dependence and association with alcohol-related measures.

Age at onset of alcohol dependence (AO-AD) is a defining feature of multiple drinking typologies. AO-AD is heritable and likely shares genetic liability with other aspects of alcohol consumption. We examine whether polygenic variation in AO-AD, based on a genome-wide association study (GWAS), was associated with AO-AD and other aspects of alcohol consumption in two independent samples. Genetic risk scores (GRS) were created based on AO-AD GWAS results from a discovery sample of 1788 regular drinkers from extended pedigrees from the Collaborative Study of the Genetics of Alcoholism (COGA). GRS were used to predict AO-AD, AD and Alcohol dependence symptom count (AD-SX), age at onset of intoxication (AO-I), as well as maxdrinks in regular drinking participants from two independent samples-the Study of Addictions: Genes and Environment (SAGE; n=2336) and an Australian sample (OZ-ALC; n=5816). GRS for AO-AD from COGA explained a modest but significant proportion of the variance in all alcohol-related phenotypes in SAGE. Despite including effect sizes associated with large numbers of single nucleotide polymorphisms (SNPs; >110 000), GRS explained, at most, 0.7% of the variance in these alcohol measures in this independent sample. In OZ-ALC, significant but even more modest associations were noted with variance estimates ranging from 0.03 to 0.16%. In conclusion, there is modest evidence that genetic variation in AO-AD is associated with liability to other aspects of alcohol involvement.

Common biological networks underlie genetic risk for alcoholism in African- and European-American populations.

Alcohol dependence (AD) is a heritable substance addiction with adverse physical and psychological consequences, representing a major health and economic burden on societies worldwide. Genes thus far implicated via linkage, candidate gene and genome-wide association studies (GWAS) account for only a small fraction of its overall risk, with effects varying across ethnic groups. Here we investigate the genetic architecture of alcoholism and report on the extent to which common, genome-wide SNPs collectively account for risk of AD in two US populations, African-Americans (AAs) and European-Americans (EAs). Analyzing GWAS data for two independent case-control sample sets, we compute polymarker scores that are significantly associated with alcoholism (P = 1.64 × 10(-3) and 2.08 × 10(-4) for EAs and AAs, respectively), reflecting the small individual effects of thousands of variants derived from patterns of allelic architecture that are population specific. Simulations show that disease models based on rare and uncommon causal variants (MAF < 0.05) best fit the observed distribution of polymarker signals. When scoring bins were annotated for gene location and examined for constituent biological networks, gene enrichment is observed for several cellular processes and functions in both EA and AA populations, transcending their underlying allelic differences. Our results reveal key insights into the complex etiology of AD, raising the possibility of an important role for rare and uncommon variants, and identify polygenic mechanisms that encompass a spectrum of disease liability, with some, such as chloride transporters and glycine metabolism genes, displaying subtle, modifying effects that are likely to escape detection in most GWAS designs.

A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.

Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6.

Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634 583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 117 families densely affected by alcohol use disorders, recruited in the Collaborative Study on the Genetics of Alcoholism. Genome-wide significant association was found with several SNPs on chromosome 21 in KCNJ6 (a potassium inward rectifier channel; KIR3.2/GIRK2), with the most significant SNP at P = 4.7 × 10(-10)). The same SNPs were also associated with EROs from central and parietal electrodes, but with less significance, suggesting that the association is frontally focused. One imputed synonymous SNP in exon four, highly correlated with our top three SNPs, was significantly associated with the frontal theta ERO phenotype. These results suggest KCNJ6 or its product GIRK2 account for some of the variations in frontal theta band oscillations. GIRK2 receptor activation contributes to slow inhibitory postsynaptic potentials that modulate neuronal excitability, and therefore influence neuronal networks.

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations.

Genome-wide association study of conduct disorder symptomatology.

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD. In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence. Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N = 872 with CD and N = 3091 without CD). We find four markers that meet the criteria for genome-wide significance (P<5 × 10(-8)) with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association. These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder.

Evaluación de la contaminación microbiológica en productos de células progenitoras hematopoyéticas. Experiencia de un laboratorio de procesamiento de CPH y Banco de Sangre de Cordón Umbilical / Microbiological evaluation in hematopoietic progenitor cell products. Experience from an HPC processing laboratory and Cord Blood Bank

Los productos de células progenitoras hematopoyéticas (CPH) representan una fuente potencial de infección en pacientes inmunosuprimidos que reciben infusión de CPH como parte de su tratamiento. La probabilidad de contaminación de cada producto difiere según la técnica de colecta y el procesamiento aplicado. En este trabajo hemos realizado un análisis retrospectivo de los resultados de cultivos microbiológicos de 1707 productos de CPH obtenidos de sus tres fuentes (médula ósea, sangre periférica y sangre de cordón umbilical) con el objetivo de determinar la proporción de unidades contaminadas. Además, fueron comparadas las distintas técnicas de colecta y las diferentes manipulaciones a las que fueron sometidos los productos. Por otro lado, se analizaron las posibles fuentes de contaminación según el microorganismo identificado y se evaluó la supervivencia de los mismos luego del descongelamiento. La prevalencia de productos de CPH con cultivos microbiológicos positivos reportados en este estudio (5,2%) se corresponde con lo descripto en la literatura. No encontramos diferencias significativas al comparar los productos según la fuente de la cual provenían las CPH. Tampoco hubo diferencias según los procedimientos aplicados a cada unidad. Los microorganismos aislados en los productos de CPH fueron los esperados de acuerdo a la fuente de la cual provenían las células. Pudo comprobarse que algunos de ellos son capaces de sobrevivir a los procesos de criopreservación y descongelamiento. La estricta adhesión a las normas de buenas prácticas de manufactura y buenas prácticas tisulares es un requisito para minimizar los riesgos de introducir microorganismos contaminantes. Disponer de un producto de CPH seguro es fundamental para el éxito de un trasplante.

Hematopoietic stem cell products (HSCP) represent a potential source of infection for immunosuprressed patients that receive HSCP infusion as part of their treatment. The probability of contamination of a HSCP product depends on the collection technique as well as the processing performed. In this work we have carried out a retrospective analysis of the results of 1707 microbiological cultures of HSCP products obtained from three different sources: bone marrow, peripheral blood and umbilical cord blood. We determined the proportion of HSCP units that were contaminated by microorganisms. Furthermore we compared the results obtained with different collection techniques and with the distinct manipulations that were used for processing. Moreover we analysed the possible sources of contamination related to the microorganisms identified and we evaluated the survival of them after thawing. The proportion of HSCP products with positive microbiological cultures obtained in this study (5,2%) correlates with that reported by other authors. We have not found significant differences between the results achieved with HSCP products from different sources. There were neither differences depending on the procedures applied. The isolated microorganisms from the HSCP products were the expected in accordance with the source of the cells. It could be demonstrated that some of them were capable of surviving the cryopreservation and thawing processes. Adherence to good manufacture practices and good tissue practices regulations is critical for minimizing the risks of introducing contaminant microorganisms. A safe HSCP product is essential for the success of a transplant.

Premio Dr. Abraham Isaías Kohan - XIII Congreso Argentino de Medicina Transfusional. Proceso de colecta de células progenitoras hematopoyéticas de sangre periférica en pediatría / Dr. Abraham Isaías Kohan Award - XIII Argentine Congress of Transfusion Medicine. Stem cell collections and associated processes in a pediatric population

Fundamento: El trasplante de células progenitoras hematopoyéticas, es una terapéutica utilizada para el tratamiento de pacientes con enfermedades hematológicas y oncológicas, entre otras. Las células progenitoras hematopoyéticas de sangre periférica se obtienen mediante leucaféresis, previa movilización del donante con factores de crecimiento hematopoyético. Objetivos: Comunicar la experiencia de colectas de células progenitoras hematopoyéticas y los procesos asociados, en una población pediátrica candidata a trasplante autólogo o alogeneico. Material y Método: Se evaluaron 53 pacientes y/o donantes para realizar colecta de CPH, entre los años 2008 y 2011. Se tomó consentimiento informado para realizar los procedimientos. Todos fueron evaluados clínicamente y mediante estudios de laboratorio. El momento de colecta se determinó por el número de las células CD34+ en sangre periférica (óptimo 10 a 20 CD34+/uL) en los pacientes y/o donantes, la decisión se tomó en equi­po: médico tratante y de hemoterapia. Resultados: Fueron evaluados 53 candidatos, se realizó colecta en 40: Grupo I autólogo 29 (72,5 %) y Grupo II alogeneico 11 (27,5%). Se realizaron 61 colectas, 50 en Grupo I (82%) y 11 en Grupo II (18%). La mediana de la dosis de movilización con G-CSF fue 12,80 ug/ Kg /día (Rango: 10-25) aplicada entre 4 y 6 días. El recuento de CD34+ en los productos obtenidos resultó en una mediana 6,50 CD34+ x10 6/Kg de receptor (Rango: 1,31-38,34). Conclusiones: Los procesos y procedimientos empleados para obtener células progenitoras hematopoyéticas para el trasplante nos permitieron cumplir los objetivos dentro del programa de garantía de la calidad y obtener resultados clínicos deseados comparables a los publicados en la literatura en este campo.

Background: The hematopoietic stem cell transplantation is a therapy used to treat patients with blood diseases and cancer, among others. Hematopoietic progenitor cells from peripheral blood are obtained by leukapheresis after donor mobilization with hematopoietic growth factors. Objectives: Communicating the experience of stem cell collections and associated processes in a pediatric population candidate for autologous or allogeneic transplantation. Methods: 53 patients and / or donors were evaluated for collection between 2008 and 2011. Informed consent was taken. AII were clinically evaluated and we also performed some laboratory testing. The timing of collection was determined by the number of CD34+ peripheral blood (10 - 20 CD34+ cells /uL) and the decision was made as a team integrated by the physician in charge and the Blood Bank physician.Results: Of the 53 candidates, collection was performed in 40. Group I: autologous 29 (72.5%) and Group II allogeneic 11 (27.5%). 61 collections were made, 50 in Group I (82%) and 11 in Group II (18%). The median dosage of G-CSF mobilization was 12.80 ug/kg/day (range: 10-25) was administered for a period of 4 to 6 days. The CD34+ count in the products resulted in a median of 6,50 x 10 6 CD34+ /kg recipient (range: 1.31 to 38.34). Conclusions: The processes employed in obtaining hematopoietic progenitor cells allowed us to meet goals under the Quality Assurance Program and achieve satisfactory clinical results comparable to those reported in the literature of the field.

Recambio plasmático terapéutico en enfermedades neurológicas pediátricas / Therapeutic plasma exchange in pediatric neurological diseases

El recambio plasmático terapéutico (RPT) es un procedimiento utilizado en el tratamiento de distintas patologías, especialmente las de etiología autoinmune. La base fisiopatológica del RPT consiste en la eliminación de mediadores inflamatorios a través de la extracción de un volumen variable de plasma del paciente y su sustitución por una solución de reposición, usualmente albúmina al 5%; utilizando separadores celulares. Objetivo: analizar la experiencia de nuestra institución en el tratamiento con RPT de pacientes con enfermedades neurológicas. Material y métodos: estudio retrospectivo, descriptivo sobre una población de 43 pacientes con enfermedad neurológica (Miastenia Gravis, Guillain Barré, Enfermedad de Devic, Encefalomielitis diseminada aguda, Polineuropatía desmielinizante inflamatoria crónica y Encefalitis de Rasmussen), tratados con una serie de RPT entre junio 1994 y junio 2009. Resultados: se pudieron evaluar 38 pacientes, por falta de información sobre los 5 restantes, observándose alguna mejoría del cuadro clínico en el 79% de los mismos. En 68% de los RPT se observó una o más complicaciones (hipocalcemia, hipotensión, parestesias). Conclusiones: en nuestra experiencia el recambio plasmático terapéutico constituye un tratamiento efectivo para las enfermedades neurológicas en las que fenómenos autoinmunes juegan un rol importante en la patogénesis, incluso en aquellas con un bajo nivel de evidencia clínica según la categorización de indicaciones de la ASFA.

Therapuetica plasma exchange (TPE) is a procedure used for the treatment of different diseases, especially those of autoimmune etiology. The pathophysiological basis of the TPE is the removal of inflammatory mediators through the extraction of a variable volume of patient plasma and its replacement by a solution, usually albumin 5%, using cell separators. objective: to analyze our institution's experience in the TPE treatment of patients with neurological diseases. Material and methods: a retrospective, descriptive study of a population of 43 patients with neurological disease ( Myasthenia Gravis, Guillain Barre syndrome, Devic's disease, Acute demyelinating polyneuropathy, Rasmussen's encephalitis) treated with a series of TPE between june 1994 and june 2009. Results: 38 patients were able to assess, for lack of information on the remaining 5. We observed some clinical improvement in 79% of them. In 68% of the TPE one or more complications (hypocalcemia, hypotension, paresthesias) were observed. Conclusions: in our experience the therapeutic plasma exchange is an effective treatment for neurological diseases in which autoimmune phenomena play an important role in pathogenesis, even in those with low levels of clinical evidence according to the categorization of indications of the ASFA.

Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence.

Alcohol dependence frequently co-occurs with cigarette smoking, another common addictive behavior. Evidence from genetic studies demonstrates that alcohol dependence and smoking cluster in families and have shared genetic vulnerability. Recently a candidate gene study in nicotine dependent cases and nondependent smoking controls reported strong associations between a missense mutation (rs16969968) in exon 5 of the CHRNA5 gene and a variant in the 3'-UTR of the CHRNA3 gene and nicotine dependence. In this study we performed a comprehensive association analysis of the CHRNA5-CHRNA3-CHRNB4 gene cluster in the Collaborative Study on the Genetics of Alcoholism (COGA) families to investigate the role of genetic variants in risk for alcohol dependence. Using the family-based association test, we observed that a different group of polymorphisms, spanning CHRNA5-CHRNA3, demonstrate association with alcohol dependence defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV) criteria. Using logistic regression we replicated this finding in an independent case-control series from the family study of cocaine dependence. These variants show low linkage disequilibrium with the SNPs previously reported to be associated with nicotine dependence and therefore represent an independent observation. Functional studies in human brain reveal that the variants associated with alcohol dependence are also associated with altered steady-state levels of CHRNA5 mRNA.

Association of the kappa-opioid system with alcohol dependence.

Opioid receptors and their endogenous peptide ligands play important roles in the reward and reinforcement of drugs such as heroin, cocaine, and alcohol. The binding of dynorphins to the kappa-opioid receptor has been shown to produce aversive states, which may prevent the development of reinforcement. We genotyped SNPs throughout OPRK1, encoding the kappa-opioid receptor, and PDYN, which encodes its ligand prodynorphin, in a group of 1860 European American individuals from 219 multiplex alcohol dependent families. Family-based analyses demonstrated associations between alcohol dependence and multiple SNPs in the promoter and 3' end of PDYN, and in intron 2 of OPRK1. Haplotype analyses further supported the association of PDYN. Thus, variations in the genes encoding both the kappa-opioid receptor and its ligand, OPRK1 and PDYN, are associated with the risk for alcohol dependence; this makes biological sense as variations in either should affect signaling through the kappa-opioid system.

La Escala Colorimetrica para Medición de Hemoglobia: evaluación metodológica de una publicación científicaa sobre pruebas diagnósticas / The colorimetric Scale for Measuring Hemoglibin: systematic evaluatión of a scientific publication about diagnostic test

La Organización Mundial de la Salud ha desarrollado un método colorimétrico para medir la concentración de hemoglobina: Escala Colorimétrica de Hemoglobina (ECH). Esta prueba es de fácil realización, económina y ha sido señalada como potencialmente útil para el diagnóstico de anemia en países en desarrollo. La Escala Colorimétrica de Hemoglobina constituye una herramienta útil para la identificaicón de anemia cuando no se encuentran disponibles hemoglobinómetros digitales u otros méodos de laboratorio. La selección de un método diagnóstico que permita detectar individuos significativametne anémicos en el momento de efectuar la donación de sangre, constituye una etapa fundamental para proteger la salud del donante y del receptor de esa unidad. El método debe ser sencillo, rápido y realizarse preferentemente a partir de una muestra de sangre capilar. El objetivo del presente estuido es evaluar el desempeño de ECH para la selección de donantes de sangre y ejemplificar la metodología que se utiliza para comparar métodos diagnósticos. Realizamos mediciones pareadas de la concentración de hemoglobina con la ECH, y del nivel de hematocrito (n=426), luego evaluamos el desempeño de la ECH comparando los resultados con un método de referencia para la medición de la cocentración de hemoglobina (n=471). Encontramos un elevado número de falsos negativos en la detección de anemia realizada por la ECH, comparando con el microhematocrito y el HemoCue. Las mediciones de Hemoglobina de la ECH mostraron gran variabilidad y poco acuerdo con las del HemoCue. Solo el 62,9% de las mediciones cae dentro de este rango. En conclusión, no recomendamos reemplazar el uso del método de microhematocrito, por la ECH, para la selección de donantes en nuestro banco de sangre.

A genome-wide screen for genes influencing conduct disorder.

While behavioral genetic studies have suggested that childhood conduct disorder is under genetic influence, studies aimed at gene identification are lacking. This study represents the first genome-wide linkage analysis directed toward identifying genes contributing to conduct disorder. Genome screens of retrospectively reported childhood conduct disorder and conduct disorder symptomatology were carried out in the genetically informative adult sample collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA). The results suggest that regions on chromosomes 19 and 2 may contain genes conferring risk to conduct disorder. Interestingly, the same region on chromosome 2 has also been linked to alcohol dependence in this sample. Childhood conduct disorder is known to be associated with the susceptibility for future alcohol problems. Taken together, these findings suggest that some of the genes contributing to alcohol dependence in adulthood may also contribute to conduct disorder in childhood.

Developmental sequence from disruptive behavior diagnosis to adolescent alcohol dependence.

OBJECTIVE: The authors sought to clinically describe the relationship of disruptive behavior disorders with both alcohol dependence and the use of a variety of substances. METHOD: The Child Semi-Structured Assessment for the Genetics of Alcoholism was used to collect data on 54 adolescents with a diagnosis of alcohol dependence. The frequency and age at onset of the disruptive behavior disorder diagnoses were examined as well as age at first use of alcohol, tobacco, marijuana, and other street drugs. RESULTS: Nearly three-quarters of the alcohol-dependent adolescents had at least one disruptive behavior disorder diagnosis. Attention deficit hyperactivity disorder (ADHD) typically occurred first, followed by conduct disorder. Substance use began with alcohol or tobacco, followed by marijuana and then other street drugs. Alcohol dependence began significantly later than the onset of either ADHD or conduct disorder and significantly later than the first use of tobacco. CONCLUSIONS: Disruptive behavior diagnoses, particularly conduct disorder, typically precede the initiation of use of a variety of substances that, in turn, precede the diagnosis of alcohol dependence in adolescents.

Focal nodular hyperplasia of the liver after intraconazole treatment.

A 38-year-old woman developed focal nodular hyperplasia of the liver after she had received a 4-month treatment with intraconazole 200 mg/d for a fungal infection of her fingernails. Because the patient underwent yearly liver ultrasound examinations because of the removal of a breast carcinoma, when the tumor was discovered incidentally, it was clear that it had developed within the past year after she had begun receiving intraconazole. Although various chemical agents and drugs have been considered as possible etiologic factors in the development of focal nodular hyperplasia of the liver, cases occurring after intraconazole therapy have not been reported before. Apart from the theoretical considerations with regard to the pathogenesis of nodular hyperplasia of the liver, this case could gain practical importance, as it shows a new adverse effect of a drug that has been used in more than 34 million patients over the past 10 years. Furthermore, this case should draw attention to the possibility of drug-induced benign hepatic tumors, as they may mimic malignant and metastatic disorders, which might be especially alarming in patients undergoing routine examinations after removal of malignant tumors, such as our patient.

Risk domains associated with an adolescent alcohol dependence diagnosis.

AIMS: To determine the contribution of familial, interpersonal, academic and early substance use factors to relative risk for an alcohol dependence (AD) diagnosis in adolescents. METHODS: Information on 619 adolescents and their 390 sets of biological parents was obtained using the adolescent version of the Child Semi-Structured Assessment for the Genetics of Alcoholism (C-SSAGA) and the adult counterpart of this instrument, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). The C-SSAGA elicits a wide range of environmental, social, and psychiatric diagnostic information. Specific domain scale scores associated with an adolescent AD were computed, and generalized estimating equations (GEE) modeling was used to determine the odds ratio (relative risk) of the specified risk domains for an alcohol dependence diagnosis. FINDINGS: Risk factors for a DSM-III-R AD diagnosis included being at least 16 years of age, as well as negative parent-child interactions, school and personal-related difficulties (including the presence of an externalizing or internalizing DSM-III-R non-alcohol-related diagnosis), and early experimentations with a variety of substances. CONCLUSIONS: An array of familial, interpersonal, academic and early substance use factors were strongly associated with adolescent AD. Given the findings of this study, further research to determine temporal relationships that might influence the onset of adolescent alcohol dependence is warranted.

A structured interview for medical school admission, Phase 1: initial procedures and results.

PURPOSE: Despite their widespread use, medical school admission interviews often are unstructured and lack reliability. This report describes the development of a structured admission interview designed to eliminate bias and provide valid information for selecting medical students, with preliminary information about the interview's reliability and validity. METHOD: After screening applications, 490 applicants to a public medical school residency program were interviewed by two faculty members using a structured interview format. Interview scores were compiled and correlated with undergraduate grade-point averages (GPAs); Medical College Admission Test (MCAT) scores; Iowa Evaluation Form (IEF) scores, an in-house evaluation of applicants' noncognitive abilities; and eventual admissions status. RESULTS: Interrater agreement was good; the percentages of rater pairs whose scores differed by one point or less ranged from 87% to 98%. Scores on the structured interview revealed low to moderate correlations with other admission criteria: 10 (p < 0.05) for cumulative GPA, 0.18 (p < 0.01) for MCAT Biological Science, 0.08 (p > 0.05) MCAT Physical Science, and 0.10 (p < 0.05) MCAT Verbal Reasoning. None of the correlations between the overall interview scores and the IEF scores reached statistical significance (p = 0.05). Higher overall scores on the structured interview did predict a greater likelihood of being accepted into the medical school and the interview score accounted for 20% of the incremental variance in admission status beyond GPA, MCAT, and IEF scores. CONCLUSIONS: The moderate-to-low correlations with other admission criteria suggest that the interview provided information about candidate credentials not obtained from other sources and accounted for a substantial proportion of the variance in admission status. This finding supports the considerable time and resources required to develop a structured interview for medical student admissions. Final judgment on the validity and utility of this interview should be made after follow-up performance data have been obtained and analyzed.

Genetics of event-related brain potentials in response to a semantic priming paradigm in families with a history of alcoholism.

Event-related brain potentials (ERPs) are altered in patients with a variety of psychiatric disorders and may represent quantitative correlates of disease liability that are more amenable to genetic analysis than disease status itself. Results of a genomewide linkage screen are presented for amplitude of the N4 and P3 components of the ERP, measured at 19 scalp locations in response to a semantic priming task for 604 individuals in 100 pedigrees ascertained as part of the Collaborative Study on the Genetics of Alcoholism. N4 and P3 amplitudes in response to three stimuli (nonwords, primed words [i.e., antonyms], and unprimed words) all showed significant heritabilities, the highest being.54. Both N4 and P3 showed significant genetic correlations across stimulus type at a given lead and across leads within a stimulus, indicating shared genetic influences among the traits. There were also substantial genetic correlations between the N4 and P3 amplitudes for a given lead, even across stimulus type. N4 amplitudes showed suggestive evidence of linkage in several chromosomal regions, and P3 amplitudes showed significant evidence of linkage to chromosome 5 and suggestive evidence of linkage to chromosome 4.