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1.
Mol Psychiatry ; 11(9): 858-66, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16770335

RESUMEN

Variation in brain monoaminergic activity is heritable and modulates risk of alcoholism and other addictions, as well as food intake and energy expenditure. Monoamine oxidase A deaminates the monoamine neurotransmitters serotonin, dopamine (DA), and noradrenaline. The monoamine oxidase A (MAOA) gene (Xp11.5) contains a length polymorphism in its promoter region (MAOA-LPR) that putatively affects transcriptional efficiency. Our goals were to test (1) whether MAOA-LPR contributes to interindividual variation in monoamine activity, assessed using levels of cerebrospinal fluid (CSF) monoamine metabolites; and (2) whether MAOA-LPR genotype influences alcoholism and/or body mass index (BMI). Male, unrelated criminal alcoholics (N=278) and controls (N=227) were collected from a homogeneous Finnish source population. CSF concentration of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were available from 208 participants. Single allele, hemizygous genotypes were grouped according to inferred effect of the MAOA alleles on transcriptional activity. MAOA-LPR genotypes had a significant effect on CSF HVA concentration (P=0.01) but explained only 3% of the total variance. There was a detectable but nonsignificant genotype effect on 5-HIAA and no effects on MHPG. Specifically, the genotype conferring high MAOA activity was associated with lower HVA levels in both alcoholics and controls, a finding that persisted after accounting for the potential confounds of alcoholism, BMI, height, and smoking. MAOA-LPR genotype predicted BMI (P<0.005), with the high-activity genotype being associated with lower BMI. MAOA-LPR genotypes were not associated with alcoholism or related psychiatric phenotypes in this data set. Our results suggest that MAOA-LPR allelic variation modulates DA turnover in the CNS, but does so in a manner contrary to our prior expectation that alleles conferring high activity would predict higher HVA levels in CSF. Our results are consistent with an emerging literature that suggests greater complexity in how variation in MAOA expression alters monoaminergic function. Finally, our work suggests that MAOA may be involved in the regulation of BMI. Independent samples are necessary to confirm this preliminary finding.


Asunto(s)
Alcoholismo/genética , Índice de Masa Corporal , Crimen , Dopamina/fisiología , Repeticiones de Minisatélite , Monoaminooxidasa/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Alcoholismo/líquido cefalorraquídeo , Finlandia , Genotipo , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Monoaminooxidasa/líquido cefalorraquídeo
2.
Int J Gynecol Cancer ; 15(4): 593-600, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16014111

RESUMEN

The purpose of this study was to determine the safety and efficacy of TLK286 (TELCYTA(TM)), a glutathione analog prodrug, in patients with platinum and paclitaxel refractory or resistant ovarian carcinoma. Thirty-six patients with measurable disease were enrolled. TLK286 was administered at 1000 mg/m2 intravenously every 3 weeks. The endpoints were objective response rate assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and survival. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria. Thirty-four platinum refractory or resistant patients (94%) were evaluable for objective tumor response. Five patients (15%) had objective tumor responses, including one durable complete response (CR) of greater than 3 years and continuing. The disease stabilization rate was 50%, including one CR (3%), four partial responses (12%), and 12 durable disease stabilizations (35%). Responses were accompanied by improvement in clinical symptoms and Eastern Cooperative Oncology Group Performance Status (ECOG PS) and decline in CA125 levels. Median survival was 423 days with survival of 60% at 1 year and 40% at 18 months. TLK286 was well tolerated in this population. TLK286 is an active agent in chemotherapy-resistant ovarian cancer. Further studies of TLK286 in platinum and paclitaxel refractory or resistant ovarian cancer are in progress.


Asunto(s)
Carcinoma/tratamiento farmacológico , Glutatión/análogos & derivados , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos Fitogénicos/farmacología , Carcinoma/patología , Cisplatino/farmacología , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Glutatión/administración & dosificación , Glutatión/efectos adversos , Glutatión/uso terapéutico , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Neoplasias Ováricas/patología , Paclitaxel/farmacología , Análisis de Supervivencia
4.
Arch Gen Psychiatry ; 55(11): 989-94, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9819067

RESUMEN

BACKGROUND: In mice, quantitative trait locus studies and behavioral evaluation of animals deleted for 5-HT1B have implicated this serotonin autoreceptor in alcohol consumption and aggressive behavior. We therefore investigated whether the 5-HT1B gene (HTR1B) is linked to alcoholism with aggressive and impulsive behavior in the human, as represented by 2 psychiatric diagnoses: antisocial personality disorder and intermittent explosive disorder comorbid with alcoholism. METHODS: Linkage was first tested in 640 Finnish subjects, including 166 alcoholic criminal offenders, 261 relatives, and 213 healthy controls. This was followed by a study in a large multigenerational family derived from a Southwestern American Indian tribe (n=418) with a high rate of alcoholism. All subjects were psychiatrically interviewed, blind-rated for psychiatric diagnoses, and typed for a HTR1B G861C polymorphism and for a closely linked short-tandem repeat locus, D6S284. Linkage was evaluated in sib pairs, and by using an association approach in which pedigree randomization corrects for nonindependence of observations on related subjects. RESULTS: In Finnish sib pairs, antisocial alcoholism showed significant evidence of linkage to HTR1B G861C (P=.04) and weak evidence with D6S284 (P=.06). By association analysis, the 183 Finnish antisocial alcoholics had a significantly higher HTR1B-861C allele frequency than the other 457 Finns we studied (P=.005). In the Southwestern American Indian tribe, significant sib pair linkage of antisocial alcoholism to HTR1B G861C (P=.01) was again observed, and there was also significant linkage to D6S284 (P=.01). CONCLUSION: These results suggest that a locus predisposing to antisocial alcoholism may be linked to HTR1B at 6q13-15.


Asunto(s)
Alcoholismo/genética , Trastorno de Personalidad Antisocial/genética , Trastornos Disruptivos, del Control de Impulso y de la Conducta/genética , Ligamiento Genético , Receptores de Serotonina/genética , Adolescente , Adulto , Alcoholismo/epidemiología , Animales , Trastorno de Personalidad Antisocial/epidemiología , Secuencia de Bases , Comorbilidad , Trastornos Disruptivos, del Control de Impulso y de la Conducta/epidemiología , Femenino , Finlandia/epidemiología , Finlandia/etnología , Genotipo , Humanos , Indígenas Norteamericanos/genética , Masculino , Ratones , Datos de Secuencia Molecular , Linaje , Polimorfismo Genético , Receptor de Serotonina 5-HT1B , Sudoeste de Estados Unidos/epidemiología , Secuencias Repetidas en Tándem/genética
5.
Arch Gen Psychiatry ; 55(7): 593-602, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9672049

RESUMEN

BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Low turnover rate of this monoamine neurotransmitter is associated with impaired impulse control. We previously reported that, in Finns, TPH genotype was associated with suicidality, a pathophysiological mechanism that may involve impaired impulse control. METHODS: Association and sib-pair linkage analyses of a polymorphism in intron 7 of the TPH gene with suicidality, alcoholism, and the Karolinska Scales of Personality were conducted in 804 Finnish alcoholic offenders, controls, and their relatives, in a sample that included 369 sib pairs. RESULTS: The association of the TPH 17 779C (L) allele to suicidality in impulsive offenders reported previously was replicated in a new group of Finnish offenders (P=.001, n=122). The intron 7 variant in the TPH gene showed significant evidence for linkage to suicidality (P=.006 in unaffected sib pairs), severe suicide attempts (P=.006 in unaffected sib pairs; regression: P=.01), alcoholism (P=.003 in unaffected sib-pairs; regression: P=.02), and Karolinska Scales of Personality socialization score (regression: P=.002). CONCLUSIONS: The status of the TPH A779C allele as a marker for suicidality was replicated and linkage with alcoholism and Karolinska Scales of Personality socialization score was also observed. A functional variant(s) in or close to the TPH gene may predispose individuals to suicidality and other behaviors thought to be influenced by serotonin.


Asunto(s)
Alcoholismo/genética , Marcadores Genéticos , Intento de Suicidio/estadística & datos numéricos , Triptófano Hidroxilasa/genética , Adulto , Alcoholismo/diagnóstico , Alcoholismo/epidemiología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/epidemiología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/genética , Familia , Finlandia/epidemiología , Ligamiento Genético , Variación Genética , Genotipo , Humanos , Intrones , Masculino , Modelos Genéticos , Personalidad/clasificación , Personalidad/genética , Polimorfismo Genético , Prisioneros/estadística & datos numéricos , Análisis de Regresión , Serotonina/genética , Intento de Suicidio/clasificación
6.
Risk Anal ; 18(6): 689-99, 1998 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9972578

RESUMEN

It is common in catastrophic food-contamination events that consumers fail to adjust instantaneously to a normal consumption level. One explanation is that consumers only gradually accept new positive information as being trustworthy. The gradual establishment of the trustworthiness of the released information depends on both positive and negative media coverage over time. We examine the individual "trust" effects by extending the prospective reference theory (Viscusi, 1989) to include a dynamic adjustment process of risk perception. Conditions that allow aggregation of changes in risk perceptions across individuals are described. The proposed model describes a general updating process of risk perceptions to media coverage and can be applied to explain the temporal impact of media coverage on consumption of a broad range of goods (food or nonfood). A case study of milk contamination is conducted to demonstrate consumer demand adjustment process to a temporarily unfavorable shock. The results suggest that effects of positive and negative information to adjustment of consumption and risk perception are asymmetric over time.


Asunto(s)
Contaminación de Alimentos , Medios de Comunicación de Masas , Riesgo , Animales , Comportamiento del Consumidor , Ingestión de Alimentos , Humanos , Leche , Modelos Estadísticos , Percepción
7.
Can J Microbiol ; 43(9): 809-18, 1997 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9336944

RESUMEN

Pseudomonas putida GR12-2R3 promotes the emergence and growth of diverse plant species. Analyses of TnphoA insertion mutations are revealing bacterial characteristics pertinent to the plant-microbe interaction. Pseudomonas putida PG269 is a TnphoA insertion derivative of GR12-2R3 that expresses canola seed exudate-inducible alkaline phosphatase (PhoA) activity. It promoted the growth of canola roots, as well as strain GR12-2R3, and outgrew its parent when they were cocultured in the presence of canola roots or in liquid seed exudate medium. (In contrast, mutant PG126 failed to promote canola root growth and was outgrown by its parent strain.) The PhoA activity of strain PG269 was induced by glucosamine and other sugars; glucosamine inhibited the growth of strain GR12-2R3 and stimulated the growth of strain PG269. Strain PG269 contained two TnphoA insertions: seiA1::TnphoA and seiB1::TnphoA. Strain PG312, which contained only insertion seiA1::TnphoA, shared all aspects of the PG269 phenotype, except the ability to outcompete strain GR12-2R3 during coculture. Insertion seiA1::TnphoA interrupted an open reading frame related in sequence to members of the MalF family of sugar transporter subunits. The PhoA-inducing fraction of canola seed exudate was hydrophilic, low in molecular weight, and heat stable. It cochromatographed with basic amino acids and amino sugars, and was inactivated by strains GR12-2R3 and PG269. Gene seiA may encode a subunit of an ABC transporter with broad specificity for glucose and related sugars whose expression can be induced by exudate sugars.


Asunto(s)
Brassica/microbiología , Metabolismo de los Hidratos de Carbono , Proteínas Portadoras/genética , Raíces de Plantas/microbiología , Pseudomonas putida/genética , Secuencia de Aminoácidos , Transporte Biológico , Comunicación Celular , Elementos Transponibles de ADN , Regulación Bacteriana de la Expresión Génica , Genes Bacterianos , Genes Reporteros , Datos de Secuencia Molecular , Mutagénesis Insercional , Semillas/química , Homología de Secuencia de Aminoácido , Microbiología del Suelo
8.
Acta Radiol ; 38(4 Pt 2): 759-69, 1997 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9245972

RESUMEN

PURPOSE: The reproductive toxicology of mangafodipir trisodium (MnDPDP, Teslascan), a new hepatobiliary MR contrast agent, was evaluated in rats and rabbits. MATERIAL AND METHODS: Male and female fertility and post-natal development were examined in rats after repeated i.v. injections of MnDPDP. The developmental toxicity in rats was investigated after repeated daily i.v. injections during organogenesis with MnDPDP, MnCl2, or DPDP, as well as with MnCl2 administered orally. The developmental toxicity of i.v. injected MnDPDP was also investigated in rabbits. RESULTS: MnDPDP (100 mumol/kg) had no adverse effects on rat fertility. However, both MnDPDP (10-40 mumol/kg) and MnCl2 (30 mumol/kg) caused skeletal abnormalities in the rat, but not in the rabbit given 20 mumol MnDPDP/kg. Maternal treatment of rats with MnDPDP (40 mumol/kg) reduced survival and body weights of neonates, and adversely affected their functional, but not physical development. No skeletal abnormalities were seen in the rat after i.v. administered DPDP (40 mumol/kg) or MnCl2 (6 mumol/kg), or after MnCl2 (400 mumol/kg) given by oral gavage. Maternal toxicity was not seen in rats or rabbits given these doses. CONCLUSION: MnDPDP caused skeletal abnormalities in foetal rats, but not rabbits, and had no effects on rat fertility. Manganese appears to be the causative agent for inducing bone abnormalities in the rat.


Asunto(s)
Medios de Contraste/toxicidad , Ácido Edético/análogos & derivados , Intoxicación por Manganeso , Fosfato de Piridoxal/análogos & derivados , Reproducción/efectos de los fármacos , Anomalías Inducidas por Medicamentos/epidemiología , Animales , Medios de Contraste/administración & dosificación , Relación Dosis-Respuesta a Droga , Ácido Edético/administración & dosificación , Ácido Edético/toxicidad , Femenino , Fertilidad/efectos de los fármacos , Inyecciones Intravenosas , Masculino , Manganeso/administración & dosificación , Embarazo , Efectos Tardíos de la Exposición Prenatal , Fosfato de Piridoxal/administración & dosificación , Fosfato de Piridoxal/toxicidad , Conejos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley
9.
Fundam Appl Toxicol ; 33(1): 11-5, 1996 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-8812204

RESUMEN

Mangafodipir trisodium injection (MnDPDP) is an intravenously administered manganese chelate undergoing clinical evaluation for magnetic resonance imaging contrast enhancement of the hepatobiliary system. The anticipated single clinical dose for adults is 5 micromol/kg body wt. MnDPDP, as well as the inorganic salt, MnCl2, was previously shown to induce a specific syndrome of skeletal abnormalities in rats. The syndrome malformations included angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. The objective of the present study was to assess the developmental toxicity of MnDPDP in a second mammalian species, the New Zealand White rabbit. MnDPDP was intravenously administered daily to groups of rabbits (22 per group) on Days 6 through 18 of pregnancy at doses of 0 (saline), 5, 20, 40, and 60 micromol/kg MnDPDP. Fetuses were examined on Day 29 of pregnancy for external, visceral, and skeletal abnormalities. Treatment with MnDPDP did not result in overt symptoms of maternal toxicity, and there were no significant effects on maternal body weight gains or feed consumption. The maternal no-observed-adverse-effect level (NOAEL), therefore, was 60 micromol/kg MnDPDP. Treatment with MnDPDP resulted in a significant increase in postimplantation loss at 60 micromol/kg, but there was no significant increase in external, visceral, or skeletal abnormalities at any dose. The developmental NOAEL for MnDPDP, therefore, was 40 micromol/kg. These results indicate that the developmental toxicity profile of MnDPDP differs considerably in the rat and rabbit. In the rat, this compound induces specific skeletal abnormalities, whereas in the rabbit, embryo/fetal toxicity is the most sensitive developmental endpoint with no evidence for the induction of specific skeletal abnormalities.


Asunto(s)
Anomalías Inducidas por Medicamentos , Medios de Contraste/toxicidad , Ácido Edético/análogos & derivados , Desarrollo Embrionario y Fetal/efectos de los fármacos , Fosfato de Piridoxal/análogos & derivados , Reproducción/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Medios de Contraste/administración & dosificación , Ácido Edético/administración & dosificación , Ácido Edético/toxicidad , Femenino , Muerte Fetal/inducido químicamente , Inyecciones Intravenosas , Embarazo , Fosfato de Piridoxal/administración & dosificación , Fosfato de Piridoxal/toxicidad , Conejos
10.
Mol Microbiol ; 21(3): 593-603, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8866481

RESUMEN

whiG and sigF encode RNA polymerase sigma factors required for sporulation in the aerial hyphae of Streptomyces coelicolor. Their expression was analysed during colony development in wild-type and sporulation-defective whi mutant strains. Each gene was transcribed from a single promoter. Unexpectedly, whiG mRNA was present at all time points, including those taken prior to aerial mycelium formation; this suggests that whiG may be regulated post-transcriptionally. Transcription of whiG did not depend upon any of the six known 'early' whi genes required for sporulation septum formation (whiA, B, G, H, I and J), placing it at the top of the hierarchy of whi loci. sigF expression appeared to be regulated at the level of transcription; sigF transcripts were detected transiently when sporulation septa were observed in the aerial hyphae. Transcription of sigF depended upon all six of the early whi genes, including whiG. The sigF promoter does not resemble the consensus sequence established for sigma WhiG-dependent promoters and E sigma WhiG did not transcribe from the sigF promoter in vitro. Consequently, the genetic dependence of sigF upon whiG is very likely to be indirect. These results show that there is a hierarchical relationship between sigma factors required for Streptomyces sporulation and also that at least five other genes are involved in this transcriptional network.


Asunto(s)
Proteínas Bacterianas/genética , Proteínas de Unión al ADN , Regulación Bacteriana de la Expresión Génica , Factor sigma , Proteínas Bacterianas/metabolismo , Secuencia de Bases , División Celular , Coenzimas , Medios de Cultivo , Cartilla de ADN , ADN Bacteriano , ARN Polimerasas Dirigidas por ADN , Datos de Secuencia Molecular , ARN Bacteriano/metabolismo , Endonucleasas Específicas del ADN y ARN con un Solo Filamento , Esporas Bacterianas , Streptomyces/genética , Streptomyces/crecimiento & desarrollo , Streptomyces/metabolismo , Transcripción Genética
11.
Arch Gen Psychiatry ; 53(3): 211-6, 1996 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8611057

RESUMEN

BACKGROUND: We investigated the interrelationships of age at onset of excessive alcohol consumption, family history of alcoholism, psychiatric comorbidity, and cerebrospinal fluid monoamine metabolite concentrations in abstinent, treatment-seeking alcoholics. METHODS: We studied 131 recently abstinent alcoholics. Supervised abstinence was maintained on a research ward at the National Institutes of Health Clinical Center for a minimum of 3 weeks. All alcoholics received a low-monoamine diet for a minimum of 3 days before lumbar puncture. Lumbar punctures were performed in the morning after an overnight fast. Monamine metabolites and tryptophan in cerebrospinal fluid were quantified with liquid chromatography by means of electrochemical detection. Psychiatric diagnoses were established from blind-rated Schedule for Affective Disorders and Schizophrenia-Lifetime version interviews administered by a research social worker. Severity and age at onset of excessive alcohol consumption were documented with a structured lifetime drinking history questionnaire and with selected alcoholism screening questionnaires (CAGE and Michigan Alcoholism Screening Test). Family history of alcoholism was obtained from the probands. RESULTS: A majority of the treatment-seeking, primarily white male alcoholics had a lifetime history of psychiatric disorders other than alcoholism. None fulfilled criteria for antisocial personality disorder. Early-onset alcoholics (onset of excessive consumption before 25 years of age) had a more severe course of alcoholism and lower mean cerebrospinal fluid 5-hydroxyindoleacetic acid concentration than late-onset alcoholics. Patients who reported both parents to be alcoholics had particularly low mean cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and tryptophan concentrations. CONCLUSION: Among treatment-seeking alcoholics, early age at onset is generally associated with a more severe course of alcoholism and lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentration.


Asunto(s)
Alcoholismo/líquido cefalorraquídeo , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Adulto , Edad de Inicio , Consumo de Bebidas Alcohólicas/líquido cefalorraquídeo , Alcoholismo/diagnóstico , Alcoholismo/epidemiología , Comorbilidad , Familia , Femenino , Ácido Homovanílico/líquido cefalorraquídeo , Humanos , Masculino , Trastornos Mentales/epidemiología , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Prevalencia , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Triptófano/líquido cefalorraquídeo
12.
Food Addit Contam ; 13(2): 141-53, 1996.
Artículo en Inglés | MEDLINE | ID: mdl-9064239

RESUMEN

Samples of sound home-grown wheat (one hard and one soft milling) were obtained, cleaned, and gamma-irradiation used to reduce numbers of viable naturally-occurring fungi. Each sample was inoculated with a toxigenic strain of Penicillium verrucosum and monitored for ochratoxin A formation. When ochratoxin A had reached a level of 60 micrograms/kg, the samples were milled into ten fractions which were analysed for ochratoxin A by an HPLC method with immunoaffinity column clean-up. Each straight-run white flour was baked into bread which was analysed in the same way. Relationships between ochratoxin A levels in naturally-contaminated wheat and the products of milling and baking were established. The recovery of ochratoxin A in wholemeal compared with the cleaned wheat was essentially complete and no significant loss occurred on baking white or wholemeal flour into bread. Recoveries in the straight-run white flours, however, were only approximately one-third for the hard wheat and two-thirds for the soft wheat of the ochratoxin A in the uncleaned wheat. The reason for this was that a much higher proportion of the ochratoxin A was found in the bran and offal fractions from hard wheat than from soft. Conversely, a much higher proportion of the ochratoxin A was found in the reduction flour from soft wheat than from hard. Scouring was examined as a possible method of decontamination of wheat prior to milling. This process removes a proportion of the pericarp (bran coat) prior to milling. The results of the study confirmed that scouring reduced the ochratoxin A level in white and wholemeal flour three-fold for both the hard and soft wheat.


Asunto(s)
Carcinógenos/metabolismo , Contaminación de Alimentos , Manipulación de Alimentos , Micotoxinas/metabolismo , Ocratoxinas/metabolismo , Triticum/química , Pan/análisis , Carcinógenos/análisis , Carcinógenos/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Harina/análisis , Irradiación de Alimentos , Micotoxinas/análisis , Micotoxinas/aislamiento & purificación , Ocratoxinas/análisis , Ocratoxinas/aislamiento & purificación , Penicillium/metabolismo , Reproducibilidad de los Resultados
13.
Health Care Law Newsl ; 10(11): 5-7, 1995 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10152639

RESUMEN

As genetic testing becomes more prevalent and the uses for genetic information multiply, we are likely to witness more demand for comprehensive state legislation on the order of the Oregon law regulating the procedures for obtaining and using genetic information. In addition, the United States Senate has expressed an interest in the subject. The Senate Labor and Human Resources Committee reportedly agreed on August 2, 1995 to include in a health insurance reform bill (S. 1028) language prohibiting health plans from using genetic information when determining eligibility, continuation, enrollment, or contribution requirements. 4 BNA's Health Law Rep. at 1218 (Aug. 10, 1995). Insurance companies continue to maintain that genetic test results are simply another factor that should rightfully be used during underwriting, much as age, medical history, and physical examinations are routinely used today. Right to privacy advocates argue that genetic testing provides employers and insurance companies with too much information and offers a great potential for discrimination. As more states wrestle with this issue, these competing interests are likely to be debated in public forums throughout the country.


Asunto(s)
Confidencialidad/legislación & jurisprudencia , Pruebas Genéticas/legislación & jurisprudencia , Gobierno Estatal , Determinación de la Elegibilidad , Indicadores de Salud , Humanos , Seguro de Salud , Oregon , Estados Unidos , Wisconsin
14.
Am J Med Genet ; 60(5): 400-8, 1995 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-8546153

RESUMEN

We tested the hypothesis that a heritable EEG trait, the low voltage alpha (LV), is associated with psychiatric disorders. Modest to moderate evidence for genetic linkage of both panic disorder and the low voltage alpha trait to the same region of chromosome 20q has recently been reported, raising the issue of whether there is a phenotypic correlation between these traits. A total of 124 subjects including 50 unrelated index subjects and 74 relatives were studied. Alpha EEG power was measured and EEG phenotypes were impressionistically classified. Subjects were psychiatrically interviewed using the SADS-L and blind-rated by RDC criteria. Alcoholics were four times more likely to be LV (including so-called borderline low voltage alpha) than were nonalcoholic, nonanxious subjects. Alcoholics with anxiety disorder are 10 times more likely to be LV. However, alcoholics without anxiety disorder were similar to nonalcoholics in alpha power. An anxiety disorder (panic disorder, phobia, or generalized anxiety) was found in 14/17 LV subjects as compared to 34/101 of the rest of the sample (P < 0.01). Support for these observations was found in the unrelated index subjects in whom no traits would be shared by familial clustering. Lower alpha power in anxiety disorders was not state-dependent, as indicated by the Spielberger Anxiety Scale. Familial covariance of alpha power was 0.25 (P < 0.01). These findings indicate there may be a shared factor underlying the transmissible low voltage alpha EEG variant and vulnerability to anxiety disorders with associated alcoholism. This factor is apparently not rare, because LV was found in approximately 10% of unrelated index subjects and 5% of subjects free of alcoholism and anxiety disorders.


Asunto(s)
Alcoholismo/genética , Ritmo alfa , Trastornos de Ansiedad/genética , Corteza Cerebelosa/fisiopatología , Alcoholismo/fisiopatología , Trastornos de Ansiedad/fisiopatología , Femenino , Humanos , Masculino
15.
JAMA ; 270(23): 2805; author reply 2808, 1993 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-8133606
16.
Alcohol Clin Exp Res ; 17(2): 199-204, 1993 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8488955

RESUMEN

We defined interpopulation differences in the frequency of the dopamine D2 receptor DRD2/Taq1 A1 allele, which has previously been associated with alcoholism. Frequencies of the A1 allele in unrelated subjects were 0.18 to 0.20 (se = 0.02 to 0.03) in several Caucasian populations previously assessed, 0.38 (+/- 0.05) in American Blacks (n = 44), 0.63 (+/- 0.07) in Jemez Pueblo Indians (n = 23), and 0.80 (+/- 0.04) in Cheyenne Indians (n = 52). The existence of large interpopulation differences in the frequency of the Taq1 alleles suggests that associations to disease status could readily be generated or masked if disease and control groups were uneven in ethnic composition. To address the possibility that the 4-fold higher frequency of the A1 allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in that population, 47 Cheyenne Indians were psychiatrically interviewed and blind-rated. However, there was no significant difference between interviewed controls (0.73 +/- 0.06, n = 24), subjects with alcoholism and/or drug abuse (0.74 +/- 0.06, n = 23) and noninterviewed population controls (0.87 +/- 0.05, n = 20). Legitimate association of the DRD2/Taq1 allele to alcoholism would presumably require it to be in linkage disequilibrium (nonrandom association) with a functional mutation at DRD2 or elsewhere. The level of disequilibrium would vary between populations and could place an upper bound on the strength of an association.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Alcoholismo/genética , Genotipo , Indígenas Norteamericanos/genética , Desequilibrio de Ligamiento , Receptores de Dopamina D2/genética , Adulto , Alelos , Población Negra , Frecuencia de los Genes , Marcadores Genéticos/genética , Humanos , Modelos Genéticos
18.
Acta Psychiatr Scand ; 86(5): 351-7, 1992 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-1283042

RESUMEN

If a genetic association between the D2 dopamine receptor genotype and alcoholism is mediated by altered dopamine function, then a stronger association might be found in alcoholics who are deviant in indices of dopamine function and by comparing alcoholics to nonalcoholics matched for ethnic origin. Therefore, we evaluated the D2/TaqI polymorphism in 29 impulsive violent alcoholic Finns, 17 nonimpulsive violent alcoholic Finns and 36 Finnish controls free of mental disorders, alcoholism and substance abuse. In 37 of the alcoholics, we measured cerebrospinal fluid (CSF) homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol. There was no relationship between D2/Taq 1 genotype and concentrations of these monoamine metabolites in this group, which exhibits lower CSF HVA and 5-HIAA as compared to controls. There was also no genotypic difference between Finnish alcoholics and nonalcoholic controls. The lack of relationship between D2/Taq1 genotype and HVA concentration was replicated in 24 Caucasian alcoholics in the United States.


Asunto(s)
Alcoholismo/genética , Ácido Homovanílico/líquido cefalorraquídeo , Receptores Dopaminérgicos/genética , Adulto , Alcoholismo/líquido cefalorraquídeo , Alelos , Etnicidad , Finlandia , Genotipo , Humanos , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Masculino , Metoxihidroxifenilglicol/líquido cefalorraquídeo , Polimorfismo Genético/genética , Receptores Dopaminérgicos/metabolismo , Estados Unidos
19.
Cult Med Psychiatry ; 16(4): 531-42, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1305531

RESUMEN

This family and small community-based study reports the occurrence of alcoholism and co-occurring substance abuse in Southern Cheyenne Indians living in western Oklahoma. Sociocultural factors complicate operationalization of clinical data into standard (DSM-III-R) psychiatric disorder terminology; understanding sociocultural factors is essential for assessing the high rate of addictive disorders in this group. To obtain reliable and valid clinical diagnoses, data from several sources were utilized within a blind rating system: 1) SADS-L, a clinician-administered research diagnostic instrument; 2) MAST; 3) relatives; 4) medical records; 5) other official documents. The sample consisted of 69 males (45 alcoholics) and 97 females (36 alcoholics). Among clinically significant substance abusers (moderate impairment of function), 22 of 24 were alcoholics. In non-alcoholics, mean MAST scores were 8.8 (males) and 5.1 (females); in alcoholics, 32.0 (males) and 38.7 (females). Mean age of onset on heavy use of alcohol was 20.1 yrs. (males) and 22.8 (females) (p = 0.047); among all alcoholics, 86% (males) and 64% (females) had early onset (< 25 yrs. old). When data from 98 unrelated subjects were analyzed separately, similar findings were observed except that mean age of onset of heavy use of alcohol was more discrepant between males and females, viz. 20.1 versus 22.8 yrs. (p = 0.02). Among those with substance abuse disorders, early age of onset was present in all but one female. In these Cheyenne, alcoholism is usually clinically severe and early in onset; it often co-occurs with substance abuse, also early in onset.


Asunto(s)
Alcoholismo/epidemiología , Comparación Transcultural , Drogas Ilícitas , Indígenas Norteamericanos/estadística & datos numéricos , Psicotrópicos , Trastornos Relacionados con Sustancias/epidemiología , Adolescente , Adulto , Alcoholismo/genética , Alcoholismo/psicología , Comorbilidad , Estudios Transversales , Femenino , Humanos , Incidencia , Indígenas Norteamericanos/psicología , Masculino , Oklahoma/epidemiología , Razón de Masculinidad , Trastornos Relacionados con Sustancias/genética , Trastornos Relacionados con Sustancias/psicología
20.
J Surg Res ; 51(4): 344-52, 1991 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-1921375

RESUMEN

Peptide growth factors produced by platelets, macrophages, epidermal, and dermal cells may play key roles in regulating healing of partial-thickness skin wounds. We examined the effects of recombinant transforming growth factor beta (TGF-beta) on cultures of epidermal and dermal cells in vitro and on healing of partial-thickness injuries in vivo. Increasing concentrations of TGF-beta (0.1, 1, and 10 ng/ml) progressively inhibited serum-stimulated DNA synthesis by up to 95% in cultures of adult human keratinocytes during 48 hr of exposure to TGF-beta. In contrast, TGF-beta (10 and 100 ng/ml) in serum-free media stimulated DNA synthesis by up to 80% compared to serum-free control cultures of adult human dermal fibroblasts. To evaluate the effects of TGF-beta on healing of partial-thickness injuries in vivo, wounds (20 x 20 x 0.6 mm) were created on the dorsal thoracolumbar region of adult pigs by an electrokeratome and were treated daily for 5 days after injury with vehicle or vehicle containing 0.1 or 1 microgram/ml TGF-beta and covered with occlusive dressing. Computerized planimetry of wound photographs demonstrated that TGF-beta treatment stimulated statistically significantly increases in the area of regenerated epidermis compared to wounds treated with saline vehicle on Days 3, 4, 5, and 7 after injury probably due to TGF-beta increasing the rate of epidermal cell migration. In addition, morphometry of biopsy specimens showed that TGF-beta treatment stimulated statistically significant increases in the cross-sectional depths of regenerated dermis compared to wounds treated with saline or Silvadene vehicles on Days 5, 6, and 8 after injury.(ABSTRACT TRUNCATED AT 250 WORDS)


Asunto(s)
Factor de Crecimiento Transformador beta/farmacología , Cicatrización de Heridas , Adulto , Animales , Células Cultivadas , ADN/biosíntesis , Epidermis/metabolismo , Epidermis/patología , Fibroblastos/metabolismo , Humanos , Queratinocitos/metabolismo , Proteínas Recombinantes , Piel/metabolismo , Piel/patología , Porcinos , Heridas y Lesiones/patología
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