RESUMO
The role of the monoamines dopamine (DA) and serotonin (5HT) and the monoamine-metabolizing enzyme monoamine oxidase A (MAOA) have been repeatedly implicated in studies of alcohol use and dependence. Genetic investigations of MAOA have yielded conflicting associations between a common polymorphism (MAOA-LPR) and risk for alcohol abuse. The present study provides direct comparison of tissue-specific MAOA expression and the level of alcohol consumption. We analyzed rhesus macaque MAOA (rhMAOA) expression in blood from males before and after 12 months of alcohol self-administration. In addition, nucleus accumbens core (NAc core) and cerebrospinal fluid (CSF) were collected from alcohol access and control (no alcohol access) subjects at the 12-month time point for comparison. The rhMAOA expression level in the blood of alcohol-naive subjects was negatively correlated with subsequent alcohol consumption level. The mRNA expression was independent of rhMAOA-LPR genotype and global promoter methylation. After 12 months of alcohol use, blood rhMAOA expression had decreased in an alcohol dose-dependent manner. Also after 12 months, rhMAOA expression in the NAc core was significantly lower in the heavy drinkers, as compared with control subjects. The CSF measured higher levels of DA and lower DOPAC/DA ratios among the heavy drinkers at the same time point. These results provide novel evidence that blood MAOA expression predicts alcohol consumption and that heavy alcohol use is linked to low MAOA expression in both the blood and NAc core. Together, the findings suggest a mechanistic link between dampened MAOA expression, elevated DA and alcohol abuse.
Assuntos
Alcoolismo/enzimologia , Monoaminoxidase/biossíntese , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/líquido cefalorraquidiano , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/sangue , Alcoolismo/líquido cefalorraquidiano , Alcoolismo/genética , Alelos , Animais , Estudos de Casos e Controles , Dopamina/líquido cefalorraquidiano , Dopamina/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Testes Genéticos , Macaca mulatta , Masculino , Monoaminoxidase/sangue , Monoaminoxidase/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Serotonina/líquido cefalorraquidiano , Serotonina/metabolismoRESUMO
Previous research suggests that people living with HIV (PLWH) sometimes internalize HIV-related stigma existing in the community and experience feelings of inferiority and shame due to their HIV status, which can have negative consequences for treatment adherence. PLWH's interpersonal concerns about how their HIV status may affect the security of their existing relationships may help explain how internalized stigma affects adherence behaviors. In a cross-sectional study conducted between March 2013 and January 2015 in Birmingham, AL, 180 PLWH recruited from an outpatient HIV clinic completed previously validated measures of internalized stigma, attachment styles, and concern about being seen while taking HIV medication. Participants also self-reported their HIV medication adherence. Higher levels of HIV-related internalized stigma, attachment-related anxiety (i.e., fear of abandonment by relationship partners), and concerns about being seen by others while taking HIV medication were all associated with worse medication adherence. The effect of HIV-related internalized stigma on medication adherence was mediated by attachment-related anxiety and by concerns about being seen by others while taking HIV medication. Given that medication adherence is vitally important for PLWH to achieve long-term positive health outcomes, understanding interpersonal factors affecting medication adherence is crucial. Interventions aimed at improving HIV treatment adherence should address interpersonal factors as well as intrapersonal factors.
Assuntos
Infecções por HIV/psicologia , Relações Interpessoais , Adesão à Medicação/psicologia , Vergonha , Estigma Social , Adulto , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Apego ao Objeto , Razão de Chances , Parceiros SexuaisRESUMO
BACKGROUND: Psoriasis is a relapsing chronic inflammatory skin disease affecting all population groups, with a peak prevalence of 3% in northern European and Scandinavian caucasians. Epidemiological studies have implicated a genetic component to psoriasis. In the past 12 years multiple genome-wide linkage analyses have identified putative susceptibility loci on several chromosomes, with a major locus in the major histocompatibility complex region. OBJECTIVES: To investigate the genetic basis of familial psoriasis in the Tunisian population using a genome-wide linkage scan in seven ultiplex psoriatic families from Tunisia. METHODS: Following single nucleotide polymorphism (SNP) genotyping on the Affymetrix 10K SNP array, we performed nonparametric linkage (NPL) multipoint analyses to identify genotypes and obtain evidence for linkage with psoriasis across the genome. RESULTS: No chromosomal region gave consistent evidence for linkage, providing evidence for genetic heterogeneity in Tunisian psoriasis families. Significant evidence for linkage of psoriasis to chromosome 2p12 was seen in one family. We also identified several regions of tentative psoriasis linkage on chromosomes 2q, 4q, 6p, 11q, 12q, 9q and 13q. One family exhibiting suggestive evidence for linkage to 17q25 (PSORS2) was identified and all affected members harboured a p.Gly117Ser mutation in CARD14 (caspase recruitment domain family, member 14), recently reported to lead to psoriasis in a large family from the U.S.A. CONCLUSIONS: Our results support the genetic heterogeneity of psoriasis in the Tunisian population, provide confirmatory evidence for a novel psoriasis locus at chromosome 2p12 and reveal a psoriasis family with a mutation at PSORS2.
Assuntos
Cromossomos Humanos Par 2/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Psoríase/genética , Adolescente , Adulto , Idoso , Proteínas Adaptadoras de Sinalização CARD , Criança , Feminino , Ligação Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genótipo , Guanilato Ciclase , Humanos , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Linhagem , Tunísia , Adulto JovemRESUMO
Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15-250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a 'position effect' has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients.
Assuntos
Mapeamento Cromossômico , Holoprosencefalia/genética , Proteínas/genética , Transativadores , Sequência de Aminoácidos , Sequência de Bases , Criança , Cromossomos Humanos Par 7 , Clonagem Molecular , Feminino , Deleção de Genes , Rearranjo Gênico , Proteínas Hedgehog , Humanos , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Fenótipo , Mapeamento por Restrição , Homologia de Sequência do Ácido Nucleico , Translocação GenéticaRESUMO
The telomeres of Xq and Yq have been observed to associate during meiosis, and in rare cases a short synaptonemal complex is present. Molecular cloning of loci from Xqter and Yqter has revealed that their sequence homology extends over 400 kilobases, which suggests the possibility of genetic exchange. This hypothesis was tested by the development of two highly informative microsatellite markers from yeast artificial chromosome clones that carried Xqter sequences and the following of their inheritance in a set of reference pedigrees from the Centre d'Etude du Polymorphisme Humain in Paris, France. From a total of 195 informative male meioses, four recombination events between these loci were observed. In three cases, paternal X alleles were inherited by male offspring, and in one case a female offspring inherited her father's Y allele. These data support the existence of genetic exchange at Xq-Yq, which defines a second pseudoautosomal region between the sex chromosomes.
Assuntos
DNA/genética , Telômero/fisiologia , Cromossomo X , Cromossomo Y , Alelos , Animais , Sequência de Bases , Linhagem Celular , Bandeamento Cromossômico , Mapeamento Cromossômico , Cromossomos Fúngicos , Clonagem Molecular , Fator VIII/genética , Feminino , Conversão Gênica , Ligação Genética , Haplótipos , Humanos , Células Híbridas , Masculino , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Linhagem , Reação em Cadeia da Polimerase/métodos , Recombinação Genética , Roedores , Saccharomyces cerevisiae/genética , Homologia de Sequência do Ácido Nucleico , Telômero/ultraestruturaRESUMO
There is evidence that substance P is a peptide neurotransmitter of some unmyelinated primary afferent nociceptors and that its release from the peripheral terminals of primary afferent fibers mediates neurogenic inflammation. The investigators examined whether substance P also contributes to the severity of adjuvant-induced arthritis, an inflammatory disease in rats. They found that, in the rat, joints that developed more severe arthritis (ankles) were more densely innervated by substance P-containing primary afferent neurons than were joints that developed less severe arthritis (knees). Infusion of substance P into the knee increased the severity of arthritis; injection of a substance P receptor antagonist did not. These results suggest a significant physiological difference between joints that develop mild and severe arthritis and indicate that release of intraneuronal substance P in joints contributes to the severity of the arthritis.
Assuntos
Artrite/fisiopatologia , Substância P/fisiologia , Animais , Artrite/induzido quimicamente , Método Duplo-Cego , Membro Posterior , Articulações/efeitos dos fármacos , Articulações/inervação , Articulações/fisiopatologia , Neurônios Aferentes/fisiologia , Ratos , Substância P/farmacologiaRESUMO
Alleles of the human dopamine D(4) receptor (D(4)R) gene (DRD4.7) have repeatedly been found to correlate with novelty seeking, substance abuse, pathological gambling, and attention-deficit hyperactivity disorder (ADHD). If these various psychopathologies are a result of attenuated D(4)R-mediated signaling, mice lacking D(4)Rs (D(4)KO) should be more impulsive than wild-type (WT) mice and exhibit more novelty seeking. However, in our study, D(4)KO and WT mice showed similar levels of impulsivity as measured by delay discounting performance and response inhibition on a Go/No-go test, suggesting that D(4)R-mediated signaling may not affect impulsivity. D(4)KO mice were more active than WT mice in the first 5 min of a novel open field test, suggesting greater novelty seeking. For both genotypes, more impulsive mice habituated less in the novel open field. These data suggest that the absence of D(4)Rs is not sufficient to cause psychopathologies associated with heightened impulsivity and novelty seeking.
Assuntos
Comportamento Exploratório/fisiologia , Comportamento Impulsivo/genética , Comportamento Impulsivo/psicologia , Receptores de Dopamina D4/deficiência , Animais , Sinais (Psicologia) , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Polimorfismo Genético , Desempenho Psicomotor/fisiologia , Receptores de Dopamina D4/genéticaRESUMO
X-linked autoimmunity-allergic disregulation syndrome (XLAAD) is an X-linked recessive immunological disorder characterized by multisystem autoimmunity, particularly early-onset type 1 diabetes mellitus, associated with manifestations of severe atopy including eczema, food allergy, and eosinophilic inflammation. Consistent with the allergic phenotype, analysis of two kindreds with XLAAD revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, we have identified in both kindreds mutations in JM2, a gene on Xp11.23 that encodes a fork head domain-containing protein. One point mutation at a splice junction site results in transcripts that encode a truncated protein lacking the fork head homology domain. The other mutation involves an in-frame, 3-bp deletion that is predicted to impair the function of a leucine zipper dimerization domain. Our results point to a critical role for JM2 in self tolerance and Th cell differentiation.
Assuntos
Doenças Autoimunes/genética , Diabetes Mellitus Tipo 1/genética , Hipersensibilidade Alimentar/genética , Ligação Genética/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Cromossomo X/genética , Sequência de Aminoácidos , Doenças Autoimunes/imunologia , Sequência de Bases , Diferenciação Celular , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/imunologia , Feminino , Hipersensibilidade Alimentar/imunologia , Fatores de Transcrição Forkhead , Haplótipos , Humanos , Zíper de Leucina , Masculino , Dados de Sequência Molecular , Mutação/genética , Proteínas Nucleares/química , Proteínas Nucleares/imunologia , Linhagem , Estrutura Terciária de Proteína , Sítios de Splice de RNA/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Síndrome , Células Th2/citologia , Células Th2/imunologia , Fatores de Transcrição/química , Fatores de Transcrição/imunologia , Cromossomo X/imunologiaRESUMO
Deletions of a tyrosine tRNA suppressor gene, SUP4-o, are mediated by recombination between short repeated delta sequences in Saccharomyces cerevisiae. The arrangement of the five solo delta sequences that surround the SUP4 locus was established by DNA sequence analysis. Seven deletion classes were identified by genomic blotting. DNA sequence analysis also showed that the delta sequences within a 6.5-kilobase region of the SUP4 locus were the endpoints of these events. In three of these classes, an adjacent interval surrounded by delta sequences was inverted in concert with the deletion. The frequency of all deletion classes decreased in strains that contained mutations in the recombination and repair gene RAD52. We present two gene conversion mechanisms by which these rearrangements could have been generated. These models may also explain deletions between repeated sequences in other systems.
Assuntos
Genes Fúngicos , Recombinação Genética , Saccharomyces cerevisiae/genética , Sequência de Bases , Deleção Cromossômica , DNA Fúngico/genética , Conversão Gênica , Mitose , Modelos Genéticos , Mutação , Aminoacil-RNA de Transferência/genética , Supressão GenéticaRESUMO
The CYC7-1 mutation in the yeast Saccharomyces cerevisiae causes the production of approximately 30 times the normal amount of iso-2-cytochrome c. Genetic analysis established that the CYC7-1 mutation is a reciprocal translocation involving the left arm of chromosome V and the right arm of chromosome XVI. The chromosome V arm was broken adjacent to the gene CYC7, which determines the primary structure of iso-2-cytochrome c, and this fragment containing the CYC7 gene was joined to the segment of chromosome XVI. It appears as though the elevation of iso-2-cytochrome c is caused by an abnormal controlling region adjacent to the structural region of the CYC7 gene.
Assuntos
Grupo dos Citocromos c/genética , Genes Reguladores , Translocação Genética , Grupo dos Citocromos c/biossíntese , Genes , Ligação Genética , Mutação , Saccharomyces cerevisiaeRESUMO
An American Medical Association committee recently recommended that physicians routinely screen patients for behaviors that put patients at risk for human immunodeficiency virus infection, yet there is evidence that this screening does not occur routinely. Faculty, fellows, and residents at a teaching hospital in a midwestern state with a low prevalence of acquired immunodeficiency syndrome were surveyed regarding their experience in screening for human immunodeficiency virus, their training related to substance abuse and human sexuality, and their confidence and ease in addressing such topics with their patients. Results indicated that only 11% routinely screened patients for high-risk behaviors. While most physicians had received training in human sexuality, most had not received training in substance abuse screening. Those trained felt more confident in addressing substance abuse and human sexuality and felt more comfortable in caring for patients known to be infected with human immunodeficiency virus. A concerted effort to encourage human immunodeficiency virus risk assessment by physicians is needed. This should include training opportunities in screening and counseling patients about sexual activities and substance abuse.
Assuntos
Síndrome da Imunodeficiência Adquirida/epidemiologia , Atitude do Pessoal de Saúde , Relações Médico-Paciente , Padrões de Prática Médica , Síndrome da Imunodeficiência Adquirida/diagnóstico , Competência Clínica , Aconselhamento , Coleta de Dados , Educação Médica , Humanos , Anamnese , Fatores de Risco , Comportamento Sexual , Transtornos Relacionados ao Uso de Substâncias/diagnósticoRESUMO
Genomic segments which contain inverted repetitions longer than 300 bp are frequently lost from recombinant libraries grown on rec+ hosts. We have found that 9% of phage lambda clones that contain 15-20-kb insertions of human or Drosophila DNA are inhibited on rec+ hosts and as a result will become under-represented in amplified genomic libraries. We have therefore examined several factors of both host and vector origin which affect the fidelity of representation of genomic sequences in recombinant DNA libraries constructed in bacteriophage lambda vectors. This loss may be diminished if the vector carries either a chi element or a functional gam gene. The most successful approach, however, involves using a host with mutations in recB, recC, and sbcB, or in recD. We have shown that recombinant clones which require such mutant hosts for growth are somewhat more likely to contain DNA derived from loci in the genome which are polymorphic than are clones recovered on conventional hosts.
Assuntos
Bacteriófago lambda/genética , DNA Recombinante , Proteínas de Escherichia coli , Vetores Genéticos , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/fisiologia , Sequência de Bases , Drosophila melanogaster/genética , Escherichia coli/enzimologia , Escherichia coli/genética , Exodesoxirribonuclease V , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/fisiologia , Humanos , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico , Proteínas Virais/genética , Proteínas Virais/fisiologiaRESUMO
Peripheral nerve complications occurred in four patients with toxic shock syndrome. Each patient had an acute carpal tunnel syndrome develop that was verified by nerve conduction studies. Recovery was rapid in two cases, but delayed in two others. Decompressive procedures were required in only one patient, with eventual recovery. Another condition, the toxic shock syndrome, must now be added to the long list of possible causes of compression of the median nerve in the wrist.
Assuntos
Síndrome do Túnel Carpal/etiologia , Choque Séptico/complicações , Adulto , Feminino , Humanos , MasculinoRESUMO
A 63-year-old man with acute psittacosis had severe hepatic damage after ingesting about 10 g of acetaminophen over a 48 hour period. Transaminase levels showed striking elevation, with a serum glutamic-oxaloacetic transaminase level of over 15,000 IU/liter, and decreased rapidly, consistent with a toxic insult. No other etiologic agents were identified by history or serologic testing to explain this degree of damage. Liver histologic findings at autopsy showed severe central necrosis. Although psittacosis may infrequently cause a similar pattern of hepatic injury, disease of this severity has not been previously reported. It is postulated that acetaminophen may have accentuated hepatic disease produced by Chlamydia psittaci in this patient.
Assuntos
Acetaminofen/efeitos adversos , Hepatopatias/etiologia , Psitacose/complicações , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , NecroseRESUMO
Nosocomial pneumonia caused by Legionella pneumophila serogroup 1 occurred in five patients after bone marrow transplantation for hematologic malignancies. Two patients died as a result of the infection despite treatment with erythromycin. Serologic screening revealed no other cases of Legionnaires' disease in 40 consecutive recipients of bone marrow transplants, giving a frequency of infection of 13 percent. These five cases represent 23 percent of the pneumonia occurring in this group of patients. Patients undergoing bone marrow transplantation are highly susceptible to infectious complications. Legionnaires' disease must now be added to the list of pathogens infecting this group of patients. Erythromycin is not generally a part of standard empiric antibiotic regimens in febrile neutropenic patients, but appears to be a reasonable addition when pneumonia does not respond to conventional, empiric treatment. Even with appropriate therapy, Legionnaires' disease remains a highly lethal infection in immunocompromised hosts.
Assuntos
Transplante de Medula Óssea , Infecção Hospitalar/etiologia , Doença dos Legionários/etiologia , Leucemia Linfoide/complicações , Leucemia Mieloide/complicações , Transtornos Mieloproliferativos/complicações , Adolescente , Adulto , Criança , Eritromicina/uso terapêutico , Feminino , Humanos , Doença dos Legionários/diagnóstico por imagem , Doença dos Legionários/tratamento farmacológico , Leucemia Linfoide/terapia , Leucemia Mieloide/terapia , Pulmão/diagnóstico por imagem , Masculino , Transtornos Mieloproliferativos/terapia , RadiografiaRESUMO
Sympathetic efferents contribute to the severity of joint injury in experimental arthritis in the rat, [Levine J. D. et al. (1986) J. Neurosci. 6, 3423-3429] and beta 2-adrenergic receptor antagonists suppress the disease [Levine J. D. et al. (1988) Proc. natn. Acad. Sci. U.S.A. 85, 4553-4556]. The present study was directed at determining the endogenous ligand for, and target of, the beta 2-receptor contribution to arthritis. We report that adrenal medullectomy significantly reduced joint injury in experimental arthritis, but that severe joint injury was re-established in adrenal medullectomized rats chronically treated with epinephrine or the beta 2-agonist, salbutamol. The ability of these two drugs to enhance joint injury in adrenal medullectomized rats was blocked by sympathectomy. These data suggest that adrenal medulla-derived epinephrine acts at beta 2-adrenoceptors on sympathetic efferent nerve terminals, to contribute to the severity of experimental arthritis.
Assuntos
Medula Suprarrenal/metabolismo , Fibras Adrenérgicas/fisiologia , Artrite/metabolismo , Epinefrina/fisiologia , Receptores Adrenérgicos beta/fisiologia , Medula Suprarrenal/fisiopatologia , Fibras Adrenérgicas/efeitos dos fármacos , Animais , Artrite/fisiopatologia , Epinefrina/farmacologia , Masculino , Ratos , Ratos Endogâmicos , Receptores Adrenérgicos beta/efeitos dos fármacos , SimpatectomiaRESUMO
This study compared the pharmacology of adrenergic agents that influence plasma extravasation in normal animals with those agents that influence tissue injury in an inflammatory disease model. Specifically we studied the effects of beta 2- and alpha 2-adrenergic receptor agonists and antagonists on bradykinin-induced plasma extravasation in normal Sprague-Dawley rats and on joint injury in rats with experimental arthritis. Plasma extravasation induced by infusion of bradykinin in the rat knee joint was attenuated by the beta 2-agonist salbutamol or by the alpha 2-antagonist yohimbine, and was enhanced by the beta 2-antagonist, ICI-118,551, or by the alpha 2-agonist, clonidine. In rats that had undergone chemical symphathectomy, bradykinin-induced plasma extravasation was markedly reduced, and there was no enhancement of bradykinin-induced plasma extravasation by either ICI-118,551 or clonidine. Although ICI-118,551 and clonidine enhanced bradykinin-induced plasma extravasation, these drugs significantly reduced joint injury in rats with adjuvant-induced arthritis. Neither salbutamol nor yohimbine, however, significantly increased joint injury in the arthritic rats, presumably because arthritis severity is already high in these animals. Consistent with this hypothesis, both salbutamol and yohimbine did significantly increase the joint injury associated with experimental arthritis in Wistar-Kyoto rats, a strain which develops a mild adjuvant arthritis. The fact that increased plasma extravasation is associated with decreased arthritis severity suggests that plasma extravasation, a major sign of acute inflammation, contributes to tissue reparative processes.
Assuntos
Artrite/fisiopatologia , Terminações Nervosas/fisiologia , Plasma/metabolismo , Sistema Nervoso Simpático/fisiologia , Animais , Artrite/diagnóstico por imagem , Artrite/metabolismo , Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Injeções Intra-Articulares , Masculino , Radiografia , Ratos , Ratos Endogâmicos , Ratos Endogâmicos WKY , Simpatomiméticos/farmacologiaRESUMO
We recently showed that acute administration of nicotine in the rat decreases bradykinin-induced plasma extravasation and that adrenal medullary-derived epinephrine, acting at a beta 2-adrenergic receptor, mediates the nicotine effect. Since agents which decrease bradykinin-induced plasma extravasation have been associated with increased joint injury in a rat model of chronic inflammation (experimental arthritis induced by subcutaneous injection of Mycobacterium butyricum) we examined the effect of chronic nicotine on both plasma extravasation and the severity of joint injury. In normal rats, bradykinin-induced plasma extravasation was decreased after nicotine administered both by repeated injection (10(-2) mg/kg, s.c., once per h for 4 h) and by continuous long-term infusion (subcutaneous mini-osmotic pump; 1.5 x 10(-3) mg/kg per h for 30 days). Nicotine-induced inhibition of bradykinin-induced plasma extravasation did not show tachyphylaxis. In rats with arthritis, chronic administration of nicotine also produced a decrease in bradykinin-induced plasma extravasation. This effect of chronic nicotine in the arthritic rats was antagonized by co-administration of hexamethonium (a nicotinic receptor antagonist), by surgical removal of the adrenal medulla, or by co-administration of ICI-118,551 (a beta 2-adrenoceptor antagonist). Chronic administration of nicotine decreased the latency to the onset of arthritis and, in a dose-dependent manner, led to an increase in the radiographic joint injury score.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Artrite Experimental/patologia , Bradicinina/antagonistas & inibidores , Nicotina/farmacologia , Medula Suprarrenal/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Artrite Experimental/diagnóstico por imagem , Bradicinina/farmacologia , Relação Dose-Resposta a Droga , Azul Evans , Frequência Cardíaca/efeitos dos fármacos , Compostos de Hexametônio/farmacologia , Técnicas In Vitro , Masculino , Propanolaminas/farmacologia , Radiografia , Ratos , Ratos Sprague-DawleyRESUMO
Autosomal recessive nonsyndromic congenital retinal nonattachment (NCRNA) comprises congenital insensitivity to light, massive retrolental mass, shallow anterior chamber, microphthalmia, and nystagmus in otherwise normal individuals. Polymerase chain reaction-based linkage analyses of polymorphic microsatellite markers in the 10q21 region on DNA samples from 106 individuals provide evidence that the NCRNA locus is within an interval of approximately 0.6-1.5 cM, flanked by the markers D10S522 and D10S1418. Haplotype analysis demonstrated a unique founder haplotype shared by 100% of the NCRNA chromosomes. These results indicate a founder effect and the strong possibility of a single mutation as the cause of the disease in the affected population. Based on these findings, it is now possible to provide relatively accurate carrier detection and prenatal diagnostic testing for families with NCRNA based on close flanking markers and the capacity to identify NCRNA chromosomes by their haplotypes.
Assuntos
Mapeamento Cromossômico , Repetições de Microssatélites/genética , Descolamento Retiniano/congênito , Adulto , Feminino , Efeito Fundador , Haplótipos , Humanos , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Descolamento Retiniano/genéticaRESUMO
Nonsyndromic congenital retinal nonattachment (NCRNA) comprises congenital insensitivity to light, massive retrolental mass, shallow anterior chamber, microphthalmia, and nystagmus. We searched for the location of the gene responsible for an autosomal recessive form of NCRNA by using DNA samples from 36 individuals from a founding population. To this end we applied homozygosity mapping and a DNA pooling strategy using genomewide screen polymorphic microsatellite markers. We used two DNA pools, one pool contained DNA from 16 individuals affected with NCRNA. The second pool contained DNA from 20 normal carrier individuals, the parents of the patients. The polymorphic microsatellite markers were polymerase chain reaction (PCR)-amplified in each DNA pool; the PCR products were electrophoresed on polyacrylamide gels and visualized by silver staining. The banding patterns from DNA pools of affected and unaffected persons were compared, and linkage was detected between the NCRNA and D10S1225, a marker in 10q21. To confirm linkage of NCRNA to chromosome 10q21 by homozygosity mapping, the patients and their carrier parents were genotyped for a number of other microsatellite polymorphic markers in the 10q21region. Statistically significant linkage was observed with multiple polymorphic markers in the 10q21 region. At straight theta = 0 with markers D10S1225, D10S1428, D10S1422, and D10S1418 maximum LOD scores of 3.74, 3.58, 3. 79, and 3.48 were generated, respectively. TDT P values for markers D10S1225 and D10S1418 were 0.0000021 and 0.000021, respectively.