RESUMO
OBJECTIVE: To investigate the effects of long-term GH in GH-deficient adults, as predicted by IGF-I levels. METHODS: Patients received GH, 5 microg/kg per day for 1 Month and 10 microg/kg per day for another 12-30 Months. Changes in body composition, cardiac structure/function, serum lipids and quality of life were measured. RESULTS: There was a significant increase in lean body mass (LBM) (2.21 kg; P<0.0001) after 6 Months, which was sustained throughout treatment. A larger increase occurred in males than females (2.97 vs 1.19 kg; P<0.0001). Total fat mass was reduced (2.56 kg; P<0.0001 (3.26 kg males, 1.63 kg females)). Responsiveness to GH varied greatly, but LBM changes correlated with IGF-I changes (P<0.004). Furthermore, thinner patients experienced greater and progressive LBM increases. There was an increase in ejection fraction (3.85+/-9.95%; P=0.0002) after 6 Months, sustained to 18 Months. These cardiac effects were equal for males and females, and did not correlate with IGF-I levels. Serum low-density lipoprotein/high-density lipoprotein ratios decreased within 6 Months, and were sustained thereafter. Quality of life improved significantly after 6 Months, an effect that was sustained/enhanced as treatment continued. No major adverse events were identified. CONCLUSIONS: Improved body composition is both reflected by IGF-I changes and predicted inversely by baseline adiposity. Other effects of GH replacement on cardiac function, dyslipidaemia and quality of life, however, do not correlate with circulating IGF-I concentrations. Our findings validate the importance of sustained GH therapy, but caution on the interpretation of IGF-I levels in monitoring the long-term effects of GH treatment.
Assuntos
Biomarcadores/sangue , Composição Corporal/efeitos dos fármacos , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Tecido Adiposo/metabolismo , Adulto , Idoso , Índice de Massa Corporal , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/psicologia , Indicadores Básicos de Saúde , Coração/efeitos dos fármacos , Humanos , Lipídeos/sangue , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do TratamentoRESUMO
GH deficiency (GHD) in adulthood is accompanied by physical and psychological impairments. One hundred fifteen patients (67 male, 48 female) with pronounced GHD were enrolled in a randomized, double-blind, placebo-controlled study with objectives that included effects on body composition, cardiac structure, and function and safety of replacement therapy with recombinant human GH (Saizen). Sixty patients (31 male, 29 female) received GH at a dose of 0.005-0.010 mg/kg.d, and 55 patients (36 male, 19 female) received placebo for 6 months. Assessment of body composition by dual-energy x-ray absorptiometry demonstrated a treatment difference in lean body mass increase of 2.1 kg (between-group comparison, P < 0.0001), which was significantly greater among males than females (P < 0.0001) [males: GH, +3.13 kg (2.42, 3.84); placebo, +0.11 kg (-0.60, 0.82); and females: GH, +0.64 kg (-0.15, 1.44); placebo: -0.90 kg (-2.20, 0.39)] [mean change 0-6 months (95% confidence limits)] and was associated with IGF-I changes. The decrease in fat mass of 2.8 kg (between-group comparison, P < 0.0001) noted by DEXA was also evident from bioelectric impedance and anthropometric measurements. Echocardiography showed comparable improvement in left ventricular systolic function after GH treatment in both genders. End-systolic volume decreased by 4.3 +/- 10.5 ml (from 35.8 +/- 17.6 ml; between-group comparison, P = 0.035) and ejection fraction increased by 5.1 +/- 10.0% (from 55.0 +/- 11.2%; between-group comparison, P = 0.048), approaching normalcy. Diastolic function did not change as assessed by isovolumic relaxation time, early diastolic flow, diastolic flow secondary to atrial contraction, or ratio of peak mitral early diastolic and atrial contraction velocity. GH treatment was well tolerated, with adverse events primarily related to effects on fluid balance. No apparent relationship between IGF-I levels and the occurrence or severity of adverse events was identified. In conclusion, GH replacement therapy in adults with GHD demonstrated beneficial effects on lean body mass composition that was more pronounced in males than females. In contrast, cardiac function improvement appears to benefit both genders equally.
Assuntos
Composição Corporal , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Erros Inatos do Metabolismo/tratamento farmacológico , Caracteres Sexuais , Adulto , Idoso , Método Duplo-Cego , Ecocardiografia , Feminino , Hormônio do Crescimento Humano/efeitos adversos , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Erros Inatos do Metabolismo/patologia , Erros Inatos do Metabolismo/fisiopatologia , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , MagrezaRESUMO
Sudden cardiac death due to ventricular tachyarrhythmia remains a significant problem in the in-hospital setting. Although the probability of survival is closely correlated with the rapidity of a response by qualified personnel, response times can be prolonged, even in specialized care units. In an effort to decrease response time, a fully automatic external cardioverter defibrillator was recently devised. This device was evaluated in the in-hospital setting to assess safety and efficacy. A total of 79 patients were studied in a multicenter trial. Patients were monitored with fully functional devices in the electrophysiology laboratory (51 patients) and in the cardiac care unit (28 patients). Performance of the device was assessed by comparing automatic responses to any sustained change in cardiac rhythm, either spontaneous or induced, to a retrospective review of stored ECG data and programmed parameters. During a total duration of 964 hours of monitoring, there were 99 episodes of sustained tachycardia. Therapy was appropriately delivered or advised in all episodes. Therapy was advised in one episode of supraventricular tachycardia. There were no episodes of inappropriate therapy delivery. There were no complications or adverse events. The device performed with a sensitivity of 100% and specificity of 98.8% with an average response time of 22 seconds. In conclusion, this automatic external defibrillator was safe, effective, and functioned as designed. Significant improvement in response time to life-threatening ventricular tachyarrhythmia in the in-hospital setting would be expected if this technology was widely adopted.
Assuntos
Cardioversão Elétrica/instrumentação , Parada Cardíaca/terapia , Taquicardia Ventricular/terapia , Fibrilação Ventricular/terapia , Adulto , Unidades de Cuidados Coronarianos , Eletrocardiografia Ambulatorial/instrumentação , Eletrodos , Desenho de Equipamento , Segurança de Equipamentos , Feminino , Parada Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Processamento de Sinais Assistido por Computador/instrumentação , Taquicardia Ventricular/etiologia , Resultado do Tratamento , Fibrilação Ventricular/etiologiaRESUMO
OBJECTIVE: To determine which factors contribute to the decision to admit individuals to psychiatric wards in general hospitals. METHOD: Data on 1,379 individuals undergoing psychiatric evaluation in eight emergency rooms in a region of central Italy were collected. A logistic regression analysis was used to evaluate the likelihood of psychiatric admission considering the independent effects of demographic, social, and clinical factors and of the history of psychiatric treatment. RESULTS: The adjusted odds ratio for psychiatric admission significantly increased with the following variables: severity of symptoms; presence of paranoid states and schizophrenic psychoses, affective psychoses and acute psychotic conditions (with neurotic disorders used as reference); a history of outpatient treatment; the presence of a staff member of a community mental health facility upon presentation at the emergency room; and the availability of beds in the psychiatric ward. CONCLUSION: The independent effect played by the presence of a staff member of a community mental health facility is of particular interest, suggesting the existence of a collaborative relationship between inpatient and outpatient services.
Assuntos
Serviços Comunitários de Saúde Mental/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Transtornos Mentais/diagnóstico , Transtornos Mentais/terapia , Adulto , Diagnóstico Diferencial , Feminino , Hospitais Gerais/estatística & dados numéricos , Humanos , Itália/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de RiscoRESUMO
BACKGROUND: Atrial arrhythmias occur commonly after cardiac surgery and are a cause of significant morbidity and increased hospital costs, yet there is no well-studied treatment strategy to deal with them expeditiously. The purpose of this study was to determine the efficacy and safety of ibutilide fumarate, an approved drug for the rapid conversion of atrial fibrillation and flutter, in patients after cardiac surgery. METHODS AND RESULTS: Patients with atrial fibrillation or flutter occurring 1 to 7 days after surgery and lasting 1 hour to 3 days were randomized to receive two 10-minute blinded infusions of placebo or 0.25, 0.5, or 1.0 mg of ibutilide fumarate. Treatment was considered successful if sinus rhythm was restored for any period of time by hour 1.5. A total of 302 patients were randomized, 201 with fibrillation and 101 with flutter. Treatment with ibutilide resulted in significantly higher conversion rates than placebo, and efficacy was dose related (placebo 15%; ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57%). Conversion rates at all doses were higher for atrial flutter than for atrial fibrillation. Mean time to conversion decreased as the dose was increased. Polymorphic ventricular tachycardia was the most serious adverse effect and occurred in 1.8% of the ibutilide-treated patients compared with 1.2% of patients who received placebo. CONCLUSIONS: Ibutilide is a useful and safe treatment alternative for the atrial arrhythmias that occur after cardiac surgery.
Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Flutter Atrial/tratamento farmacológico , Procedimentos Cirúrgicos Cardíacos , Complicações Pós-Operatórias/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Flutter Atrial/etiologia , Flutter Atrial/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Taquicardia Ventricular/induzido quimicamenteRESUMO
BACKGROUND: The most important factor for improving out-of-hospital ventricular fibrillation survival rates is early defibrillation. This can be achieved if small, lightweight, inexpensive automatic external defibrillators are widely disseminated. Because automatic external defibrillator size and cost are directly affected by defibrillation waveform shape and because of the favorable experience with truncated biphasic waveforms in implantable cardioverter-defibrillators, we compared the efficacy of a truncated biphasic waveform with that of a standard damped sine monophasic waveform for transthoracic defibrillation. METHODS AND RESULTS: The principal goal of this multicenter, prospective, randomized, blinded study was to compare the first-shock transthoracic defibrillation efficacy of a 130-J truncated biphasic waveform with that of a standard 200-J monophasic damped sine wave pulse using anterior thoracic pads in the course of implantable cardioverter-defibrillator testing. Pad-pad ECGs were also examined after transthoracic defibrillation. After the elimination of data for 24 patients who did not meet all protocol criteria, the results from 294 patients were analyzed. The 130-J truncated biphasic pulse and the 200-J damped sine wave monophasic pulse resulted in first-shock efficacy rates of 86% and 86%, respectively (P = .97). ST-segment levels measured 10 seconds after the shock in 151 patients in sinus rhythm were -0.26 +/- 1.58 and -1.86 +/- 1.93 mm for the 130- and 200-J shocks, respectively (P < .0001). CONCLUSIONS: We found that 130-J biphasic truncated transthoracic shocks defibrillate as well as the 200-J monophasic damped sine wave shocks that are traditionally used in standard transthoracic defibrillators and result in fewer ECG abnormalities after the shock.
Assuntos
Cardioversão Elétrica/métodos , Fibrilação Ventricular/terapia , Adolescente , Adulto , Idoso , Eletrocardiografia , Estudos de Avaliação como Assunto , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego , Resultado do Tratamento , Fibrilação Ventricular/fisiopatologiaRESUMO
Overexpression of c-Abl tyrosine kinase can be growth inhibitory in certain fibroblast cell lines. Using a series of conditional chimeras between Abl and Src, we have now further dissected the Abl protein to determine which domains are required for this function. We found that growth inhibition, unlike transformation by oncogenic forms of Abl, is dependent on the presence of the cognate SH2 and tyrosine kinase domains. Since growth inhibition correlates with low tyrosine kinase activity, it may involve highly specific interactions of target proteins with both domains without the processivity of phosphorylation associated with oncogenic Abl.
Assuntos
Inibidores do Crescimento/farmacologia , Proteínas Tirosina Quinases/farmacologia , Proteínas Proto-Oncogênicas c-abl/farmacologia , Células 3T3 , Animais , Transformação Celular Neoplásica , Inibidores do Crescimento/química , Inibidores do Crescimento/genética , Camundongos , Modelos Biológicos , Estrutura Molecular , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-abl/química , Proteínas Proto-Oncogênicas c-abl/genética , Receptores de Estrogênio/química , Receptores de Estrogênio/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/farmacologia , Relação Estrutura-Atividade , Domínios de Homologia de srcRESUMO
Activated forms of the nuclear and cytoplasmic tyrosine kinase c-Abl are completely cytoplasmic and oncogenic. The overexpression of c-Abl, and in certain fibroblast cell lines even of v-Abl, leads to a cell cycle arrest revealing an alternative Abl function. To facilitate the analysis of this growth inhibitory function we have taken advantage of regulable Abl-estrogen receptor (ABL:ER) fusion proteins. Oncogenic in the presence of estrogen, they are reversibly switched to inhibit cell proliferation upon removal of hormone. Using this system, we demonstrate that inhibition is effected by Abl derivatives which we have previously shown to be hypo-phosphorylated and to have low kinase activity. Since an almost exclusively cytoplasmic ABL:ER protein is fully growth inhibitory, relevant interactions may occur in the cytoplasm. We identify the cell cycle arrest as an early G1 or G0-like block. Interestingly, growth inhibition correlates with an altered expression pattern of early serum response genes; c-Jun mRNA and c-Fos protein levels are elevated in Abl-blocked cells. In view of the two functional modes of overexpressed Abl proteins, one can speculate that normal c-Abl may be involved in relaying growth regulatory signals from the membrane to the nucleus.
Assuntos
Ciclo Celular , Mitose , Proteínas Proto-Oncogênicas c-abl/metabolismo , Células 3T3 , Animais , Sequência de Bases , Citoplasma/metabolismo , Primers do DNA/química , Expressão Gênica , Genes fos , Genes jun , Genes myc , Inibidores do Crescimento , Técnicas In Vitro , Camundongos , Dados de Sequência Molecular , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro/genéticaRESUMO
Two minimal scaffold-associated regions (SARs) from Drosophila were tested in stably transformed cells for their effects on the expression of reporter genes. The expression of genes bounded by two SARs is consistently stimulated by about 20- to 40-fold, if the average of a pool of cell transformants is analyzed. However, analysis of individual, stable cell transformants demonstrates that flanking SAR elements do not confer position-independent expression on the reporter gene and that the extent of position-dependent variegation is similarly large with or without the flanking SAR elements. The SAR stimulation of expression is observed in stable but not in transiently transfected cell lines. The Drosophila scs and scs' boundary elements, which do not bind to the nuclear matrix in vitro, are only about one-tenth as active as SARs in stimulating expression in stable transformants. Interestingly, the SAR stimulatory effect can be blocked by a fragment containing CpG islands (approximately 70% GC), if positioned between the SAR and the enhancer. In contrast, when inserted in the same position, control fragments, such as the scs/scs' elements, do not interfere with SAR function.
Assuntos
Cloranfenicol O-Acetiltransferase/genética , DNA/química , Expressão Gênica , Animais , Composição de Bases , Drosophila/genética , Elementos Facilitadores Genéticos , Genes Reporter , Proteínas de Choque Térmico HSP70/genética , Células HeLa , Histonas/genética , Humanos , Células L/metabolismo , Camundongos , Regiões Promotoras Genéticas , Saccharomyces cerevisiae/genética , Vírus 40 dos Símios/genética , Transcrição Gênica , TransfecçãoAssuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios/farmacologia , Receptores de Esteroides/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Proteínas de Schizosaccharomyces pombe , Fatores de Transcrição , Adenoviridae/genética , Proteínas E1A de Adenovirus/metabolismo , Adsorção , Animais , Sítios de Ligação , Ligação Competitiva , Carvão Vegetal , Meios de Cultura , Proteínas Fúngicas/metabolismo , Regulação da Expressão Gênica/fisiologia , Humanos , Ligantes , MAP Quinase Quinase Quinases/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Ratos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiaeRESUMO
Patients who have survived myocardial infarction may be at risk for recurrent infarction or sudden death within the first year. Clinical factors that identify high-risk patients include the following: Poor left ventricular function Presence of spontaneous ventricular ectopy Abnormal signal-averaged electrocardiogram Decreased heart rate variability Exercise-induced depression of the ST segment Inducible ventricular tachyarrhythmia When these high-risk patients are identified, appropriate strategies (eg, use of antiarrhythmic agents or an implantable cardioverter-defibrillator) may improve outcome.
Assuntos
Arritmias Cardíacas/epidemiologia , Morte Súbita Cardíaca/epidemiologia , Infarto do Miocárdio/complicações , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia/normas , Eletrocardiografia Ambulatorial/normas , Teste de Esforço/normas , Humanos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Processamento de Sinais Assistido por Computador , Volume Sistólico , Taxa de SobrevidaRESUMO
In an effort to identify trans-acting factors regulating specific genes, we cloned a novel human gene, DBP-5. The cDNA clone contains a predicted open reading frame coding for a potential 1,179 amino acid protein. The mRNA corresponding to DBP-5 is ubiquitously distributed, and the gene is phylogenetically conserved. Immunofluorescence analyses with several cell lines indicate that the protein is localized to the nucleus. Sequence analysis revealed unusual features of the predicted protein structure, including four completely conserved repeats. The phylogenetic conservation of DBP-5, the ubiquity of its expression, its nuclear localization, and its ability to bind DNA sequences, raise the possibility that DBP-5 may play a role in the organization of interphase chromatin and/or in transcriptional regulation.
Assuntos
Proteínas de Ligação a DNA/genética , DNA/genética , Proteínas Nucleares/genética , Sequência de Aminoácidos , Especificidade de Anticorpos , Sequência de Bases , Clonagem Molecular , DNA/metabolismo , Sondas de DNA , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Células HeLa , Humanos , Dados de Sequência Molecular , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Sequências Repetitivas de Ácido Nucleico , Distribuição TecidualRESUMO
Invasive electrophysiologic studies were performed in 102 patients with sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) using an aggressive programmed electrical stimulation (PES) protocol. The study was repeated after 2.0 +/- 2.9 days in all patients with no intercurrent changes in antiarrhythmic therapy. Patients with coronary artery disease (n = 72) were identified and PES results of these patients were analyzed and compared with results of patients without coronary artery disease. Multiple clinical and electrophysiologic factors were analyzed to determine any association with concordance of PES responses. No significant difference in concordance of PES responses was found in the 2 groups of patients. PES responses were groups into 3 categories: (1) noninducible, (2) nonsustained VT, and (3) sustained VT. Kappa values of PES responses of noninducible and sustained VT in both groups were higher and therefore the PES responses were more reproducible than nonsustained VT. The induction of sustained monomorphic VT was more reproducible than a PES response of nonsustained or sustained polymorphic VT. Inducible sustained VT with a rate of greater than or equal to 250 beats/min was less reproducible than induction of sustained VT with a rate less than 250 beats/min. Induction of VT by 3 extrastimuli was less reproducible than with any other mode. This short-term variability may account for false negatives associated with PES-directed antiarrhythmic therapy. Because of these findings, it is recommended that nonsustained VT and sustained polymorphic or rapid polymorphic VT should not be used as PES end points to guide antiarrhythmic therapy.
Assuntos
Estimulação Cardíaca Artificial , Doença das Coronárias/complicações , Sistema de Condução Cardíaco/fisiopatologia , Taquicardia/diagnóstico , Fibrilação Ventricular/diagnóstico , Antiarrítmicos/uso terapêutico , Cateterismo Cardíaco , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Taquicardia/tratamento farmacológico , Taquicardia/etiologia , Fibrilação Ventricular/tratamento farmacológico , Fibrilação Ventricular/etiologiaRESUMO
BACKGROUND AND PURPOSE: Cardiac and cerebrovascular complications associated with cocaine abuse have increasingly been reported, but concurrent development of cocaine-induced cardiac disease and stroke has rarely been reported. CASE DESCRIPTION: A 37-year-old man with a remote history of intravenous heroin and amphetamine use, cardiomyopathy, and recent cocaine use developed chest pain and ventricular tachycardia 30 minutes after intranasal cocaine hydrochloride use and jogging on a cold winter morning. Ventricular tachycardia was converted to atrial fibrillation. He was proven to have a small myocardial infarction. Within 6 hours of cocaine use he suffered a left hemisphere stroke. Cardiac electrophysiologic evaluation revealed inducible ventricular tachycardia. CONCLUSIONS: To our knowledge, this is the first report of concurrent myocardial infarction, life-threatening ventricular arrhythmias, and cerebral infarction temporally related to cocaine use. It is probable that one mechanism by which cocaine use causes stroke is to trigger expression of a known cardiac source of embolism.
Assuntos
Infarto Cerebral/induzido quimicamente , Cocaína/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Administração Intranasal , Adulto , Infarto Cerebral/complicações , Temperatura Baixa , Humanos , Corrida Moderada , Masculino , Infarto do Miocárdio/complicaçõesRESUMO
This study narrows down the localization of the gene coding for the cerebellar degeneration-related protein (CDR 34) to the upper boundary of the FRAXA and reports the finding of two common RFLPs respectively identified at an RsaI site flanking the 3' end of the gene and at a Hincll site flanking its 5' end. Segregation analysis carried out in the CEPH-pedigrees for the new CDR/RsaI-RFLP versus other polymorphic loci of the region has established a tight linkage with the markers DXS105/DX98 and absence of measurable linkage with two clusters of markers respectively located proximally to the FRAXA (F9, DXS102, DXS51, and DXS369) or distally to it (DXS52, DXS304). In addition, two recombinants were found among 23 scorable sibs identified in the Sardinian pedigrees segregating for the Martin-Bell Syndrome (MBS) and the CDR/RsaI variants. The overall evaluation of the in situ and genetic data reported suggest that the CDR locus 1) is located at the upper boundary of the FRAXA site; 2) is distal to DXS51 and proximal to DXS 389; and 3) segregates in a close linkage association with the loci DXS98 and DXS105 and, to a lesser extent, with the locus for MBS.
Assuntos
Antígenos de Diferenciação/genética , Autoantígenos/genética , Proteínas do Tecido Nervoso/genética , Degenerações Espinocerebelares/genética , Cromossomo X , Antígenos CD34 , Mapeamento Cromossômico , Sondas de DNA , Feminino , Síndrome do Cromossomo X Frágil/genética , França , Humanos , Itália , Escore Lod , Masculino , Linhagem , Recombinação Genética , Utah , VenezuelaRESUMO
HLA-DR class II molecules are expressed by a variety of nonlymphoid cells, including the respiratory epithelium. However, it is not known if ciliated bronchial epithelial cells express the HLA-DR genes, if the expression of class II molecules on their surface can be modulated by immune mediators and, finally, if these cells, like other HLA-DR-positive epithelial cells, have the potential to serve as antigen-presenting cells. To answer these questions, we collected ciliated bronchial epithelial cells by brushing and by suction during fiberoptic bronchoscopy and by scraping surgically resected bronchi. The number of cells recovered by brushing or suction during fiberoptic bronchoscopy was similar (P greater than 0.2), but lower than that obtained by scraping surgically resected bronchi (P less than 0.01); however, compared with brushing, suction of ciliated bronchial epithelial cells resulted in a better viability (P less than 0.05). HLA-DR antigens on ciliated bronchial epithelial cells were detected by immunofluorescence using the PTF 29.12 and the L243 monoclonal antibodies, both recognizing HLA-DR molecules on the vast majority of ciliated bronchial epithelial cells. Cytoplasmic dot blot analysis demonstrated that ciliated bronchial epithelial cells had mRNA HLA-DR transcripts, and Northern blot hybridizations showed that the size of the HLA-DR messages was the same observed in other HLA-DR-positive cells. Interestingly, ciliated bronchial epithelial cells showed a significant decline of HLA-DR expression after 5 days in culture, but the addition of gamma-interferon to the cell cultures was associated with the persistence of the expression of class II antigens on the cell surface (P less than 0.01 with control cultures at 5 days). Finally, while ciliated bronchial epithelial cells were ineffective in stimulating allogeneic T cell proliferation in a 6-day primary mixed leukocyte reaction (MLR), the addition of phorbol myristate acetate to the MLR was able to induce a significant T cell proliferation (P less than 0.001, all comparisons). Thus, human ciliated bronchial epithelial cells express HLA-DR surface antigens and have mRNA molecules for the HLA-DR genes, and the expression of the surface class II antigens can be modulated in vitro by immune mediators.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Células Apresentadoras de Antígenos , Brônquios/imunologia , Antígenos HLA-DR/biossíntese , Interferon gama/fisiologia , Adulto , Antígenos de Superfície/biossíntese , Brônquios/metabolismo , Brônquios/cirurgia , Broncoscopia , Cílios , Células Epiteliais , Epitélio/imunologia , Epitélio/metabolismo , Feminino , Antígenos HLA-DR/genética , Humanos , Técnicas In Vitro , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Linfócitos T/fisiologiaRESUMO
Familial hypercholesterolemia (FH) is an autosomal dominant metabolic disorder caused by several different mutations in the low density lipoprotein (LDL) receptor gene. This large number of different mutations, often undetectable in Southern blotting, makes it impossible directly to diagnose the disease. However, restriction fragment length polymorphisms (RFLPs) can be used to follow the inheritance of the defective gene in FH families. In the present study, we report the use of three RFLPs, detected by PvuII, ApaLI and AvaII restriction enzymes, to determine the haplotypes of normal and defective LDL receptor genes in 61 families with FH and in 128 normal individuals. Two of the nine haplotypes were significantly more often associated with the affected genes, whereas one was significantly less frequent. Although none of the associations was strong enough to allow diagnosis in individuals, it was possible, using the three RFLPs, to identify the haplotype of the affected gene in 57 families and to carry out unequivocal diagnosis in 67% of the cases. In four families, PvuII and AvaII detected an abnormal fragment co-segregating with the disease, thus increasing the percentage of diagnosis to 73.4% of the cases.
Assuntos
Hiperlipoproteinemia Tipo II/diagnóstico , Polimorfismo de Fragmento de Restrição , Receptores de LDL/genética , Alelos , Sondas de DNA , Feminino , Haplótipos , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , LinhagemRESUMO
The safety and efficacy of oral sotalol, an investigational beta-adrenergic blocker with class III antiarrhythmic drug properties, were examined in a multicenter study in 236 patients with sustained ventricular tachyarrhythmias. In 104 patients, the index arrhythmia was a cardiac arrest, and all patients had undergone at least 3 previous unsuccessful antiarrhythmic trials (mean = 5 per patient). In the 106 patients assessed by programmed electrical stimulation, sotalol completely suppressed induction of ventricular tachycardia (VT) in 33 (31%) and rendered VT slower (greater than 100 ms prolongation of cycle length) or more difficult to induce in 29 (27%). Using continuous 24-hour ambulatory monitoring methods, sotalol complete- and partial-response rates were 51 and 12%, respectively. Of the 236 acute-phase patients, 151 were discharged receiving long-term sotalol therapy. The median sotalol dose was 480 mg/day. At a mean follow-up of 346 +/- 92 days, 27 patients (18%) had recurrence of sustained arrhythmia; 9, sudden death; 11, sustained VT; 5, automatic defibrillator discharge; and 2, syncope. Adverse effects forced discontinuation of therapy in 10 patients (7%): 6 secondary to symptomatic bradyarrhythmia, 2 due to refractory heart failure, 1 due to torsades de pointes, and 1 from bronchospasm. Life-table analysis of sotalol's overall long-term efficacy at 6, 12 and 18 months were 80, 76 and 72%, respectively. Although mean follow-up was short (less than 1 year), neither acute-phase programmed stimulation nor 24-hour ambulatory monitoring responses were significantly predictive of subsequent arrhythmic outcome. Proarrhythmia was documented in 18 patients (7%), 17 during the acute phase and 1 during long-term follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Sotalol/uso terapêutico , Taquicardia/tratamento farmacológico , Estimulação Cardíaca Artificial , Feminino , Ventrículos do Coração , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Sotalol/efeitos adversos , Taquicardia/fisiopatologia , Fatores de TempoRESUMO
The safety and efficacy of long-term amiodarone therapy were examined in 12 patients who had previously developed torsade de pointes as a complication of previous antiarrhythmic therapy. The QTc intervals were determined at the time of torsade de pointes (570 +/- 40 ms), after 7 days of amiodarone loading (490 +/- 70 ms), and after 3 months of chronic amiodarone administration (580 +/- 80 ms). Compared to a drug-free control period, QTc was significantly prolonged (P less than 0.05) at the time of torsade de pointes, after amiodarone loading, and after 3 months of amiodarone therapy. The QTc intervals at the time of torsade de pointes and after chronic amiodarone treatment were not significantly different. At 16 +/- 7 months of follow-up, all patients remained free of subsequent torsade de pointes, syncope, or sudden death. In addition, 5 of 6 patients with a history of sustained ventricular tachycardia remained free from arrhythmic recurrence despite persistence of inducible ventricular tachycardia during programmed stimulation studies done before discharge. We conclude that amiodarone can often be used safely and effectively in patients who have previously had an episode of drug-mediated torsade de pointes. Amiodarone-induced QTc prolongation, even when marked, does not predict recurrent torsade de pointes. These observations also suggest that the propensity for a drug to produce this arrhythmia is dependent on other electrophysiologic effects in addition to its ability to simply lengthen repolarization.