RESUMO
Using a sensitive transfection-tumorigenicity assay, we have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antiphosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type III and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.
Assuntos
Transformação Celular Neoplásica/genética , Leucemia Mieloide/genética , Proteínas Oncogênicas/genética , Proteínas Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases , Receptores de Superfície Celular/metabolismo , Sequência de Aminoácidos , Animais , Baculoviridae/metabolismo , Sequência de Bases , Northern Blotting , Southern Blotting , Clonagem Molecular , Fibronectinas/genética , Expressão Gênica/fisiologia , Humanos , Imunoglobulinas/genética , Camundongos , Dados de Sequência Molecular , Proteínas Oncogênicas/metabolismo , Reação em Cadeia da Polimerase , Proteínas Tirosina Quinases/fisiologia , Proteínas Proto-Oncogênicas , Receptores de Superfície Celular/genética , Alinhamento de Sequência , Células Tumorais Cultivadas , Receptor Tirosina Quinase AxlRESUMO
In the United States, childhood asthma morbidity and prevalence rates are the highest in less affluent urban minority communities. More than 80% of childhood asthmatics are allergic to one or more inhalant allergens. We evaluated whether socioeconomic status was associated with a differential in the levels and types of indoor home allergens. Dust samples for an ELISA allergen assay were collected from the homes of 499 families as part of a metropolitan Boston, Massachusetts, longitudinal birth cohort study of home allergens and asthma in children with a parental history of asthma or allergy. The proportion of homes with maximum home allergen levels in the highest category was 42% for dust mite allergen (> or = 10 microg/g Der p 1 or Der f 1), 13% for cockroach allergen (> or = 2 U/g Bla g 1 or Bla g 2), 26% for cat allergen (> or = 8 microg/g Fel d 1), and 20% for dog allergen (> or = 10 microg/g Can f 1). Homes in the high-poverty area (> 20% of the population below the poverty level) were more likely to have high cockroach allergen levels than homes in the low-poverty area [51 vs. 3%; OR, 33; 95% confidence interval (CI), 12-90], but less likely to have high levels of dust mite allergen (16 vs. 53%; OR, 0.2; CI, 0.1-0.4). Lower family income, less maternal education, and race/ethnicity (black or Hispanic vs. white) were also associated with a lower risk of high dust mite levels and a greater risk of high cockroach allergen levels. Within a single U.S. metropolitan area we found marked between-community differences in the types of allergens present in the home, but not necessarily in the overall burden of allergen exposure.
Assuntos
Poluição do Ar em Ambientes Fechados/análise , Alérgenos/análise , Habitação/economia , Pobreza , Adulto , Poluição do Ar em Ambientes Fechados/economia , Animais , Asma/etiologia , Boston , Gatos , Criança , Pré-Escolar , Baratas , Cães , Poeira , Feminino , Humanos , Renda , Masculino , Ácaros , Fatores de Risco , Classe SocialRESUMO
Despite improved understanding of the basic mechanisms underlying asthma, morbidity and mortality remain high, especially in the "inner cities." The treatment of choice in status asthmaticus includes high doses of inhaled beta 2-agonists, systemic corticosteroids, and supplemental oxygen. The roles of theophylline and anticholinergics remain controversial, although in general these agents appear to add little to the bronchodilator effect of inhaled beta-agonists in most patients. Anti-leukotriene medications have not yet been evaluated in acute asthma. Other therapies, such as magnesium sulfate and heliox, have their advocates but are not recommended as part of routine care. If pharmacological therapy does not reverse severe airflow obstruction in the asthmatic attack, mechanical ventilation may be temporarily required. Based on our current understanding of ventilator-induced lung injury, optimal ventilation of asthmatic patients avoids excessive lung inflation by limiting minute ventilation and prolonging expiratory time, despite consequent hypercapnia. Unless respiratory function is extremely unstable, the use of paralytic agents is discouraged because of the increased risk of intensive care myopathy. Patients who have suffered respiratory failure due to asthma are at increased risk for subsequent death due to asthma (14% mortality at 3 years) and should receive very close medical follow-up. In general, severe asthmatic attacks can best be prevented by early intervention in the outpatient setting. In the words of Dr. Thomas Petty, "... the best treatment of status asthmaticus is to treat it three days before it occurs".
Assuntos
Antiasmáticos/uso terapêutico , Respiração Artificial , Estado Asmático , Doença Aguda , Diagnóstico Diferencial , Humanos , Prognóstico , Índice de Gravidade de Doença , Estado Asmático/diagnóstico , Estado Asmático/epidemiologia , Estado Asmático/fisiopatologia , Estado Asmático/terapia , Desmame do RespiradorRESUMO
Asthma is common among older persons, affecting approximately 4 to 8% of those above the age of 65 years. Despite its prevalence, late onset asthma may be misdiagnosed and inadequately treated, with important negative consequences for the patient's health. The histopathology of late onset disease appears to be similar to that of asthma in general, with persistent airway inflammation a characteristic feature. It is less clear, however, that allergic exposure and sensitisation play the same role in the development of disease in adults as they do in children. Atopy is less common among those with late onset asthma, and the prevalence of elevated immunoglobulin E levels is lower among those aged over 55 years of age than younger patients. Occupational asthma is an aetiological consideration unique to adult onset disease, with important implications for treatment. The differential diagnosis for cough, wheeze, and dyspnoea in the elderly is broad, and includes chronic obstructive bronchitis, bronchiectasis, congestive heart failure, lung cancer with endobronchial lesion and vocal cord dysfunction. Keys to accurate diagnosis include a good history and physical examination, the demonstration of reversible airways obstruction on pulmonary function tests and a favorable response to treatment. Inhaled corticosteroid therapy is recommended for patients with persistent disease, and careful instruction in the use of metered-dose inhalers is particularly important for the elderly.
Assuntos
Asma , Idade de Início , Idoso , Asma/diagnóstico , Asma/epidemiologia , Asma/terapia , Geriatria , HumanosRESUMO
To determine whether the prevalence of resistance to commonly used oral antimicrobial agents varied over time, we compared the in vitro susceptibilities of 217 strains of Haemophilus influenzae recovered from nasopharyngeal secretions of children in a day-care center studied longitudinally between 1979 and 1987. The overall rate of beta-lactamase production in these strains was 18%, with rates of 57% in type b isolates (n = 21) and 14% in non-type b isolates (n = 196). The percentages of isolates for which MICs were less than or equal to 1.0 micrograms/ml for amoxicillin alone, amoxicillin in combination with clavulanic acid, and cefuroxime alone were 82, 92, and 93%, respectively. The percentage of strains for which cefaclor MICs were less than or equal to 1.0 micrograms/ml was only 0.5%. Isolates for which chloramphenicol MICs were greater than 2.0 micrograms/ml or for which trimethoprim-sulfamethoxazole MICs were greater than 0.5/9.5 micrograms/ml were uncommon: 1 and less than 1%, respectively. High concentrations of erythromycin alone and in combination with sulfisoxazole were required to inhibit the majority of test strains; there was no evidence of erythromycin-sulfisoxazole synergy. In vitro susceptibility to commonly used oral antimicrobial agents remained at a constant level when H. influenzae isolates collected from children in a day-care center during 1979 through 1983 were compared with strains collected during 1984 through 1987.
Assuntos
Antibacterianos/farmacologia , Creches , Haemophilus influenzae/efeitos dos fármacos , Resistência Microbiana a Medicamentos , Quimioterapia Combinada/farmacologia , Haemophilus influenzae/enzimologia , Humanos , Lactente , Estudos Longitudinais , Testes de Sensibilidade Microbiana , Nasofaringe/microbiologia , beta-Lactamases/biossíntese , beta-LactamasRESUMO
BACKGROUND: Inhaled corticosteroids remain underused among United States-based clinicians in treating mild-to-moderate adult asthma. OBJECTIVE: The purpose of this investigation was to estimate the clinical impact, health-related quality of life, cost, and cost-effectiveness of inhaled corticosteroid therapy in a population of patients aged 18 years and over with FEV(1) = 60% to 100% of predicted normal. METHODS: We performed a cost-effectiveness analysis of quick relievers (eg, short-acting beta-agonists) on an as-needed basis plus inhaled corticosteroid therapy versus quick relievers alone. A mathematical simulation model was developed to forecast symptoms, acute exacerbations, quality-adjusted life-years (QALYs), health care costs, and cost-effectiveness, measured in both dollars per QALY gained and dollars per symptom-free day gained. All evaluation outcomes were discounted at an annual rate of 3% and measured over a 10-year planning horizon. Data on the natural history of disease, drug efficacy, patient preferences, and economic costs were obtained from a variety of observational cohorts, randomized trials, and patient surveys. RESULTS: Over a 10-year period, use of inhaled corticosteroids increases total health costs from roughly $5,200 to $8,400 and improves QALYs from 6.8 to 7.0, implying an incremental cost of $13,500 per QALY gained. Costs per symptom-free day gained are $7.50. Both per-person acute exacerbations and hospitalizations are reduced by 33%. The cost-effectiveness findings are sensitive to the assumed efficacy and side-effects of inhaled corticosteroid therapy. CONCLUSIONS: Inhaled corticosteroids appear to deliver good comparative value in adults with mild-to-moderate asthma. Although more research is needed to understand their impact on preferences regarding side effects and compliance, these findings might be useful for priority-setting in limited resource situations.
Assuntos
Corticosteroides/economia , Corticosteroides/uso terapêutico , Asma/economia , Modelos Teóricos , Administração por Inalação , Corticosteroides/administração & dosagem , Adulto , Asma/diagnóstico , Asma/prevenção & controle , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Volume Expiratório Forçado , Hospitalização/economia , Humanos , Cadeias de Markov , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: FEV(1) is endorsed by the National Asthma Education and Prevention Program as a means for grading asthma severity. However, few data exist on the relationship between FEV(1) and asthma outcomes during long-term follow-up. OBJECTIVE: We explored the relationship between the percent predicted FEV(1) (FEV(1)%) and subsequent asthma attacks in a longitudinal study of pediatric lung health. METHODS: A retrospective cohort of 13,842 children (100,292 observations) seen annually over a 15-year interval was analyzed for measurement of pulmonary function, and a respiratory questionnaire was completed. Up to grade 9, a standard questionnaire was completed by a parent or guardian; thereafter it was completed by the patient. For each observation, the report of an attack during the past year was paired with FEV(1) recorded at the field survey 1 year earlier. RESULTS: A progressive decrease in the proportion of individuals reporting an attack was associated with increasing decile of FEV(1)%. Two categorization schemes for FEV(1)% were examined: a scheme based on the National Asthma Education and Prevention Program recommendations (<60%, 60%-80%, and >80%), and an alternative scheme (<80%, 80%-100%, and >100%). In multivariate models, FEV(1)% was an independent predictor of attacks: among the parental report group, the odds ratios were 2.1 (95% CI, 1.3-3.4) and 1.4 (95% CI, 1.2-1.6) for FEV(1)% < 60% and FEV(1)% of 60% to 80% compared with FEV(1)% > 80%, respectively; and among the self-report group, odds ratios were 5.3 (95% CI, 2.2-12.9) and 1.4 (95% CI, 1.2-1.7) for FEV(1)% < 60% and FEV(1)% of 60% to 80% compared with FEV(1)% > 80%, respectively. With the alternative classification scheme, the relationship was similar, but the difference in risk between categories of FEV(1)% decreased. CONCLUSION: The strong association between FEV(1)% and risk of asthma attack over the subsequent year supports an emphasis on objective measures of lung function in assessment of risk for adverse asthma outcomes.
Assuntos
Asma/epidemiologia , Volume Expiratório Forçado , Adolescente , Asma/fisiopatologia , Criança , Estudos de Coortes , Humanos , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Vitamin D deficiency is a major risk factor for bone loss and fracture. Although hypovitaminosis D has been detected frequently in elderly and housebound people, the prevalence of vitamin D deficiency among patients hospitalized on a general medical service is unknown. METHODS: We assessed vitamin D intake, ultraviolet-light exposure, and risk factors for hypovitaminosis D and measured serum 25-hydroxyvitamin D, parathyroid hormone, and ionized calcium in 290 consecutive patients on a general medical ward. RESULTS: A total of 164 patients (57 percent) were considered vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, < or = 15 ng per milliliter), of whom 65 (22 percent) were considered severely vitamin D-deficient (serum concentration of 25-hydroxyvitamin D, <8 ng per milliliter). Serum 25-hydroxyvitamin D concentrations were related inversely to parathyroid hormone concentrations. Lower vitamin D intake, less exposure to ultraviolet light, anticonvulsant-drug therapy, renal dialysis, nephrotic syndrome, hypertension, diabetes mellitus, winter season, higher serum concentrations of parathyroid hormone and alkaline phosphatase, and lower serum concentrations of ionized calcium and albumin were significant univariate predictors of hypovitaminosis D. Sixty-nine percent of the patients who consumed less than the recommended daily allowance of vitamin D and 43 percent of the patients with vitamin D intakes above the recommended daily allowance were vitamin D-deficient. Inadequate vitamin D intake, winter season, and housebound status were independent predictors of hypovitaminosis D in a multivariate model. In a subgroup of 77 patients less than 65 years of age without known risk factors for hypovitaminosis D, the prevalence of vitamin D deficiency was 42 percent. CONCLUSIONS: Hypovitaminosis D is common in general medical inpatients, including those with vitamin D intakes exceeding the recommended daily allowance and those without apparent risk factors for vitamin D deficiency.