RESUMEN
BACKGROUND: Younger maternal age at birth is associated with increased risk of asthma in offspring in European descent populations, but has not been studied in Latino populations. OBJECTIVES: We sought to examine the relationship between maternal age at birth and prevalence of asthma in a nationwide study of Latino children. METHODS: We included 3473 Latino children aged 8-21 years (1696 subjects with physician-diagnosed asthma and 1777 healthy controls) from five US centres and Puerto Rico recruited from July 2008 through November 2011. We used multiple logistic regression models to examine the effect of maternal age at birth on asthma in offspring overall and in analyses stratified by ethnic subgroup (Mexican American, Puerto Rican and other Latino). Secondary analyses evaluated the effects of siblings, acculturation and income on this relationship. RESULTS: Maternal age < 20 years was significantly associated with decreased odds of asthma in offspring, independent of other risk factors (OR = 0.73, 95% CI: 0.57-0.93). In subgroup analyses, the protective effect of younger maternal age was observed only in Mexican Americans (OR = 0.53, 95% CI: 0.36, 0.79). In Puerto Ricans, older maternal age was associated with decreased odds of asthma (OR = 0.65, 95% CI: 0.44-0.97). In further stratified models, the protective effect of younger maternal age in Mexican Americans was seen only in children without older siblings (OR = 0.44, 95% CI: 0.23-0.81). CONCLUSION AND CLINICAL RELEVANCE: In contrast to European descent populations, younger maternal age was associated with decreased odds of asthma in offspring in Mexican American women. Asthma is common in urban minority populations but the factors underlying the varying prevalence among different Latino ethnicities in the United States is not well understood. Maternal age represents one factor that may help to explain this variability.
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Asma/epidemiología , Asma/etiología , Hispánicos o Latinos , Edad Materna , Adolescente , Estudios de Casos y Controles , Niño , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Masculino , Vigilancia de la Población , Factores de Riesgo , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Hughes-Stovin syndrome (HSS) is a systemic disease characterized by widespread vascular thrombosis and pulmonary vasculitis with serious morbidity and mortality. The HSS International Study Group is a multidisciplinary taskforce aiming to study HSS, in order to generate consensus recommendations regarding diagnosis and treatment. METHODS: We included 57 published cases of HSS (43 males) and collected data regarding: clinical presentation, associated complications, hemoptysis severity, laboratory and computed tomography pulmonary angiography (CTPA) findings, treatment modalities and cause of death. RESULTS: At initial presentation, DVT was observed in 29(33.3 %), thrombophlebitis in 3(5.3%), hemoptysis in 24(42.1%), and diplopia and seizures in 1 patient each. During the course of disease, DVT occurred in 48(84.2%) patients, and superficial thrombophlebitis was observed in 29(50.9%). Hemoptysis occurred in 53(93.0%) patients and was fatal in 12(21.1%). Pulmonary artery (PA) aneurysms (PAAs) were bilateral in 53(93%) patients. PAA were located within the main PA in 11(19.3%), lobar in 50(87.7%), interlobar in 13(22.8%) and segmental in 42(73.7%). Fatal outcomes were more common in patients with inferior vena cava thrombosis (p = 0.039) and ruptured PAAs (p < 0.001). Death was less common in patients treated with corticosteroids (p < 0.001), cyclophosphamide (p < 0.008), azathioprine (p < 0.008), combined immune modulators (p < 0.001). No patients had uveitis; 6(10.5%) had genital ulcers and 11(19.3%) had oral ulcers. CONCLUSIONS: HSS may lead to serious morbidity and mortality if left untreated. PAAs, adherent in-situ thrombosis and aneurysmal wall enhancement are characteristic CTPA signs of HSS pulmonary vasculitis. Combined immune modulators contribute to favorable outcomes.
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Aneurisma , Síndrome de Behçet , Vasculitis , Trombosis de la Vena , Humanos , Masculino , Arteria PulmonarRESUMEN
The dramatic decline in unionization during the last decade is investigated with the use of survey data from 1977 and 1984. First, it is found that only a small fraction of the decline in unionization can be accounted for by shifts in labor force structure. Second, there has been a substantial drop in demand for union representation among nonunion workers that can be accounted for by an increase in the job satisfaction of nonunion workers and a decrease in nonunion workers' reports that unions improve wages and working conditions. Finally, there has been a substantial increase in employer resistance to unionization that is likely to have made it more difficult for unions to organize even those workers who desire union representation. Increased foreign and increased nonunion domestic competition (particularly in deregulated industries) may be key underlying causes of these changes.
RESUMEN
The ability of cells to tolerate hypoxia is critical to their survival, but varies greatly among different cell types. Despite alterations in many cellular responses during hypoxic exposure, pulmonary arterial endothelial cells (PAEC) retain their viability and cellular integrity. Under similar experimental conditions, other cell types, exemplified by renal tubular epithelial cells, are extremely hypoxia sensitive and are rapidly and irreversibly damaged. To investigate potential mechanisms by which PAEC maintain cellular and functional integrity under these conditions, we compared the turnover of adenine and guanine nucleotides in hypoxia tolerant PAEC and in hypoxia-sensitive renal tubular endothelial cells under various hypoxic conditions. Under several different hypoxic conditions, hypoxia-tolerant PAEC maintained or actually increased ATP levels and the percentage of these nucleotides found in the high energy phosphates, ATP and GTP. In contrast, in hypoxia-sensitive renal tubular endothelial cells, the same high energy phosphates were rapidly depleted. Yet, in both cell types, there were minor alterations in the uptake of the precusor nucleotide and its incorporation into the appropriate purine nucleotide phosphates and marked decreases in ATPase and GTPase activity. This maintenance of high energy phosphates in hypoxic PAEC suggests that there exists tight regulation of ATP and GTP turnover in these cells and that preservation of these nucleotides may contribute to the tolerance of PAEC to acute and chronic hypoxia.
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Adenosina Trifosfato/metabolismo , Endotelio Vascular/fisiología , Guanosina Trifosfato/metabolismo , Mitocondrias/metabolismo , Adenosina/metabolismo , Adenosina Trifosfatasas/metabolismo , Animales , Transporte Biológico , Bovinos , Hipoxia de la Célula , Supervivencia Celular , Células Cultivadas , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Epitelio/metabolismo , Epitelio/fisiología , GTP Fosfohidrolasas/metabolismo , Guanosina/metabolismo , Túbulos Renales , Arteria PulmonarRESUMEN
Vascular endothelial cells (EC) are the initial cells within the vascular wall exposed to decreases in blood ambient oxygen concentration. The mechanisms by which they tolerate low levels of oxygen are unknown, but may parallel the response to other cellular stresses, such as heat shock. After 4-8 h of hypoxia, we found a decrease in total protein synthesis in both cultured bovine aortic and pulmonary arterial EC. SDS-PAGE and autoradiographic analysis of [35S]methionine-labeled proteins demonstrated the concomitant induction of a specific set of proteins (Mr 34, 36, 47, and 56 kD) in both cell types. These hypoxia-associated proteins (HAPs) were cell-associated and up-regulated in a time- and oxygen concentration-dependent manner. Comparison of these proteins with heat shock proteins (HSPs) demonstrated that HAPs were distinct from HSPs. EC maintained chronically in 3% O2 continued to synthesize elevated levels of HAPs, yet further up-regulated these proteins when exposed to 0% O2. The presence of five times the normal media glucose concentration did not alter the appearance of HAPs. Hypoxia sensitive renal tubular epithelial cells up-regulated no proteins corresponding to HAPs and were irreversibly damaged within 8 h of exposure to 0% O2. In vitro translation experiments demonstrated that the steady-state level of several mRNAs was higher in the anoxic EC than in normoxic EC and encoded for proteins of Mr 32, 35, 37, 40, and 48 kD that were different from proteins encoded by HSP mRNAs. The induction of HAPs during acute hypoxia and their continued synthesis in chronic hypoxia suggest that HAPs may be important in the maintenance of endothelial cell integrity under conditions of decreased ambient oxygen.
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Endotelio Vascular/metabolismo , Proteínas de Choque Térmico/metabolismo , Hipoxia/metabolismo , Animales , Bovinos , Células Cultivadas , Expresión Génica , Glucosa/metabolismo , Proteínas de Choque Térmico/genética , Técnicas In Vitro , Peso Molecular , Biosíntesis de Proteínas , ARN Mensajero/genética , Transcripción GenéticaRESUMEN
Homocysteine is a risk factor for the development of atherosclerosis and its thrombotic complications. We have employed an animal model to explore the hypothesis that an increase in reactive oxygen species and a subsequent loss of nitric oxide bioactivity contribute to endothelial dysfunction in mild hyperhomocysteinemia. We examined endothelial function and in vivo oxidant burden in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene, by studying isolated, precontracted aortic rings and mesenteric arterioles in situ. CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin. Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type. Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal. Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface. Importantly, endothelial dysfunction appears early in CBS(-/+) mice in the absence of structural arterial abnormalities. Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia.
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Endotelio Vascular/fisiopatología , Hiperhomocisteinemia/fisiopatología , Acetilcolina/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/patología , Aorta/fisiopatología , Arteriosclerosis/etiología , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Dinoprost/análogos & derivados , Dinoprost/metabolismo , Modelos Animales de Enfermedad , F2-Isoprostanos , Heterocigoto , Humanos , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/patología , Técnicas In Vitro , Peróxidos Lipídicos/metabolismo , Ratones , Ratones Mutantes , Nitroprusiato/farmacología , Especies Reactivas de Oxígeno/metabolismo , Factores de Riesgo , Trombosis/etiología , Tirosina/análogos & derivados , Tirosina/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is induced by hypoxia in endothelial cells (EC). Upregulation occurs primarily at the level of transcription and occurs to a much greater extent in EC than in other cell types. To characterize EC specific hypoxia response elements within the GAPDH gene, we performed transient transfection studies in EC, fibroblasts and smooth muscle cells using portions of the GAPDH promoter linked to a CAT reporter gene. These initial studies identified an EC specific hypoxia responsive region that was further characterized (using SV40-promoter-CAT reporter constructs) as a 19-nucleotide sequence (-130 to -112) containing both an hypoxia inducible factor-1 (HIF-1)-binding site and a novel flanking sequence. Electrophoretic mobility shift assays confirmed inducible EC protein binding to this fragment. Mutation of either the HIF-1-binding site or the flanking sequence resulted in complete loss of function and loss of inducible protein binding. Thus, a single HIF-1-binding site is necessary, but not sufficient, for hypoxic regulation of GAPDH in EC. Furthermore, the novel HIF-1 flanking sequence required for GAPDH upregulation and the protein(s) that bind to it may be EC specific.
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Endotelio Vascular/enzimología , Regulación Enzimológica de la Expresión Génica , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Oxígeno/metabolismo , Animales , Bovinos , Células Cultivadas , Elementos de Facilitación Genéticos/genética , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Hipoxia/genéticaRESUMEN
Atherosclerotic lesions contain multiple cell types including smooth muscle cells, macrophages, and T lymphocytes. The development of an extralymphatic T lymphocyte focus of inflammation in this condition requires chemoattractant-induced cell migration and growth factor-induced cell activation. In a previous study, we described a novel 13-15-kDa T lymphocyte-specific chemotactic cytokine, endothelial cell-derived lymphocyte chemoattractant activity (ED-LCA), secreted by serotonin-stimulated bovine aortic endothelial cells that is distinct from previously identified endothelial cell-derived interleukins (IL) 1, 6, and 8. Because of the association between T lymphocyte chemotactic and growth factor activity, in the current study we investigated the effect of ED-LCA on T cell growth. We assessed its capacity to induce markers of the passage of T cells from the resting (G0) state into the G1 phase of the cell cycle, such as receptors for IL-2 (IL-2R) and transferrin (TFR) and class II major histocompatibility complex antigens (HLA-DR). Incubation of G0 freshly isolated human T lymphocytes for 48 h with chromatographically resolved, partially purified ED-LCA resulted in a threefold increase in expression of the p55 subunit of IL-2R, a threefold increase in TFR, and a twofold increase in HLA-DR. Passage into the G1 phase of the cell cycle was confirmed by cell cycle analysis employing acridine orange. Evaluation of CD4+ and CD8+ T cell subsets by double-antibody labeling demonstrated that the p55 subunit of IL-2R was induced in both T cell subsets. Although incubation of human T cells with ED-LCA alone did not induce proliferation, addition of exogenous IL-2 to T cells pulsed with ED-LCA for 24 h caused a proliferative response with a stimulation index of 3. By up-regulating functional cell surface receptors for IL-2, ED-LCA is a competence growth factor for T lymphocytes and primes them to respond to IL-2. By virtue of its effect on T cells, as a chemotactic and competence factor, this endothelial cell-derived mitoattractant could participate with other T cell growth factors like IL-2 in the recruitment and amplification of the extralymphatic T cell component of atherosclerosis.
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Factores Quimiotácticos/metabolismo , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Sustancias de Crecimiento/metabolismo , Serotonina/farmacología , Linfocitos T/fisiología , Animales , Aorta/citología , Bovinos , Ciclo Celular , División Celular/fisiología , Movimiento Celular/fisiología , Células Cultivadas , Factores Quimiotácticos/farmacología , Factores Quimiotácticos/fisiología , Endotelio Vascular/efectos de los fármacos , Sustancias de Crecimiento/farmacología , Sustancias de Crecimiento/fisiología , Antígenos HLA-DR/análisis , Humanos , Interleucina-2/metabolismo , Interleucina-2/fisiología , ARN/análisis , ARN/genética , Receptores de Interleucina-2/análisis , Receptores de Interleucina-2/metabolismo , Receptores de Interleucina-2/fisiología , Receptores de Transferrina/análisis , Linfocitos T/química , Linfocitos T/ultraestructuraRESUMEN
Endothelial cells (EC) are hypoxia-tolerant and their capacity to proliferate in low oxygen tension is essential to maintain vascular endothelium integrity. The present study addresses whether hypoxia alters the expression of insulin-like growth factor (IGF) and IGF binding protein (IGFBP) genes in bovine aortic EC (BAEC) and bovine pulmonary artery EC (BPAEC). EC were cultured in normoxic (21%) conditions and exposed to 0% oxygen for 24, 48, or 72 h; some cells were reoxygenated by exposure to 21% oxygen for 24 or 48 h following hypoxia. IGF-I peptide and mRNA levels were very low in both cell types, and decreased further with exposure to hypoxia. Ligand blotting showed that both cell types synthesized 24 kDa (IGFBP-4), 30 kDa (IGFBP-5 and/or IGFBP-6), 43 kDa and 48 kDa IGFBPs (IGFBP-3 glycosylation variants). IGFBP-4 was the predominant IGFBP expressed by both cell types and did not change with exposure to hypoxia. Hypoxia caused a significant increase in IGFBP-3 secretion in BPAEC but not in BAEC. IGFBP-3 stable mRNA levels in BPAEC were increased correspondingly. IGFBP-5 was expressed only in BAEC and decreased with exposure to hypoxia. IGFBP-6 mRNA expression was low and increased in both cell types with exposure to hypoxia. These results demonstrate that EC IGFBP baseline expression as well as its expression in hypoxia vary in different vascular beds and suggest that the IGFBPs may be the dominant paracrine regulators of proliferation of EC as well as maintenance of endothelium integrity during hypoxia.
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Endotelio Vascular/metabolismo , Hipoxia/metabolismo , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Somatomedinas/biosíntesis , Animales , Aorta , Northern Blotting , Western Blotting , Bovinos , Células Cultivadas , Immunoblotting , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteína 5 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Proteína 6 de Unión a Factor de Crecimiento Similar a la Insulina/biosíntesis , Factor I del Crecimiento Similar a la Insulina/biosíntesis , Factor II del Crecimiento Similar a la Insulina/biosíntesis , Masculino , Arteria PulmonarRESUMEN
Primary pulmonary hypertension (PPH) is a rare disorder with an annual incidence of 1 to 2 per million people. The aetiology of this disorder is unknown, but it appears to result from an abnormal interaction of environmental and genetic factors leading to a vasculopathy. The pulmonary arteries in these patients exhibit a spectrum of pathological lesions ranging from the early medial hypertrophy to the end-stage fibrotic plexiform lesions. This characteristic pathology is also observed in pulmonary hypertension resulting from connective tissue disease (particularly systemic sclerosis), HIV infection, portal hypertension and certain toxins. PPH is a condition that is difficult to diagnose and treat, with a median survival of 2.8 years in historical studies. One of the difficulties in treating patients with PHH is that the subacute nature of disease presentation often prevents an accurate diagnosis during the early stages of the illness. Progressive dyspnoea on exertion is the most common presenting symptom. Diagnostic evaluation should include electrocardiography, chest radiograph and echocardiography, and laboratory and other studies to evaluate for secondary causes (e.g. pulmonary function tests, chest computed tomography and ventilation/perfusion scans, pulmonary arteriogram, cardiopulmonary testing, right heart catherisation). PHH is a disorder for which there is no known cure. Current medical and surgical treatment options for patients with PHH include anticoagulation, vasodilators and transplantation. Calcium channel antagonists are currently the oral drugs of choice for the treatment of patients with New York Heart Association (NYHA) Class II disease. These agents, in particular the dihydropyridine compounds, have beneficial effects on haemodynamics and right ventricular function, and possibly increased survival. Epoprostenol is administered by intravenous infusion, and studies have demonstrated short- and long-term improvements in symptoms, haemodynamics and survival. It is well tolerated and has become the treatment of choice for patients with NYHA Class III and IV disease. Inotropic agents are used as a bridge to transplant, which is indicated in patients who do not respond to maximal medical therapy. Experience has shown that single lung, double lung and heart-lung transplantation are approximately of equal efficacy. Currently, single lung transplant appears to be the procedure of choice. Newer agents, such as sildenafil, beraprost and bosentan, are presently being evaluated for the treatment of this disorder. Future study should include elucidation of the pathogenic mechanisms in the development of this vasculopathy, which will hopefully lead to the development of improved treatment options for patients with PHH.
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Anticoagulantes/uso terapéutico , Antihipertensivos/uso terapéutico , Hipertensión Pulmonar/terapia , Vasodilatadores/uso terapéutico , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Trasplante de Pulmón , Pruebas de Función RespiratoriaRESUMEN
Six patients, age 32 +/- 5 yr, had biopsy-proven foreign body granulomatosis secondary to the chronic injection of crushed, suspended pentazocine tablets. All patients complained of exercise-induced dyspnea. Measurements were made of mean pulmonary artery pressures (PAP), cardiac outputs (CO), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR) at rest and following 9 minutes of steady-state upright exercise. Following this, 50 mg of hydralazine was administered orally. The exercise PAP increased, and exercise PVR following hydralazine rose also. Exercise-induced dyspnea improved in all patients. In patients with foreign body granulomatosis, exercise-induced increases in PAP and PVR are common. This increase in PAP and PVR can be ameliorated somewhat by the acute oral administration of hydralazine. Exercise-induced dyspnea also improves.
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Granuloma/complicaciones , Hemodinámica/efectos de los fármacos , Hidralazina/administración & dosificación , Hipertensión Pulmonar/tratamiento farmacológico , Administración Oral , Adulto , Disnea/tratamiento farmacológico , Granuloma/etiología , Humanos , Hidralazina/farmacología , Hidralazina/uso terapéutico , Masculino , Esfuerzo Físico , Descanso , Talco/efectos adversosRESUMEN
We describe a patient with biopsy-proven pulmonary talc granulomas (secondary to the long-term intravenous injection of crushed tablets of pentazocine) who had two episodes of transient pulmonary hypertension following the injection of this oral medication. We established a canine model and measured the right lymph duct flow, mean pulmonary arterial pressures, and pulmonary vascular resistance to determine the short-term effects on hemodynamics and the flow of lymph after intravenous administration of crushed pentazocine tablets (3 to 4 mg/kg of body weight) or pure talc (2.5 to 3 mg/kg). A typical response to both agents consisted of short-term elevations of mean pulmonary arterial pressure and pulmonary vascular resistance to approximately twice baseline values, with a slow decrement over 30 to 45 minutes. The average flow of lymph tripled, peaking at approximately two hours after injection. The lymph contained high levels of albumin. We concluded that the talc filler in oral tablets of pentazocine induces the pulmonary hypertension, probably by mechanical obstruction of the pulmonary vasculature. Association with this transient pulmonary hypertension is an increase in the permeability of the pulmonary microvasculature.
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Hipertensión Pulmonar/inducido químicamente , Pentazocina/efectos adversos , Adulto , Animales , Perros , Granuloma/inducido químicamente , Hemodinámica/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Enfermedades Pulmonares/inducido químicamente , Linfa/efectos de los fármacos , Masculino , Modelos Biológicos , Pentazocina/farmacología , Circulación Pulmonar/efectos de los fármacos , Radiografía Torácica , Comprimidos , Talco/efectos adversos , Resistencia Vascular/efectos de los fármacosRESUMEN
STUDY OBJECTIVE: To determine if Mycobacterium gordonae is an opportunistic respiratory tract pathogen in patients infected with human immunodeficiency virus, type 1 (HIV-1). DESIGN: Retrospective review of medical records of all patients with positive cultures for M gordonae from 1987 to 1989. PATIENTS: Fifteen patients had positive sputum cultures for M gordonae: five patients had AIDS or had HIV-1 infections with less than or equal to 180 CD4 cells/cu mm, and ten patients had no clinical evidence of HIV-1 infection. RESULTS: Three of the five HIV-1 infected patients had clinical, roentgenographic, and microbiologic evidence of pulmonary infection due to M gordonae that responded to antimycobacterial therapy. One of the two remaining HIV-1 infected patients had disseminated M tuberculosis and possible coinfection with M gordonae, and the other was lost to follow-up. None of the ten patients without evidence of HIV-1 infection was considered to have M gordonae respiratory tract infection. CONCLUSIONS: Sputum isolates of M gordonae should be considered potential opportunistic respiratory tract pathogens in patients with advanced HIV-1 infection and with otherwise unexplained pulmonary infection.
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Síndrome de Inmunodeficiencia Adquirida/complicaciones , VIH-1 , Infecciones por Mycobacterium no Tuberculosas/complicaciones , Infecciones Oportunistas/complicaciones , Tuberculosis Pulmonar/complicaciones , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/tratamiento farmacológicoRESUMEN
Using the thiocarbamide model of acute lung injury in rats, we found that alpha-naphthylthiourea (ANTU) caused lung endothelial cell injury, as evidenced by increased permeability edema and decreased angiotensin I conversion. These effects were associated with enhanced pulmonary vascular reactivity. Recurrent ANTU lung injury caused pulmonary hypertension. The water-soluble thiocarbamide thiourea caused cultured vascular endothelial cells to release neutrophil chemoattractant activity. We speculate that endothelial cell injury may modulate the function of vascular smooth muscle and blood leukocytes.
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Enfermedades Pulmonares/fisiopatología , Pulmón/irrigación sanguínea , Angiotensina II/fisiología , Animales , Endotelio , Hipertensión Pulmonar/fisiopatología , Enfermedades Pulmonares/inducido químicamente , Masculino , Músculo Liso Vascular/fisiopatología , Neutrófilos/fisiología , Edema Pulmonar/fisiopatología , Ratas , Ratas Endogámicas , Tiourea/análogos & derivadosRESUMEN
The effect of an endurance triathlon (2.4-mile swim, 112-mile bicycle ride, 26.2-mile run, in succession) on plasma total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) A-I and B levels, and LDL particle size was determined in 34 male and six female participants 6 to 12 hours before and immediately after the completion of the triathlon. Plasma TG decreased significantly (70% decrease) in both men and women. In men the change in plasma TG was inversely associated with baseline TG values (P less than .0001). Plasma TC and LDL cholesterol did not change significantly in male athletes but decreased significantly in women. A significant increase in HDL cholesterol was observed in both men (18% increase, P less than .0001) and women (5% increase, P less than .01). In men the increase in HDL cholesterol was inversely correlated with the decrease in triglycerides (P less than .0002). Plasma apo A-I levels increased significantly only in the male group (P less than .005), whereas plasma apo B levels decreased significantly in both men and women (P less than .0005). LDL particle size increased in seven males, whereas in the remaining males and all females no change in LDL size was observed. The increase in LDL particle size in these seven subjects was associated with a greater decline in plasma TG compared with the remaining men (P less than .005) and women (P less than .03). These results indicate that prolonged strenuous physical exercise can induce acute modifications of plasma lipoproteins, which may in part be related to enhanced lipolysis.
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Apolipoproteínas/sangre , Lípidos/sangre , Lipoproteínas LDL/sangre , Lipoproteínas/sangre , Resistencia Física , Esfuerzo Físico , Apolipoproteína A-I , Apolipoproteínas A/sangre , Apolipoproteínas B/sangre , Colesterol/sangre , Electroforesis en Gel de Poliacrilamida , Femenino , Humanos , Masculino , Tamaño de la Partícula , Albúmina Sérica/análisis , Triglicéridos/sangreRESUMEN
BACKGROUND: Recombinant hirudin (r-hirudin) is a highly specific and selective thrombin inhibitor. Since 1997, it has been approved for the treatment of heparin-induced thrombocytopenia (HIT type II). Renal function impairment drastically prolongs the elimination half-life time. In cases of bleeding or overdosage, there is currently no antidote available. Hemofiltration has been reported to be useful in r-hirudin elimination. In this study, we determined sieving coefficients (SCs) and drug clearances for two different hemofilters currently used in clinical medicine and intensive care. METHODS: We developed an in vitro postdilution hemofiltration model using 500 ml heparinized (2 IU unfractionated heparin/ml) fresh human blood and bicarbonate substitution fluid. The investigated membranes were high-flux polysulfone F50 (1.0 m2, Fresenius) and AN69 Nephral 200 (1.05 m2, Hospal Cobe). After equilibration, a bolus of Lepirudin was injected into the postfilter port to achieve a r-hirudin blood level of approximately 15 microg/ml. Serial blood and ultrafiltrate samples were taken for the determination of hirudin levels (chromogenic assay) and control parameters. SC and clearances were calculated according to standard formulae. RESULTS: The observed SCs and clearances differed significantly between F50 and Nephral 200 (0.60+/-0.17 and 21.0+/-5.9 ml/min, respectively, vs. 0.44+/-0.09 and 15.5+/-3.0 ml/min, respectively; P = 0.001). The determination of prothrombin fragments showed no coagulation activation during the experiments. The hematocrit values remained stable. CONCLUSIONS: Our data show that r-hirudin can be eliminated by hemofiltration. The elimination obviously depends on the membrane material with high-flux polysulfone being more effective than AN69. These findings may be important in cases of overdosage and for r-hirudin dosage guidelines in continuous hemofiltration.
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Hemofiltración/métodos , Hirudinas/farmacocinética , Adolescente , Adulto , Heparina/sangre , Heparina/farmacología , Hirudinas/sangre , Humanos , Inactivación Metabólica , Membranas Artificiales , Persona de Mediana Edad , Protrombina/análisis , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacocinéticaRESUMEN
Pulmonary hypertension and foreign body granulomas are recognized sequelae of chronic intravenous drug abuse. We have recently described the development of transient pulmonary hypertension and increased permeability pulmonary edema after the intravenous injection of crushed, suspended pentazocine tablets in both humans and dogs. To determine the role of vasoactive substances in the development of this transient pulmonary hypertension, we measured pulmonary hemodynamics and accumulation of arachidonic acid metabolites in dogs during the infusion of indomethacin, a cyclooxygenase inhibitor, diethylcarbamazine (DEC), a lipoxygenase inhibitor, and FPL 55712, a receptor antagonist for leukotriene C4/D4 (LTC4/D4). Following the intravenous administration of crushed, suspended pentazocine tablets (3-4 mg/kg of body weight), mean pulmonary artery pressure increased from 14 +/- 2 mmHg to 30 +/- 6 mmHg (p less than 0.05) at 60 secs with a concomitant increase in plasma concentrations of 6-keto-PGF1 alpha from 187 +/- 92 pg/ml to 732 +/- 104 pg/ml and thromboxane B2 from 206 +/- 83 pg/ml to 1362 +/- 117 pg/ml (both p less than 0.05). Indomethacin prevented the increase in both cyclooxygenase metabolites, but had no effect on the pulmonary hypertension. In contrast, DEC had no effect on the increase in cyclooxygenase products, but blocked the pulmonary hypertension. FPL 55712 did not effect either the increase in cyclooxygenase metabolites or the pulmonary hypertension. We conclude that the transient pulmonary hypertension, induced by the intravenous injection of crushed, suspended pentazocine tablets, is not mediated by cyclooxygenase products but may be mediated by lipoxygenase product(s) other than LTC4/D4.
Asunto(s)
Reacción a Cuerpo Extraño/inducido químicamente , Granuloma de Cuerpo Extraño/inducido químicamente , Hipertensión Pulmonar/inducido químicamente , Enfermedades Pulmonares/inducido químicamente , Pentazocina/toxicidad , 6-Cetoprostaglandina F1 alfa/sangre , Animales , Ácido Araquidónico , Ácidos Araquidónicos/metabolismo , Presión Sanguínea/efectos de los fármacos , Cromonas/farmacología , Inhibidores de la Ciclooxigenasa , Dietilcarbamazina/farmacología , Perros , Hemodinámica , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Indometacina/farmacología , Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa , Pulmón/irrigación sanguínea , Pulmón/patología , Pentazocina/administración & dosificación , Prostaglandina-Endoperóxido Sintasas/metabolismo , Tromboxano B2/sangre , Resistencia Vascular/efectos de los fármacosRESUMEN
The effects of hippocampal and lateral septum lesions were compared in rats tested in a water maze spatial memory task, and the effect of chlordiazepoxide (CDP) was examined. There was a significant interaction for lesion and CDP in the septal lesioned subjects, with the lesioned animals performing worse than control animals, and CDP improving the performance of lesioned animals. CDP had no effect on impaired performance in hippocampal lesioned animals.