RESUMEN
A subset of families with co-dominant or recessive inheritance has been described in several genes previously associated with dominant inheritance. Those recessive families displayed similar, more severe, or even completely different phenotypes to their dominant counterparts. We report the first patients harboring homozygous disease-related variants in three genes that were previously associated with dominant inheritance: a loss-of-function variant in the CACNA1A gene and two missense variants in the RET and SLC20A2 genes, respectively. All patients presented with a more severe clinical phenotype than the corresponding typical dominant form. We suggest that co-dominant or recessive inheritance for these three genes could explain the phenotypic differences from those documented in their cognate dominant phenotypes. Our results reinforce that geneticists should be aware of the possible different forms of inheritance in genes when WES variant interpretation is performed. We also evidence the need to refine phenotypes and inheritance patterns associated with genes in order to avoid failures during WES analysis and thus, raising the WES diagnostic capacity in the benefit of patients.
Asunto(s)
Canales de Calcio/genética , Genes Dominantes , Mutación con Pérdida de Función , Fenotipo , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/genética , Adulto , Alelos , Femenino , Humanos , Recién Nacido , Masculino , LinajeRESUMEN
BACKGROUND: Patients with ulcerative colitis (UC) have an increased risk of developing colorectal cancer (CRC); however, the magnitude of this effect is open to debate. AIM: To assess the risk of CRC in UC patients by systematic review and meta-analysis. METHODS: A systematic literature search was performed up to November 2013. We selected studies describing the incidence and prevalence of CRC in patients with UC. Articles were assessed for quality using the Newcastle-Ottawa Scale. Cumulative incidence and incidence rates of CRC were combined and analysed using the generic inverse variance method. Sub-analyses were performed to identify factors associated with an increased risk of developing CRC. RESULTS: A total of 81 studies (181 923 patients) met the inclusion criteria. The incidence rate of CRC in patients with UC was 1.58 per 1000 patient-years (py) [95% confidence interval (CI), 1.391.76]. Results were heterogeneous (I2 = 8189%). The incidence rate was 4.02/1000 py (95%CI = 2.745.31) in studies that only included patients with extensive colitis, and 1.24/1000 py (95%CI = 1.011.47) in population-based studies. The incidence rate was 0.91/1000 py (95%CI = 0.611.2) in the first decade of disease, 4.07/1000 py (95%CI = 2.585.56) in the second, and 4.55/1000 py (95%CI = 2.646.46) in the third. The incidence rate decreased from 4.29/1000 py in the studies published in the 1950s to 1.21/1000 py in studies published in the last decade. CONCLUSIONS: The risk of patients with ulcerative colitis developing colorectal cancer has decreased steadily over the last six decades, but the extent and duration of the disease increase this risk.
Asunto(s)
Colitis Ulcerosa/epidemiología , Neoplasias Colorrectales/epidemiología , Colitis Ulcerosa/complicaciones , Neoplasias Colorrectales/etiología , Humanos , Incidencia , Prevalencia , RiesgoRESUMEN
Diagnosing oncogenic osteomalacia is still a challenge. The disorder is characterized by osteomalacia caused by renal phosphate wasting and low serum concentration of 1,25-dihydroxyvitamin D3 occurring in the presence of a tumor that produces high levels of fibroblast growth factor 23. However, it is possible that the disease is much more misdiagnosed than rare. We present the case of a 42-year-old man with a long-term history of undiagnosed progressive muscle weakness. His laboratory results mainly showed low serum phosphate. Surgical removal of a nasal hemangiopericytoma that had been diagnosed five years earlier, brought him to a symptom-free condition. Even though knowing the underlying etiology would explain his osteomalacia, the patient sought medical help from countless physicians for five consecutive years, and only after adequate treatment a rewarding outcome was achieved. Arq Bras Endocrinol Metab. 2012;56(8):570-3.
A osteomalacia oncogênica é um diagnóstico clínico desafiador, caracterizado pela perda renal de fosfato e baixos níveis de 1,25-di-hidroxivitamina D3, ocorrendo na presença de um tumor produtor de altos níveis de fator de crescimento de fibroblasto 23. No entanto, é possível que se trate muito mais de uma falha de diagnóstico clínico do que propriamente uma doença rara. Os autores relatam o caso de um homem de 42 anos com histórico de fraqueza muscular progressiva por cinco anos e restrição à cadeira de rodas, sem diagnóstico. Seus exames laboratoriais evidenciavam baixos níveis de fósforo. A remoção cirúrgica de um hemangiopericitoma detectado previamente em cavidade nasal levou à resolução completa dos sintomas. Os autores enfatizam que, mesmo com a etiologia já evidenciada, o paciente consultou diversos clínicos no decorrer dos cinco anos até que fossem instituídos o diagnóstico e o tratamento adequados. Arq Bras Endocrinol Metab. 2012;56(8):570-3.
Asunto(s)
Adulto , Humanos , Masculino , Hemangiopericitoma/complicaciones , Neoplasias de Tejido Conjuntivo/etiología , Neoplasias Nasales/complicaciones , Errores Diagnósticos , Hemangiopericitoma/diagnóstico , Neoplasias de Tejido Conjuntivo/diagnóstico , Neoplasias Nasales/diagnósticoRESUMEN
Diagnosing oncogenic osteomalacia is still a challenge. The disorder is characterized by osteomalacia caused by renal phosphate wasting and low serum concentration of 1,25-dihydroxyvitamin D3 occurring in the presence of a tumor that produces high levels of fibroblast growth factor 23. However, it is possible that the disease is much more misdiagnosed than rare. We present the case of a 42-year-old man with a long-term history of undiagnosed progressive muscle weakness. His laboratory results mainly showed low serum phosphate. Surgical removal of a nasal hemangiopericytoma that had been diagnosed five years earlier, brought him to a symptom-free condition. Even though knowing the underlying etiology would explain his osteomalacia, the patient sought medical help from countless physicians for five consecutive years, and only after adequate treatment a rewarding outcome was achieved.
Asunto(s)
Hemangiopericitoma/complicaciones , Neoplasias de Tejido Conjuntivo/etiología , Neoplasias Nasales/complicaciones , Adulto , Errores Diagnósticos , Hemangiopericitoma/diagnóstico , Humanos , Masculino , Neoplasias de Tejido Conjuntivo/diagnóstico , Neoplasias Nasales/diagnóstico , Osteomalacia , Síndromes ParaneoplásicosRESUMEN
Allogeneic transplantation remains the standard of care for patients with Hurler syndrome. As enzyme replacement therapy (ERT) has become available, controversy has emerged in regards to whether the use of enzyme in the peri-transplant period is appropriate. An analysis was performed on 74 patients with Hurler syndrome transplanted at the University of Minnesota between 1990 and 2003, before our use of ERT associated with transplant, with the intention of determining if patients at higher risk during the transplant can be identified based on evaluations and events before transplantation. Age, the presence of hydrocephalus, a history of cardiovascular issues or upper airway obstruction before transplant was not associated with significant differences in survival. In contrast, patients who had a history of lower airway disease, including reactive airway disease or bronchiolitis, or a history of pneumonia, had a significantly inferior outcome based on OS. The risk for serious respiratory complications was also assessed by evaluating the incidence of intubation. Overall, 31% of these patients were intubated. The risk of intubation was higher in older patients and in those with a history of lower airway disease. These findings have implications for the care of patients with high-risk features.
Asunto(s)
Mucopolisacaridosis I/diagnóstico , Mucopolisacaridosis I/terapia , Bronquiolitis , Preescolar , Terapia de Reemplazo Enzimático , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Recién Nacido , Masculino , Minnesota , Mucopolisacaridosis I/mortalidad , Neumonía , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
OBJECTIVE: Insulin and glucose levels in response to premeal insulin lispro or repaglinide were evaluated in adult patients with cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia. RESEARCH DESIGN AND METHODS: Seven patients with CFRD were fed 1,000-kcal liquid mixed meals. Three study conditions were administered in random order on separate mornings: 1) no premeal diabetes medication, 2) insulin lispro, 0.1 unit/kg body wt premeal and 3) repaglinide 1 mg premeal. Glucose and insulin levels were measured every 20 min for 5 h. RESULTS: Fasting insulin and glucose levels were normal in patients with CFRD, but the peak glucose level was elevated. Insulin lispro significantly decreased the peak glucose level (P = 0.0004) and the 2-h (P = 0.001) and 5-h (P < 0.0001) glucose area under the curve (AUC). Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03). Neither drug completely normalized cystic fibrosis glucose excursion at the doses used for this study. Insulin lispro significantly increased the 5-h insulin AUC (P = 0.04). CONCLUSIONS: In response to subcutaneous insulin lispro, postprandial glucose excursion was significantly diminished and insulin secretion was enhanced compared with a control meal in which no medication was given to patients with CFRD. The oral agent repaglinide resulted in lesser corrections in these parameters. Neither drug completely normalized glucose or insulin levels, suggesting that the doses chosen for this study were suboptimal. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on glucose metabolic control as well as overall nutrition and body weight are needed to help determine optimal medical treatment of CFRD.
Asunto(s)
Glucemia/metabolismo , Carbamatos/uso terapéutico , Fibrosis Quística/complicaciones , Diabetes Mellitus/sangre , Insulina/análogos & derivados , Insulina/sangre , Insulina/uso terapéutico , Piperidinas/uso terapéutico , Adulto , Carbamatos/administración & dosificación , Diabetes Mellitus/etiología , Femenino , Alimentos , Humanos , Hipoglucemia/etiología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Insulina/administración & dosificación , Insulina Lispro , Masculino , Piperidinas/administración & dosificaciónRESUMEN
In a model of idiopathic pneumonia syndrome after bone marrow transplantation (BMT), injection of allogeneic T cells induces nitric oxide (.NO), and the addition of cyclophosphamide (Cy) generates superoxide (O.) and a tissue-damaging nitrating oxidant. We hypothesized that.NO and O. balance are major determinants of post-BMT survival and inflammation. Inducible nitric oxide synthase (iNOS) deletional mutant mice (-/-) given donor bone marrow and spleen T cells (BMS) exhibited improved survival compared with matched BMS controls. Bronchoalveolar lavage fluids obtained on day 7 post-BMT from iNOS(-/-) BMS mice contained less tumor necrosis factor-alpha and interferon-gamma, indicating that.NO stimulated the production of proinflammatory cytokines. However, despite suppressed inflammation and decreased nitrotyrosine staining, iNOS(-/-) mice given both donor T cells and Cy (BMS + Cy) died earlier than iNOS-sufficient BMS + Cy mice. Alveolar macrophages from iNOS(-/-) BMS + Cy mice did not produce.NO but persisted to generate strong oxidants as assessed by the oxidation of the intracellular fluorescent probe 2',7'-dichlorofluorescin. We concluded that.NO amplifies T cell-dependent inflammation and addition of Cy exacerbates.NO-dependent mortality. However, the lack of.NO during Cy-induced oxidant stress decreases survival of T cell-recipient mice, most likely by generation of.NO-independent toxic oxidants.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Óxido Nítrico Sintasa/genética , Estrés Oxidativo/inmunología , Neumonía/inmunología , Tirosina/análogos & derivados , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Ciclofosfamida/farmacología , Femenino , Inmunosupresores/farmacología , Interferón gamma/análisis , Macrófagos/inmunología , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Nitratos/análisis , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II , Nitritos/análisis , Estrés Oxidativo/efectos de los fármacos , Neumonía/etiología , Neumonía/mortalidad , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T/trasplante , Factor de Necrosis Tumoral alfa/análisis , Tirosina/análisis , Tirosina/metabolismoRESUMEN
Cystic fibrosis (CF) patients are reported to experience chronic protein catabolism. Since diabetes or impaired glucose tolerance (IGT) is common in CF, we hypothesized that their protein catabolic state is related to reduced insulin secretion or reduced insulin action. A total of 12 clinically stable adult CF patients with abnormal glucose tolerance and 12 age-, sex-, and lean body mass-matched healthy control subjects underwent protein turnover studies using L-[1-(13)C]leucine, L-[(15)N]phenylalanine, and L-[(2)H(4)]tyrosine, with and without exogenous insulin infusion. In the baseline fasting state, protein metabolism was entirely normal in CF patients, with no evidence of increased protein catabolism. In contrast, striking abnormalities were seen in CF patients when insulin was infused, since they did not experience normal suppression of the appearance rates of leucine, phenylalanine, or tyrosine (indexes of protein breakdown). At an insulin concentration of 45 +/- 2 microU/ml, normal control subjects suppressed the leucine appearance rate by 19 +/- 5% (P < 0.01), ketoisocaproate appearance rate by 10 +/- 3% (P = 0.03), tyrosine appearance rate by 11 +/- 2% (P = 0.03), and phenylalanine appearance rate by 6 +/- 3% (P = 0.07). Phenylalanine conversion to tyrosine decreased by 22 +/- 7% (P = 0.03). At a similar insulin concentration of 44 +/- 3 microU/ml, normal suppression of amino acid appearance did not occur in CF. The leucine appearance rate decreased by 4 +/- 2% (P = 0.65), ketoisocaproate appearance rate by 1 +/- 2% (P = 0.94), tyrosine appearance rate by 0 +/- 6% (P = 0.56), phenylalanine appearance rate by 5 +/- 6% (P = 0.34), and phenylalanine conversion to tyrosine by 5 +/- 6% (P = 0.95). Poor suppression of the amino acid appearance rate in CF was not related to previously documented glucose tolerance status (IGT or CF-related diabetes without fasting hyperglycemia), fasting insulin levels, the acute insulin response, insulin sensitivity, cytokine or counterregulatory hormone levels, resting energy expenditure, caloric intake, pulmonary function, or clinical status. Protein synthesis was not significantly affected by insulin infusion in either normal control subjects or CF patients. In conclusion, clinically stable adult CF patients have normal indexes of protein breakdown and synthesis in the fasting state. In contrast, elevation of plasma insulin to physiological postprandial levels fails to normally suppress indexes of protein breakdown. It is therefore likely that inability to spare protein during the postprandial state is the cause of protein catabolism in these patients.
Asunto(s)
Fibrosis Quística/fisiopatología , Intolerancia a la Glucosa , Proteínas/metabolismo , Adulto , Aminoácidos/metabolismo , Metabolismo Energético , Ayuno/metabolismo , Femenino , Humanos , Insulina/metabolismo , Insulina/farmacología , Secreción de Insulina , Masculino , Valores de ReferenciaRESUMEN
We have previously shown an association between growth factor-induced upregulation of surfactant protein (SP)-A and suppression of alveolar inflammation in our murine model of donor T cell-dependent lung dysfunction after bone-marrow transplantation, referred to as idiopathic pneumonia syndrome (IPS). We hypothesized that SP-A protects the lung in vivo from IPS injury by downregulation of alveolar inflammation. Human SP-A (100 microg), purified by n-butanol extraction or preparative isoelectric focusing, was transtracheally instilled on Day 4 after BMT during a time of in vivo donor T-cell activation. At 48 h after treatment, immunohistochemical staining of lung sections showed that SP-A did not alter T cell- dependent cellular infiltration. However, macrophages from SP-A-instilled mice were less injured and spontaneously produced less tumor necrosis factor-alpha than did cells from buffer-instilled mice. Although exogenous SP-A did not significantly alter bronchoalveolar lavage fluid (BALF) high levels of total protein (TP), an inverse correlation between BALF SP-A and TP concentrations (r = -0.65; P = 0.02) was observed in SP-A-treated but not in buffer-instilled mice. The only difference between the effects of the two sources of SP-A was that butanol-extracted SP-A, but not isoelectric focusing-purified SP-A, suppressed the interferon-gamma/nitric oxide pathway. We conclude that SP-A downregulates T cell-dependent alveolar inflammation by multiple pathways leading to decreased IPS injury.
Asunto(s)
Neumonía/tratamiento farmacológico , Neumonía/inmunología , Proteolípidos/administración & dosificación , Surfactantes Pulmonares/administración & dosificación , Linfocitos T/efectos de los fármacos , Animales , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/inmunología , Líquido del Lavado Bronquioalveolar/química , Modelos Animales de Enfermedad , Femenino , Humanos , Instilación de Medicamentos , Interferón gamma/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Activación de Macrófagos/efectos de los fármacos , Macrófagos Alveolares/efectos de los fármacos , Macrófagos Alveolares/inmunología , Ratones , Ratones Endogámicos , Neumonía/etiología , Neumonía/patología , Neumonía/prevención & control , Proteolípidos/análisis , Proteolípidos/aislamiento & purificación , Edema Pulmonar/tratamiento farmacológico , Edema Pulmonar/inmunología , Proteína A Asociada a Surfactante Pulmonar , Proteínas Asociadas a Surfactante Pulmonar , Surfactantes Pulmonares/análisis , Surfactantes Pulmonares/aislamiento & purificación , Índice de Severidad de la Enfermedad , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
In patients with cystic fibrosis, CF-related diabetes mellitus (CFRD) has been associated with increased morbidity and mortality. Whether glucose intolerance is also associated with poor outcomes is unclear. To better define these relationships we prospectively followed a group of 152 patients with CF without diabetes for 4 yr. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CFRD without fasting hyperglycemia (CFRD-No FH). FEV(1), FVC, and body mass index (BMI) were measured at baseline and quarterly. At baseline 45% of the patients had NGT, 38.8% had IGT, and 15.8% had CFRD-No FH. FEV(1), FVC, and BMI at baseline were comparable among these groups (all p > 0.1). After 4 yr an overall decline in FEV(1) and FVC occurred, with no change in BMI. The rates of decline for FEV(1) and FVC correlated with the glucose tolerance groups, with the highest rates of decline occurring among the CFRD-No FH group. In addition, patients in the lowest quartile for insulin production at baseline experienced the highest rates of pulmonary function decline over time, suggesting a relationship between insulin deficiency and clinical deterioration. We conclude that the degree of glucose intolerance is a strong determinant of future lung function decline in patients with CF.
Asunto(s)
Fibrosis Quística/diagnóstico , Diabetes Mellitus Tipo 1/diagnóstico , Volumen Espiratorio Forzado/fisiología , Prueba de Tolerancia a la Glucosa , Adolescente , Adulto , Niño , Fibrosis Quística/fisiopatología , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Insulina/sangre , Masculino , Pronóstico , Capacidad Vital/fisiologíaRESUMEN
UNLABELLED: Recent reports indicate that inhaled nitric oxide (iNO) causes selective pulmonary vasodilation, increases arterial oxygen tension, and may decrease the use of extracorporeal membrane oxygenation (ECMO) in infants with persistent pulmonary hypertension of the newborn (PPHN). Despite these reports, the optimal dose and timing of iNO administration in PPHN remains unclear. OBJECTIVES: To test the hypotheses that in PPHN 1) iNO at 2 parts per million (ppm) is effective at acutely increasing oxygenation as measured by oxygenation index (OI); 2) early use of 2 ppm of iNO is more effective than control (0 ppm) in preventing clinical deterioration and need for iNO at 20 ppm; and 3) for those infants who fail the initial treatment protocol (0 or 2 ppm) iNO at 20 ppm is effective at acutely decreasing OI. STUDY DESIGN: A randomized, controlled trial of iNO in 3 nurseries in a single metropolitan area. Thirty-eight children, average gestational age of 37.3 weeks and average age <1 day were enrolled. Thirty-five of 38 infants had echocardiographic evidence of pulmonary hypertension. On enrollment, median OI in the control group, iNO at 0 ppm, (n = 23) was 33.1, compared with 36.9 in the 2-ppm iNO group (n = 15). RESULTS: Initial treatment with iNO at 2 ppm for an average of 1 hour was not associated with a significant decrease in OI. Twenty of 23 (87%) control patients and 14 of 15 (92%) of the low-dose iNO group demonstrated clinical deterioration and were treated with iNO at 20 ppm. In the control group, treatment with iNO at 20 ppm decreased the median OI from 42.6 to 23.8, whereas in the 2-ppm iNO group with a change in iNO from 2 to 20 ppm, the median OI did not change (42.6 to 42.0). Five of 15 patients in the low-dose nitric oxide group required ECMO and 2 died, compared with 7 of 23 requiring ECMO and 5 deaths in the control group. CONCLUSION: In infants with PPHN, iNO 1): at 2 ppm does not acutely improve oxygenation or prevent clinical deterioration, but does attenuate the rate of clinical deterioration; and 2) at 20 ppm acutely improves oxygenation in infants initially treated with 0 ppm, but not in infants previously treated with iNO at 2 ppm. Initial treatment with a subtherapeutic dose of iNO may diminish the clinical response to 20 ppm of iNO and have adverse clinical sequelae.
Asunto(s)
Óxido Nítrico/administración & dosificación , Síndrome de Circulación Fetal Persistente/terapia , Insuficiencia Respiratoria/terapia , Vasodilatadores/administración & dosificación , Administración por Inhalación , Oxigenación por Membrana Extracorpórea , Femenino , Humanos , Recién Nacido , Masculino , Óxido Nítrico/efectos adversos , Oxígeno/administración & dosificación , Oxígeno/sangre , Presión Parcial , Síndrome de Circulación Fetal Persistente/sangre , Síndrome de Circulación Fetal Persistente/complicaciones , Respiración Artificial , Insuficiencia Respiratoria/sangre , Insuficiencia Respiratoria/complicaciones , Insuficiencia del Tratamiento , Vasodilatadores/efectos adversosRESUMEN
Evidence suggests that nitric oxide (NO) causes perinatal pulmonary vasodilation through K+-channel activation. We hypothesized that this effect worked through cGMP-dependent kinase-mediated activation of Ca2+-activated K+ channel that requires release of intracellular Ca2+ from a ryanodine-sensitive store. We studied the effects of 1) K+-channel blockade with tetraethylammonium, 4-aminopyridine, a voltage-dependent K+-channel blocker, or glibenclamide, an ATP-sensitive K+-channel blocker; 2) cyclic nucleotide-sensitive kinase blockade with either KT-5823, a guanylate-sensitive kinase blocker, or H-89, an adenylate-sensitive kinase blocker; and 3) blockade of intracellular Ca2+ release with ryanodine on NO-induced pulmonary vasodilation in acutely prepared late-gestation fetal lambs. N-nitro-L-arginine, a competitive inhibitor of endothelium-derived NO synthase, was infused into the left pulmonary artery, and tracheotomy was placed. The animals were ventilated with 100% oxygen for 20 min, followed by ventilation with 100% oxygen and inhaled NO at 20 parts/million (ppm) for 20 min. This represents the control period. In separate protocols, the animals received an intrapulmonary infusion of the different blockers and were ventilated as above. Tetraethylammonium (n = 6 animals) and KT-5823 (n = 4 animals) attenuated the response, whereas ryanodine (n = 5 animals) blocked NO-induced perinatal pulmonary vasodilation. 4-Aminopyridine (n = 5 animals), glibenclamide (n = 5 animals), and H-89 (n = 4 animals) did not affect NO-induced pulmonary vasodilation. We conclude that NO causes perinatal pulmonary vasodilation through cGMP-dependent kinase-mediated activation of Ca2+-activated K+ channels and release of Ca2+ from ryanodine-sensitive stores.
Asunto(s)
Calcio/metabolismo , Feto/efectos de los fármacos , Membranas Intracelulares/metabolismo , Óxido Nítrico/farmacología , Canales de Potasio/fisiología , Circulación Pulmonar/efectos de los fármacos , Vasodilatación/fisiología , Animales , Bloqueadores de los Canales de Calcio/farmacología , Inhibidores Enzimáticos/farmacología , Nucleótidos Cíclicos/fisiología , Fosfotransferasas/antagonistas & inhibidores , Fosfotransferasas/metabolismo , Bloqueadores de los Canales de Potasio , Rianodina/farmacología , Ovinos/embriologíaRESUMEN
In a murine bone-marrow transplant (BMT) model designed to determine risk factors for lung dysfunction in irradiated mice, we reported that cyclophosphamide (Cy)-induced injury and lethality depended on the infusion of donor spleen T cells. In the study reported here, we hypothesized that alveolar macrophage (AM)-derived reactive oxygen/nitrogen species are associated with lung dysfunction caused by allogeneic T cells, which stimulate nitric oxide (.NO) production, and by Cy, which stimulates superoxide production.NO reacts with superoxide to form peroxynitrite, a tissue-damaging oxidant. On Day 7 after allogeneic BMT, bronchoalveolar lavage fluid (BALF) obtained from mice injected with T cells contained increased levels of nitrite, which was associated with increased lactate dehydrogenase and protein levels, both of which are indices of lung injury. The injury was most severe in mice receiving both T cells and Cy. Messenger RNA (mRNA) for inducible nitric oxide synthase was detected only in murine lungs injected with T cells +/- Cy. AMs obtained on Day 7 after BMT from mice receiving T cells +/- Cy spontaneously generated between 20 and 40 microM nitrite in culture, versus < 2 microM generated by macrophages obtained from mice undergoing BMT but not receiving T cells. The level of 3-nitrotyrosine, the stable byproduct of the reaction of peroxynitrite with tyrosine residues, was increased in the BALF proteins of mice injected with both T cells and Cy. We conclude that allogeneic T cells stimulate macrophage-derived.NO, and that the addition of Cy favors peroxynitrite formation. Peroxynitrite generation clarifies the dependence of Cy-induced lung injury and lethality on the presence of allogeneic T cells.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Ciclofosfamida/farmacología , Pulmón/metabolismo , Nitratos/metabolismo , Linfocitos T/metabolismo , Animales , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Femenino , L-Lactato Deshidrogenasa/análisis , Pulmón/efectos de los fármacos , Macrófagos Alveolares/citología , Macrófagos Alveolares/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Factores de Tiempo , Tirosina/análogos & derivados , Tirosina/análisisAsunto(s)
Aspergilosis Broncopulmonar Alérgica/inmunología , Fibrosis Quística/inmunología , Subgrupos de Linfocitos T/inmunología , Antígenos Fúngicos , Aspergillus/inmunología , Fibrosis Quística/complicaciones , Humanos , Inmunidad Celular , Interferón gamma/inmunología , Interleucina-4/inmunología , Interleucina-5/inmunologíaRESUMEN
BACKGROUND: High-altitude pulmonary edema (HAPE) is characterized by pulmonary hypertension, increased pulmonary capillary permeability, and hypoxemia. Treatment is limited to descent to lower altitude and administration of oxygen. METHODS AND RESULTS: We studied the acute effects of inhaled nitric oxide (NO), 50% oxygen, and a mixture of NO plus 50% oxygen on hemodynamics and gas exchange in 14 patients with HAPE. Each gas mixture was given in random order for 30 minutes followed by 30 minutes washout with room air. All patients had severe HAPE as judged by Lake Louise score (6.4+/-0.7), PaO2 (35+/-3. 1 mm Hg), and alveolar to arterial oxygen tension difference (AaDO2) (26+/-3 mm Hg). NO had a selective effect on the pulmonary vasculature and did not alter systemic hemodynamics. Compared with room air, pulmonary vascular resistance fell 36% with NO (P<0.001), 23% with oxygen (P<0.001 versus air, P<0.05 versus NO alone), and 54% with NO plus 50% oxygen (P<0.001 versus air, P<0.005 versus oxygen and versus NO). NO alone improved PaO2 (+14%) and AaDO2 (-31%). Compared with 50% oxygen alone, NO plus 50% oxygen had a greater effect on AaDO2 (-18%) and PaO2 (+21%). CONCLUSIONS: Inhaled NO may have a therapeutic role in the management of HAPE. The combined use of inhaled NO and oxygen has additive effects on pulmonary hemodynamics and even greater effects on gas exchange. These findings indicate that oxygen and NO may act on separate but interactive mechanisms in the pulmonary vasculature.
Asunto(s)
Óxido Nítrico/uso terapéutico , Oxígeno/uso terapéutico , Edema Pulmonar/tratamiento farmacológico , Vasodilatadores/uso terapéutico , Administración por Inhalación , Adulto , Altitud , Interacciones Farmacológicas , Humanos , Masculino , Óxido Nítrico/administración & dosificación , Oxígeno/administración & dosificación , Edema Pulmonar/diagnóstico , Edema Pulmonar/diagnóstico por imagen , Presión Esfenoidal Pulmonar/efectos de los fármacos , Radiografía , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/administración & dosificaciónRESUMEN
BACKGROUND: Lung disease accounts for most of the mortality in patients with cystic fibrosis (CF). Lung transplantation is an option for patients severely impaired, being recommended when life expectancy is estimated to be <2 years. Our objectives were to evaluate in our patient population the validity of currently accepted criteria for low life expectancy and to identify other potentially useful criteria. METHODS: Data were retrieved from CF patients followed up at our center who reached and kept an FEV1 <30% predicted. A life table was created and stratified according to characteristics believed to be of importance. In addition, the rate of decline in percent predicted FEV1 was analyzed. These characteristics were evaluated as predictors of risk of death. RESULTS: The median survival was 3.9 years (95% confidence interval, 2.88 to 4.12 years), with no significant differences according to gender, nutritional status, presence of diabetes, or decade in which the patient was cared for. Only by age was there a significant difference in the median survival (p<0.05). By proportional hazards regression, only the rate of decline in percent predicted FEV1 was a significant predictor of the risk of death, with a borderline effect from younger age (p=0.06). CONCLUSION: In our patient population, a cutoff value of FEV1 of < 30% predicted is not a reliable predictor of high risk of death within 2 years. The yearly rate of decline of percent predicted FEV1 is a better parameter to identify those patients at high risk for death.