RESUMO
BACKGROUND: Improving maternal health has been a primary goal of international health agencies for many years, with the aim of reducing maternal and child deaths and improving access to antenatal care (ANC) services, particularly in low-and-middle-income countries (LMICs). Health interventions with these aims have received more attention from a clinical effectiveness perspective than for cost impact and economic efficiency. METHODS: We collected data on resource use and costs as part of a large, multi-country study assessing the use of routine antenatal screening ultrasound (US) with the aim of considering the implications for economic efficiency. We assessed typical antenatal outpatient and hospital-based (facility) care for pregnant women, in general, with selective complication-related data collection in women participating in a large maternal health registry and clinical trial in five LMICs. We estimated average costs from a facility/health system perspective for outpatient and inpatient services. We converted all country-level currency cost estimates to 2015 United States dollars (USD). We compared average costs across countries for ANC visits, deliveries, higher-risk pregnancies, and complications, and conducted sensitivity analyses. RESULTS: Our study included sites in five countries representing different regions. Overall, the relative cost of individual ANC and delivery-related healthcare use was consistent among countries, generally corresponding to country-specific income levels. ANC outpatient visit cost estimates per patient among countries ranged from 15 to 30 USD, based on average counts for visits with and without US. Estimates for antenatal screening US visits were more costly than non-US visits. Costs associated with higher-risk pregnancies were influenced by rates of hospital delivery by cesarean section (mean per person delivery cost estimate range: 25-65 USD). CONCLUSIONS: Despite substantial differences among countries in infrastructures and health system capacity, there were similarities in resource allocation, delivery location, and country-level challenges. Overall, there was no clear suggestion that adding antenatal screening US would result in either major cost savings or major cost increases. However, antenatal screening US would have higher training and maintenance costs. Given the lack of clinical effectiveness evidence and greater resource constraints of LMICs, it is unlikely that introducing antenatal screening US would be economically efficient in these settings--on the demand side (i.e., patients) or supply side (i.e., healthcare providers). TRIAL REGISTRATION: Trial number: NCT01990625 (First posted: November 21, 2013 on https://clinicaltrials.gov ).
Assuntos
Cesárea , Países em Desenvolvimento , Criança , Feminino , Humanos , Pobreza , Gravidez , Gestantes , Cuidado Pré-NatalRESUMO
The phase III Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors Trial (BENEFIT-EXT) study compared more or less intensive belatacept-based immunosuppression with cyclosporine (CsA)-based immunosuppression in recipients of extended criteria donor kidneys. In this post hoc analysis, patient outcomes were assessed according to donor kidney subtype. In total, 68.9% of patients received an expanded criteria donor kidney (United Network for Organ Sharing definition), 10.1% received a donation after cardiac death kidney, and 21.0% received a kidney with an anticipated cold ischemic time ≥24 h. Over 7 years, time to death or graft loss was similar between belatacept- and CsA-based immunosuppression, regardless of donor kidney subtype. In all three donor kidney cohorts, estimated mean GFR increased over months 1-84 for belatacept-based treatment but declined for CsA-based treatment. The estimated differences in GFR significantly favored each belatacept-based regimen versus the CsA-based regimen in the three subgroups (p < 0.0001 for overall treatment effect). No differences in the safety profile of belatacept were observed by donor kidney subtype.
Assuntos
Abatacepte/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Doadores de Tecidos , Feminino , Seguimentos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , SegurançaRESUMO
The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial randomized patients receiving a living or standard criteria deceased donor kidney transplant to a more (MI) or less intensive (LI) regimen of belatacept or cyclosporine A (CsA). The 5-year results of the long-term extension (LTE) cohort are reported. A total of 456 (68.5% of intent-to-treat) patients entered the LTE at 36 months; 406 patients (89%) completed 60 months. Between Months 36 and 60, death occurred in 2%, 1% and 5% of belatacept MI, belatacept LI and CsA patients, respectively; graft loss occurred in 0% belatacept and 2% of CsA patients. Acute rejection between Months 36 and 60 was rare: zero belatacept MI, one belatacept LI and one CsA. Rates for infections and malignancies for Months 36-60 were generally similar across belatacept groups and CsA, respectively: fungal infections (14%, 15%, 12%), viral infections (21%, 18%, 16%) and malignancies (6%, 6%, 9%). No new posttransplant lymphoproliferative disorder cases occurred after 36 months. Mean calculated GFR (MDRD, mL/min/1.73 m(2) ) at Month 60 was 74 for belatacept MI, 76 for belatacept LI and 53 for CsA. These results show that the renal function benefit and safety profile observed in belatacept-treated patients in the early posttransplant period was sustained through 5 years.
Assuntos
Ciclosporina/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Transplante de Rim , Abatacepte , Adulto , Estudos de Coortes , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Agências Internacionais , Testes de Função Renal , Transtornos Linfoproliferativos/prevenção & controle , Masculino , Complicações Pós-Operatórias/prevenção & controle , Prognóstico , Segurança , Fatores de TempoRESUMO
The clinical profile of belatacept in kidney transplant recipients was evaluated to determine if earlier results in the BENEFIT study were sustained at 3 years. BENEFIT is a randomized 3 year, phase III study in adults receiving a kidney transplant from a living or standard criteria deceased donor. Patients were randomized to a more (MI) or less intensive (LI) regimen of belatacept, or cyclosporine. 471/666 patients completed ≥3 years of therapy. A total of 92% (MI), 92% (LI), and 89% (cyclosporine) of patients survived with a functioning graft. The mean calculated GFR (cGFR) was â¼21 mL/min/1.73 m(2) higher in the belatacept groups versus cyclosporine at year 3. From month 3 to month 36, the mean cGFR increased in the belatacept groups by +1.0 mL/min/1.73 m(2) /year (MI) and +1.2 mL/min/1.73 m(2) /year (LI) versus a decline of -2.0 mL/min/1.73 m(2) /year (cyclosporine). One cyclosporine-treated patient experienced acute rejection between year 2 and year 3. There were no new safety signals and no new posttransplant lymphoproliferative disorder (PTLD) cases after month 18. Belatacept-treated patients maintained a high rate of patient and graft survival that was comparable to cyclosporine-treated patients, despite an early increased occurrence of acute rejection and PTLD.
Assuntos
Ciclosporina/uso terapêutico , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim , Abatacepte , Adulto , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Resultado do TratamentoRESUMO
Belatacept, a costimulation blocker, may preserve renal function and improve long-term outcomes versus calcineurin inhibitors in kidney transplantation. This Phase III study (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial) assessed a more intensive (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adults receiving a kidney transplant from living or standard criteria deceased donors. The co-primary endpoints at 12 months were patient/graft survival, a composite renal impairment endpoint (percent with a measured glomerular filtration rate (mGFR) <60 mL/min/1.73 m(2) at Month 12 or a decrease in mGFR > or =10 mL/min/1.73 m(2) Month 3-Month 12) and the incidence of acute rejection. At Month 12, both belatacept regimens had similar patient/graft survival versus cyclosporine (MI: 95%, LI: 97% and cyclosporine: 93%), and were associated with superior renal function as measured by the composite renal impairment endpoint (MI: 55%; LI: 54% and cyclosporine: 78%; p < or = 0.001 MI or LI versus cyclosporine) and by the mGFR (65, 63 and 50 mL/min for MI, LI and cyclosporine; p < or = 0.001 MI or LI versus cyclosporine). Belatacept patients experienced a higher incidence (MI: 22%, LI: 17% and cyclosporine: 7%) and grade of acute rejection episodes. Safety was generally similar between groups, but posttransplant lymphoproliferative disorder was more common in the belatacept groups. Belatacept was associated with superior renal function and similar patient/graft survival versus cyclosporine at 1 year posttransplant, despite a higher rate of early acute rejection.
Assuntos
Ciclosporina/uso terapêutico , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Abatacepte , Adulto , Feminino , Taxa de Filtração Glomerular , Humanos , Terapia de Imunossupressão , Incidência , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/prevenção & controle , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de TempoRESUMO
The synthesis, cell origin, and physiologic role of eicosanoids were investigated in a model of mesangial cell immune injury induced by a monoclonal antibody against the rat thymocyte antigen Thy 1.1 also expressed in rat mesangial cells. A single intravenous injection of the antibody resulted in enhanced glomerular synthesis of thromboxane (Tx)B2, leukotriene (LT)B4, and 12-hydroxyeicosatetraenoic acid (HETE), whereas that of PGE2 and PGF2 alpha was either unaltered or impaired. The enhanced eicosanoid synthesis was associated with decrements in glomerular filtration rate (GFR) and renal blood flow (RBF). Complement activation mediated both the increments in TxB2, LTB4, and 12-HETE and the decrements in GFR and RBF. The decrements in GFR were abolished by the TxA2 receptor antagonist SQ-29,548. Although both neutrophiles and Ia (+) leukocytes infiltrated glomeruli, glomerular LTB4 originated mainly from the latter. Platelets entirely accounted for the enhanced 12-HETE synthesis in isolated glomeruli and to a lesser extent for that of LTB4 and TxB2. Glomerular PGE2 and PGF2 alpha originated from mesangial cells as their impaired synthesis coincided with extensive mesangial cell lysis. The observations indicate that in mesangial cell immune injury vasoactive and proinflammatory eicosanoids originate from recruited or activated Ia (+) leukocytes and platelets and may exert paracrine effects on mesangial cells.
Assuntos
Eicosanoides/biossíntese , Mesângio Glomerular/metabolismo , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antígenos de Superfície/imunologia , Taxa de Filtração Glomerular , Mesângio Glomerular/patologia , Mesângio Glomerular/efeitos da radiação , Ácidos Hidroxieicosatetraenoicos/biossíntese , Leucócitos , Leucotrieno B4/biossíntese , Masculino , Camundongos , Prostaglandinas/biossíntese , Ratos , Ratos Endogâmicos , Circulação Renal , Tromboxano B2/biossíntese , Antígenos Thy-1RESUMO
The role of leukocytes and platelets and of leukocyte- and platelet-derived eicosanoids in mediating acute changes in renal and glomerular hemodynamics was assessed in a model of antibody-induced mesangial cell injury in the rat. After a single intravenous injection (6 mg/kg) of the monoclonal antibody (ER4) against the mesangial cell membrane antigen Thy 1, significant decrements in glomerular filtration rate (GFR) and renal blood flow (RBF) were observed at 1 h, and were associated with increments in glomerular LC (+) leukocyte counts and in the synthesis of thromboxane (Tx)B2, leukotriene (LT)B4, and 12-hydroxyeicosatetraenoic acid (HETE). In rats with immune leukopenia, the rise in glomerular LC (+) leukocytes and in eicosanoid synthesis were abolished and the fall in GFR and RBF after administration of ER4 were completely ameliorated. Likewise, pretreatment of rats with both a thromboxane synthase and a 5-lipoxygenase inhibitor also blocked the fall in GFR and RBF and the rise in glomerular synthesis of TxB2 and LTB4 produced by ER4 without changing glomerular LC (+) leukocyte counts. Selective inhibition of thromboxane or 5-lipoxygenase alone only partially ameliorated the decrements in GFR and RBF produced by ER4. In animals with immune thrombocytopenia, the elevated glomerular synthesis of 12-HETE and fall in RBF but not GFR was ameliorated after administration of ER4. The ER4 antibody-induced fall in GFR was mainly caused by a marked decrement in the ultrafiltration coefficient, Kf, which was dependent on TxA2 and 5-lipoxygenase products, since pretreatment of animals with a thromboxane receptor antagonist or with a 5-lipoxygenase inhibitor partially ameliorated this decrement. Structural changes such as infiltration of glomerular capillaries by leukocytes and endothelial cell damage may also have accounted for the fall in Kf. These observations indicate that in antibody-mediated mesangial cell injury, infiltrating leukocytes and platelets mediate the changes in renal hemodynamics via synthesis of thromboxane and arachidonate 5-lipoxygenation products.
Assuntos
Eicosanoides/fisiologia , Mesângio Glomerular/imunologia , Hemodinâmica , Doenças do Complexo Imune/fisiopatologia , Animais , Antígenos de Superfície/imunologia , Plaquetas/fisiologia , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Doenças do Complexo Imune/patologia , Leucócitos/fisiologia , Depleção Linfocítica , Masculino , Glicoproteínas de Membrana/imunologia , Microscopia Eletrônica , Ratos , Antígenos Thy-1RESUMO
BACKGROUND AND PURPOSE: Degenerative changes are commonly found in spine imaging but often occur in pain-free individuals as well as those with back pain. We sought to estimate the prevalence, by age, of common degenerative spine conditions by performing a systematic review studying the prevalence of spine degeneration on imaging in asymptomatic individuals. MATERIALS AND METHODS: We performed a systematic review of articles reporting the prevalence of imaging findings (CT or MR imaging) in asymptomatic individuals from published English literature through April 2014. Two reviewers evaluated each manuscript. We selected age groupings by decade (20, 30, 40, 50, 60, 70, 80 years), determining age-specific prevalence estimates. For each imaging finding, we fit a generalized linear mixed-effects model for the age-specific prevalence estimate clustering in the study, adjusting for the midpoint of the reported age interval. RESULTS: Thirty-three articles reporting imaging findings for 3110 asymptomatic individuals met our study inclusion criteria. The prevalence of disk degeneration in asymptomatic individuals increased from 37% of 20-year-old individuals to 96% of 80-year-old individuals. Disk bulge prevalence increased from 30% of those 20 years of age to 84% of those 80 years of age. Disk protrusion prevalence increased from 29% of those 20 years of age to 43% of those 80 years of age. The prevalence of annular fissure increased from 19% of those 20 years of age to 29% of those 80 years of age. CONCLUSIONS: Imaging findings of spine degeneration are present in high proportions of asymptomatic individuals, increasing with age. Many imaging-based degenerative features are likely part of normal aging and unassociated with pain. These imaging findings must be interpreted in the context of the patient's clinical condition.
Assuntos
Envelhecimento/patologia , Degeneração do Disco Intervertebral/epidemiologia , Degeneração do Disco Intervertebral/patologia , Dor nas Costas/epidemiologia , Dor nas Costas/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prevalência , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: The shortage of cadaveric donors for kidney transplantation has prompted many centers to use cadaver kidneys from pediatric donors. Use of kidneys from pediatric donors has been shown to have a lower graft survival. METHODS: Recipients receiving cadaver kidneys from pediatric and adult donors between 1988 and 1995 were analyzed. The data were obtained from United Network of Organ Sharing database. The actuarial kidney transplant graft survival was estimated by the Kaplan-Meier method. A logistic regression analysis was used to identify various risk factors for 1-year graft failure. Odds ratios (OR) were estimated for various risk factors. RESULTS: Kidney transplant survival rates for donor age <18 years (n=12,838) at 1, 2, 3, 4, and 5 years were 81.5%, 76.3%, 71.3%, 66.4%, and 61.7%, respectively. The corresponding results for adult donors from age 18 to 50 years (n=35, 442) were 83.5%, 78.4%, 73.1%, 67.9%, and 62.4%, respectively, Log-rank test P<0.01. Pediatric donors were further divided into three groups according to donor age: group I (0-5 years), group II (6-11 years), and group III (12-17 years). The actuarial survival rates for 1, 3, and 5 years for group I (n=2198) were 73.6%, 63.3%, and 55.6%, respectively. The corresponding values for group II (n=2873) were 78.0%, 67.5%, and 57.8% and for group III (n=7767) were 85%, 75.0%, and 64.8%, respectively, P<0.01. Although the recipients of group I had lower graft survival, en bloc grafts (n=751) had much better 1-, 3-, and 5-year graft survival rates (76.3%, 67.7%, and 60.7%, respectively) compared with single grafts (n=1447; 72.2%, 61.1%, and 53.2%, P=0.02) from donors 0 to 5 years. Graft thrombosis as a cause of graft failure was seen in 10% of group I compared with 6% in group II and 5% in group III. In group I, lower OR were seen when an en bloc transplant was performed (0.688, P<0.01) and when donor body weight was>15 kg (0.547, P<0.01). However, OR were elevated in recipients of previous transplants (1.556, P<0.01), with prolonged cold ischemic time (1.097, P=0.03), for black recipients (1.288, P=0.03), and for recipients with body mass index> or =25 (1.286, P=0.02). Progressive increase in the donor age was associated with lower OR in group II (0.894, P<0.01). CONCLUSIONS: (1) Overall, poorer graft survival was seen in pediatric donor transplants, (2) transplant kidney survival with en bloc kidneys was better than a single kidney from donors 0-5 years, (3) progressive increase in donor age was associated with improved graft survival when the donors were 6-11 years, whereas progressive increase in donor weight was associated with improved graft survival when the donors were 0-5 years.
Assuntos
Sobrevivência de Enxerto/fisiologia , Transplante de Rim/fisiologia , Rim , Doadores de Tecidos/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Índice de Massa Corporal , Peso Corporal , Cadáver , Criança , Pré-Escolar , Etnicidade , Feminino , Humanos , Isquemia , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Preservação de Órgãos , Grupos Raciais , Reoperação , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo , Estados UnidosRESUMO
BACKGROUND: Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. METHODS: Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. RESULTS: There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5-40%) compared with 6% (range, 0-10%) in those with acute rejection (P=0.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2-15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15-30%) in those patients who had acute rejection (P=0.0159). CONCLUSION: Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.
Assuntos
Imunossupressores/efeitos adversos , Transplante de Rim , Ácido Micofenólico/análogos & derivados , Infecções por Papillomavirus/induzido quimicamente , Polyomavirus , Doença Aguda , Adulto , Antígenos CD20/análise , Linfócitos B/patologia , Feminino , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Imuno-Histoquímica/métodos , Rim/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Coloração e Rotulagem , Linfócitos T Citotóxicos/patologia , Tacrolimo/efeitos adversos , Infecções Tumorais por Vírus/induzido quimicamente , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/patologiaRESUMO
BACKGROUND: We assessed the effect of a cytokine inhibitor, compound SKF 86002 (a bicyclic imidazole), on changes in renal hemodynamics (renal blood flow and glomerular filtration rate) that occur acutely following immune injury of glomerular mesangial cells. METHODS: Injury was induced in Munich-Wistar rats by the administration of a monoclonal antibody against the mesangial cell membrane antigen Thy 1.1. An acute drop in renal blood flow (RBF) and glomerular filtration rate (GFR) occurred within one hour of injury. RESULTS: Pretreatment of animals with the cytokine inhibitor SKF 86002 prevented this drop. SKF 86002 had no effect on glomerular synthesis of vasoconstrictor eicosanoids. CONCLUSIONS: The observations indicate that in mesangial cell immune injury, cytokines mediate renal hemodynamic impairment.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/antagonistas & inibidores , Mesângio Glomerular/imunologia , Imidazóis/farmacologia , Circulação Renal/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Anticorpos Monoclonais , Eicosanoides/biossíntese , Taxa de Filtração Glomerular/efeitos dos fármacos , Mesângio Glomerular/metabolismo , Mesângio Glomerular/fisiologia , Mediadores da Inflamação/fisiologia , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Post-transplantation lymphoproliferative disorder (PTLD) is a significant complication of solid organ transplantation. Most PTLD is of the B-cell subtype, although T-cell subtype PTLD uncommonly occurs. T-cell PTLDs are usually aggressive neoplasms and shorten patient and allograft survivals significantly. We present a single-center case series of 4 patients who developed T-cell large granular lymphocytic (LGL) leukemia, a rare T-cell PTLD characterized by large granular lymphocytes that have characteristic azurophilic granules and a highly variable clinical course.
Assuntos
Leucemia Linfoide/etiologia , Transplante de Órgãos/efeitos adversos , Idoso , Feminino , Humanos , Leucemia Linfoide/diagnóstico , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Clinical tools for predicting poor outcomes in asthma patients are lacking. This study investigated the association of asthma control and subsequent severe asthma-related healthcare events in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. METHODS: The extent of asthma control problems was determined from baseline values of the Asthma Therapy Assessment Questionnaire (ATAQ). Patients self-reported the presence of severe asthma-related events at 6- and 12-month follow up. Poisson regression models determined the adjusted association between baseline control and the likelihood of severe asthma-related events. RESULTS: At baseline, 2942 patients (mean age, 49.6 years; female, 71.9%) had an ATAQ score (no control problems, 17.0%; 1 control problem, 20.0%; 2 control problems, 30.8%; 3 or 4 control problems, 32.2%) and at least one severe asthma-related event. After adjustment, subjects with three or four control problems were at greater risk for unscheduled office visits [relative risk (RR) = 2.8; 95% confidence interval (CI): 2.4-3.2], course of oral steroids (RR = 2.9; 95% CI: 2.5-3.3), emergency room visits (RR = 4.1; 95% CI: 2.7-6.2) or hospitalization (RR = 13.6; 95% CI: 7.4-24.9), vs no control problems. Progressively poorer levels of asthma control are associated with increasing risk of severe asthma-related events. CONCLUSIONS: This study provides evidence of an association between poor asthma control and future severe asthma-related healthcare events. A validated questionnaire may help clinicians identify patients requiring intervention to prevent future severe asthma-related events.
Assuntos
Asma/fisiopatologia , Inquéritos e Questionários , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Gerenciamento Clínico , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
In glomerulonephritis there is co-activation of the arachidonic acid cyclooxygenase pathway toward synthesis of prostaglandins (PG) and thromboxane (Tx) and of lipoxypenase pathways toward synthesis of hydroxyeicosatetraenoic acids (HETEs) and leukotrienes (LTs). Cyclooxygenase inhibition with non-steroidal anti-inflammatory drugs results in enhanced glomerular LT synthesis with potentially adverse effects on the severity of the inflammation. The effect of Tx inhibition or antagonism on LT synthesis is unknown. Because TxA2 is the most abundant eicosanoid synthesized in nephritic glomeruli, and because TxA2 synthase inhibitors and receptor antagonists are now available for the treatment of glomerulonephritis, it becomes important to address this question. In this study we assessed the effect of a TxA2 synthase inhibitor, Dazmegrel, and a TxA2 receptor antagonist, SQ-29 548, on glomerular PGE2, LTB4, and 12-HETE synthesis in a model of mesangial nephritis induced in the rat by the administration of a monoclonal antibody against the Thy 1.1 antigen of rat mesangial cells. Dazmegrel, in doses sufficient to effectively block glomerular TxA2 synthesis, significantly increased 12-HETE and PGE2 synthesis without an effect on the synthesis of LTB4. SQ-29 548 had no effect on glomerular PGE2, LTB4, or 12-HETE production. Because PGE2 preserves kidney function in glomerulonephritis, and because 12-HETE inhibits 5-lipoxygenase, the enhanced PGE2 and 12-HETE production within nephritic glomeruli after TxA2 synthase inhibition may be a superior anti-inflammatory strategy when compared with TxA2 receptor antagonism.
Assuntos
Dinoprostona/biossíntese , Glomérulos Renais/lesões , Glomérulos Renais/metabolismo , Leucotrieno B4/biossíntese , Tromboxano A2/antagonistas & inibidores , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biossíntese , Animais , Soro Antilinfocitário/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes , Modelos Animais de Doenças , Ácidos Graxos Insaturados , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulonefrite Membranoproliferativa/metabolismo , Hidrazinas/farmacologia , Glomérulos Renais/imunologia , Macrófagos/patologia , Ratos , Ratos Wistar , Tromboxano-A Sintase/antagonistas & inibidores , Antígenos Thy-1RESUMO
The pathophysiologic role of thromboxane and of arachidonate 5-lipoxygenation products in mediating changes in glomerular filtration rate (GFR) and renal blood flow (RBF) was investigated in a rat model of mesangial cell immune injury induced by a monoclonal antibody (ER4) directed against the mesangial cell membrane antigen, Thy 1. Following a single intravenous dose of the ER4 antibody acute decrements in GFR and RBF occurred at 1 h and were associated with enhanced glomerular leukocyte infiltration and synthesis of thromboxane A2, 12-HETE and LTB4. Pretreatment of animals with the thromboxane synthase inhibitor, Furegrelate, or the thromboxane receptor antagonist SQ-29,548 ameliorated or completely abolished the decrements in GFR and RBF without reducing glomerular leukocyte infiltration. Pretreatment with the arachidonate 5-lipoxygenase inhibitor MK-886 partially ameliorated the decrements in GFR and RBF, reduced the glomerular leukocyte infiltration and completely inhibited the glomerular LTB4 synthesis. Combined treatment with Furegrelate and MK-886 completely abolished the decrements in GFR and RBF as well as the glomerular synthesis of thromboxane, LTB4 and 12-HETE without altering glomerular leukocyte infiltration. These observations indicate that in mesangial cell immune injury thromboxane A2 and arachidonate 5-lipoxygenation products originating from infiltrating inflammatory cells mediate the decrements in GFR and RBF. Selective inhibition of these eicosanoids could be of benefit in clinical forms of mesangial nephritis.
Assuntos
Eicosanoides/fisiologia , Mesângio Glomerular/fisiopatologia , Animais , Anticorpos Monoclonais , Benzofuranos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Ácidos Graxos Insaturados , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Mesângio Glomerular/imunologia , Mesângio Glomerular/lesões , Hidrazinas/farmacologia , Indóis/farmacologia , Antagonistas de Leucotrienos , Inibidores de Lipoxigenase , Ratos , Ratos Wistar , Receptores de Tromboxanos/antagonistas & inibidores , Circulação Renal/efeitos dos fármacos , Circulação Renal/fisiologia , Tromboxano-A Sintase/antagonistas & inibidoresRESUMO
The role of arachidonate 12- and 5-lipoxygenation eicosanoids in mediating acute changes in renal hemodynamics was assessed in nephrotoxic serum nephritis (NSN) in the rat. Following a single intravenous injection of nephrotoxic serum (NTS), significant decrements in glomerular filtration rate (GFR) and renal blood flow (RBF) occurred at one hour, and were associated with increments in glomerular polymorphonuclear leukocyte (PMN) counts and in the synthesis of thromboxane (Tx) B2, leukotriene (LT) B4 and 12-hydroxyeicosatetraenoic acid (12-HETE). Pretreatment of rats with the arachidonate 12-lipoxygenase inhibitor, baicalein, partially but significantly ameliorated the decrements in GFR and RBF, and blocked the enhanced glomerular synthesis of 12-HETE following administration of NTS. Likewise, pretreatment of rats with the arachidonate 5-lipoxygenase inhibitor, U-66858, partially ameliorated the decrements in GFR and RBF induced by NTS. Combined pretreatment of rats with baicalein and U-66858 ameliorated the decrements in GFR and RBF to an extent no different to that of U-66858 alone. In rats pretreated with the LTB4 receptor antagonist, U-75302, GFR and RBF remained depressed to levels no different than in animals which received NTS alone. These observations indicate that in NSN, the acute decrements in GFR and RBF are partially mediated by 12-HETE and arachidonate 5-lipoxygenation products. Leukotrienes other than LTB4, such as LTD4 and LTC4, are the likely candidates.
Assuntos
Araquidonato 12-Lipoxigenase/fisiologia , Araquidonato 5-Lipoxigenase/fisiologia , Glomerulonefrite/fisiopatologia , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Animais , Membrana Basal/imunologia , Taxa de Filtração Glomerular , Glomerulonefrite/enzimologia , Hemodinâmica , Ácidos Hidroxieicosatetraenoicos/fisiologia , Glomérulos Renais/imunologia , Leucotrieno B4/fisiologia , Masculino , Ratos , Circulação RenalRESUMO
We assessed the renal hemodynamic changes occurring acutely after glomerular mesangial cell immune injury and the effects of thromboxane receptor antagonism on these changes. A single intravenous proteinuric dose of a monoclonal antibody raised against the rat thymocyte antigen Thy 1.1 (ER4), which is also expressed in rat mesangial cells, induced acute decrements in glomerular filtration rate and in renal blood flow in male Munich-Wistar rats. One hour after administration of 4 to 6 mg/kg of ER4 antibody, glomerular filtration rate and renal blood flow decreased by 80 and 36%, respectively. These decrements were associated with significant increments in basal thromboxane B2 synthesis in isolated glomeruli and no changes in glomerular prostaglandin E2 synthesis. Pretreatment of animals with the thromboxane receptor antagonist SQ-29,548 (2 mg/kg) significantly ameliorated decrements in glomerular filtration rate and renal blood flow. Pretreatment with a structurally dissimilar thromboxane receptor antagonist, L-670,596 (3 mg/kg) had no effect. Both antagonists at the doses employed abolished the decrements in renal blood flow induced by systemic administration of the thromboxane mimetic U-46619. Whereas the SQ-29,548 antagonist had no effect on glomerular leukotriene B4 and 12-hydroxyeicosatetraenoic acid synthesis, the L-670,596 thromboxane receptor antagonist significantly inhibited glomerular synthesis of these eicosanoids in immunologically injured glomeruli. These observations indicate that in mesangial cell immune injury the protective effect of thromboxane A2 receptor antagonism on glomerular filtration rate and renal blood flow is not solely due to inhibition of the vasoconstrictor effects of thromboxane A2. An effect on the synthesis of arachidonate lipoxygenation products may also play a role.
Assuntos
Mesângio Glomerular/lesões , Receptores de Prostaglandina/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Soro Antilinfocitário/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes , Carbazóis/farmacologia , Eicosanoides/biossíntese , Ácidos Graxos Insaturados , Taxa de Filtração Glomerular/efeitos dos fármacos , Mesângio Glomerular/imunologia , Mesângio Glomerular/fisiopatologia , Hidrazinas/farmacologia , Masculino , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Ratos , Ratos Endogâmicos , Receptores de Prostaglandina/fisiologia , Receptores de Tromboxanos , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/fisiologiaRESUMO
Using a polyclonal antibody against authentic thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor protein, we assessed the distribution of this receptor in the normal rat kidney by routine methods of immunofluorescence microscopy. The receptor localized both in glomeruli and in tubules. In the former, the distribution of the receptor was most prominent along the lumen of glomerular capillary loops. Parietal epithelial cells of the Bowman's capsule, podocytes and mesangial cells also demonstrated immunostainable receptor. In the tubules, the receptor localized most prominently at the base of the brush border of proximal tubules and at the luminal surface of thick ascending limbs and distal convoluted tubules. These observations point to sites that are likely to be targeted by thromboxane A2 in forms of renal injury characterized by enhanced synthesis of this eicosanoid.
Assuntos
Rim/metabolismo , Receptores de Prostaglandina/metabolismo , Receptores de Tromboxanos/metabolismo , Animais , Anticorpos , Masculino , Microscopia de Fluorescência , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina/imunologia , Receptores de Tromboxanos/imunologia , Receptores de Tromboxano A2 e Prostaglandina H2 , Distribuição TecidualRESUMO
Researchers developing or using health-related quality of life (HRQOL) instruments can benefit from knowledge of state-of-the-art formatting methods for self-administered questionnaires. Three objectives in formatting design are: (1) to reduce errors in respondent navigation through the questionnaire that lead to item non-response and question misinterpretation; (2) to reduce respondent and administrative burden; and (3) to enhance respondent motivation in question answering and compliance with the request to participate. Based on an extensive literature review to identify techniques that have been shown to meet these objectives, we developed specific guidelines for HRQOL instruments concerning all aspects of questionnaire formatting. These guidelines represent well-motivated recommendations for improving HRQOL instruments, although their overall impact has not been empirically tested. We applied the guidelines to several HRQOL instruments that are widely used internationally, and obtained approval from the developers for all formatting changes to their instruments. Applying cognitive design principles and empirically substantiated formatting techniques produces an HRQOL instrument formatting with six critical attributes: simple, consistent, organized, natural, clear and attractive. The present paper contributes to the emerging research literature on the cognitive processes by which respondents answer HRQOL questions and demonstrates how 'cognitive aspects of survey methodology' research can improve HRQOL data collection efforts.
Assuntos
Ciência Cognitiva/métodos , Psicometria/métodos , Qualidade de Vida , Inquéritos e Questionários , HumanosRESUMO
Renal glomerular injury frequently results in proliferation of a specialized supporting cell of the glomerular capillary known as the mesangial cell. In various forms of renal injury there is enhanced glomerular synthesis of specific eicosanoids of the arachidonic cyclooxygenase and lipoxygenase pathways including prostaglandin (PG) F2 alpha, thromboxane (Tx) A2, the hydroxyeicosatetraenoic acids 12-HETE and 5-HETE, and the leukotrienes LTB4 and LTD4 and attempts have been made to link these eicosanoids with injury-induced mesangial cell growth. In this study, the growth promoting effect of these eicosanoids on glomerular mesangial cells was correlated with activation of two growth regulatory enzymes: phospholipase C (PLC) and protein kinase C (PKC). PGF2 alpha, and TxA2 endoperoxide analog U-46619, and LTD4 significantly enhanced DNA synthesis [(as assessed by [3H]thymidine (TdR) incorporation)] in relatively quiescent (0.5% serum) mesangial cells, activated PLC [as assessed by increased 1,4,5-inositol tris-phosphate (IP3) generation and diacylglycerol (DAG) synthesis], and activated PKC (as assessed by translocation of the enzyme activity from the cytosol to the membrane). The effect of PGF2 alpha on IP3 generation was not blocked by the TxA2 receptor antagonist, SQ-29,548. PGF2 alpha was the most effective eicosanoid in inducing all three events, and concentrations that enhanced TdR incorporation (1 microM) also activated PLC and PKC. In contrast, concentrations of U-46619 and LTD4 which enhanced TdR incorporation (1 microM), also activated PLC, but were insufficient to also activate PKC. Our observations indicate that the growth-promoting effect of PGF2 alpha, U-46619, and LTD4 can best be correlated with PLC activation. In addition, PGF2 alpha does not mediate PLC activation through binding to the TxA2 receptor.