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1.
Am J Manag Care ; 23(6 Suppl): S95-S104, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28715904

RESUMEN

A roundtable panel of national and regional managed care decision makers and providers met to discuss pulmonary arterial hypertension (PAH) and strategies for management. As a rare, complex disease with high economic costs and potentially devastating outcomes, PAH necessitates that managed care providers balance optimal care with efficient use of healthcare resources. PAH specialists are recognized by health plans as knowledgeable experts and integral partners in managing patients and resources. The diagnosis of PAH must be confirmed by a right heart catheterization. Available therapies are indicated almost exclusively for patients with PAH (riociguat is also indicated in chronic thromboembolic pulmonary hypertension) and target 1 of 3 pathways: endothelin receptor antagonists for the endothelin pathway; phosphodiesterase type-5 inhibitors and soluble guanylate cyclase stimulators for the nitric oxide pathway; and prostanoids as well as a prostacyclin receptor agonist for the prostacyclin pathway, with combination therapy becoming more common. Even in the modern treatment era, as shown in the REVEAL and French registries, PAH is often diagnosed years after symptoms first appear, which leads to a poor prognosis and increased burden on the healthcare system. Facilitating treatment of patients with PAH through centers of excellence, and coordinating care management between health plans and providers with evidence-based approaches can lead to both better results for patients and lower healthcare costs. When PAH experts have access to the right treatments for the right patients at the right time, they can work with insurers to improve the health of patients with PAH while helping to reduce the impact on the healthcare system.


Asunto(s)
Hipertensión Pulmonar/terapia , Costo de Enfermedad , Análisis Costo-Beneficio , Costos de la Atención en Salud , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/economía , Resultado del Tratamiento
2.
Am J Manag Care ; 20(6 Suppl): S115-22, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24716456

RESUMEN

Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature that leads to right ventricular dysfunction, right ventricular failure, and premature death. There are a number of medications already on the market, representing different therapeutic classes and possessing multiple mechanisms of action. Three new agents were approved by the US Food and Drug Administration in 2013, and others are currently in development. Recent advancements in PAH have resulted in increased survival and improved quality of life; however, no therapy provides a cure. Experts in the field are now utilizing clinical trial designs and end points that better reflect the disease progression among patients with this chronic disease. Although randomized placebo-controlled monotherapy trials are considered the strongest design, ethical and practical considerations have led to an increasing number of randomized trials designed to compare a PAH-specific treatment with placebo as an add-on to standard therapy. As many patients who enroll in clinical trials are already being treated for their condition, it may be unethical to withdraw or delay lifesaving therapies. The most widely used primary end point for PAH trials, change in 6-minute walk distance (6MWD) from baseline, has substantial limitations. Although it is generally reproducible, inexpensive, and relatively easy to conduct, the 6MWD is not designed to assess disease progression. Recent data have shown that 6MWD has inconsistent correlation with key indicators of disease progression such as hospitalization due to PAH, worsening right-sided heart failure, and death. The Task Force on End Points and Clinical Trial Design that met at the 4th World Symposium on Pulmonary Hypertension (WSPH) in 2008 in Dana Point, California, questioned the clinical relevance of the 6MWD as a primary end point and recommended the use of a composite end point--time to clinical worsening (TTCW)--in phase 3 or pivotal trials. TTCW may include time from randomization to PAH-related hospitalization, need for interventional procedures (ie, lung transplantation or balloon atrial septostomy), and mortality. More recently, at the 5th WSPH, held in 2013 in Nice, France, experts reiterated these recommendations. They further noted that, as clinical trials increasingly allow background therapies and are longer in duration, it may be more meaningful to use primary end points that measure "clinical worsening" rather than 6MWD. This paradigm shift will not only lead to a clearer demonstration of efficacy and safety as new agents come on the market, but will provide important information on long-term benefits (ie, the effects of drugs on clinical deterioration) that can assist payers as they strive to make value-based formulary decisions and provide cost-effective high-quality care.


Asunto(s)
Ensayos Clínicos como Asunto/métodos , Determinación de Punto Final , Hipertensión Pulmonar/terapia , Costo de Enfermedad , Quimioterapia Combinada , Prueba de Esfuerzo , Humanos , Hipertensión Pulmonar/economía , Guías de Práctica Clínica como Asunto
3.
F1000Prime Rep ; 6: 109, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25580263

RESUMEN

Development of sphingosine-1-phosphate receptor 1 (S1P1) modulators to dampen inflammation and its sequelae is becoming increasingly promising for treating medical conditions characterized by significant immunopathology. As shown by the non-selective S1P receptor modulator FTY720 (fingolimod [Gilenya(®)]) in the treatment of relapsing-remitting multiple sclerosis (MS), the ability to use S1P1 modulation to precisely block immune cell traffic-immunomodulation-while maintaining immunosurveillance, has opened therapeutic opportunities in various other immune-derived chronic pathologies, including inflammatory bowel disease (IBD), lupus, psoriasis, as well as, potentially, in early acute viral respiratory infection. Proof-of-concept studies across validated animal models with S1P receptor modulators highly selective for S1P1, such as BAF-312 (Siponimod), KRP-203, ONO-4641 (Ceralifimod), ponesimod and RPC-1063, and emerging clinical trials for safety and efficacy in humans, particularly in MS, ulcerative colitis (UC) and psoriasis, have set the stage for us to consider additional testing in various other autoimmune diseases.

4.
J Biol Chem ; 287(52): 43599-606, 2012 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-23109340

RESUMEN

Coat protein II (COPII)-coated vesicles transport proteins and lipids from the endoplasmic reticulum to the Golgi. Crucial for the initiation of COPII coat assembly is Sec12, a guanine nucleotide exchange factor responsible for activating the small G protein Sar1. Once activated, Sar1/GTP binds to endoplasmic reticulum membranes and recruits COPII coat components (Sec23/24 and Sec13/31). Here, we report the 1.36 Å resolution crystal structure of the catalytically active, 38-kDa cytoplasmic portion of Saccharomyces cerevisiae Sec12. Sec12 adopts a ß propeller fold. Conserved residues cluster around a loop we term the "K loop," which extends from the N-terminal propeller blade. Structure-guided site-directed mutagenesis, in conjunction with in vitro and in vivo functional studies, reveals that this region of Sec12 is catalytically essential, presumably because it makes direct contact with Sar1. Strikingly, the crystal structure also reveals that a single potassium ion stabilizes the K loop; bound potassium is, moreover, essential for optimum guanine nucleotide exchange activity in vitro. Thus, our results reveal a novel role for a potassium-stabilized loop in catalyzing guanine nucleotide exchange.


Asunto(s)
Factores de Intercambio de Guanina Nucleótido/química , Glicoproteínas de Membrana/química , Proteínas de Unión al GTP Monoméricas/química , Potasio/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/química , Proteínas de Transporte Vesicular/química , Vesículas Cubiertas por Proteínas de Revestimiento/química , Vesículas Cubiertas por Proteínas de Revestimiento/genética , Vesículas Cubiertas por Proteínas de Revestimiento/metabolismo , Cationes Monovalentes/química , Cationes Monovalentes/metabolismo , Cristalografía por Rayos X , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Unión al GTP Monoméricas/genética , Proteínas de Unión al GTP Monoméricas/metabolismo , Potasio/metabolismo , Estructura Secundaria de Proteína , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Relación Estructura-Actividad , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo
5.
Prog Cardiovasc Dis ; 55(2): 119-27, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23009908

RESUMEN

Pulmonary hypertension in the setting of parenchymal lung disease and conditions associated with chronic hypoxemia is commonly encountered in clinical practice and may adversely affect patients' function and mortality. Diagnosis of this subgroup of pulmonary hypertension has evolved but still requires right heart catheterization for confirmation. The primary treatment goal is optimization of the underlying parenchymal lung or hypoxemia-associated condition prior to consideration of pharmacologic therapy. Limited published experience with pulmonary hypertension-specific medications for treatment of WHO Group 3 pulmonary hypertension suggests symptomatic and functional benefit in selected individuals. The potential for worsening ventilation-perfusion matching must be considered in these cases, however, since there is a paucity of data regarding the optimal approach to treatment selection. Ongoing medication trials and further investigation of mechanisms of hypoxic pulmonary vasoconstriction provide hope for these patients who in the past often had only lung transplantation as a potential treatment option.


Asunto(s)
Hipertensión Pulmonar , Hipoxia/complicaciones , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Humanos , Hipertensión Pulmonar/clasificación , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/etiología , Presión Esfenoidal Pulmonar , Organización Mundial de la Salud
6.
J Heart Lung Transplant ; 30(7): 743-54, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21420318

RESUMEN

BACKGROUND: Induction therapy with alemtuzumab, followed by lower than conventional intensity post-transplant immunosuppression (eg, tacrolimus monotherapy), has been associated with reduced morbidity and mortality in abdominal and heart transplantation. We examined 5-year outcomes in lung recipients receiving alemtuzumab in conjunction with reduced-intensity post-transplant immunosuppression (early lower-dose tacrolimus; lower-dose steroids, with or without mycophenolate mofetil), compared with lung recipients receiving other induction agents or no induction in association with post-transplant immunosuppression. METHODS: A retrospective analysis was performed using prospectively collected data from a single-site clinical database of 336 lung recipients (aged ≥ 18) who received allografts between 1998 and 2005, classified by induction type: alemtuzumab, 127; Thymoglobulin, 43; daclizumab, 73; and none, 93. Survival analyses examined patient and graft survival, and freedom from acute cellular rejection (ACR), lymphocytic bronchiolitis, obliterative bronchiolitis (OB), bronchiolitis obliterans syndrome (BOS), and post-transplant lymphoproliferative disorder (PTLD). RESULTS: Five-year patient and graft survival differed by group (p = 0.046, p = 0.038, respectively). Alemtuzumab patient/graft survival rates were 59%/59%. Survival rates were 60%/44% for Thymoglobulin, 47%/46% for no induction, and 44%/41% for daclizumab. Freedom from ACR, lymphocytic bronchiolitis, OB, and BOS differed by group (all values, p < 0.008); alemtuzumab recipients showed greater 5-year freedom from each outcome (30%/82%/86%/54%) than Thymoglobulin (20%/54%/62%/27%), daclizumab (19%/55%/70%/43%), and no-induction groups (18%/70%/69%/46%). The groups did not differ in PTLD rates (≥ 94% free of PTLD at 5 years; p = 0.864). Effects were unchanged after controlling for potential covariates. CONCLUSIONS: Alemtuzumab induction may be associated with improved outcomes in lung transplantation. Randomized controlled trials are needed to establish any effects of this agent.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Trasplante de Pulmón/métodos , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Suero Antilinfocítico/uso terapéutico , Bronquiolitis/etiología , Daclizumab , Femenino , Estudios de Seguimiento , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunoglobulina G/uso terapéutico , Trasplante de Pulmón/efectos adversos , Trasplante de Pulmón/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento
7.
Transplantation ; 90(11): 1215-9, 2010 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-20881664

RESUMEN

BACKGROUND: Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients. However, no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients. METHODS: We prospectively determined the concentrations of amphotericin B in the epithelial lining fluid (ELF) and plasma after aerosolized nebulization (AeroEclipse), of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients. One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject. High-performance liquid chromatography and high-performance liquid chromatography-MS-MS were used to measure amphotericin B. RESULTS: Concentrations of amphotericin B in ELF (median, 25-75 IQR) were at 4 hr (n=5) 7.20 µg/mL (1.3-17.6), 24 hr (n=6) 8.26 µg/mL (3.9-82.7), 48 hr (n=5) 2.15 µg/mL (1.4-5.5), 72 hr (n=4) 1.25 µg/mL (0.75-5.5), 96 hr (n=6) 0.86 µg/mL (0.55-1.4), 120 hr (n=4) 1.04 µg/mL (0.44-1.6), 144 hr (n=1), 4.25 µg/mL, 168 hr (n=3) 1.14 µg/mL, and 192 hr (n=1) 1 µg/mL. The plasma concentration of the drug remained below 0.08 µg/mL at all time points. During the study, the side effects noted included wheezing, coughing, and 12% decline in forced expiratory volume in 1 sec. CONCLUSIONS: We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.


Asunto(s)
Anfotericina B/administración & dosificación , Anfotericina B/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Aspergilosis Pulmonar Invasiva/prevención & control , Trasplante de Pulmón , Pulmón/metabolismo , Administración por Inhalación , Aerosoles , Anfotericina B/efectos adversos , Anfotericina B/sangre , Antifúngicos/efectos adversos , Antifúngicos/sangre , Líquido del Lavado Bronquioalveolar/química , Broncoscopía , Cromatografía Líquida de Alta Presión , Esquema de Medicación , Femenino , Humanos , Aspergilosis Pulmonar Invasiva/etiología , Trasplante de Pulmón/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Mucosa Respiratoria/metabolismo , Espectrometría de Masas en Tándem , Distribución Tisular
8.
J Pain Symptom Manage ; 40(2): 246-55, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20541897

RESUMEN

Although the literature continues to portray chronic rejection after lung transplantation as ominous with no known treatment, no studies have examined family and clinician caregivers' perceptions of the diagnosis of chronic rejection and its impact on the course of clinical care. We explored the meaning and impact of chronic rejection from the perspective of family (n=10) and clinician (n=3) caregivers. We found that family caregivers considered the onset of chronic rejection to be inevitable, irreversible, unpredictable, and going back to pretransplant. Clinicians considered chronic rejection as a harbinger of deterioration and peril and expressed trepidation about informing recipients and their family caregivers about the diagnosis. Despite the heightened caregiving duties and challenges of treating chronic rejection, its unpredictable course and the prospect of retransplant instilled hope for stabilization or cure among most clinicians and caregivers, leading them to support recipients' wishes to pursue potentially futile treatments. Until recipients were no longer competent, caregivers believed all treatment options (including retransplant) had been exhausted, or suffering was prolonged, caregivers were reluctant to halt extraordinary treatment measures. Caregivers perceived that certainty regarding poor prognosis was required for palliative care and that palliative care was end-of-life care. Consequently, trials of aggressive treatment typically precluded palliative care.


Asunto(s)
Cuidadores/psicología , Familia/psicología , Rechazo de Injerto/psicología , Trasplante de Pulmón/psicología , Adulto , Anciano , Costo de Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida/psicología , Estrés Psicológico/psicología , Encuestas y Cuestionarios
9.
PLoS One ; 4(5): e5689, 2009 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-19479048

RESUMEN

BACKGROUND: Silicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFalpha) plays a central role in the pathogenesis of silicosis. TNFalpha signaling is mediated by the transcription factor, Nuclear Factor (NF)-kappaB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-kappaB activation represents a potential therapeutic strategy for silicosis. METHODS/FINDINGS: In the present work we evaluated the lung transplant database (May 1986-July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFalpha expressing macrophage and NF-kappaB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16-7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8-15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22-0.9 yr) following lung transplantation (2.4 yr; CI:1.5-3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-kappaB activation with a pharmacologic inhibitor (BAY 11-7085) of IkappaB alpha phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IkappaB alpha mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica. CONCLUSIONS: Although limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-kappaB protects from silica-induced lung injury, epithelial cell specific NF-kappaB inhibition appears to aggravate the outcome of experimental silicosis.


Asunto(s)
FN-kappa B/antagonistas & inhibidores , Silicosis/prevención & control , Animales , Citocinas/genética , Citocinas/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Genes Dominantes , Humanos , Proteínas I-kappa B/metabolismo , Pulmón/metabolismo , Pulmón/patología , Trasplante de Pulmón , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Inhibidor NF-kappaB alfa , FN-kappa B/genética , FN-kappa B/metabolismo , Nitrilos/farmacología , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Dióxido de Silicio , Silicosis/diagnóstico , Silicosis/genética , Sulfonas/farmacología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
10.
Transplantation ; 87(5): 719-25, 2009 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-19295317

RESUMEN

BACKGROUND: Cytomegalovirus (CMV), human herpesvirus-6 and -7 (HHV-6 and -7) are beta-herpesviruses that commonly reactivate and have been proposed to trigger acute rejection and chronic allograft injury. We assessed the contribution of these viruses in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS: Quantitative real-time polymerase chain reaction of bronchoalveolar lavage samples were performed for CMV, HHV-6 and -7 in a prospective cohort of lung transplant recipients. A time-dependent Cox regression analysis was used to correlate the risk of BOS and acute rejection in patients with and without beta-herpesviruses infection. RESULTS: Ninety-three patients were included in the study over a period of 3 years. A total of 581 samples from bronchoalveolar lavage were obtained. Sixty-one patients (65.6%) had at least one positive result for one of the beta-herpesviruses: 48 patients (51.6%) for CMV and 19 patients (20.4%) for both HHV-6 and -7. Median peak viral load was 3419 copies/mL for CMV, 258 copies/mL for HHV-6, and 665 copies/mL for HHV-7. Acute rejection (>or=grade 2) occurred in 46.2% and BOS (>or=stage 1) in 19.4% of the patients. In the Cox regression model the relative risk of acute rejection or BOS was not increased in patients with any beta-herpesviruses reactivation. Acute rejection was the only independently associated risk factor for BOS. CONCLUSIONS: In lung transplant recipients receiving prolonged antiviral prophylaxis, reactivation of beta-herpesviruses within the allograft was common. However, despite high viral loads in many patients, virus replication was not associated with the development of rejection or BOS.


Asunto(s)
Antivirales/uso terapéutico , Bronquiolitis Obliterante/epidemiología , Bronquiolitis Obliterante/cirugía , Infecciones por Citomegalovirus/prevención & control , Trasplante de Pulmón/efectos adversos , Adulto , Antifúngicos/uso terapéutico , Bronquiolitis Obliterante/complicaciones , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/epidemiología , Quimioterapia Combinada , Femenino , Ganciclovir/análogos & derivados , Ganciclovir/uso terapéutico , Rechazo de Injerto/epidemiología , Herpesvirus Humano 6/aislamiento & purificación , Herpesvirus Humano 7/aislamiento & purificación , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Pulmón/inmunología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pirimidinas/uso terapéutico , Síndrome , Triazoles/uso terapéutico , Valganciclovir , Voriconazol
11.
Crit Care Med ; 37(4): 1288-92, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19242344

RESUMEN

OBJECTIVE: Although lung transplantation is a widely used treatment modality for patients with end-stage lung disease, its long-term outcomes are limited. Including palliative approaches in the care of lung transplant recipients may be beneficial; however, systematic information regarding the utilization of palliative care services for lung recipients is lacking. DESIGN AND SETTING: Of the 27 transplant centers meeting the inclusion criteria (an annual lung transplant volume >or=15 for the past 5 years and the availability of palliative care or pain services at the center), 74 clinicians representing either the transplant or palliative care program from 18 centers completed surveys. RESULTS: Both transplant and palliative care clinician respondents strongly favored the idea of integrating palliative care into lung transplant care. However, the number of palliative care referrals made during the last year was low (

Asunto(s)
Trasplante de Pulmón , Cuidados Paliativos/estadística & datos numéricos , Derivación y Consulta/estadística & datos numéricos , Humanos , Estados Unidos
12.
Am J Respir Crit Care Med ; 178(7): 765-73, 2008 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-18617642

RESUMEN

RATIONALE: Repeated antigen-driven proliferations cause CD28 on T cells to down-regulate. We hypothesized that alloantigen-induced proliferations could cause CD28 down-regulation in lung transplant recipients. OBJECTIVES: To ascertain if CD28 down-regulation on CD4 T cells associated with manifestations of allograft dysfunction in lung transplant recipients. METHODS: Peripheral blood CD4 T cells from 65 recipients were analyzed by flow cytometry, cytokine multiplex and proliferative assays, and correlated with clinical events. MEASUREMENTS AND MAIN RESULTS: Findings that CD28 was present on less than 90% of total CD4 T cells were predominantly seen among the recipients with bronchiolitis obliterans syndrome (specificity = 88%). Perforin and granzyme B were produced by >50% of the CD4(+)CD28(null) cells, but less than 6% of autologous CD4(+)CD28(+) cells (P < 0.006). CD4(+)CD28(null) cells also had increased productions of proinflammatory cytokines, but less frequently expressed regulatory T-cell marker FoxP3 (2.1 +/- 1.3%), compared with autologous CD4(+)CD28(+) (9.5 +/- 1.4; P = 0.01). Cyclosporine A (100 ng/ml) inhibited proliferation of CD4(+)CD28(null) cells by 33 +/- 11% versus 68 +/- 12% inhibition of CD4(+)CD28(+) (P = 0.025). FEV(1) fell 6 months later (0.35 +/- 0.04 L) in recipients with CD4(+)CD28(+)/CD4(total) less than 90% (CD28% Low) compared with 0.08 +/- 0.08 L among CD4(+)CD28(+)/CD4(total) (CD28% High) greater than 90% (CD28% High) recipients (P = 0.013). Two-year freedom from death or retransplantation in CD28% Low recipients was 32 +/- 10% versus 78 +/- 6% among the CD28% High subjects (P < 0.0001). CONCLUSIONS: CD28 down-regulation on CD4 cells is associated with bronchiolitis obliterans syndrome and poor outcomes in lung transplantation recipients. CD4(+)CD28(null) cells have unusual, potentially pathogenic characteristics, and could be important in the progression of allograft dysfunction. These findings may illuminate a novel paradigm of transplantation immunopathogenesis, and suggest that CD28 measurements could identify recipients at risk for clinical deteriorations.


Asunto(s)
Bronquiolitis Obliterante/inmunología , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Rechazo de Injerto/inmunología , Subgrupos Linfocitarios/metabolismo , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Estudios de Cohortes , Regulación hacia Abajo , Femenino , Humanos , Trasplante de Pulmón/efectos adversos , Subgrupos Linfocitarios/inmunología , Masculino , Persona de Mediana Edad
13.
Transplantation ; 85(8 Suppl): S64-8, 2008 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-18425040

RESUMEN

Predictors of survival after lung transplant were analyzed in a large cohort of 990 lung transplanted patients from a single center. The overall survival was 41.6%, (41.5% in males, and 41.8% in females), the average length of the follow up was 45.84+/-51.98 months (range 0-282.47 months). Females tend to live longer than males: 50.75+/-55.41 months versus 40.64+/-47.60 months, respectively. Males had a risk of dying during the follow up that was 1.18 (95% CI 1.01-1.40) relative to females, after adjusting for ethnicity, age, smoking status, diagnosis and donor characteristics. Females who had at least one full term pregnancy during their life had better survival rates than females who had no full term pregnancies. Our results of a better survival after lung transplant in females, and among them in those who had at least a full term pregnancy support the hypothesis of a hormonal contribution to survival and of the development of immunotolerance after pregnancy. This model could be useful for understanding the role of immunity in cancer development.


Asunto(s)
Trasplante de Pulmón/mortalidad , Neoplasias/epidemiología , Sobrevivientes/estadística & datos numéricos , Femenino , Humanos , Enfermedades Pulmonares/clasificación , Enfermedades Pulmonares/mortalidad , Masculino , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/mortalidad , Fumar/epidemiología , Análisis de Supervivencia
14.
Transplantation ; 85(8 Suppl): S69-71, 2008 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-18425041

RESUMEN

We present here new molecular tools such as gene expression microarrays as promising biomarkers for diagnosis and prognosis in lung cancer as well as for an early diagnosis of malignancy after lung transplantation. Data regarding gender differences in survival, recently collected in a single-institution study, may allow better targeting of immunosuppression goals to maintain effectiveness while minimizing cancer development and progression. Combining these differing types of data using an integrative approach that is the central theme of systems biology may allow us to provide powerful and more individualized risks of cancer after lung transplantation.


Asunto(s)
Trasplante de Pulmón/efectos adversos , Neoplasias/epidemiología , Complicaciones Posoperatorias/epidemiología , Adulto , Causas de Muerte , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/mortalidad , Humanos , Infecciones/epidemiología , Infecciones/mortalidad , Masculino , Neoplasias/mortalidad , Complicaciones Posoperatorias/mortalidad , Caracteres Sexuales , Factores de Tiempo
15.
Am J Crit Care ; 17(3): 246-53, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18450681

RESUMEN

BACKGROUND: Despite the overall negative impact of chronic rejection on quality of life and survival after lung transplant, the specific clinical indicators of deterioration have not been identified. OBJECTIVES: To describe the course of illness after the onset of chronic rejection, including demographic and transplant variables, morbidity, mortality, health resource utilization, and end-of-life care, and to identify clinical indicators of deterioration in health and limited survival after the onset of chronic rejection. METHODS: The medical records of 311 recipients of lung transplants between 1998 and 2004 were reviewed retrospectively to identify 60 recipients who experienced chronic rejection. RESULTS: Median survival after chronic rejection was 31.34 months. Time to rejection (mean, 26.05 months; SD, 16.85) was significantly correlated with overall survival without need of a retransplant (r = 0.64; P < .001). The earlier the onset of chronic rejection or the need for oxygen at home, the shorter was the period of survival after chronic rejection and the more frequent were hospital and intensive care unit admissions and prolonged stays. Of the 26 recipients who died, 65% died at the transplant center, and all but 1 died in the intensive care unit; 3 died after multiple attempts of cardiopulmonary resuscitation; life support was ultimately withdrawn in 69%. CONCLUSIONS: Lung transplant recipients who experience chronic graft rejection have high rates of morbidity, mortality, and health resource utilization; however, the course of illness after chronic rejection is highly variable.


Asunto(s)
Rechazo de Injerto/mortalidad , Rechazo de Injerto/fisiopatología , Servicios de Salud/estadística & datos numéricos , Trasplante de Pulmón , Cuidado Terminal/estadística & datos numéricos , Enfermedad Crónica , Demografía , Femenino , Indicadores de Salud , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo
16.
J Heart Lung Transplant ; 26(12): 1229-42, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18096473

RESUMEN

In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.


Asunto(s)
Rechazo de Injerto/diagnóstico , Rechazo de Injerto/patología , Trasplante de Pulmón/patología , Terminología como Asunto , Biopsia , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/patología , Diagnóstico Diferencial , Rechazo de Injerto/clasificación , Humanos , Agencias Internacionales , Neumonía/diagnóstico , Neumonía/patología , Sociedades Médicas
17.
Methods Enzymol ; 430: 31-44, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17913633

RESUMEN

Translation initiation is a key step for regulating the synthesis of several proteins. In bacteria, translation initiation involves the interaction of the mRNA with the ribosomal small subunit. Additionally, translation initiation factors 1, 2, and 3, and the initiator tRNA, also assemble on the ribosomal small subunit and are essential for efficiently recruiting an mRNA for protein biosynthesis. In the following chapter, we describe fluorescence-based methods for studying the interaction of mRNA with the bacterial initiation complex. Model mRNAs with a covalently attached fluorescent probe showed an increase in fluorescence intensity when bound to the bacterial initiation complex. Utilizing the increase in fluorescence intensity upon mRNA binding to the bacterial initiation complex, we determined the equilibrium binding constants and the association and dissociation rate constants. These methods are important for quantitatively analyzing the effects of mRNA secondary structure and the role of the initiation factors in recruitment of mRNA by the bacterial initiation complex.


Asunto(s)
Proteínas Bacterianas/metabolismo , Biosíntesis de Proteínas , ARN Bacteriano/metabolismo , ARN Mensajero/metabolismo , Colorantes Fluorescentes/metabolismo , Sustancias Macromoleculares , Factores Procarióticos de Iniciación/metabolismo , ARN de Transferencia de Metionina/metabolismo , Subunidades Ribosómicas Pequeñas Bacterianas/metabolismo , Sitio de Iniciación de la Transcripción
18.
J Heart Lung Transplant ; 26(8): 862-4, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17692793

RESUMEN

Human metapneumovirus (hMPV) has recently been shown to be a prominent cause of respiratory infections in immunocompromised hosts, and is associated with high morbidity and mortality. We report a case of hMPV pneumonia in a lung transplant recipient presenting with respiratory failure and sepsis syndrome. hMPV was diagnosed by polymerase chain reaction, and treated with intravenous ribavirin with a successful outcome.


Asunto(s)
Antivirales/administración & dosificación , Trasplante de Pulmón , Metapneumovirus/aislamiento & purificación , Infecciones por Paramyxoviridae/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Ribavirina/administración & dosificación , Biopsia , Broncoscopía , ADN Viral/análisis , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Pulmón/patología , Pulmón/virología , Metapneumovirus/genética , Persona de Mediana Edad , Infecciones por Paramyxoviridae/diagnóstico , Infecciones por Paramyxoviridae/virología , Neumonía Viral/diagnóstico , Neumonía Viral/virología , Complicaciones Posoperatorias , Enfermedad Pulmonar Obstructiva Crónica/cirugía
19.
Prog Transplant ; 17(1): 29-35, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17484242

RESUMEN

UNLABELLED: Context-Recent modifications to the QLTP (Questionnaire for Lung Transplant Patients), including changing items from dichotomous to multiple dimension scaling, adding psychological symptoms, and converting to an electronic format (e-QLTP), made it necessary to reevaluate its reliability, validity, recipient satisfaction, and feasibility of administering the e-QLTP in the clinical setting. Purpose-To report the final modifications, psychometric properties, recipient satisfaction, and feasibility of administering the e-QLTP, a patient report outcome measure of symptoms and activity tolerance. Methods-Sixty lung recipients completed the original QLTP and the e-QLTP and rated their satisfaction with the e-version during a routine posttransplant evaluation; 65% (38 of 60) also completed a retest version. Correlations were computed for retest stability, concurrent validity between versions of the QLTP, and construct validity among the subscales of the e-QLTP and forced expiratory volumes in 1 second. Using the After Scenario Questionnaire, participants rated their satisfaction with the ease, amount of time, and support information when completing the e-QLTP. RESULTS: The e-QLTP and subscales were internally consistent (alpha = .73 - .90) and stable (intraclass correlations = .47 - .93). Significant correlations (P = .001) were found between the e-QLTP and the original QLTP (r = 0.53-0.56) and between the e-QLTP subscales and forced expiratory volumes in 1 second (r = 0.51 - 0.53). The overall mean satisfaction score was 1.27 (+/- 0.47). Conclusions-The e-QLTP is a reliable and valid measure of physical and psychological symptoms after lung transplantation. It is feasible to complete in the clinical setting and recipients are highly satisfied with its use. Its computerized functionality enhances assessment and management of symptoms over time.


Asunto(s)
Indicadores de Salud , Trasplante de Pulmón , Encuestas y Cuestionarios , Actividades Cotidianas , Adolescente , Adulto , Anciano , Estudios Transversales , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Psicometría , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
20.
Transplantation ; 83(10): 1330-6, 2007 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-17519782

RESUMEN

BACKGROUND: The clinical utility of Platelia Aspergillus enzyme immunoassay (EIA) for galactomannan (GM) antigen detection in bronchoalveolar lavage (BAL) for the diagnosis of invasive aspergillosis (IA) in lung transplant recipients is not known. METHODS: BAL fluid samples from consecutive lung transplant recipients who underwent bronchoscopy were prospectively analyzed for GM. RESULTS: A total of 333 BAL samples from 116 patients were tested. Invasive aspergillosis was documented in 5.2% (6/116) of the patients. Samples analyzed included 9 BALs from two patients with proven IA, 19 BALs from four patients with probable IA, and 305 BALs from 110 patients without IA. At the index cutoff value of > or =0.5, the sensitivity was 60%; specificity was 95%, with positive and negative likelihood ratios of 14 and 0.41, respectively. Increasing the index cutoff value to > or =1.0 yielded a sensitivity of 60%, a specificity of 98%, and the positive and negative likelihood ratios of 28 and 0.40, respectively. Two of six patients with IA receiving antifungal prophylaxis had false-negative results. CONCLUSIONS: A Platelia EIA index cut-off > or =1.0 in the BAL fluid in a lung transplant recipient with a compatible clinical illness may be considered as suggestive of IA.


Asunto(s)
Antígenos Fúngicos/análisis , Aspergilosis/diagnóstico , Líquido del Lavado Bronquioalveolar/química , Trasplante de Pulmón/patología , Mananos/análisis , Complicaciones Posoperatorias/diagnóstico , Adolescente , Adulto , Anciano , Quimioterapia Combinada , Femenino , Galactosa/análogos & derivados , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Pulmón/inmunología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/microbiología , Curva ROC
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