RESUMEN
BACKGROUND: This systematic review and meta-analysis aims at assessing the composition and performance of care management models evaluated in the last decade and their impact on patient important outcomes. METHODS: A comprehensive literature search of electronic bibliographic databases was performed to identify care management trials in type 2 diabetes. Random effects meta-analysis was used when feasible to pool outcome measures. RESULTS: Fifty-two studies were eligible. Most commonly reported were surrogate outcomes (such as HbA1c and LDL), followed by process measures (clinic visit or testing frequency). Less frequently reported were quality of life, patient satisfaction, self-care, and healthcare utilization. Most care management modalities were carved out from primary care. Meta-analysis demonstrated a statistically significant but trivial reduction of HbA1c (weighted difference in means -0.21%, 95% confidence interval -0.40 to -0.03, p < .03) and LDL-cholesterol (weighted difference in means -3.38 mg/dL, 95% confidence interval -6.27 to -0.49, p < .02). CONCLUSIONS: Most care management programs for patients with type 2 diabetes are 'carved-out', accomplish limited effects on metabolic outcomes, and have unknown effects on patient important outcomes. Comparative effectiveness research of different models of care management is needed to inform the design of medical homes for patients with chronic conditions.
Asunto(s)
Diabetes Mellitus Tipo 2/terapia , Manejo de la Enfermedad , Evaluación de Procesos y Resultados en Atención de Salud , Medicina Basada en la Evidencia/normas , Humanos , Estados UnidosRESUMEN
The Vpr protein of HIV-1 functions as a vital accessory gene by regulating various cellular functions, including cell differentiation, apoptosis, nuclear factor of kappaB (NF-kappaB) suppression and cell-cycle arrest of the host cell. Several reports have indicated that Vpr complexes with the glucocorticoid receptor (GR), but it remains unclear whether the GR pathway is required for Vpr to function. Here, we report that Vpr uses the GR pathway as a recruitment vehicle for the NF-kappaB co-activating protein, poly(ADP-ribose) polymerase-1 (PARP-1). The GR interaction with Vpr is both necessary and sufficient to facilitate this interaction by potentiating the formation of a Vpr-GR-PARP-1 complex. The recruitment of PARP-1 by the Vpr-GR complex prevents its nuclear localization, which is necessary for Vpr to suppress NF-kappaB. The association of GR with PARP-1 is not observed with steroid (glucocorticoid) treatment, indicating that the GR association with PARP-1 is a gain of function that is solely attributed to HIV-1 Vpr. These data provide important insights into Vpr biology and its role in HIV pathogenesis.
Asunto(s)
Núcleo Celular/metabolismo , Productos del Gen vpr/fisiología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Receptores de Glucocorticoides/metabolismo , Transporte Activo de Núcleo Celular , Animales , Antígenos Bacterianos/farmacología , Línea Celular , Chlorocebus aethiops , Enterotoxinas/farmacología , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Productos del Gen vpr/metabolismo , Productos del Gen vpr/farmacología , Infecciones por VIH/metabolismo , Infecciones por VIH/fisiopatología , Células HeLa , Humanos , Quinasa I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Interleucina-1/sangre , Interleucina-12/sangre , Células Jurkat , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Mifepristona/farmacología , Mutación/genética , Inhibidor NF-kappaB alfa , FN-kappa B/genética , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/genética , Unión Proteica/efectos de los fármacos , Mapeo de Interacción de Proteínas , ARN Interferente Pequeño/genética , Receptores de Glucocorticoides/genética , Factor de Transcripción ReIA/metabolismo , Transfección , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Células U937 , Productos del Gen vpr del Virus de la Inmunodeficiencia HumanaRESUMEN
The HIV-1 accessory protein Vpr exhibits many interesting features related to macrophage and T cell biology. As a viral protein or as a soluble molecule it can suppress immune cell activation and cytokine production in vitro in part by targeted inhibition of NF-kappaB. In this regard we sought to test its effects in vivo on an NF-kappaB-dependent immune pathway. We examined the activity of Vpr in a lethal toxin-mediated challenge model in mice. Intravenous delivery of Vpr was sufficient to protect mice from lethal challenge with staphylococcal endotoxin B (SEB). Furthermore, Vpr protected host CD4+ T cells from in vivo depletion likely by preventing induction of AICD of SEB-exposed cells in a post-toxin-binding fashion. Understanding the biology of Vpr's activities in this model may allow for new insight into potential mechanisms of hyperinflammatory disease and into Vpr pathobiology in the context of HIV infection.