RESUMEN
AIMS/HYPOTHESIS: The aim of the study was to investigate the association between vitamin D intake and status and the risk of islet autoimmunity (IA) and subsequent type 1 diabetes in children at increased risk of type 1 diabetes. METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) in Denver, CO, USA, has been following children at increased risk of diabetes since 1993. As of February 2011, 198 children developed IA during follow-up of 2,644 DAISY children. Vitamin D intake and plasma 25-hydroxyvitamin D [25(OH)D] were measured longitudinally. Proportional hazards regression analyses of time to IA, or type 1 diabetes in IA-positive children, were conducted, with vitamin D intake and 25(OH)D as time-varying covariates. HRs were calculated for a standard deviation difference in exposure, with adjustment for confounders. RESULTS: Intake of vitamin D was not associated with the risk of IA (adjusted HR 1.13; 95% CI 0.95, 1.35; p = 0.18) nor progression to diabetes in IA-positive children (adjusted HR 1.30; 95% CI 0.91, 1.86; p = 0.15). Moreover, 25(OH)D level was not associated with the risk of IA (adjusted HR 1.12; 95% CI 0.88, 1.43; p = 0.36), nor progression to diabetes in IA-positive children (adjusted HR 0.91; 95% CI 0.68, 1.22; p = 0.54). In the 128 children in whom we measured 25(OH)D at 9 months of age, 25(OH)D was not associated with risk of IA (n = 30 IA-positive children) (adjusted HR 1.02; 95% CI 0.96, 1.07; p = 0.58). CONCLUSIONS/INTERPRETATION: Neither vitamin D intake nor 25(OH)D levels throughout childhood were associated with the risk of IA or progression to type 1 diabetes in our population.
Asunto(s)
Autoinmunidad , Calcifediol/sangre , Diabetes Mellitus Tipo 1/etiología , Diabetes Mellitus Tipo 1/inmunología , Islotes Pancreáticos/inmunología , Deficiencia de Vitamina D/fisiopatología , Vitamina D/administración & dosificación , 25-Hidroxivitamina D 2/sangre , Niño , Preescolar , Estudios de Cohortes , Colorado/epidemiología , Dieta/efectos adversos , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Estudios Prospectivos , Riesgo , Encuestas y Cuestionarios , Vitamina D/efectos adversosRESUMEN
OBJECTIVE: To provide an example of implementation of a new program that enhances access to mental health care in primary care. METHOD: A general and specialized mental health service was redesigned to introduce open access to comprehensive mental health care in a primary care clinic. Key variables measured before and after implementation of the clinic included numbers of completed referrals, waiting time for appointments and clinic productivity. Workload and pre/post-implementation waiting time data were gathered through a computerized electronic monitoring system. RESULTS: Waiting time for new appointments was shortened from a mean of 33 days to 19 min. Clinician productivity and evaluations of new referrals more than doubled. These improvements have been sustained for 4 years. CONCLUSION: Moving mental health services into primary care, initiating open access and increasing use of technological aids led to dramatic improvements in access to mental health care and efficient use of resources. Implementation and sustainability of the program were enhanced by using a quality improvement approach.
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Prestación Integrada de Atención de Salud/organización & administración , Implementación de Plan de Salud/organización & administración , Accesibilidad a los Servicios de Salud/organización & administración , Servicios de Salud Mental/organización & administración , Atención Primaria de Salud/organización & administración , Veteranos , Eficiencia Organizacional , Encuestas de Atención de la Salud , Humanos , Satisfacción del Paciente , Garantía de la Calidad de Atención de Salud/organización & administración , Derivación y Consulta/organización & administración , Población Rural , Estados Unidos , Listas de EsperaRESUMEN
Accumulation of mesangial matrix is a pivotal event in the pathophysiology of diabetic nephropathy. The molecular triggers for matrix production are still being defined. Here, suppression subtractive hybridization identified 15 genes differentially induced when primary human mesangial cells are exposed to high glucose (30 mM versus 5 mM) in vitro. These genes included (a) known regulators of mesangial cell activation in diabetic nephropathy (fibronectin, caldesmon, thrombospondin, and plasminogen activator inhibitor-1), (b) novel genes, and (c) known genes whose induction by high glucose has not been reported. Prominent among the latter were genes encoding cytoskeleton-associated proteins and connective tissue growth factor (CTGF), a modulator of fibroblast matrix production. In parallel experiments, elevated CTGF mRNA levels were demonstrated in glomeruli of rats with streptozotocin-induced diabetic nephropathy. Mannitol provoked less mesangial cell CTGF expression in vitro than high glucose, excluding hyperosmolality as the key stimulus. The addition of recombinant CTGF to cultured mesangial cells enhanced expression of extracellular matrix proteins. High glucose stimulated expression of transforming growth factor beta1 (TGF-beta1), and addition of TGF-beta1 to mesangial cells triggered CTGF expression. CTGF expression induced by high glucose was partially suppressed by anti-TGF-beta1 antibody and by the protein kinase C inhibitor GF 109203X. Together, these data suggest that 1) high glucose stimulates mesangial CTGF expression by TGFbeta1-dependent and protein kinase C dependent pathways, and 2) CTGF may be a mediator of TGFbeta1-driven matrix production within a diabetic milieu.
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Regulación de la Expresión Génica/efectos de los fármacos , Mesangio Glomerular/metabolismo , Glucosa/farmacología , Sustancias de Crecimiento/genética , Proteínas Inmediatas-Precoces , Péptidos y Proteínas de Señalización Intercelular , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Células Cultivadas , Clonación Molecular , Factor de Crecimiento del Tejido Conjuntivo , ADN Complementario , Nefropatías Diabéticas/patología , Mesangio Glomerular/patología , Humanos , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Proteína Quinasa C/metabolismo , Ratas , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The resolution phase of inflammation is being increasingly recognized as a dynamic multifaceted process whose components may be amenable to pharmacological manipulation for therapeutic gain. Here, we review evidence that the lipoxins (LX), a family of lipoxygenase-derived eicosanoids generated during cell-cell interactions within the vascular lumen, are potential endogenous inhibitors of polymorphonuclear neutrophil (PMN) recruitment during glomerular inflammation. LX are generated in nanogram quantities in kidneys of rats with Concanavalin A-ferritin (Con A-F) immune complex glomerulonephritis and of mice with acute nephrotoxic serum nephritis (NSN). PMN-platelet transcellular pathways appear to be the major route to LX formation in these settings, PMN donating the labile epoxide intermediate leukotriene A4 for conversion by platelet LX synthase to LXA4. Complementary approaches using monoclonal antibodies and gene knockout suggest that PMN-platelet adhesion through P-selectin promotes transcellular LXA4 biosynthesis in vitro and in vivo. In support of a modulatory role in PMN trafficking; LXA4 and LXB4, the LX generated in greatest quantities by mammalian cells, inhibit PMN chemotaxis, adhesion to endothelial cells, and migration across endothelium and epithelium induced leukotrienes and some other mediators in vitro. Exposure of PMN to LXA4 ex vivo attenuates their recruitment in Con A-F glomerulonephritis. Furthermore, PMN recruitment is exaggerated during NSN in P-selectin knockout mice, coincident with reduced efficiency of transcellular LXA4 generation and reduced renal LXA4 levels. Replenishment of platelet P-selectin by transfusion of null mice with wild-type platelets reverses this defect in LXA4 synthesis and approximates PMN infiltrates in null and wild-type animals. Against this background, LXA4 stable analogues have been designed that retain the biologic activity of native LXA4 in vitro and should be useful tools for probing the therapeutic potential of LXA4 in disease. In the presence of aspirin, endothelial cell cyclooxygenase II (COX-II) transforms arachidonic acid to 15R-hydroxyeicosatetraenoic acid which, in the context of PMN-endothelial cell interaction, is converted by PMN 5-lipoxygenase to 15-epi-LX. Intriguingly, these novel LX also attenuate PMN adhesion and transmigration in model in vitro systems. Together, these observations suggest that LX may not only play important regulatory roles in the "stop programs" of renal inflammation, but also contribute to the anti-inflammatory activity of aspirin and related inhibitors of COX-II.
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Quimiotaxis de Leucocito/inmunología , Eicosanoides/inmunología , Glomerulonefritis/inmunología , Neutrófilos/inmunología , Enfermedad Aguda , Animales , Glomerulonefritis/fisiopatología , Neutrófilos/citologíaRESUMEN
Leukotriene (LT) and lipoxin (LX) levels were monitored in ionophore-stimulated coincubations of polymorphonuclear neutrophils (PMN) and microvascular kidney glomerular endothelial cells (GEN) to determine the profile of lipoxygenase (LO) products generated during cell-cell interactions and the relative contributions of transcellular pathways to LO product biosynthesis in this setting. LTB4 and LTC4 were the major products formed, as determined by reverse-phase high-performance liquid chromatography and radioimmunoassay. LTB4 and LTC4 levels were increased by 23 and 185%, respectively, in coincubations of PMN and GEN, compared with incubations of PMN alone. In contrast, LXA4 and LXB4 levels were not changed in the presence of GEN. These data suggested that GEN utilize PMN-derived LTA4 to generate LT. In keeping with this hypothesis, LT biosynthesis was enhanced if PMN were primed with human granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that augments LTA4 biosynthesis by activated PMN. The influence of LT on PMN adhesion to GEN was also assessed, since adhesion appears to be a pivotal event in recruitment of PMN in acute glomerulonephritis. Under basal conditions, LTB4 provoked low levels of adhesion via a PMN-directed CD11/CD18-dependent mechanism. The level of adhesion was markedly enhanced by prior priming of PMN with GM-CSF or activation of GEN with tumor necrosis factor-alpha (TNF). LTB4 was as potent in this regard as the complement component C5a, platelet-activating factor (PAF), and interleukin-8 (IL-8), other mediators that contribute to the entrapment of PMN in inflamed glomeruli. LTC4 also provoked PMN-GEN adhesion via a CD11/CD18-dependent mechanism, but, in contrast to LTB4, via actions with GEN. This action of LTC4 appeared to be mediated, at least in part, by induction of PAF synthesis by GEN. Interestingly, LT-induced PMN-GEN adhesion was markedly attenuated following remodeling of PMN phospholipids with 15(S)-hydroxyeicosatetraenoic acid, a product of 15-LO, which has been implicated as an anti-inflammatory eicosanoid in some experimental and human inflammatory diseases. Taken together, these results provide further evidence that 1) transcellular biosynthetic pathways may amplify the profiles of inflammatory mediators and thereby contribute to leukocyte recruitment in acute glomerulonephritis and 2) that products of the 5-LO and 15-LO pathways may exert opposing actions on PMN trafficking during glomerular inflammation in vivo.
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Adhesión Celular , Endotelio Vascular/fisiología , Expresión Génica/fisiología , Molécula 1 de Adhesión Intercelular/biosíntesis , Glomérulos Renales/irrigación sanguínea , Lipooxigenasa/metabolismo , Neutrófilos/fisiología , Circulación Renal , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Bovinos , Células Cultivadas , Quimiotaxis de Leucocito/efectos de los fármacos , Clonación Molecular , ADN Complementario/aislamiento & purificación , Eicosanoides/biosíntesis , Expresión Génica/efectos de los fármacos , Humanos , Leucotrieno B4/análisis , Leucotrieno B4/biosíntesis , Leucotrieno C4/análisis , Leucotrieno C4/biosíntesis , Datos de Secuencia Molecular , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
The mechanisms by which uranyl nitrate (UN) is toxic to the proximal tubule are incompletely understood. To define these further we studied potassium (K+) transport and oxygen consumption (QO2) in rabbit proximal tubule suspensions in vitro immediately after exposure to UN using extracellular O2- and K+-sensitive electrodes. UN caused a cumulative dose-dependent inhibition of proximal tubule QO2, with a threshold concentration of 5 x 10(-5) M. Kinetic analysis suggested two patterns of cell injury: a higher affinity inhibition of QO2 with a Ki of 5 x 10(-4) M, and a lower affinity inhibition of QO2 with a Ki of 10 mM. QO2 was studied in detail in the presence of these Ki concentrations of UN to define the initial cellular events. The results indicated that different cellular processes displayed different sensitivities to UN. At submillimolar concentrations UN caused progressive selective inhibition of ouabain-insensitive QO2 (15% inhibition at 2 minutes). Ouabain-sensitive QO2 and nystatin-stimulated QO2 were not affected, suggesting that Na+,K+-ATPase activity and its coupling to mitochondrial ATP synthesis were intact. Direct measurement of proximal tubule net K+ flux confirmed that Na+,K+-ATPase activity was unchanged. Similarly, UN did not inhibit basal (state 4) or ADP-stimulated (state 3) mitochondrial QO2 in digitonin-permeabilized tubules, confirming that the mitochondria were intact. In contrast, higher concentrations of UN (greater than or equal to 1 mM) caused rapid inhibition of QO2 and net K+ efflux, due to inhibition of Na+,K+-ATPase activity and mitochondrial injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Túbulos Renales Proximales/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Potasio/metabolismo , Uranio/toxicidad , Nitrato de Uranilo/toxicidad , Adenosina Difosfato/farmacología , Animales , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Digitonina/farmacología , Ditiotreitol/farmacología , Femenino , Glutatión/fisiología , Técnicas In Vitro , Túbulos Renales Proximales/metabolismo , Mitocondrias/efectos de los fármacos , Nistatina/farmacología , Ouabaína/farmacología , Permeabilidad , ConejosRESUMEN
Blood pressure is affected by many genetic and environmental factors and their complex interactions. The elucidation of the pathophysiological mechanisms of essential hypertension remains one of the most formidable challenges in medicine today. A large number of pathophysiological abnormalities have been described in essential hypertension such as defects in Na, K and Ca metabolism, increased sympathetic activity, vascular supersensitivity to endogenous neurohumoral constricting agents and decreased sensitivity to endogenous vasodilators. Evidence is accumulating which suggests that Mg may play an important role in the prevention and control of hypertension. Mg affects the metabolism of Na, K and Ca and the abnormalities in ion transport reported in experimental hypertension are similar to those reported in experimental Mg deficiency. In experimental studies, Mg has been established as an important regulator of vascular tone. Hypertension has been shown to develop in Mg deficient rats. There are a number of epidemiological studies demonstrating a negative correlation between Mg intake and hypertension. Parenteral treatment with magnesium sulphate is well established as successful in reducing hypertension in preeclampsia. Two recent studies indicate that oral supplementation of Mg can lower blood pressure in patients with essential hypertension. Mg may also be important in drug treatment of hypertension and diuretics may result in enhanced losses of magnesium. There is evidence that Mg deficiency may induce resistance to the effects of antihypertensive agents.