RESUMEN
The UK Multiple Sclerosis Register (UKMSR) is a large cohort study designed to capture 'real world' information about living with multiple sclerosis (MS) in the UK from diverse sources. The primary source of data is directly from people with Multiple Sclerosis (pwMS) captured by longitudinal questionnaires via an internet portal. This population's diagnosis of MS is self-reported and therefore unverified. The second data source is clinical data which is captured from MS Specialist Treatment centres across the UK. This includes a clinically confirmed diagnosis of MS (by Macdonald criteria) for consented patients. A proportion of the internet population have also been consented at their hospital making comparisons possible. This dataset is called the 'linked dataset'. The purpose of this paper is to examine the characteristics of the three datasets: the self-reported portal data, clinical data and linked data, in order to assess the validity of the self-reported portal data. The internet (nâ¯=â¯11,021) and clinical (nâ¯=â¯3,003) populations were studied for key shared characteristics. We found them to be closely matched for mean age at diagnosis (clinicalâ¯=â¯37.39, portalâ¯=â¯39.28) and gender ratio (female %, portalâ¯=â¯73.1, clinicalâ¯=â¯75.2). The Two Sample Kolmogorov-Smirnov test was for the continuous variables to examine is they were drawn from the same distribution. The null hypothesis was rejected only for age at diagnosis (Dâ¯=â¯0.078, pâ¯<â¯0.01). The populations therefore, were drawn from different distributions, as there are more patients with relapsing disease in the clinical cohort. In all other analyses performed, the populations were shown to be drawn from the same distribution. Our analysis has shown that the UKMSR portal population is highly analogous to the entirely clinical (validated) population. This supports the validity of the self-reported diagnosis and therefore that the portal population can be utilised as a viable and valid cohort of people with Multiple Sclerosis for study.
Asunto(s)
Esclerosis Múltiple/epidemiología , Sistema de Registros , Adulto , Femenino , Humanos , Internet , Masculino , Persona de Mediana Edad , Autoinforme , Reino UnidoRESUMEN
The afferent nervous supply to the thymus gland has been investigated by means of the retrograde transport of horseradish peroxidase. It has been shown that the thymus receives an afferent supply from the nodose ganglia of the vagus and from the dorsal root ganglia C1-C7. The afferent innervation of the right and left thymic lobes is bilaterally organized; the fibers of a small celled population of nodose ganglion neurons cross outside the thymus and those of a larger celled population cross within the thymus gland. The functional implications of these findings are discussed in the context of central nervous system-immune system interactions.
Asunto(s)
Timo/inervación , Vías Aferentes/fisiología , Animales , Vías Eferentes/fisiología , Masculino , Neuronas/citología , Ganglio Nudoso/citología , Ganglio Nudoso/fisiología , Ratas , Ratas EndogámicasRESUMEN
A Sprague-Dawley rat kidney perfusion technique was used in situ to study the effect of verapamil, ouabain, and ethacrynic acid on renal calcium retention. The technique involves perfusion of the kidneys via the abdominal aorta and then through the left and right renal arteries and dorsal aorta. Verapamil (1 mM) in Krebs-improved Ringer solution increased calcium retention in the kidneys by approximately 117% compared with controls. With Na-free Krebs-improved Ringer solution, calcium retention increased by only 92%. However, in Krebs-improved Ringer solutions containing 59 and 122 mequivalents of Na, calcium retention in the kidney increased by 46 and 43%, respectively, compared with controls. With Krebs-improved Ringer solution containing 15 mM ouabain, calcium retention in the kidney decreased by 29.5%, whereas with 15 mM ouabain plus 1 mM ethacrynic acid in the perfusate, the effect on calcium retention in the kidney was insignificant compared with controls. These results suggest that two sodium-dependent calcium-transporting systems exist at the peritubular side of the kidney tubules: (1) a Na(+)-Ca+2 countertransport system sensitive to verapamil and (2) a Na(+)-Ca+2 cotransport system sensitive to the intracellular concentration of sodium.
Asunto(s)
Calcio/metabolismo , Ácido Etacrínico/farmacología , Riñón/efectos de los fármacos , Ouabaína/farmacología , Verapamilo/farmacología , Animales , Proteínas de Unión al Calcio/metabolismo , Femenino , Riñón/metabolismo , Cinética , Perfusión , Ratas , Ratas Sprague-Dawley , Sodio/fisiologíaRESUMEN
A cell surface adsorption isotherm approach is investigated with normal and diabetic (streptozotocin-induced) rat hepatocytes utilizing mathematical modeling. Freshly prepared monodispersed viable rat hepatocytes in Ca(2+)- and Mg(2+)-free phosphate buffer are obtained by collagenase perfusion and used in this study. [3H]ouabain is used as a ligand that specifically binds with the alpha 1 and alpha 2 isoforms of the alpha-protein subunit of the hepatocyte-membrane-incorporated Na-K-ATPase. The model that fits the experimental data assumes the presence of multiple receptors on the cell surface, and only when a specific fraction of the total number of one receptor have effectively reacted will the other receptor initiate reaction with the ligand. The results suggest the existence of two receptors, in normal and diabetic hepatocytes, interacting with ouabain and having different equilibrium constants. The alpha 2 isoform interacts more strongly with ouabain than the alpha 1 isoform in both types of cells. The alpha 1 isoform of the diabetic hepatocytes has stronger affinity with the glycoside than the alpha 1 isoform of the normal hepatocytes, while alpha 2 of the diabetics shows weaker affinity than alpha 2 of the normal hepatocytes. Therefore, the alpha 1 and alpha 2 isoforms of Na-K-ATPase in hepatocyte-cell-membrane have different affinities for ouabain and have been conformationally and/or structurally altered in chronic diabetes.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Hígado/metabolismo , Ouabaína/farmacocinética , Adsorción , Animales , Cinética , Hígado/citología , Sustancias Macromoleculares , Masculino , Matemática , Ouabaína/metabolismo , Ratas , Ratas Sprague-Dawley , Sensibilidad y Especificidad , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , TritioRESUMEN
A Sprague-Dawley rat kidney perfusion technique was used in situ to study the effects of cis-dichloro-diamine platinum, PdCl2 (2,6-diaminopyridine), and RhCl3 (2,6-diaminopyridine) on sodium and calcium retention in the whole kidney. The technique involves perfusion of both kidneys via the abdominal aorta and then through the right and left renal arteries and dorsal aorta. Compared to controls, kidneys perfused independently with the three coordination compounds showed approximately equal to 45% decrease and approximately equal to 117% increase in Na+ and Ca2+ retention, respectively. Perfusates containing the coordination compounds in addition to 15 mM ouabain showed approximately equal to 76% decrease in Na+ and insignificant increase in renal Ca2+ retention. Hence, one can rule out the presence of voltage-gated Ca(2+)-channels at the basolateral side due to membrane depolarization. These results suggest that the three metal coordination compounds showed identical nephrotoxic effects on the handling of Na+ and Ca2+ ions by inhibiting both the Na(+)-Ca(2+)-anti-porter and the Na(+)-H(+)-exchanger with laxing effects on nonvoltage-gated Ca(2+)-channels at the basolateral side. However, their effects on the Na(+)-K(+)-ATPase and the Na(+)-Ca2+ symporter was insignificant.
Asunto(s)
Antineoplásicos/toxicidad , Cisplatino/toxicidad , Paladio/toxicidad , Rodio/toxicidad , Análisis de Varianza , Animales , Antineoplásicos/administración & dosificación , Calcio/metabolismo , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Cisplatino/administración & dosificación , Femenino , Ouabaína/administración & dosificación , Ouabaína/farmacología , Paladio/administración & dosificación , Ratas , Ratas Sprague-Dawley , Rodio/administración & dosificación , Sodio/metabolismo , Intercambiadores de Sodio-Hidrógeno/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/efectos de los fármacos , ATPasa Intercambiadora de Sodio-Potasio/metabolismoAsunto(s)
Ingeniería Biomédica/tendencias , Servicio de Mantenimiento e Ingeniería en Hospital/tendencias , Servicios Contratados/estadística & datos numéricos , Competencia Económica , Predicción , Reestructuración Hospitalaria/tendencias , Programas Controlados de Atención en Salud/tendencias , Comercialización de los Servicios de Salud/tendencias , Estados UnidosRESUMEN
Growth hormone (GH)-deficiency is usually associated with elevated adiposity, hyperleptinemia, and increased fracture risk. Since leptin is thought to enhance cortical bone formation, we have investigated the contribution of elevated adiposity and hyperleptinemia on femoral strength in rodent models of GH deficiency. Quantification of the transpubertal development of femoral strength in the moderately GH-deficient/hyperleptinemic Tgr rat and the profoundly GH-deficient/hypoleptinemic dw/dw rat revealed that the mechanical properties of cortical bone in these two models were similarly compromised, a 25-30% reduction in failure load being entirely due to impairment of geometric variables. In contrast, murine models of partial (GH antagonist transgenic) and complete (GH receptor-null) loss of GH signaling and elevated adiposity showed an impairment of femoral cortical strength proportionate to the reduction of GH signaling. To determine whether impaired femoral strength is exacerbated by obesity/hyperleptinemia, femoral strength was assessed in dw/dw rats following two developmental manipulations that elevate abdominal adiposity and circulating leptin, neonatal monosodium glutamate (MSG) treatment, and maintenance on an elevated fat diet. The additional impairment of femoral strength following MSG treatment is likely to have resulted from a reduction in residual activity of the hypothalamo-pituitary-GH-IGF-I axis, but consumption of elevated dietary fat, which did not reduce circulating IGF-I, failed to exacerbate the compromised femoral strength in dw/dw rats. Taken together, our data indicate that the obesity and hyperleptinemia usually associated with GH deficiency do not exert a significant influence over the strength of cortical bone.
Asunto(s)
Adiposidad/fisiología , Densidad Ósea/fisiología , Fémur/fisiología , Hormona del Crecimiento/deficiencia , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Hormona del Crecimiento/metabolismo , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Obesidad/metabolismo , Obesidad/patología , Ratas , Transducción de SeñalRESUMEN
The elevation in baseline circulating growth hormone (GH) that occurs in pregnant rats is thought to arise from increased pituitary GH secretion, but the underlying mechanism remains unclear. Distribution, Fourier and algorithmic analyses confirmed that the pregnancy-induced increase in circulating GH in 3-week pregnant rats was due to a 13-fold increase in baseline circulating GH (P < 0.01), without any significant alteration in the parameters of episodic secretion. Electron microscopy revealed that pregnancy resulted in a reduction in the proportion of mammosomatotrophs (P < 0.01) and an increase in type II lactotrophs (P < 0.05), without any significant change in the somatotroph population. However, the density of the secretory granules in somatotrophs from 3-week pregnant rats was reduced (P < 0.05), and their distribution markedly polarised; the granules being grouped nearest the vasculature. Pituitary GH content was not increased, but steady-state GH mRNA levels declined progressively during pregnancy (P < 0.05). In situ hybridisation revealed that pregnancy was accompanied by a suppression of GH-releasing hormone mRNA expression in the arcuate nuclei (P < 0.05) and enhanced somatostatin mRNA expression in the periventricular nuclei (P < 0.05), an expression pattern normally associated with increased GH feedback. Although gastric ghrelin mRNA expression was elevated by 50% in 3-week pregnant rats (P < 0.01), circulating ghrelin, GH-secretagogue receptor mRNA expression and the GH response to a bolus i.v. injection of exogenous ghrelin were all largely unaffected during pregnancy. Although trace amounts of 'pituitary' GH could be detected in the placenta with radioimmunoassay, significant GH-immunoreactivity could not be observed by immunohistochemistry, indicating that rat placenta itself does not produce 'pituitary' GH. Although not excluding the possibility that the pregnancy-associated elevation in baseline circulating GH could arise from alternative extra-pituitary sources (e.g. the ovary), our data indicate that this phenomenon is most likely to result from a direct alteration of somatotroph function.
Asunto(s)
Ghrelina/fisiología , Hormona del Crecimiento/sangre , Preñez , Adiposidad/fisiología , Animales , Anticuerpos Monoclonales/metabolismo , Peso Corporal/fisiología , Femenino , Ghrelina/genética , Ghrelina/metabolismo , Ghrelina/farmacología , Hormona del Crecimiento/genética , Hormona del Crecimiento/metabolismo , Crecimiento y Desarrollo/fisiología , Hormonas Hipotalámicas/metabolismo , Masculino , Placenta/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Somatotrofos/fisiología , Factores de Tiempo , Regulación hacia ArribaRESUMEN
This work represents a study of the binding and distribution of three different calcium channel blockers in the Sprague-Dawley rat liver, using an in situ perfusion technique. For this purpose, [3H] desmethoxyverapamil, [3H] PN200-110 (isradipine) and [3H] azidopine were used as binding probes interacting with calcium channels. The perfusion steps of the liver involved both portal vein and thoracic inferior vena cava cannulations as inlet and outlet respectively. The subhepatic inferior vena cava was ligated to prevent leakage of the perfusate. Buffer, containing the tracer drug, was administered via the portal vein at a rate of 1 mL/min and perfusate collected at the same rate within specified time intervals during 50 min. The concentration of the tracer solutes in the perfusate's outlet increased with time, and steady state was observed for all tracers at > or = 40 min. The effect of adding cold isradipine to tracer desmethoxyverapamil, or cold verapamil to tracer PN200-110 were also assessed. First order rate constants for hepatocellular influx, efflux and calcium channel binding of the tracer substances were obtained using a simplified model from Goresky et al. These constants were mathematically manipulated and changed into permeability constants, second order binding constants, and residency times. Tracer solute influx across hepatocellular membranes is solubility-diffusion controlled, is inversely related to the molecular weights and is different in value from the efflux constants. Cold isradipine reduced the binding constant of desmethoxyverapamil by 36%, while cold verapamil reduced the binding constant of PN200-110 by 23%. Azidopine cellular distribution was low, however, binding to its receptor was analogous to desmethoxyverapamil and PN200-110. Moreover, PN200-110 had the highest residency time with no effect of cold verapamil on its receptor binding, while desmethoxyverapamil had the lowest residency time which significantly increased in the presence of cold isradipine.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacocinética , Hígado/metabolismo , Animales , Azidas/farmacocinética , Canales de Calcio/metabolismo , Radioisótopos de Carbono , Dihidropiridinas/farmacocinética , Inulina/metabolismo , Isradipino/metabolismo , Isradipino/farmacocinética , Hígado/efectos de los fármacos , Modelos Biológicos , Perfusión , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Tritio , Urea/metabolismo , Verapamilo/análogos & derivados , Verapamilo/farmacocinéticaRESUMEN
A heart-perfusion technique was employed to measure 125I-insulin binding on capillary endothelial and myocyte cell membranes in Sprague-Dawley rats. Animals were anesthetized, and the anterior chest wall excised to expose the mediastinal contents. The right and left superior and inferior venae cavae were dissected and tied, and another tie was passed around the aorta. A polyethylene catheter was introduced into the aortic lumen from cephalad to caudad to sit with its tip above the aortic valve. Another catheter was introduced into the cavity of the right atrium and both were anchored by sutures. Oxygenated Ringer-Lock buffer containing 20 mM/L K+ and 125I-insulin was perfused at a rate of 1 mL/min via the aortic catheter. Concomitantly, the distal ascending aorta and venae cavae were ligated. The effluent was collected from the right atrial catheter at the same infusion rate. Animals were divided into two groups, the normal group and streptozotocin-induced diabetic group. Heart perfusion was done on both groups either without or after treatment with detergent (CHAPS) to remove the capillary endothelial lining. A physical model for 125I-insulin sequestration as a ligand to its receptors on endothelial and/or myocyte plasma membranes was proposed. The model described a reversible binding of ligand on cellular surface receptor concentration to fit a conservation equation and a first order Bessel function. The binding constants (kn), reversal constants (k-n), dissociation constants kd = k-n/kn, and residency time constants tau = 1/k-n of 125I-insulin in normal untreated, normal CHAPS-treated, diabetic untreated, and diabetic CHAPS-treated hearts were estimated using a theoretically generated curve-fit to the data. Since insulin receptor binding on the capillary endothelial cell surfaces may serve to transport insulin from the intravascular to the subendothelial space, and since streptozotocin-induced diabetes was shown to diminish receptor autophosphorylation and kinase activity and hence internalization of insulin, then one can conclude the following from the data. In the normal heart, removal of the capillary endothelial lining with CHAPS did not alter kn, k-n, kd, and tau of insulin binding as compared to the normal untreated, whereas in the diabetic untreated heart these constants were altered, compared to the diabetic treated. Furthermore, the kn and k-n values in the diabetic CHAPS-treated hearts were the same as for the normals untreated and CHAPS-treated, respectively. In conclusion, the dissociation constants and residency time constants of all groups indicated the possible existence of two types of insulin receptors: the capillary endothelial cell surface insulin receptors with lower residency time (low affinity receptor or combination of insulin and IGF-1 receptors) and the myocyte plasma membrane insulin receptors with higher residency times (high affinity).