RESUMEN
The stroke classification developed for use in the Oxfordshire Community Stroke Project (OCSP) is simple, clinically meaningful and requires no investigations. However, its inter-rater reliability in a community setting is unknown. We aimed to assess the inter-rater reliability of this classification among neurologists and nurses within a community-based stroke incidence study. Fifty-four stroke patients with cerebral infarction who were registered in the North East Melbourne Stroke Incidence Study (NEMESIS) were assigned OCSP classifications by two neurologists and one of seven research nurses. There was moderate agreement between neurologists (kappa = 0.53), fair agreement between neurologist 1 and nurse (kappa = 0.31) and moderate agreement between neurologist 2 and nurse (kappa = 0.45). Disagreement about the neurological signs was an important reason for classification differences. The OCSP classification can be easily applied in a community setting with moderate inter-rater reliability and is thus a useful instrument for commun ity-based epidemiological studies.
Asunto(s)
Neurología/normas , Variaciones Dependientes del Observador , Especialidades de Enfermería/normas , Accidente Cerebrovascular/patología , Australia , Servicios de Salud Comunitaria , Humanos , Incidencia , Estudios ProspectivosRESUMEN
Presynaptic nicotinic acetylcholine receptors (nAChRs) on striatal synaptosomes stimulate dopamine release. Partial inhibition by the alpha3beta2-selective alpha-conotoxin-MII indicates heterogeneity of presynaptic nAChRs on dopamine terminals. We have used this alpha-conotoxin and UB-165, a novel hybrid of epibatidine and anatoxin-a, to address the hypothesis that the alpha-conotoxin-MII-insensitive subtype is composed of alpha4 and beta2 subunits. UB-165 shows intermediate potency, compared with the parent molecules, at alpha4beta2* and alpha3-containing binding sites, and resembles epibatidine in its high discrimination of these sites over alpha7-type and muscle binding sites. (+/-)-Epibatidine, (+/-)-anatoxin-a, and (+/-)-UB-165 stimulated [(3)H]-dopamine release from striatal synaptosomes with EC(50) values of 2.4, 134, and 88 nM, and relative efficacies of 1:0.4:0.2, respectively. alpha-Conotoxin-MII inhibited release evoked by these agonists by 48, 56, and 88%, respectively, suggesting that (+/-)-UB-165 is a very poor agonist at the alpha-conotoxin-MII-insensitive nAChR subtype. In assays of (86)Rb(+) efflux from thalamic synaptosomes, a model of an alpha4beta2* nAChR response, (+/-)-UB-165 was a very weak partial agonist; the low efficacy of (+/-)-UB-165 at alpha4beta2 nAChR was confirmed in Xenopus oocytes expressing various combinations of human nAChR subunits. In contrast, (+/-)-UB-165 and (+/-)-anatoxin-a were similarly efficacious and similarly sensitive to alpha-conotoxin-MII in increasing intracellular Ca(2+) in SH-SY5Y cells, a functional assay for native alpha3-containing nAChR. These data support the involvement of alpha4beta2* nAChR in the presynaptic modulation of striatal dopamine release and illustrate the utility of exploiting a novel partial agonist, together with a selective antagonist, to dissect the functional roles of nAChR subtypes in the brain.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Hidrocarburos Aromáticos con Puentes/metabolismo , Conotoxinas/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Agonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/metabolismo , Piridinas/metabolismo , Receptores Nicotínicos/metabolismo , Sinaptosomas/metabolismo , Animales , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/farmacología , Unión Competitiva , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/farmacología , Células Cultivadas , Conotoxinas/farmacología , Cuerpo Estriado/efectos de los fármacos , Toxinas de Cianobacterias , Humanos , Toxinas Marinas/metabolismo , Toxinas Marinas/farmacología , Microcistinas , Neurotoxinas/metabolismo , Neurotoxinas/farmacología , Nicotina/metabolismo , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Piridinas/farmacología , Ratas , Receptores Nicotínicos/efectos de los fármacos , Sinaptosomas/efectos de los fármacos , Tropanos , XenopusRESUMEN
The reliability of the National Institutes of Health Stroke Scale (NIHSS) for use by trained neurologists in clinical trials of acute stroke has been established in several hospital-based studies. However, it also has the potential for application in community-based settings and to be used by nonneurologists: issues which have not been explored before. Hence, we aimed to determine the reliability of the NIHSS when administered by research nurses within the existing North Eastern Melbourne Stroke Incidence Study. Using the NIHSS, thirty-one consecutively registered stroke patients were assessed by 2 neurologists and 1 of 2 trained research nurses. The interrater reliability of observations was compared using weighted and unweighted kappa statistics and intraclass correlation coefficients (ICC). There was a high level of agreement for total scores between the 2 neurologists (ICC = 0.95) and between each neurologist and research nurse (ICC = 0.92 and 0.96). While there was moderate to excellent agreement among neurologists and research nurse (weighted kappa > 0.4) for the majority of the NIHSS items, there was poor agreement for the component 'limb ataxia'. Overall, agreement between nurse and neurologist for individual items was not significantly different from agreement between neurologists. It appears that in both hospital and community settings, trained research nurses can administer the NIHSS with a reliability similar to stroke-trained neurologists. This ability could be used to advantage in large community-based trials and epidemiological studies.
Asunto(s)
Medicina Comunitaria , Neurología , Enfermeras y Enfermeros , Variaciones Dependientes del Observador , Accidente Cerebrovascular/diagnóstico , Australia/epidemiología , Humanos , Incidencia , National Institutes of Health (U.S.) , Accidente Cerebrovascular/epidemiología , Estados UnidosRESUMEN
We explore the significance of pi-cation interactions in the binding of ligands to nicotinic acetylcholine receptors. Specifically, the Austin method of semiempirical molecular orbital theory is utilized to estimate the interaction of aromatic amino acid side chains with the cation-containing heterocyclic ring fragments of nicotinic ligands. Variational interaction energies (E(i)) of side chain-ligand fragment pairs are shown to be distance-dependent and follow a Morse-like potential function. The tryptophan side chain shows the most pronounced interaction with the cation fragments, followed by tyrosine and phenylalanine. For a given side chain, cationic fragments exhibit characteristically different E(i) profiles, with the azabicyclo[2.2.1]heptane fragment of the potent nicotinic ligand epibatidine eliciting the greatest interaction energy of the study set. Most significantly, the minimum energy values calculated for numerous fragments correlate with the binding affinity of the parent ligands- we show this to be the case for heteropentameric (alpha4beta2) and homopentameric (alpha7) nicotinic acetylcholine receptor subtypes. Furthermore, intermolecular distances corresponding to the Morse-like potential minimum also correlate with high-affinity binding. A number of parallel calculations were conducted at the Hartree-Fock 6-31G ab initio level of theory in an effort to substantiate these findings.
Asunto(s)
Receptores Nicotínicos/química , Aminoácidos/química , Ligandos , Modelos Moleculares , Conformación Molecular , Teoría Cuántica , Relación Estructura-ActividadAsunto(s)
Alelos , Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Antígenos HLA-D/genética , Interleucina-4/genética , Proteínas de la Membrana/genética , Linfocitos T Colaboradores-Inductores/citología , Animales , Diferenciación Celular/genética , Humanos , Polimorfismo GenéticoRESUMEN
Chronic nicotine up-regulates the number of high affinity nicotinic acetylcholine receptors (nAChRs) in mammalian brain. Here, we studied up-regulation of the nAChR composed of alpha4 and beta2 subunits in the M10 cell line by using [3H]epibatidine to measure nAChR in cells in situ and in membrane preparations. Cultures were exposed to drugs for 2 days before assay. All agonists up-regulated [3H]epibatidine binding sites with EC50 values typically 10-100-fold higher than their respective Ki values from competition binding assays. Maximum up-regulation ranged from 40% to 250% above control values. Maximally effective concentrations of the less efficacious agonists methylcarbamylcholine or (+/-)-epibatidine together with nicotine resulted in less up-regulation than that produced by nicotine alone, showing that they are partial up-regulatory agonists. The antagonists dihydro-beta-erythroidine, methyllycaconitine, d-tubocurarine, hexamethonium, decamethonium, and mecamylamine either failed to up-regulate [3H]epibatidine binding sites or up-regulated mildly at high concentrations. When tested at non-up-regulating concentrations, only d-tubocurarine significantly inhibited agonist-induced up-regulation; this inhibition seemed to be noncompetitive. Comparison of [3H]epibatidine displacement in intact M10 cells and membrane preparations by membrane-impermeant ligands indicated that 85% of [3H]epibatidine binding sites are intracellular. On chronic treatment with agonist, the proportion of surface receptors did not change significantly, indicating that most up-regulated [3H]epibatidine binding sites are internal. However, up-regulation is mediated at the cell surface because the impermeant ligand tetramethylammonium was as efficacious as nicotine in eliciting up-regulation, and methylcarbamylcholine (i.e., impermeant but with low efficacy) blocked nicotine induced up-regulation. Thus, agonists elicit up-regulation (mainly of intracellular receptors) by interacting with cell surface nAChRs that are not compatible with either an active or high affinity desensitized conformation.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Receptores Nicotínicos/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Sitios de Unión , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Línea Celular , Relación Dosis-Respuesta a Droga , Cinética , Antagonistas Nicotínicos/farmacología , Piridinas/metabolismo , Receptores Nicotínicos/metabolismo , TritioRESUMEN
BACKGROUND: Many patients with severe acute pancreatitis develop organ system failure during the first few days of illness, and this accounts for the majority of early deaths. No specific therapy is available and treatment remains supportive. METHODS: In a randomized controlled trial conducted in 11 hospitals in the West of Scotland, 50 patients with predicted severe acute pancreatitis were selected from 188 screened over a 14-month period. Patients received placebo or lexipafant, a potent platelet-activating factor antagonist, by continuous intravenous infusion at a dose of 100 mg/day for up to 7 days. Early systemic complications were assessed by the measurement of organ failure scores. RESULTS: There was a significantly greater fall in organ failure score in the treatment group during the 7 days of study (mean and median changes in organ failure score were 0.17 and 0 in the placebo group versus -1.42 and -1 in the treatment group; P = 0.003, Wilcoxon rank sum test), associated with trends towards a reduction in mortality and a reduced incidence of systemic complications. CONCLUSION: These results suggest that lexipafant may be a useful adjunct to full supportive care in the early management of patients with severe acute pancreatitis.
Asunto(s)
Imidazoles/uso terapéutico , Leucina/análogos & derivados , Pancreatitis/tratamiento farmacológico , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Infusiones Intravenosas , Tiempo de Internación , Leucina/uso terapéutico , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/prevención & control , Resultado del TratamientoAsunto(s)
Receptores Nicotínicos/biosíntesis , Acetilcolina/farmacología , Animales , Unión Competitiva , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Línea Celular , Membrana Celular/metabolismo , Ratones , Agonistas Nicotínicos/metabolismo , Piridinas/metabolismo , Compuestos de Amonio Cuaternario/farmacología , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Transfección , Regulación hacia ArribaRESUMEN
The purpose of this study was to introduce the principles of initial hospital assessment and treatment of injured patients, tailored to the facilities and resources available in Nigeria. A 3-day didactic and laboratory course was presented by four trauma surgeons. The didactic session stressed the initial assessment and treatment of injured patients. The caprine laboratory taught the performance of common resuscitation manoeuvres: cricothyroidotomy, tube thoracostomy, i.v. cut-down, diagnostic peritoneal lavage, etc. The mean pre-course test score was 49.3 per cent and the mean post-course test score was 69.5 per cent; 93.5 per cent of the 124 participants increased their test scores. This represents a significant increase in knowledge in Nigerian physicians. Academic medical centres are encouraged to make such courses available in developing countries.
Asunto(s)
Países en Desarrollo , Educación Médica Continua , Resucitación/educación , Traumatología/educación , Animales , Cabras , Humanos , Nigeria , Resucitación/métodos , Traumatología/métodos , TriajeRESUMEN
The pathophysiology of systemic organ failure in acute pancreatitis has been the subject of debate for many years but there is growing evidence that increase production of pro-inflammatory cytokines plays an important role. from this work and from the results of studies in experimental pancreatitis there exists a rationale for the use of PAF antagonists in the treatment of acute pancreatitis. Two pilot studies have now demonstrated a beneficial effect of the PAF antagonist Lexipafant on acute pancreatitis which may lead to an important advance in the treatment of these patients. A multicentre trial aiming to recruit 300 patients with severe acute pancreatitis is now underway in the UK, the results of which will be awaited with interest.
Asunto(s)
Imidazoles/uso terapéutico , Leucina/análogos & derivados , Pancreatitis/tratamiento farmacológico , Factor de Activación Plaquetaria/antagonistas & inhibidores , Enfermedad Aguda , Animales , Ensayos Clínicos como Asunto , Humanos , Leucina/uso terapéutico , Monocitos/efectos de los fármacos , Monocitos/fisiología , Pancreatitis/patología , Factor de Activación Plaquetaria/fisiologíaRESUMEN
Recent studies have shown that mucocutaneous leishmaniasis (MCL), a severe and debilitating form of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis infection, is accompanied by high circulating levels of tumor necrosis factor (TNF)-alpha. Analysis of TNF polymorphisms in Venezuelan ACL patients and endemic unaffected controls demonstrates a high relative risk (RR) of 7.5 (P < 0.001) of MCL disease in homozygotes for allele 2 of a polymorphism in intron 2 of the TNF-beta gene, especially in females (RR = 9.5; P < 0.001) compared with males (RR = 4; P < 0.05). A significantly higher frequency (P < 0.05) of allele 2 at the -308-basepair TNF-alpha gene polymorphism was also observed in MCL patients (0.18) compared with endemic control subjects (0.069), again associated with a high relative risk of disease (RR = 3.5; P < 0.05) even in the heterozygous condition. Because both the TNF-alpha and TNF-beta polymorphisms have previously been linked with functional differences in TNF-alpha levels, these data suggest that susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-alpha production.
Asunto(s)
Leishmaniasis Mucocutánea/genética , Linfotoxina-alfa/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Alelos , Secuencia de Bases , Niño , Femenino , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Intrones/genética , Leishmaniasis Mucocutánea/metabolismo , Linfotoxina-alfa/biosíntesis , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Riesgo , Factor de Necrosis Tumoral alfa/biosíntesis , Venezuela/epidemiologíaRESUMEN
Antibody (IgG) responses to mycobacterial (BCG; PPD; Mycobacterium leprae soluble antigen, MLSA) and leishmanial (Leishmania mexicana LV4) antigens were measured in 208 initially PPD and leishmanin skin-test negative volunteers divided into four vaccine groups as follows: 68 received BCG plus killed promastigotes (group A), 47 received BCG alone (group B), 47 received killed promastigotes alone (group C), and 46 formed the diluent control (placebo, group D). Three vaccine doses were administered at 8-12 week intervals. Vaccinees were bled immediately prior to each vaccination, and again at 3- and 12-month follow-up. Skin tests were performed prevaccination, and again at the 3- and 12-month follow-up. Anti-BCG, anti-PPD and anti-MLSA IgG levels increased significantly in groups A and B receiving BCG. The presence of leishmanial antigen (with BCG) in the inoculum suppressed the IgG response to Mycobacterium tuberculosis/Mycobacterium bovis-related (PPD and BCG), but not M. leprae-related (MLSA)-related, antigens. A small but significant increase (relative to prevaccination level) in response to MLSA, but not to BCG or PPD was observed in the non-BCG-vaccinated groups. The background level of response to mycobacterial and leishmanial antigens was higher in the Venezuelan vaccinees than in non-endemic (British) volunteers. Responses to leishmanial antigen were not enhanced in the two vaccine groups receiving killed promastigotes (with/without BCG) compared with the BCG alone and placebo groups. Instead, all vaccine groups showed a pattern of response consistent with either (i) a response to the skin-test antigen or, more likely, (ii) seasonal endemic exposure to leishmanial antigen. Interestingly, this endemic response to leishmanial antigen was enhanced in the vaccine groups receiving BCG, despite the fact that group B received no leishmanial antigen in the vaccine inoculum. When prevaccination IgG levels (mean + 3 standard deviations) were used to determine a negative cut-off, a low percentage (< 38%) of vaccinees converted to responder status for either anti-mycobacterial or anti-leishmanial responses, and those who did would be classified as 'low-responder' status compared with titres observed in severe forms of disease. Hence, although there was evidence for a background endemic response to both leishmanial and mycobacterial antigens, there was no evidence that vaccination per se led to a potentially disease exacerbatory level of TH2-associated antibody response especially with respect to the anti-leishmanial response.(ABSTRACT TRUNCATED AT 400 WORDS)