RESUMEN
OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. DESIGN: A descriptive study. SETTING: The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. MAIN OUTCOME MEASURES: Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. RESULTS: The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. CONCLUSIONS: We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.
Asunto(s)
Esclerosis Múltiple/epidemiología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Medicina General/estadística & datos numéricos , Geografía , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Población , Prevalencia , Factores Sexuales , Resultado del Tratamiento , Reino Unido/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To assess the epidemiology and treatment of storage symptoms suggestive of overactive bladder (OAB) and voiding symptoms suggestive of bladder outlet obstruction (BOO) because of benign prostatic hyperplasia in UK general practice. PATIENTS AND METHODS: This was a retrospective analysis of data collected between 2000 and 2006 and entered in The Health Improvement Network general practice database, containing medical records for > 1 million men (aged >or= 18 years) in the UK. Using Read codes, we analysed the prevalence of storage and voiding lower urinary tract symptoms (LUTS) as well as prescribing trends for 5alpha-reductase inhibitors (5ARIs) and alpha-blockers for LUTS secondary to BOO and antimuscarinics for OAB. RESULTS: In 2006, the prevalence of diagnosed LUTS/OAB was only 0.3% and the recorded prevalence of LUTS/BOO was only 2.2%. Treatment rates also remained low throughout the study period. In the 12 months before 1 January 2006, only 25% of men diagnosed with OAB and 6-7% of men with storage LUTS received antimuscarinics, whereas 36% of men with a record of LUTS/BOO received alpha-blockers and/or 5ARIs. Alpha-blockers were prescribed to approximately 10% of men diagnosed with OAB or storage LUTS who did not have any recorded BOO diagnosis or symptoms. CONCLUSION: Diagnosis of both storage and voiding LUTS occurs at much lower rates than indicated by prevalence estimates. Despite the availability of effective prescription therapies, many men with storage and/or voiding LUTS may not be receiving appropriate treatment in UK general practice.
Asunto(s)
Obstrucción del Cuello de la Vejiga Urinaria/diagnóstico , Vejiga Urinaria Hiperactiva/diagnóstico , Adolescente , Adulto , Anciano , Utilización de Medicamentos/estadística & datos numéricos , Métodos Epidemiológicos , Medicina Familiar y Comunitaria/normas , Humanos , Masculino , Persona de Mediana Edad , Reino Unido/epidemiología , Obstrucción del Cuello de la Vejiga Urinaria/tratamiento farmacológico , Obstrucción del Cuello de la Vejiga Urinaria/epidemiología , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/epidemiologíaRESUMEN
The gram-negative anaerobe Dichelobacter nodosus is the causative agent of footrot in sheep. The authors have previously characterized two genetic elements, the intA (vap) and intB elements, which integrate into the genome of D. nodosus. In the virulent strain A198 there are two copies of the intA element. One copy is integrated into the 3' end of the tRNA-serGCU gene, close to the aspartokinase (askA) gene, and the second copy is integrated into the 3' end of the tRNA-serGGA gene, next to the polynucleotide phosphorylase (pnpA) gene. In this study, a new genetic element was identified in the benign strain C305, the intC element, integrated into the 3' end of the tRNA-serGCU gene, next to askA. The intC element was found in most D. nodosus strains, both benign and virulent, which were examined, and was integrated into tRNA-serGCU in most strains. Between the askA and tRNA-serGCU genes, a gene (designated glpA), was identified whose predicted protein product has very high amino acid identity with RsmA from the plant pathogen Erwinia carotovora. RsmA acts as a global repressor of pathogenicity in E. carotovora, by repressing the production of extracellular enzymes. In virulent strains of D. nodosus the intA element was found to be integrated next to pnpA, and either the intA or intC element was integrated next to glpA. By contrast, all but one of the benign strains had intB at one or both of these two positions, and the one exception had neither intA, intB nor intC at one position. The loss of the intC element from the virulent strain 1311 resulted in loss of thermostable protease activity, a virulence factor in D. nodosus. A model for virulence is proposed whereby integration of the intA and intC genetic elements modulates virulence by altering the expression of glpA, pnpA, tRNA-serGCU and tRNA-serGGA.
Asunto(s)
Dichelobacter nodosus/genética , Dichelobacter nodosus/patogenicidad , Endopeptidasas/metabolismo , Regiones no Traducidas 3'/genética , Secuencia de Aminoácidos , Animales , Aspartato Quinasa/genética , Secuencia de Bases , Clonación Molecular , Elementos Transponibles de ADN/genética , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Dichelobacter nodosus/enzimología , Endopeptidasas/química , Endopeptidasas/genética , Estabilidad de Enzimas , Datos de Secuencia Molecular , Mapeo Físico de Cromosoma , Polirribonucleótido Nucleotidiltransferasa/genética , ARN Bacteriano/genética , ARN Bacteriano/metabolismo , ARN de Transferencia de Serina/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Alineación de Secuencia , Eliminación de Secuencia/genética , Ovinos , Transcripción Genética , Virulencia/genéticaRESUMEN
Dichelobacter nodosus is the principal causative agent of ovine footrot. Nucleotide (nt) sequences from the D. nodosus genome have been isolated and a series of overlapping lambda clones defining vap (virulence-associated protein) regions 1, 2 and 3 have been reported [Katz et al., J. Bacteriol. 176 (1994) 2663-2669]. In the present study, the limits of the virulence-associated (va) DNA around vap regions 1 and 3 were determined by dot-blot hybridization experiments using plasmid subclones to probe genomic DNA from the D. nodosus virulent strain A198 and the benign strain C305. This va region was found to be approx. 11.9 kb in length, and to be interrupted by a short DNA segment which is also found in the benign D. nodosus strain. Sequence analysis of the entire region revealed an ORF, intA, which is very similar to the integrases of bacteriophages phi R73, P4 and Sf6. Bacteriophages phi R73 and P4 integrate into the 3' ends of tRNA genes, with the integrase genes adjacent to the tRNA genes. A similar arrangement was found in the D. nodosus va region. A 19-bp nt sequence was found to be repeated at the ends of the va region, and may represent the bacteriphage attachment site. These findings suggest that D. nodosus may have acquired these DNA sequences by the integration of a bacteriophage, or an integrative plasmid that contains a bacteriophage-related integrase gene. The high similarity of the D. nodosus integrase to integrases from coliphages suggests that these va sequences may be transferred between distantly related bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Bacteriófagos/genética , ADN Nucleotidiltransferasas/genética , Genes Bacterianos , Bacterias Anaerobias Gramnegativas/genética , Secuencia de Aminoácidos , Secuencia de Bases , Elementos Transponibles de ADN , ADN Bacteriano/genética , Panadizo Interdigital/microbiología , Genoma Bacteriano , Bacterias Anaerobias Gramnegativas/enzimología , Bacterias Anaerobias Gramnegativas/patogenicidad , Integrasas , Datos de Secuencia Molecular , Familia de Multigenes , Hibridación de Ácido Nucleico , Plásmidos , ARN de Transferencia de Serina/genética , Secuencias Repetitivas de Ácidos Nucleicos , Origen de Réplica , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Virulencia/genética , Integración ViralRESUMEN
Extracts of bovine anterior pituitary glands contain significant amounts of material with immunological properties similar to those of the common, alpha, subunit isolated from the pituitary glycoprotein hormones. Purification of this "free alpha-like" material and analysis show it to contain an additional site of glycosylation not present in the alpha subunit isolated from intact glycoprotein hormones. This additional oligosaccharide is O-linked to a threonine residue corresponding to threonine-43 of bovine lutropin-alpha. Carbohydrate analysis shows 1.7 mol of sialic acid, 0.8 mol of galactose and 0.9 mol of galactosamine/mol of oligosaccharide. A similar structure for the free alpha-like material as compared to bovine lutropin-alpha is evident from equal potency in an anti-lutropin-alpha radioimmunoassay, a similar amino acid composition and similar but not identical peptide maps. The free alpha-like material is distinct from lutropin-alpha in that the free alpha-material contains sialic acid and galactose, has a slightly higher apparent molecular weight, an increased negative charge, and will not reassociate with native lutropin-beta. Peptide maps of the tryptic peptides of the free alpha-like material show additional differences (other than the O-linked oligosaccharide) when compared to peptide maps of lutropin-alpha; thus additional modifications are probably present.
Asunto(s)
Glicoproteínas/aislamiento & purificación , Oligosacáridos/análisis , Péptidos/aislamiento & purificación , Adenohipófisis/análisis , Hormonas Adenohipofisarias/aislamiento & purificación , Aminoácidos/análisis , Animales , Bovinos , Sustancias Macromoleculares , Fragmentos de Péptidos/análisis , TripsinaRESUMEN
A complex between bovine lutropin (LH) and monovalent antibodies (Fab fragments) directed against its alpha subunit, which is common to the glycoprotein hormones, has been purified by gel filtration and chromatography on concanavalin A-Sepharose. The complex is heterogenous with respect to molecular size; 70--80% of the hormone is complexed with either two or three Fab fragments. The LH-Fab alpha complexes retain only about 13% receptor binding activity as compared to LH when measured in a radioligand receptor assay in which the radiolabeled ligand is human choriogonadotropin. (Use of the human hormone as labeled ligand permits direct measurement of competition between receptor and the bovine complex because the alpha portion of the human hormone does not cross react significantly with antibodies directed against bovine alpha subunits.) Complex formation does not lead to dissociation of the lutropin into its subunits, as shown with a homologous LH-beta immunoassay which distinguishes free beta subunit from intact LH. Complexing of LH with Fab-alpha fragments also causes little or no change in the affinity of the hormone's beta subunit for anti-LH-beta antibodies indicating that significant changes in beta subunit conformation did not occur. The data show that at least two well-separated antigenic regions on the alpha subunit are exposed to the surface in the intact hormone. They are also in agreement with the proposal that the loss of binding activity to receptor is due to steric effects rather than to changes in conformation or dissociation, and that there may be sites on the alpha subunit which interact directly with the receptor.
Asunto(s)
Sitios de Unión de Anticuerpos , Fragmentos Fab de Inmunoglobulinas/metabolismo , Hormona Luteinizante/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Bovinos , Cromatografía , Cromatografía en Gel , Fragmentos Fab de Inmunoglobulinas/aislamiento & purificación , Hormona Luteinizante/inmunología , Hormona Luteinizante/aislamiento & purificación , Peso Molecular , Radioinmunoensayo , Ensayo de Unión RadioliganteRESUMEN
Affinity chromatography on concanavalin A-Sepharose is a time saving step in both large and small scale isolations of the bovine pituitary glycoprotein hormones. After ion-exchange chromatography, the final yield of purified lutropin is 40-50% of material in starting concentrates and of purified thyrotropin is approximately 20%. The final products have the same electrophoretic and immunological properties and amino acid compositions as previous preparations. Less than 3% of the immunoreactive lutropin, follitropin and thyrotropin are present as non-glycosylated forms in either crude pituitary extracts or concentrates. Thyrotropin and follitropin elute from the immobilized lectin as a single fraction, whereas lutropin separates into two glycosylated fractions. Gel filtration of both crude extracts and the glycoprotein fractions shows that less than 5% of the immunoreactivity of the hormones is present as material of apparently high molecular weight. Substantial alpha subunit immunoreactivity, however, is in three fractions (as found by others in human pituitary extracts) corresponding to "high molecular weight material" (7%), intact hormones (46%) and free subunit (47%).
Asunto(s)
Hormona Folículo Estimulante/aislamiento & purificación , Hormona Luteinizante/aislamiento & purificación , Tirotropina/aislamiento & purificación , Animales , Bovinos , Cromatografía de Afinidad , Concanavalina A , Peso Molecular , HipófisisRESUMEN
A young man presented with rapidly developing Cushing's syndrome which was due to the ectopic secretion of ACTH and beta-MSH-like material from hepatic tumour deposits, possibly originating from biliary radicals. This association of the ectopic ACTH syndrome has not previously been described. During the 22 month course of the illness the plasma immunoreactive ACTH and 'beta-MSH' concentrations rose by logarithmic progression. The plasma calcitonin concentration was also raised but did not change during the last 12 months. At any stage of the illness the plasma concentration of the ecotopically produced hormones was stable except that after hydrocortisone there were inconstant variations. During the course of the illness the ectopic ACTH became biologically less potent. This ineffectural ACTH was present in the plasma, in the tumour, and in the medium in which the tumour was cultured, in a large molecular weight form. This 'big ACTH' differed from the normal ACTH found in the patient's pituitary and from authentic ACTH in its immunochemical character: the C-terminal antigenic determinant (33-39 region of ACTH) was masked in the large molecular weight form but was uncovered after extraction in neutral buffer and this 'big ACTH' was more readily extracted from the tumour at pH 7.0. The tumour tissue also contained immunoreactive beta-MSH-like material and immunoreactive calcitonin which resembled calcitonin M chromatographically.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Calcitonina/metabolismo , Neoplasias Hepáticas/metabolismo , Síndromes Paraneoplásicos Endocrinos/fisiopatología , Adolescente , Hormona Adrenocorticotrópica/sangre , Síndrome de Cushing/etiología , Humanos , Neoplasias Hepáticas/análisis , Neoplasias Hepáticas/complicaciones , Masculino , Hormonas Estimuladoras de los Melanocitos/metabolismo , Peso Molecular , Factores de TiempoRESUMEN
ACTH levels measured by N- and C-terminal immunoassays and cytochemical bioassay, were measured in fourteen lung tumours not associated with the ectopic ACTH syndrome and in macroscopically normal lung tissue taken from the same patients at thoracotomy. Significant concentrations of immunocative (greater than 3 ng/g wet weight) and bioactive (greater than 0.2 ng/g wet weight) ACTH were found in all the carcinoid and oat cell tumours (n=9), a combined tumour (poorly differentiated adenocarcinoma with large cell carcinoid elements), and a poorly differentiated squamous cell tumour. All the carcinoid tumours contained more C- than N-terminal ACTH immunoactivity. The squamous cell tumours (n=2), anaplastic tumours (n=2) and adenocarcinoma contained insignificant ACTH levels. There was a good correlation between the ACTH levels and the presence of secretory granules in the tumours examined ultrastructually. All the macroscopically normal samples of lung tissue contained immuno and bioactive ACTH-like material, the levels of which correlated well with ACTH levels in the tumour tissue. It is suggested that all lung tumours of carcinoid or oat cell type synthesize ACTH-like materials although clinical evidence of the ectopic ACTH syndrome may be absent. The presence of ACTH-like materials in non-tumorous lung tissue in patients with lung cancer may indicate a low level of ACTH production throughout the lung or sequestration of ACTH containing granules secreted by the tumour.
Asunto(s)
Hormona Adrenocorticotrópica/biosíntesis , Neoplasias Pulmonares/metabolismo , Adenocarcinoma/metabolismo , Adulto , Anciano , Carcinoma Adenoide Quístico/metabolismo , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Femenino , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/ultraestructura , Masculino , Persona de Mediana EdadRESUMEN
Monolayer tissue culture has been used as a system in which to study aspects of ectopic hormone secretion. Of a series of twenty-four human bronchial carcinomas, nineteen were successfully established in culture and the supernatant medium from each tested for peptide hormones by radioimmunoassay. Six tumours were found to produce adrenocorticotrophin (ACTH), four to release calcitonin (CT) and one to release both of these hormones. No growth hormone or insulin was detected throughout the series. Net in vitro synthesis of both ACTH and CT was demonstrated by recovery of more hormone during culture than was originally contained in the explanted tumour tissue. The production of hormone by four out of six proliferative cultures established, and its persistence through many subculture passages, confirms ectopic hormone production as a stable heritable characteristic of some lung tumours. The ability of hormone-producing bronchial tumour cells to respond to factors known to influence hormone output from normal endocrine cells was tested. ACTH release was stimulated in one tumour by Pitressin and CT in another by gastrin. In addition, the release of CT from the same tumour cell line was shown to be inhibited by the accumulation of high external concentrations of CT as has been reported for normal C-cells.
Asunto(s)
Neoplasias de los Bronquios/metabolismo , Hormonas Ectópicas/biosíntesis , Adenocarcinoma/metabolismo , Hormona Adrenocorticotrópica/biosíntesis , Hormona Adrenocorticotrópica/metabolismo , Calcitonina/biosíntesis , Calcitonina/metabolismo , Antígeno Carcinoembrionario/biosíntesis , Tumor Carcinoide/metabolismo , Carcinoma de Células Pequeñas/metabolismo , Células Cultivadas , Técnicas de Cultivo , Hormonas Ectópicas/metabolismo , Humanos , RadioinmunoensayoRESUMEN
A radioimmunoassay is described for the measurement of human "beta-melanocyte-stimulating hormone" ("betah-MSH"). Two antisera have been used, one of which cross-reacts with synthetic betah-MSH as well as with the two larger pituitary peptides betah- and gammah-lipotropin (betah- and gammah-LPH) and the other mainly with betah-MSH and gammah-LPH. The sensitivity and reliability of the assay have been improved by employing a simple plasma extraction procedure, and the shelf-life of the iodinated betah-MSH tracer has been increased more than five-fold by storage in a concentrated human serum albumin solution. Using a 5 ml plasma sample the detection limit is 6 pg/ml. The mean resting "betah-MSH" level in normal subjects is 21 pg/ml (range 13-38 pg/ml) at 9 AM and 12 pg/ml (range 6-20 pg/ml) at 9 PM. Levels are considerably elevated (51-12,000 pg/ml) in patients with Addison's disease. Nelson's syndrome, Cushing's disease and the "ectopic" ACTH syndrome. After administration of insulin or pyrogen, the concentration of plasma "betah-MSH" increases in parallel with that of ACTH and they are approximately equivalent on a molar basis. The stability of purified betah- and gammah-LPH and endogenous "betah-MSH" when incubated in vitro in fresh blood or plasma are similar, in contrast to the less stable peptide synthetic betah-MSH. It is suggested that "betah-MSH" immunoreactivity in human plasma is due to betah- and gammah-LPH rather than betah-MSH.