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BACKGROUND/OBJECTIVES: Inter-individual variability in weight loss during obesity treatment is complex and poorly understood. Here we use whole body and tissue approaches to investigate fuel oxidation characteristics in skeletal muscle fibers, cells and distinct circulating protein biomarkers before and after a high fat meal (HFM) challenge in those who lost the most (obese diet-sensitive; ODS) vs the least (obese diet-resistant; ODR) amount of weight in a highly controlled weight management program. SUBJECTS/METHODS: In 20 weight stable-matched ODS and ODR women who previously completed a standardized clinical weight loss program, we analyzed whole-body energetics and metabolic parameters in vastus lateralis biopsies and plasma samples that were obtained in the fasting state and 6 h after a defined HFM, equivalent to 35% of total daily energy requirements. RESULTS: At baseline (fasting) and post-HFM, muscle fatty acid oxidation and maximal oxidative phosphorylation were significantly greater in ODS vs ODR, as was reactive oxygen species emission. Plasma proteomics of 1130 proteins pre and 1, 2, 5 and 6 h after the HFM demonstrated distinct group and interaction differences. Group differences identified S-formyl glutathione hydratase, heat shock 70 kDA protein 1A/B (HSP72), and eukaryotic translation initiation factor 5 (eIF5) to be higher in ODS vs ODR. Group-time differences included aryl hydrocarbon interacting protein (AIP), peptidylpropyl isomerase D (PPID) and tyrosine protein-kinase Fgr, which increased in ODR vs ODS over time. HSP72 levels correlated with muscle oxidation and citrate synthase activity. These proteins circulate in exosomes; exosomes isolated from ODS plasma increased resting, leak and maximal respiration rates in C2C12 myotubes by 58%, 21% and 51%, respectively, vs those isolated from ODR plasma. CONCLUSIONS: Findings demonstrate distinct muscle metabolism and plasma proteomics in fasting and post-HFM states corresponding in diet-sensitive vs diet-resistant obese women.
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Proteínas Sanguíneas/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Obesidad , Proteoma/metabolismo , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Estudios de Casos y Controles , Dieta , Exosomas/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatología , Obesidad/sangre , Obesidad/dietoterapia , Obesidad/epidemiología , Obesidad/metabolismo , Proteoma/análisis , Insuficiencia del TratamientoRESUMEN
Pocket proteins (pRb, p107 and p130) are well studied in their role of regulating cell cycle progression. Increasing evidence suggests that these proteins also control early differentiation and even later stages of cell maturation, such as migration. However, pocket proteins also regulate apoptosis, and many of the developmental defects in knock out models have been attributed to increased cell death. Here, we eliminate ectopic apoptosis in the developing brain through the deletion of Bax, and show that pocket proteins are required for radial migration independent of their role in cell death regulation. Following loss of pRb and p107, a population of cortical neurons fails to pass through the intermediate zone into the cortical plate. Importantly, these neurons are born at the appropriate time and this migration defect cannot be rescued by eliminating ectopic cell death. In addition, we show that pRb and p107 regulate radial migration through a cell autonomous mechanism since pRb/p107 deficient neurons fail to migrate to the correct cortical layer within a wild type brain. These results define a novel role of pocket proteins in regulating cortical lamination through a cell autonomous mechanism independent of their role in apoptosis.
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Apoptosis , Proteína de Retinoblastoma/genética , Proteína p107 Similar a la del Retinoblastoma/genética , Animales , Muerte Celular , Diferenciación Celular , Femenino , Ratones Noqueados , Neuronas/metabolismoRESUMEN
OBJECTIVE: To compare the effectiveness of acupuncture with other relevant physical treatments for alleviating pain due to knee osteoarthritis. DESIGN: Systematic review with network meta-analysis, to allow comparison of treatments within a coherent framework. Comprehensive searches were undertaken up to January 2013 to identify randomised controlled trials in patients with osteoarthritis of the knee, which reported pain. RESULTS: Of 156 eligible studies, 114 trials (covering 22 treatments and 9,709 patients) provided data suitable for analysis. Most trials studied short-term effects and many were classed as being of poor quality with high risk of bias, commonly associated with lack of blinding (which was sometimes impossible to achieve). End of treatment results showed that eight interventions: interferential therapy, acupuncture, TENS, pulsed electrical stimulation, balneotherapy, aerobic exercise, sham acupuncture, and muscle-strengthening exercise produced a statistically significant reduction in pain when compared with standard care. In a sensitivity analysis of satisfactory and good quality studies, most studies were of acupuncture (11 trials) or muscle-strengthening exercise (9 trials); both interventions were statistically significantly better than standard care, with acupuncture being statistically significantly better than muscle-strengthening exercise (standardised mean difference: 0.49, 95% credible interval 0.00-0.98). CONCLUSIONS: As a summary of the current available research, the network meta-analysis results indicate that acupuncture can be considered as one of the more effective physical treatments for alleviating osteoarthritis knee pain in the short-term. However, much of the evidence in this area of research is of poor quality, meaning there is uncertainty about the efficacy of many physical treatments.
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Analgesia por Acupuntura/métodos , Artralgia/terapia , Osteoartritis de la Rodilla/terapia , Modalidades de Fisioterapia , Artralgia/etiología , Humanos , Osteoartritis de la Rodilla/complicaciones , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Growing evidence highlights a role for mitochondrial dysfunction and oxidative stress as underlying contributors to Parkinson's disease (PD) pathogenesis. DJ-1 (PARK7) is a recently identified recessive familial PD gene. Its loss leads to increased susceptibility of neurons to oxidative stress and death. However, its mechanism of action is not fully understood. Presently, we report that DJ-1 deficiency in cell lines, cultured neurons, mouse brain and lymphoblast cells derived from DJ-1 patients display aberrant mitochondrial morphology. We also show that these DJ-1-dependent mitochondrial defects contribute to oxidative stress-induced sensitivity to cell death since reversal of this fragmented mitochondrial phenotype abrogates neuronal cell death. Reactive oxygen species (ROS) appear to play a critical role in the observed defects, as ROS scavengers rescue the phenotype and mitochondria isolated from DJ-1 deficient animals produce more ROS compared with control. Importantly, the aberrant mitochondrial phenotype can be rescued by the expression of Pink1 and Parkin, two PD-linked genes involved in regulating mitochondrial dynamics and quality control. Finally, we show that DJ-1 deficiency leads to altered autophagy in murine and human cells. Our findings define a mechanism by which the DJ-1-dependent mitochondrial defects contribute to the increased sensitivity to oxidative stress-induced cell death that has been previously reported.
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Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Mitocondrias/genética , Mitocondrias/patología , Proteínas Oncogénicas/deficiencia , Proteínas Oncogénicas/genética , Enfermedad de Parkinson/genética , Acetilcisteína/farmacología , Animales , Autofagia/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Línea Celular , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Proteínas Mutantes/metabolismo , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Neostriado/patología , Neostriado/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/patología , Neuronas/ultraestructura , Enfermedad de Parkinson/patología , Peroxirredoxinas , Fenotipo , Proteína Desglicasa DJ-1 , Proteínas Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbß3, α4ß7/α4ß1 and αLß2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvß3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvß6 and αvß1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.
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Integrinas/antagonistas & inhibidores , Integrinas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Animales , Descubrimiento de Drogas/métodos , Humanos , Unión Proteica/efectos de los fármacosRESUMEN
Galectin-3 is a beta-galactoside-binding mammalian lectin and part of the 15 member galectin family that are evolutionarily highly conserved. It is the only chimeric protein with a C-terminal carbohydrate recognition domain (CRD) linked to a proline, glycine, and tyrosine rich additional N-terminal domain. Galectin-3 binds several cell surface glycoproteins via its CRD domain as well as undergoing oligomerization, via binding at the N-terminal or the CRD, resulting in the formation of a galectin-3 lattice on the cell surface. The galectin-3 lattice has been regarded as being a crucial mechanism whereby extracellular galectin-3 modulates cellular signalling by prolonging retention time or retarding lateral movement of cell surface receptors in the plasma membrane. As such galectin-3 can regulate various cellular functions such as diffusion, compartmentalization and endocytosis of plasma membrane glycoproteins and glycolipids and the functionality of membrane receptors. In multiple models of organ fibrosis, it has been demonstrated that galectin-3 is potently pro-fibrotic and modulates the activity of fibroblasts and macrophages in chronically inflamed organs. Increased galectin-3 expression also activates myofibroblasts resulting in scar formation and may therefore impact common fibrotic pathways leading to fibrosis in multiple organs. Over the last decade there has been a marked increase in the scientific literature investigating galectin-3 in a range of fibrotic diseases as well as the clinical development of new galectin-3 inhibitors. In this review we will examine the role of galectin-3 in fibrosis, the therapeutic strategies for inhibiting galectin-3 in fibrotic disease and the clinical landscape to date.
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Endocitosis , Fibrosis/tratamiento farmacológico , Galectinas/antagonistas & inhibidores , Inflamación/prevención & control , Animales , Proteínas Sanguíneas/antagonistas & inhibidores , Fibrosis/metabolismo , Fibrosis/patología , Galectinas/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patologíaRESUMEN
BACKGROUND: Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens. METHODS: We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed. RESULTS: 5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer). CONCLUSION: This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring.
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Neoplasias/epidemiología , Enfermedades Profesionales/epidemiología , Exposición Profesional/efectos adversos , Ocupaciones/estadística & datos numéricos , Enfermedades de los Trabajadores Agrícolas/epidemiología , Amianto , Carcinógenos , Alquitrán/efectos adversos , Femenino , Humanos , Incidencia , Industrias , Masculino , Mesotelioma/inducido químicamente , Reino Unido/epidemiologíaRESUMEN
Cytokine single nucleotide polymorphisms and consequent production levels have been associated with acute graft-vs-host disease (aGVHD) development. The aim of this pilot study was to determine whether polymorphisms in tumor necrosis factor (TNF), lymphotoxin alpha (LTA) and transforming growth factor beta 1 (TGFB1) showed any association with aGVHD severity. Novel alleles and polymorphisms were identified for each cytokine locus. Genotype distributions were examined in 38 recipient-donor pairs (all chronic myelogenous leukemia in the first chronic phase) with either low-grade (grades 0-I) or high-grade (grades III-IV) aGVHD. Although no significant differences were found, some trends were noted in genotype distributions among aGVHD-grade groups. Power calculations determined that substantially more pairs would be required to show significant associations in distributions among aGVHD-grade groups.
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Frecuencia de los Genes/genética , Enfermedad Injerto contra Huésped/genética , Linfotoxina-alfa/genética , Factor de Crecimiento Transformador beta1/genética , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas , Adulto JovenRESUMEN
In this report, we have examined the requirement for the retinoblastoma (Rb) gene family in neuronal determination with a focus on the developing neocortex. To determine whether pRb is required for neuronal determination in vivo, we crossed the Rb-/- mice with transgenic mice expressing beta-galactosidase from the early, panneuronal Talpha1 alpha-tubulin promoter (Talpha1:nlacZ). In E12.5 Rb-/- embryos, the Talpha1:nlacZ transgene was robustly expressed throughout the developing nervous system. However, by E14. 5, there were perturbations in Talpha1:nlacZ expression throughout the nervous system, including deficits in the forebrain and retina. To more precisely define the temporal requirement for pRb in neuronal determination, we functionally ablated the pRb family in wild-type cortical progenitor cells that undergo the transition to postmitotic neurons in vitro by expression of a mutant adenovirus E1A protein. These studies revealed that induction of Talpha1:nlacZ did not require proteins of the pRb family. However, in their absence, determined, Talpha1:nlacZ-positive cortical neurons underwent apoptosis, presumably as a consequence of "mixed signals" deriving from their inability to undergo terminal mitosis. In contrast, when the pRb family was ablated in postmitotic cortical neurons, there was no effect on neuronal survival, nor did it cause the postmitotic neurons to reenter the cell cycle. Together, these studies define a critical temporal window of requirement for the pRb family; these proteins are not required for induction of neuronal gene expression or for the maintenance of postmitotic neurons, but are essential for determined neurons to exit the cell cycle and survive.
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Regulación del Desarrollo de la Expresión Génica , Neuronas/química , Neuronas/citología , Proteína de Retinoblastoma/genética , Animales , Biotina , Diferenciación Celular/fisiología , Supervivencia Celular/genética , Corteza Cerebral/citología , Corteza Cerebral/embriología , Fragmentación del ADN , Nucleótidos de Desoxiuracil , Operón Lac , Ratones , Ratones Transgénicos , Mitosis/fisiología , Médula Espinal/citología , Médula Espinal/embriología , Coloración y Etiquetado , Células Madre/química , Células Madre/citología , Factores de Tiempo , Tubulina (Proteína)/genéticaRESUMEN
The retinoblastoma (RB) protein is present at low levels in early mouse embryos and in pluripotent P19 embryonal carcinoma cells; however, the levels of RB rise dramatically in neuroectoderm formed both in embryos and in differentiating cultures of P19 cells. To investigate the effect of inactivating RB and related proteins p107 and p130, we transfected P19 cells with genes encoding mutated versions of the adenovirus E1A protein that bind RB and related proteins. When these E1A-expressing P19 cells were induced to differentiate into neuroectoderm, there was a striking rise in the expression of c-fos and extensive cell death. The ultrastructural and biochemical characteristics of the dying cells were indicative of apoptosis. The dying cells were those committed to the neural lineages because neurons and astrocytes were lost from differentiating cultures. Cell death was dependent on the ability of the E1A protein to bind RB and related proteins. Our results suggest that proteins of the RB family are essential for the development of the neural lineages and that the absence of functional RB activity triggers apoptosis of differentiating neuroectodermal cells.
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Proteínas E1A de Adenovirus/metabolismo , Apoptosis , Sistema Nervioso/embriología , Fosfoproteínas , Proteína de Retinoblastoma/metabolismo , Proteínas E1A de Adenovirus/genética , Animales , Astrocitos/patología , Carcinoma Embrionario , Diferenciación Celular , Daño del ADN , Ectodermo , Regulación de la Expresión Génica/efectos de los fármacos , Genes Virales/genética , Ratones , Músculos/embriología , Sistema Nervioso/efectos de los fármacos , Sistema Nervioso/patología , Sistema Nervioso/ultraestructura , Neuronas/patología , Proteínas Nucleares/metabolismo , Unión Proteica , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Proteína p107 Similar a la del Retinoblastoma , Proteína p130 Similar a la del Retinoblastoma , Eliminación de Secuencia , Células Madre/fisiología , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
p53 is a transcriptional activator which has been implicated as a key regulator of neuronal cell death after acute injury. We have shown previously that p53-mediated neuronal cell death involves a Bax-dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified. In the present study, we demonstrate that p53 directly upregulates Apaf1 transcription as a critical step in the induction of neuronal cell death. Using DNA microarray analysis of total RNA isolated from neurons undergoing p53-induced apoptosis a 5-6-fold upregulation of Apaf1 mRNA was detected. Induction of neuronal cell death by camptothecin, a DNA-damaging agent that functions through a p53-dependent mechanism, resulted in increased Apaf1 mRNA in p53-positive, but not p53-deficient neurons. In both in vitro and in vivo neuronal cell death processes of p53-induced cell death, Apaf1 protein levels were increased. We addressed whether p53 directly regulates Apaf1 transcription via the two p53 consensus binding sites in the Apaf1 promoter. Electrophoretic mobility shift assays demonstrated p53-DNA binding activity at both p53 consensus binding sequences in extracts obtained from neurons undergoing p53-induced cell death, but not in healthy control cultures or when p53 or the p53 binding sites were inactivated by mutation. In transient transfections in a neuronal cell line with p53 and Apaf1 promoter-luciferase constructs, p53 directly activated the Apaf1 promoter via both p53 sites. The importance of Apaf1 as a p53 target gene in neuronal cell death was evaluated by examining p53-induced apoptotic pathways in primary cultures of Apaf1-deficient neurons. Neurons treated with camptothecin were significantly protected in the absence of Apaf1 relative to those derived from wild-type littermates. Together, these results demonstrate that Apaf1 is a key transcriptional target for p53 that plays a pivotal role in the regulation of apoptosis after neuronal injury.
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Apoptosis , Neuronas/metabolismo , Proteínas/genética , Activación Transcripcional , Proteína p53 Supresora de Tumor/fisiología , Animales , Factor Apoptótico 1 Activador de Proteasas , Secuencia de Bases , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Camptotecina/farmacología , Línea Celular , Células Cultivadas , Ratones , Ratones Transgénicos , Neuronas/patología , Regiones Promotoras Genéticas , Biosíntesis de Proteínas , Proteínas/fisiología , ARN Mensajero/biosíntesisRESUMEN
Programmed cell death is an ongoing process in both the developing and the mature nervous system. The tumor suppressor gene, p53, can induce apoptosis in a number of different cell types. Recently, the enhanced expression of p53 has been observed during acute neurological disease. To determine whether p53 overexpression could influence neuronal survival, we used a recombinant adenovirus vector carrying wild type p53 to transduce postmitotic neurons. A control consisting of the same adenovirus vector background but carrying the lacZ reporter expression cassette was used to establish working parameters for the effective genetic manipulation of sympathetic neurons. We have found that recombinant adenovirus can be used at titers sufficiently high (10 to 50 multiplicity of infection) to transduce the majority of the neuronal population without perturbing survival, electrophysiological function, or cytoarchitecture. Moreover, we demonstrate that overexpression of wild type p53 is sufficient to induce programmed cell death in neurons. The observation that p53 is capable of inducing apoptosis in postmitotic neurons has major implications for the mechanisms of cell death in the traumatized mature nervous system.
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Adenoviridae , Apoptosis/fisiología , Técnicas de Transferencia de Gen , Neuronas/citología , Proteína p53 Supresora de Tumor/genética , Animales , Biotina , Supervivencia Celular/genética , Senescencia Celular/fisiología , Fragmentación del ADN , Nucleótidos de Desoxiuracil , Electrofisiología , Expresión Génica/fisiología , Microscopía Electrónica , Mitosis/fisiología , Neuronas/fisiología , Neuronas/ultraestructura , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/genética , Simplexvirus , Coloración y Etiquetado , Ganglio Cervical Superior/citología , Sistema Nervioso Simpático/citología , Transducción GenéticaRESUMEN
OBJECTIVES: To establish uptake of influenza vaccine amongst care home clinical staff in Greater Nottingham, and to investigate what could be done to improve vaccine uptake in this group. STUDY DESIGN: Postal questionnaire surveys were used. In the first instance, a total sample survey was used. In the second instance, a sample of care home staff was surveyed, randomized at the care home level. METHODS: A postal questionnaire completed by care home matrons was used to obtain a preliminary estimate of staff vaccine uptake. Individual staff questionnaires were then used to validate this finding, and measure attitudes, beliefs and behaviours associated with vaccination. RESULTS: Vaccine uptake among those working in care homes with nursing was found to be low. Vaccine uptake was higher in homes with a policy recommending vaccination of staff. Most respondents who had received vaccination reported that they had done so because of an existing medical condition, rather than because of being a healthcare worker. A statistically significant relationship (P=0.02) was found between individuals' reported beliefs on how well they could resist influenza and their vaccination status. CONCLUSIONS: All care homes for the elderly should have a vaccination policy which recommends staff vaccination. Educational campaigns, vaccination in the workplace and free provision of the influenza vaccine may help to improve vaccine uptake in this group.
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Técnicos Medios en Salud/psicología , Actitud del Personal de Salud , Hogares para Ancianos , Vacunas contra la Influenza/administración & dosificación , Casas de Salud , Conocimientos, Actitudes y Práctica en Salud , Humanos , Control de Infecciones/métodos , Gripe Humana/prevención & control , Gripe Humana/transmisión , Oportunidad Relativa , Política Organizacional , Distribución Aleatoria , Muestreo , Encuestas y Cuestionarios , Reino UnidoRESUMEN
OBJECTIVE: To determine the SNOT 22 score in a normal population. STUDY DESIGN: Analysis of SNOT 22 scores participants with no sinonasal disease. SETTING: Bath, UK. PARTICIPANTS: 116 participants from a local hospital and tennis club. RESULTS: Results were obtained from 54 men and 62 women with a mean age of 40 (range 19-75). SNOT score ranged from 0-50 with a mean score of 9.3 (95% confidence interval range of 7.5-11.1). The modal score was 0 and the median score 7 (95% confidence interval range of 5-8). CONCLUSION: Due to the scewed nature of the data, the median score (7) is taken as the normal SNOT 22 score. We recommend that in an clincial situation a SNOT 22 score of 7 be used a a guide for "normal", and that care should be taken when suggesting treatment on patients with a score below this level.
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Obstrucción Nasal/diagnóstico , Encuestas y Cuestionarios , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Valores de Referencia , Rinitis/diagnóstico , Sinusitis/diagnósticoRESUMEN
OBJECTIVES: We set out to determine the psychometric validation of a disease-specific health related quality of life instrument for use in chronic rhinosinusitis, the 22 item Sinonasal Outcome Test (SNOT-22), a modification of a pre-existing instrument, the SNOT-20. DESIGN, SETTING AND PARTICIPANTS: The National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis was a prospective cohort study collecting data on 3128 adult patients undergoing sinonasal surgery in 87 NHS hospitals in England and Wales. Data were collected preoperatively and at 3 months after surgery, and analysed to determine validity of the SNOT-22. Test-retest reliability was assessed in a separate cohort of patients in a single centre. MAIN OUTCOME MEASURES: The SNOT-22, a derivative of the SNOT-20 was the main outcome measure. Patients were also asked to report whether they felt better, the same or worse following surgery. To evaluate the SNOT-22, the internal consistency, responsiveness, known group differences and validity were analysed. RESULTS: Preoperative SNOT-22 scores were completed by 2803 patients. 3-month postoperative SNOT-22 scores were available for 2284 patients of all patients who completed a preoperative form (81.5% response rate). The Cronbach's alpha scores for the SNOT-22 were 0.91 indicating high internal consistency. The test-retest reliability coefficient was 0.93, indicating high reliability of repeated measures. The SNOT-22 was able to discriminate between patients known to suffer with chronic rhinosinusitis and a group of healthy controls (P < 0.0001, t = 85.3). It was also able to identify statistically significant differences in sub-groups of patients with chronic rhinosinusitis. There was a statistically significant (P < 0.0001, t = 39.94) decrease in patient reported SNOT-22 scores at 3 months. At 3 months the overall effect size in all patients was 0.81, which is considered large. We found the minimally important difference that is the smallest change in SNOT-22 score that can be detected by a patient, to be 8.9 points. CONCLUSIONS: We have found the SNOT-22 to be valid and easy to use. It can be used to facilitate routine clinical practice to highlight the impact of chronic rhinosinusitis on the patient's quality of life, and may also be used to measure the outcome of surgical intervention. The minimally important difference allows us to interpret scores in a clinical context, and may help to improve patient selection for surgery.
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Evaluación de Resultado en la Atención de Salud , Psicometría , Calidad de Vida , Rinitis/cirugía , Sinusitis/cirugía , Encuestas y Cuestionarios , Adolescente , Adulto , Anciano , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
When introduced into P19 embryonal carcinoma cells, recombinant genes encoding MyoD converted only a small percentage (< 3%) of the transfected cells into skeletal muscle. We isolated stably transfected cells that expressed the MyoD transcript. These P19[MyoD] cells continued to express markers characteristic of undifferentiated stem cells but also expressed myf-5 and the myotonic dystrophy kinase, transcripts normally present in myoblasts but absent from P19 cells. Aggregation of P19[MyoD] cells induced the expression of myogenin, desmin, and the retinoblastoma protein and resulted in the rapid and abundant development of skeletal muscle. Both the embryonic and the slow isoforms of myosin heavy chain were present in this muscle, indicating that it resembled skeletal muscle formed from primary myoblasts. Since aggregation of P19 cells normally results in inefficient differentiation and the development of only low levels of cardiac muscle but no skeletal muscle, we conclude that MyoD imposes the skeletal muscle program on P19 cells and that the differentiation of these cells requires inductive events provided by cell aggregation.
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Músculos/citología , Proteína MioD/fisiología , Animales , Carcinoma Embrionario , Agregación Celular , Diferenciación Celular , Técnicas In Vitro , Ratones , Proteínas Musculares/metabolismo , Células Tumorales CultivadasRESUMEN
The inability to reliably express foreign proteins in postmitotic neurons has hampered numerous studies in the field of neurobiology. Within the past several years, a number of viral vectors that overcome this problem under controlled conditions in vitro have been developed. In particular, recombinant adenoviruses have proved to be efficient, non-cytotoxic vectors for manipulating neurons in dissociated and organotypic cultures, when used at low viral titres. In contrast, vectors derived from herpes simplex virus 1 still suffer from concerns regarding cellular cytotoxicity, in spite of several generations of vector development; however, recent advances in amplicon technology may solve this problem. Finally, several new-generation vectors, including those generated from adeno-associated virus, show great promise as neuronal gene-transfer vectors in vivo.
Asunto(s)
Técnicas de Transferencia de Gen , Vectores Genéticos , Neuronas/citología , Transfección/métodos , Virus , Adenoviridae/genética , Animales , Células Cultivadas , Dependovirus/genética , Herpesvirus Humano 1/genética , Humanos , Técnicas de Cultivo de ÓrganosRESUMEN
The incidence and determinants of cross-transmission in an adult intensive care unit (ICU) were examined under normal conditions. Four hundred and thirty patients were followed for 3947 patient-days. Cross-transmitted pathogens were identified by genetic typing. A cross-transmission episode was defined as when two or more patients had indistinguishable isolates and had been treated in the ICU during intervals up to seven days apart. The direction of cross-transmission was confirmed if the incriminated pathogen was isolated from the donor before admission of the recipient; otherwise, both patients could potentially be a donor or a recipient. These patients were excluded from the risk factor analysis. Recipients of pathogens were compared with those who were not involved in cross-transmission. Out of 22 056 examined specimens, 275 isolates were typed and 40 episodes of cross-transmission were detected. The overall incidence of cross-transmission was 10.7 [95% confidence intervals (CI) 7.6-14.5] per 1000 patient-days. In multivariate analysis, those who were nursed in an understaffed environment [odds ratio (OR) = 3.3, 95% CI 1.4-7.8], had a nasogastric tube (OR = 2.9, 95% CI 1.1-7.8) and were ventilated (OR = 2.5, 95% CI 1.1-6.0) for all of their stay, compared with none or part of their stay, showed an increase in the risk of cross-transmission. Repeated bronchoscopy (OR = 5.1, 95% CI 1.04-25) compared with no bronchoscopy and immunosuppresion (OR = 3.9, 95% CI 1.2-12.5) also increased the risk. This study showed that cross-transmission of nosocomial pathogens in the ICU is associated with understaffing, immunosuppression and factors that result in multiple staff/patient contacts, thus emphasizing the importance of hand hygiene.
Asunto(s)
Bacterias/patogenicidad , Infecciones Bacterianas/etiología , Infección Hospitalaria/transmisión , Control de Infecciones/métodos , Unidades de Cuidados Intensivos , Adulto , Anciano , Bacterias/genética , Bacterias/aislamiento & purificación , Infecciones Bacterianas/clasificación , Infección Hospitalaria/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Urinary incontinence is a common but under-reported condition. Approximately 17% of women are affected by detrusor overactivity at some time in their lives. Pharmacological treatment of this condition used to be severely limited by the side-effects of the drugs and the associated poor patient compliance. Recently, however, the tolerability and effectiveness of pharmacotherapy have been improved by the introduction of new drugs and alternative methods of drug delivery. This review assesses the effectiveness and tolerability of these new treatments. Anticholinergic agents, botulinum toxin and neuromodulation are also discussed.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Antagonistas Colinérgicos/uso terapéutico , Estimulación Eléctrica , Incontinencia Urinaria/terapia , Femenino , HumanosRESUMEN
PURPOSE: To evaluate the clinical and radiological outcomes following implantation of the Furlong hydroxyapatite ceramic-coated femoral stem in total hip arthroplasty. METHODS: A longitudinal cohort of 116 consecutive patients (134 hips) was followed up prospectively. The follow-up period was at least 13 years (range, 13- 15 years). Clinical and radiological assessments were made using the Merle d'Aubigne and Postel score and Engh score for fixation and stability, respectively. Osteointegration was assessed radiographically by examining the bone implant interface using the method described by Gruen. RESULTS: 22 patients died during the study period and 6 were lost to follow-up. The respective mean Merle d'Aubigne and Postel scores for pain, range of movement, and ability to walk were 2.2, 2.8, and 2.4 preoperatively and 5.8, 4.8, and 5.4 postoperatively. Engh described satisfactory bony ongrowth as 10 points or more; the mean Engh score for fixation and stability was 24.7 (fixation=10, stability=14.7). One femoral stem was revised for a periprosthetic fracture caused by a fall, but none was revised for loosening. This gave a 99% survival at 13 years (95% confidence interval 94-100). CONCLUSION: The long-term results of this hydroxyapatite ceramic-coated femoral prosthesis are very satisfactory.