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Sex-related differences in brain and behavior are apparent across the life course, but the exact set of processes that guide their emergence in utero remains a topic of vigorous scientific inquiry. Here, we evaluate sex and gestational age (GA)-related change in functional connectivity (FC) within and between brain wide networks. Using resting-state functional magnetic resonance imaging we examined FC in 118 human fetuses between 25.9 and 39.6 weeks GA (70 male; 48 female). Infomap was applied to the functional connectome to identify discrete prenatal brain networks in utero. A consensus procedure produced an optimal model comprised of 16 distinct fetal neural networks distributed throughout the cortex and subcortical regions. We used enrichment analysis to assess network-level clustering of strong FC-GA correlations separately in each sex group, and to identify network pairs exhibiting distinct patterns of GA-related change in FC between males and females. We discovered both within and between network FC-GA associations that varied with sex. Specifically, associations between GA and posterior cingulate-temporal pole and fronto-cerebellar FC were observed in females only, whereas the association between GA and increased intracerebellar FC was stronger in males. These observations confirm that sexual dimorphism in functional brain systems emerges during human gestation.
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Mapeo Encefálico/métodos , Encéfalo/embriología , Desarrollo Fetal/fisiología , Atención Prenatal/métodos , Caracteres Sexuales , Femenino , Humanos , Masculino , EmbarazoRESUMEN
SETTING: We conducted a qualitative exploration into the palatability and acceptability of a novel fixed-dose combination (FDC) anti-tuberculosis drug. This study was nested in the SHINE (Shorter treatment for minimal TB in children) trial, which compares the safety and efficacy of treating non-severe drug-susceptible tuberculosis (TB) with a 6 vs. 4 months anti-tuberculosis regimen in children aged 0-16 years. Participants were recruited in Cape Town, South Africa.OBJECTIVE: To describe the palatability and acceptability of a FDC of rifampicin, isoniazid and pyrazinamide among South African children and their caregivers in the SHINE trial.METHODS: We conducted 20 clinic observations of treatment administration, during which we conducted 16 semi-structured interviews with children and their caregivers. Data were organised thematically to report on experiences with administering and ingesting the FDC.RESULTS: Children and caregivers' experiences varied from delight to disgust. In general, participants said that the FDC compared favourably to other formulations. Pragmatic challenges such as dissolving the FDC and the time required to administer the FDC impeded caregivers' ability to integrate treatment into their daily routines. Drug manipulation was common among caregivers to improve TB treatment administration.CONCLUSION: This novel FDC appears acceptable for children, albeit with practical challenges to administration. Scale-up of FDC use should include supplementary intervention components to support caregivers.
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Antituberculosos/uso terapéutico , Satisfacción del Paciente , Tuberculosis Pulmonar/tratamiento farmacológico , Administración Oral , Adolescente , Antituberculosos/administración & dosificación , Estudios de Casos y Controles , Niño , Servicios de Salud del Niño , Preescolar , Esquema de Medicación , Femenino , Humanos , Lactante , Recién Nacido , Entrevistas como Asunto , Masculino , SudáfricaRESUMEN
As the UK witnesses a decline in the number of edentulous adults, there is a simultaneous reduction in the number of cases available to undergraduate dental students for the teaching of complete dentures. When edentulous adults are unable to function with conventional complete dentures, particularly pertaining to the mandibular denture, an implant-supported mandibular overdenture has been evidenced as the gold standard for edentulous patients. The evidence in favour of mandibular implant-supported overdentures is one of the most robust evidence bases for any clinical treatment and similarly it has been shown that undergraduate students are equally as capable in the provision of implant-supported overdentures as experienced prosthodontists. Yet there appears to be a disparity in the General Dental Council's undergraduate learning outcomes pertaining to care for edentulous adults. Furthermore, the UK seems to be falling behind in this respect in comparison to our European, American and Australian colleagues. This review looks at the evidence for the provision of implant-supported overdentures in the setting of the undergraduate dental curriculum, the potential barriers within this teaching forum and how well prepared UK undergraduates are for the clinical management of edentulous patients in the future.
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Competencia Clínica , Educación de Posgrado en Odontología , Boca Edéntula , Necesidades y Demandas de Servicios de Salud , Humanos , Boca Edéntula/terapia , Reino UnidoRESUMEN
BACKGROUND: As children mature, they become increasingly independent and less reliant on caregiver support. Changes in brain systems are likely to stimulate and guide this process. One mechanistic hypothesis suggests that changes in neural systems that process reward and threat support the increase in exploratory behavior observed in the transition to adolescence. This study examines the basic tenets of this hypothesis by performing functional magnetic resonance imaging (fMRI) during well-established reward and threat processing tasks in 40 children and adolescents, aged 9-15 years. METHOD: fMRI responses in the striatum and amygdala are fit to a model predicting that striatal reward and amygdala threat-responses will be unrelated in younger participants (aged 9-12 years), while older participants (aged 13-15 years) will differentially engage these structures. RESULTS: Our data are consistent with this model. Activity in the striatum and amygdala are comparable in younger children, but in older children, they are inversely related; those more responsive to reward show a reduced threat-response. Analyses testing age as a continuous variable yield consistent results. In addition, the proportion of threat to reward-response relates to self-reported approach behavior in older but not younger youth, exposing behavioral relevance in the relative level of activity in these structures. CONCLUSIONS: Results are consistent with the notion that both individual and developmental differences drive reward-seeking behavior in adolescence. While these response patterns may serve adaptive functions in the shift to independence, skew in these systems may relate to increased rates of emotional psychopathology and risk-taking observed in adolescence.
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Conducta del Adolescente/fisiología , Desarrollo del Adolescente/fisiología , Amígdala del Cerebelo/fisiología , Mapeo Encefálico/métodos , Miedo/fisiología , Neostriado/fisiología , Recompensa , Adolescente , Factores de Edad , Amígdala del Cerebelo/diagnóstico por imagen , Niño , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Neostriado/diagnóstico por imagenRESUMEN
A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes in HIV infection, but measuring adherence is difficult. We investigated whether responses to a questionnaire eliciting caregiver beliefs in medicines were associated with adherence of their child (median age 2.8 years), and whether this in turn was associated with viral suppression. We used the validated beliefs in medicine questionnaire (BMQ) to measure caregiver beliefs, and medication event monitoring system caps to measure adherence. We found significant associations between BMQ scores and adherence, and between adherence and viral suppression. Among children initiating Antiretroviral therapy (ART), we also found significant associations between BMQ 'necessity' scores, and BMQ 'necessity-concerns' scores, and later viral suppression. This suggests that the BMQ may be a valuable tool when used alongside other adherence measures, and that it remains important to keep caregivers well informed about the long-term necessity of their child's ART.
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Fármacos Anti-VIH/uso terapéutico , Actitud Frente a la Salud , Cuidadores , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , África del Sur del Sahara , Alquinos , Benzoxazinas/uso terapéutico , Niño , Preescolar , Ciclopropanos , Didesoxinucleósidos/uso terapéutico , Femenino , Humanos , Lactante , Lamivudine/uso terapéutico , Modelos Lineales , Modelos Logísticos , Masculino , Análisis Multivariante , Nevirapina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estavudina/uso terapéutico , Encuestas y Cuestionarios , Uganda , Zambia , Zidovudina/uso terapéuticoRESUMEN
Connections between the amygdala and medial prefrontal cortex (mPFC) are considered critical for the expression and regulation of emotional behavior. Abnormalities in frontoamygdala circuitry are reported across several internalizing conditions and associated risk factors (for example, childhood trauma), which may underlie the strong phenotypic overlap and co-occurrence of internalizing conditions. However, it is unclear if these findings converge on the same localized areas of mPFC or adjacent anterior cingulate cortex (ACC). Examining 46 resting-state functional connectivity magnetic resonance imaging studies of internalizing conditions or risk factors (for example, early adversity and family history), we conducted an activation likelihood estimation meta-analysis of frontoamygdala circuitry. We included all reported amygdala to frontal coordinate locations that fell within a liberal anatomically defined frontal mask. Peak effects across studies were centered in two focal subareas of the ACC: pregenual (pgACC) and subgenual (sgACC). Using publicly available maps and databases of healthy individuals, we found that observed subareas have unique connectivity profiles, patterns of neural co-activation across a range of neuropsychological tasks, and distribution of tasks spanning various behavioral domains within peak regions, also known as 'functional fingerprints'. These results suggest disruptions in unique amygdala-ACC subcircuits across internalizing, genetic and environmental risk studies. Based on functional characterizations and the studies contributing to each peak, observed amygdala-ACC subcircuits may reflect separate transdiagnostic neural signatures. In particular, they may reflect common neurobiological substrates involved in developmental risk (sgACC), or the broad expression of emotional psychopathology (pgACC) across disease boundaries.
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Síntomas Afectivos/fisiopatología , Amígdala del Cerebelo/fisiopatología , Giro del Cíngulo/fisiopatología , Control Interno-Externo , Red Nerviosa/fisiopatología , Corteza Prefrontal/fisiopatología , Amígdala del Cerebelo/diagnóstico por imagen , Mapeo Encefálico/métodos , Giro del Cíngulo/diagnóstico por imagen , Humanos , Imagenología Tridimensional , Imagen por Resonancia Magnética , Red Nerviosa/diagnóstico por imagen , Tomografía de Emisión de Positrones , Corteza Prefrontal/diagnóstico por imagenRESUMEN
N K-edge near-edge X-ray absorption fine-structure (NEXAFS) spectra of imidazole in concentrated aqueous solutions have been acquired. The NEXAFS spectra of the solution species differ significantly from those of imidazole monomers in the gas phase and in the solid state of imidazole, demonstrating the strong sensitivity of NEXAFS to the local chemical and structural environment. In a concentration range from 0.5 to 8.2 mol L(-1) the NEXAFS spectrum of aqueous imidazole does not change strongly, confirming previous suggestions that imidazole self-associates are already present at concentrations more dilute than the range investigated here. We show that various types of electronic structure calculations (Gaussian, StoBe, CASTEP) provide a consistent and complete interpretation of all features in the gas phase and solid state spectra based on ground state electronic structure. This suggests that such computational modelling of experimental NEXAFS will permit an incisive analysis of the molecular interactions of organic solutes in solutions. It is confirmed that microhydrated clusters with a single imidazole molecule are poor models of imidazole in aqueous solution. Our analysis indicates that models including both a hydrogen-bonded network of hydrate molecules, and imidazole-imidazole interactions, are necessary to explain the electronic structure evident in the NEXAFS spectra.
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INTRODUCTION: An electronic portfolio was introduced for undergraduate students in the School of Dental Sciences at Newcastle University. Its introduction was evaluated in terms of both staff and student response. METHODS: A quantitative-qualitative methodology was adopted. Student views were examined quantitatively using a Likert scale based questionnaire both pre- and post-introduction of the eportfolio. Staff views were examined qualitatively by the use of focus groups. RESULTS AND DISCUSSION: Findings included that the system was easy to use and it provided a large quantity of high quality data. The aim of the system to improve reflection and feedback was not perceived as a benefit by staff or students. The need for training was highlighted and a major disadvantage of the system was its time consuming nature. The evaluation has lead to further development of the system and continued evaluation will be important.
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Documentación , Docentes de Odontología , Estudiantes de Odontología/psicología , Adulto , Educación en Odontología , Evaluación Educacional/métodos , Inglaterra , Retroalimentación , Femenino , Grupos Focales , Humanos , Masculino , Competencia Profesional , Estadísticas no Paramétricas , Encuestas y CuestionariosRESUMEN
Major Depressive Disorder (MDD) has been conceptualized as a neural network-level disease. Few studies of the neural bases of depression, however, have used analytical techniques that are capable of testing network-level hypotheses of neural dysfunction in this disorder. Moreover, of those that have, fewer still have attempted to determine the directionality of influence within functionally abnormal networks of structures. We used multivariate GC analysis, a technique that estimates the extent to which preceding neural activity in one or more seed regions predicts subsequent activity in target brain regions, to analyze blood-oxygen-level-dependent (BOLD) data collected during eyes-closed rest from depressed and never-depressed persons. We found that activation in the hippocampus predicted subsequent increases in ventral anterior cingulate cortex (vACC) activity in depression, and that activity in the medial prefrontal cortex and vACC were mutually reinforcing in MDD. Hippocampal and vACC activation in depressed participants predicted subsequent decreases in dorsal cortical activity. This study shows that, on a moment-by-moment basis, there is increased excitatory activity among limbic and paralimbic structures, as well as increased inhibition in the activity of dorsal cortical structures, by limbic structures in depression; these aberrant patterns of effective connectivity implicate disturbances in the mesostriatal dopamine system in depression. These findings advance the neural theory of depression by detailing specific patterns of limbic excitation in MDD, by making explicit the primary role of limbic inhibition of dorsal cortex in the cortico-limbic relation posited to underlie depression, and by presenting an integrated neurofunctional account of altered dopamine function in this disorder.
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Mapeo Encefálico , Encéfalo/irrigación sanguínea , Trastorno Depresivo Mayor/patología , Adolescente , Adulto , Encéfalo/patología , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oxígeno/sangre , Adulto JovenRESUMEN
BACKGROUND: Fixed-dose combination scored dispersible stavudine, lamivudine, and nevirapine minitablets (Triomune Baby and Junior; Cipla Ltd) are simpler and cheaper than liquid formulations and have correct dose ratios for human immunodeficiency virus-infected children. However, they cannot be used for dose escalation (DE) of nevirapine. METHODS: Children were randomized to initiate antiretroviral therapy with full-dose (FD) nevirapine (Triomune Baby or Junior in the morning and evening) versus DE (half-dose nevirapine for 14 days [Triomune in the morning and stavudine-lamivudine {Lamivir-S} in the evening], then FD), in accordance with World Health Organization weight-band dosing tables. The primary end point was nevirapine-related clinical or laboratory grade 3 or 4 adverse events (AEs). RESULTS: In total, 211 children (median [interquartile range {IQR}] age, 5 [ 2-9 ] years; median [IQR] CD4 cell percentage, 13% [8%-18%]) were enrolled and followed up for a median (IQR) of 92 (68-116) weeks. There were 31 grade 3 or 4 AEs that were definitely/probably or uncertainly related to nevirapine in the FD group (18.0 per 100 child-years), compared with 29 in the DE group (16.5 per 100 child-years) (incidence rate ratio, 1.09; 95% confidence interval, 0.63–1.87; P = .74). All were asymptomatic; 11 versus 3 were single grade 3 or 4 elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, all of which resolved without a change in nevirapine dose or interruption. Thirteen (12%) FD versus 2 (2%) DE children had grade 1 (2 in FD) or grade 2 (11 in FD and 2 in DE) rashes. Three (2 in FD and 1 in DE) substituted efavirenz, 3 (FD) continued FD nevirapine, and 9 (8 in FD and 1 in DE) temporarily interrupted nevirapine, followed by successful DE. Predictors of nevirapine rash were older age (P = .003) and higher CD4 cell count for age (P = .03). Twenty-two children died (12 in FD and 10 in DE), 1 FD and 5 DE children at <4 weeks; none were considered to be drug related by independent review. CONCLUSIONS: Rash was more frequent with FD nevirapine, but 88% had no clinical toxicity; elevated AST or ALT levels were transient and resolved spontaneously, suggesting that routine laboratory monitoring has limited value. Dual pediatric stavudine-lamivudine minitablets are preferred for safe and simple DE; if unavailable, initiating FD Triomune requires timely review for rash, which could be managed by temporary reduction to half-dose Triomune or efavirenz substitution. TRIAL REGISTRATION: Current Controlled Trials identifier: ISRCTN31084535 .
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Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/tratamiento farmacológico , Nevirapina/administración & dosificación , Nevirapina/efectos adversos , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas , Niño , Exantema/inducido químicamente , Humanos , Lamivudine/administración & dosificación , Estavudina/farmacología , ZambiaRESUMEN
This article represents the consensus from a meeting of the British Society of Prosthetic Dentistry's Education Group which met to discuss implant dentistry at the undergraduate dental student level. The consensus recognises the need to embed the teaching of implant supported prostheses if such a treatment modality is to be widely practised after graduation. This short article makes some recommendations as well as detailing some challenges and barriers that need to be overcome if implant dentistry is to be successfully embedded in an undergraduate dental curriculum.
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Conferencias de Consenso como Asunto , Implantes Dentales , Educación en Odontología , Prostodoncia/educación , Competencia Clínica , Curriculum , Prótesis Dental de Soporte Implantado , Humanos , Planificación de Atención al Paciente , Desarrollo de Programa , Enseñanza/métodos , Reino UnidoRESUMEN
AIMS/HYPOTHESIS: The aim of this study was to determine the pattern of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin on cardiovascular events in patients with type 2 diabetes and no prior history of cardiovascular disease (CVD). MATERIALS AND METHODS: A post hoc analysis of data from the Collaborative Atorvastatin Diabetes Study (CARDS), a randomised, placebo-controlled trial of 2,838 patients with type 2 diabetes, was performed. Patients received atorvastatin (10 mg daily) or placebo and were evaluated for cardiovascular and other outcomes over a median follow-up period of 3.9 years. Cox proportional hazards modelling was carried out, and the hazard ratios calculated for various times after randomisation to treatment were investigated. RESULTS: A reduction in the primary endpoint of major CVD events was apparent and statistically significant as soon as 18 months after treatment initiation. The effect of atorvastatin on CHD events was apparent by 6 months, and at 1 year was similar to the 37% relative risk reduction observed at trial closure. CONCLUSIONS/INTERPRETATION: Atorvastatin alters the pathogenesis of CVD rapidly, such that the effect on cardiovascular events is apparent within months of initiation of therapy.
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Anticolesterolemiantes/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/complicaciones , Ácidos Heptanoicos/uso terapéutico , Pirroles/uso terapéutico , Atorvastatina , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Incidencia , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: To study the effect of age at death, sex, ethnic group, date of death, underlying cause of death and social class on the frequency of reporting diabetes on death certificates in known cases of diabetes. METHODS: Data were extracted from certificates recording 981 deaths which occurred between 1985 and 1999 in people aged 45 years or more who participated in the UK Prospective Diabetes Study, to which 23 English, Scottish and Northern Ireland centres contributed. Diabetes (9th revision of the International Classification of Diseases; ICD-9 250) entered on parts 1A-1C or 2A-2C of the death certificate was considered as reporting diabetes. Logistic regression analyses were used to determine independent factors associated with the reporting of diabetes. RESULTS: Diabetes was reported on 42% (419/981) of all death certificates and on 46% (249/546) of those with underlying cardiovascular disease causes. Reporting of diabetes was independently associated on all death certificates with per year of age increase (OR 1.02; 95% CI 1.001-1.04, P = 0.037), underlying cause of death (non-cardiovascular causes OR 0.76; 95% CI 0.59-0.98, P = 0.035) and social class (classes I-II OR 1.00; class III OR 1.35; 95% CI 0.96-1.89, P = 0.084, classes IV-V OR 1.48; 95% CI 1.05-2.10, P = 0.027). Stratification by age, sex, and underlying cause of death also revealed significant differences in the frequency of reporting diabetes over time. CONCLUSIONS: The rate of reporting of diabetes on cardiovascular disease death certificates remains poor. This may indicate a lack of awareness of the importance of diabetes as a risk factor for cardiovascular disease.
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Enfermedades Cardiovasculares/mortalidad , Causas de Muerte , Certificado de Defunción , Diabetes Mellitus/mortalidad , Distribución por Edad , Anciano , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Distribución por Sexo , Clase Social , Reino Unido/epidemiologíaRESUMEN
AIM: To describe baseline characteristics of patients in the Collaborative AtoRvastatin Diabetes Study (CARDS), a randomized, placebo-controlled trial of lipid lowering with atorvastatin 10 mg daily for the primary prevention of major cardiovascular events in patients with Type 2 diabetes. METHODS: The main eligibility criteria were Type 2 diabetes, age 40-75 years, no previous history of coronary heart disease, stroke or other major cardiovascular events, a documented history of at least one of retinopathy, micro- or macroalbuminuria, hypertension or current smoking, LDL-cholesterol < or = 4.14 mmol/l and triglycerides < or = 6.78 mmol/l. RESULTS: Randomization of 2838 persons (909 women) into CARDS was completed in June 2001. At entry, mean age was 62 years, 12% were over 70 years old and median duration of diabetes was 6 years. Median fasting lipid levels were total cholesterol 5.4 mmol/l, LDL-cholesterol 3.1 mmol/l, HDL-cholesterol 1.4 mmol/l and triglyceride 1.7 mmol/l. There was a documented history of retinopathy in 30% of patients, micro/macroalbuminuria in 11% (additionally 17% had micro/macroalbuminuria based on two elevated pretreatment measurements of albumin-creatinine ratios), hypertension in 79% and 23% were current smokers. CONCLUSION: CARDS will contribute importantly to the evidence for the macrovascular and microvascular benefits of lipid lowering with atorvastatin in patients with Type 2 diabetes. The results are likely to have important implications for the management of patients.
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Anticolesterolemiantes/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Pirroles/uso terapéutico , Adulto , Anciano , Atorvastatina , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Enfermedad Coronaria/sangre , Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
SimSET is Monte Carlo simulation software for emission tomography. This paper describes a simple but effective scheme for parallel execution of SimSET using NetSolve, a client-server system for distributed computation. NetSolve (version 1.4.1) is "grid middleware" which enables a user (the client) to run specific computations remotely and simultaneously on a grid of networked computers (the servers). Since the servers do not have to be identical machines, computation may take place in a heterogeneous environment. To take advantage of diversity in machines and their workloads, a client-side scheduler was implemented for the Monte Carlo simulation. The scheduler partitions the total decay events by taking into account the inherent compute-speeds and recent average workloads, i.e., the scheduler assigns more decay events to processors expected to give faster service and fewer decay events to those expected to give slower service. When compute-speeds and sustained workloads are taken into account, the speed-up is essentially linear in the number of equivalent "maximum-service" processors. One modification in the SimSET code (version 2.6.2.3) was made to ensure that the total number of decay events specified by the user is maintained in the distributed simulation. No other modifications in the standard SimSET code were made. Each processor runs complete SimSET code for its assignment of decay events, independently of others running simultaneously. Empirical results are reported for simulation of a clinical-quality lung perfusion study.
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Redes de Comunicación de Computadores , Simulación por Computador , Programas Informáticos , Tomografía Computarizada de Emisión , Metodologías Computacionales , Sistemas de Administración de Bases de Datos , Humanos , Método de MontecarloRESUMEN
The effect of statin therapy on subclasses of LDL, VLDL and HDL lipoproteins is unclear. We compared changes in serum lipids, apolipoproteins and nuclear magnetic resonance (NMR) spectroscopy measured lipoprotein subclass concentration and average particle size over a minimum 6 months treatment period of atorvastatin 10 mg vs. placebo in 122 men and women. All subjects had type 2 diabetes and a modest dyslipidaemia (mean LDL-cholesterol 3.2 mmol/l and median triglycerides 1.8 mmol/l) and had a previous myocardial infarction. Compared with placebo, atorvastatin therapy was associated with a greater decrease in medium VLDL (median within person change -13.4 vs. -5.9 nmol/l, P<0.001 adjusted for baseline level), small VLDL (median change -17.8 vs. -8.1 nmol/l, P=0.002), large LDL (mean within person change -167.9 vs. -48.6 nmol/l, P<0.001) and medium LDL (median within person change -101.8 vs. -22.3 nmol/l, P=0.017). Atorvastatin therapy was also associated with a greater increase in large HDL than placebo (median change 1.40 vs. 0.80 micromol/l, P=0.02) and there was little change in small HDL so that average HDL particle size increased significantly with atorvastatin (P=0.04). In addition to reducing levels of (enzymatically measured) triglyceride, LDL-cholesterol and apolipoprotein B in diabetic patients, atorvastatin significantly reduces NMR measured medium and small VLDL and large and medium LDL, and increases large HDL.
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Ácidos Heptanoicos/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Hiperlipidemias/tratamiento farmacológico , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Isquemia Miocárdica/tratamiento farmacológico , Pirroles/administración & dosificación , Anciano , Atorvastatina , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Método Doble Ciego , Femenino , Humanos , Hiperlipidemias/complicaciones , Hiperlipidemias/diagnóstico , Lipoproteínas HDL/efectos de los fármacos , Lipoproteínas LDL/efectos de los fármacos , Lipoproteínas VLDL/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Isquemia Miocárdica/diagnóstico , Cooperación del Paciente , Probabilidad , Valores de Referencia , Medición de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: There are few data on the role of lipid lowering in the primary prevention of coronary heart disease (CHD) in diabetic patients. This paper describes the design of a collaborative clinical trial between Diabetes UK, the NHS Research and Development Directorate and Pfizer UK, that addresses this question. METHODS: The Collaborative AtoRvastatin Diabetes Study (CARDS) is a multicentre, randomized, placebo-controlled, double-blind clinical trial of primary prevention of cardiovascular disease in patients with Type 2 diabetes. The primary objective is to investigate whether treatment with the hydroxymethylglutaryl coenzyme A reductase inhibitor, atorvastatin, reduces the incidence of major cardiovascular events. At entry patients have at least one other risk factor for CHD in addition to diabetes, namely current smoking, hypertension, retinopathy, or micro- or macroalbuminuria. At randomization patients have been selected for a serum low-density lipoprotein (LDL) cholesterol concentration < or = 4.14 mmol/l (160 mg/dl) and triglycerides < or = 6.78 mmol/l (600 mg/dl). Randomization was completed in June 2001. Patients will be followed until 304 primary endpoints have accrued (expected date early 2005). The trial includes 2838 men and women aged 40-75 years. This report describes the design and administration of the study and reviews the evidence to date of the effectiveness of lipid-lowering therapy in Type 2 diabetes. CONCLUSIONS: The case for lipid-lowering therapy for the primary prevention of CHD in diabetes has not been demonstrated. CARDS will provide essential information on the extent of any benefits and adverse effects of lipid-lowering therapy in diabetic patients without prior CHD.
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Anticolesterolemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Heptanoicos/uso terapéutico , Pirroles/uso terapéutico , Adulto , Anciano , Atorvastatina , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Humanos , Lípidos/sangre , Lipoproteínas/sangre , Persona de Mediana Edad , Selección de Paciente , Placebos , Proyectos de InvestigaciónRESUMEN
BACKGROUND: The management of colon injuries that require resection is an unresolved issue because the existing practices are derived mainly from class III evidence. Because of the inability of any single trauma center to accumulate enough cases for meaningful statistical analysis, a multicenter prospective study was performed to compare primary anastomosis with diversion and identify the risk factors for colon-related abdominal complications. METHODS: This was a prospective study from 19 trauma centers and included patients with colon resection because of penetrating trauma, who survived at least 72 hours. Multivariate logistic regression analysis was used to compare outcomes in patients with primary anastomosis or diversion and identify independent risk factors for the development of abdominal complications. RESULTS: Two hundred ninety-seven patients fulfilled the criteria for inclusion and analysis. Overall, 197 patients (66.3%) were managed by primary anastomosis and 100 (33.7%) by diversion. The overall colon-related mortality was 1.3% (four deaths in the diversion group, no deaths in the primary anastomosis group, p = 0.012). Colon-related abdominal complications occurred in 24% of all patients (primary repair, 22%; diversion, 27%; p = 0.373). Multivariate analysis including all potential risk factors with p values < 0.2 identified three independent risk factors for abdominal complications: severe fecal contamination, transfusion of > or = 4 units of blood within the first 24 hours, and single-agent antibiotic prophylaxis. The type of colon management was not found to be a risk factor. Comparison of primary anastomosis with diversion using multivariate analysis adjusting for the above three identified risk factors or the risk factors previously described in the literature (shock at admission, delay > 6 hours to operating room, penetrating abdominal trauma index > 25, severe fecal contamination, and transfusion of > 6 units blood) showed no statistically significant difference in outcome. Similarly, multivariate analysis and comparison of the two methods of colon management in high-risk patients showed no difference in outcome. CONCLUSION: The surgical method of colon management after resection for penetrating trauma does not affect the incidence of abdominal complications, irrespective of associated risk factors. Severe fecal contamination, transfusion of > or = 4 units of blood within the first 24 hours, and single-agent antibiotic prophylaxis are independent risk factors for abdominal complications. In view of these findings, the reduced quality of life, and the need for a subsequent operation in colostomy patients, primary anastomosis should be considered in all such patients.
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Colectomía/métodos , Colon/lesiones , Colon/cirugía , Heridas Penetrantes/cirugía , Adulto , Anastomosis Quirúrgica , Femenino , Humanos , Tiempo de Internación , Masculino , Complicaciones Posoperatorias , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Although the presence of an olfactory impairment in Parkinson's disease (PD) has been recognized for 25 years, its cause remains unclear. Here we suggest a contributing factor to this impairment, namely, that PD impairs active sniffing of odorants. We tested 10 men and 10 women with clinically typical PD, and 20 age- and gender-matched healthy controls, in four olfactory tasks: (i) the University of Pennsylvania smell identification test; (ii and iii) detection threshold tests for the odorants vanillin and propionic acid; and (iv) a two-alternative forced-choice detection paradigm during which sniff parameters (airflow peak rate, mean rate, volume, and duration) were recorded with a pneomatotachograph-coupled spirometer. An additional experiment tested the effect of intentionally increasing sniff vigor on olfactory performance in 20 additional patients. PD patients were significantly impaired in olfactory identification (P < 0.0001) and detection (P < 0.007). As predicted, PD patients were also significantly impaired at sniffing, demonstrating significantly reduced sniff airflow rate (P < 0.01) and volume (P < 0.002). Furthermore, a patient's ability to sniff predicted his or her performance on olfactory tasks, i.e., the more poorly patients sniffed, the worse their performance on olfaction tests (P < 0.009). Finally, increasing sniff vigor improved olfactory performance in those patients whose baseline performance had been poorest (P < 0.05). These findings implicate a sniffing impairment as a component of the olfactory impairment in PD and further depict sniffing as an important component of human olfaction.