Vascular risk factors,cognition and dementia incidence over 6 years in the Sydney Older Persons Study

The specific contributions of factors associated with an increased risk of stroke to cognitive decline and vascular dementia in elderly people remain somewhat unclear. We investigated the prevalence of vascular risk factors (RFs) and their role on the incidence of dementia, cognitive decline and death over a 6-year period in a sample of 377 non-demented community dwellers aged 75 years and over at the time of study entry. Presence and history of vascular RFs and cognitive decline over 6 years were ascertained using direct interviews, medical and cognitive examinations. Hypertension and history of heart disease were very common affecting about 50% of the participants. At 6 years, 114 (30%) participants had died, and 63 (16.7%) met diagnostic criteria for dementia. Hypertension was significantly associated with a greater cognitive decline but not with dementia. Smoking and stroke diagnosis showed a significant positive association with death. Reported hypercholesterolaemia was found to be associated with a protective effect for the development of dementia, for cognitive decline and for death over the 6-year period. All other associations were non-significant. Figures of dementia incidence are similar to previous studies in contrast to the lack of anticipated effects of the vascular RFs. The results indicate that in very old participants, the impact of vascular RFs changes with time and may no longer contribute to the development of dementia and cognitive decline.     

Approaches to multisite clinical trials: the National Institute of Mental Health perspective

The Division of Services and Intervention Research of the National Institute of Mental Health (NIMH) utilizes a variety of methodologies and approaches in the development of its clinical trials program. In this article, we describe the need for large multisite trials; the mechanisms for addressing this need; and the various approaches that have been used. In the course of carrying out this initiative, we have created opportunities for the Institute and its trial investigators to receive advice and input from the field. We describe the role and function of the trial coordinating center and NIMH staff. We identify the first steps to be taken in the initiation of a trial and highlight the opportunity for ancillary studies. Finally, we enumerate some of the pitfalls of large clinical trials and discuss measures taken to anticipate and address them.     

Are MRI white matter lesions clinically significant in the 'old-old'? Evidence from the Sydney Older Persons Study

BACKGROUND: The number of individuals aged over 80 years is the fastest increasing group in developed countries. White matter lesions (WML) observed on magnetic resonance imaging (MRI) have uncertain clinical significance, particularly in the old. OBJECTIVES: To determine the prevalence of periventricular and deep WML in survivors of an original cohort of randomly selected elderly community dwellers, and to examine their associations with clinical markers of vascular and extrapyramidal disorders of ageing, as well as quantitative cognitive measures. METHODS: Brain MRI, lifestyle interview, cognitive testing and medical examination were administered to 122 participants from the Sydney Older Persons Study 6-year review (mean age: 85.5 years). Apolipoprotein E (ApoE) genotype was also established. Presence and severity of periventricular and deep WML were ascertained using semi-quantitative rating methods and their relations to the cognitive and clinical variables investigated. RESULTS: Periventricular WML were present in all participants in similar severity for all three regions sampled. In contrast, a gradient of severity was observed for the deep WML: most severe in the parietal region, followed by the frontal and occipital regions, and least severe in the temporal region. Associations with gender or with the ApoE epsilon4 allele were non-significant. WML were inconsistently associated with age and cognitive functioning or with the clinical markers of dementia. No frontal specificity emerged. Examination of individual lesion types did not change the general pattern of associations. Supporting evidence for a threshold effect was observed on some measures. CONCLUSIONS: WML are extremely common in elderly, non-demented individuals. Unlike in younger individuals, MRI abnormalities may not be evidence of a current pathological process and their importance may change with advancing age.     

How to retrain the cardiothoracic surgeon

It is both an exciting and challenging time for cardiothoracic surgeons. Declining case volumes and diminishing reimbursement are causing a major disruption in the way practicing cardiothoracic surgeons approach their specialty and graduating cardiothoracic surgery residents seek employment. However, new advances in the treatment of cardiovascular diseases, such as endoluminal grafting for diseases of the thoracic aortic, are rapidly becoming available. It will take a significant commitment on behalf of busy practicing cardiothoracic surgeons to 'retrain' and develop the necessary skill-set to become proficient in catheter-based therapies and other emerging therapeutic modalities. We review the factors that contributed to the rise of cardiothoracic surgery as a specialty, the current state of the specialty and the potential that endovascular surgery offers cardiothoracic surgeons and examine the obstacles and solutions for retraining cardiothoracic surgeons.     

Outcomes of inferonasal Baerveldt glaucoma drainage implant surgery

PURPOSE: To determine the outcomes of inferonasal Baerveldt glaucoma implant (BGI) surgery. PATIENTS AND METHODS: A retrospective, non-comparative case series of 182 eyes of 182 patients who underwent inferonasal placement of a Baerveldt glaucoma implant. The main outcome measures included intraocular pressure, number of glaucoma medications, best corrected visual acuity, and complications. RESULTS: Patients were followed for an average (+/- SD) of 19 +/- 15 months. Median Snellen visual acuity was unchanged at last follow-up. Intraocular pressure was reduced from a mean (+/- SD) of 28.6 +/- 11.5 mm Hg preoperatively to 13.4 +/- 5.7 mm Hg at most recent follow-up (P < 0.001). The number of antiglaucoma medications was reduced from a mean (+/- SD) of 2.7 +/- 1.3 preoperatively to 1.1 +/- 1.1 at most recent follow-up. Nineteen eyes met our criteria for failure, yielding a cumulative percent survival of 92% at 12 months, 88% at 24 months, and 77% at 44 months. The most common complications were hyphema (14 eyes, 8%), choroidal effusion (12 eyes, 7%), and corneal decompensation (19 eyes, 10%). Endophthalmitis and diplopia occurred rarely (1 eye, <1%; 3 eyes, 2%, respectively). CONCLUSIONS: Inferonasal Baerveldt glaucoma implant placement appears to be a safe and effective surgical option that may be helpful in certain clinical situations.     

Kinetic and efficacy analysis of RNA interference in stably and transiently expressing cell lines

RNA interference, particularly through the use of small interfering RNA (siRNA), has become an important laboratory tool for both fundamental and applied investigations. However, it is currently unknown whether siRNA-mediated knockdown of transiently expressed proteins is an acceptable quantitative surrogate for stably expressed proteins. Further, the best means by which to transfect cells with functionally active siRNA are poorly defined, and determination of the best reagent and transfection conditions for a particular cell line is a burdensome prerequisite for RNA interference studies. We therefore established the optimal transfection conditions for six commercial siRNA delivery reagents in three cell lines (HR5-CL11, HeLa, and NIH/3T3) transiently or stably expressing the firefly luciferase gene. The delivery efficiency, knockdown kinetics, and cytotoxicity of the reagents were evaluated. siPORT Amine, X-tremeGENE, and TransIT-siQUEST achieved the best knockdown and consistency of performance among the three cell lines. Delivery efficiency varied and was cell line dependent in some cases. The knockdown kinetics were reagent-dependent, and knockdown was generally more rapid in the stably transfected cells. Cytotoxicity of the reagents was variable. GeneSilencer was the least cytotoxic reagent for all three cell lines, and TransIT-siQUEST was the most cytotoxic to the HeLa and HR5-CL11 cell lines. These comparative results provide an initial basis for reagent selection and experimental design for RNA interference studies in HeLa, NIH/3T3, and their respective derivative cell lines.     

Biophysical and Structural Characterization of Polyethylenimine-Mediated siRNA Delivery in Vitro

Purpose The goals of this study were as follows: 1) to evaluate the efficacy of different polyethylenimine (PEI) structures for siRNA delivery in a model system, and 2) to determine the biophysical and structural characteristics of PEI that relate to siRNA delivery.Materials and Methods Biophysical characterization (effective diameter and zeta potential), cytotoxicities, relative binding affinities and in vitro transfection efficiencies were determined using nanocomplexes formed from PEI's of 800, 25,000, (both branched) and 22,000 (linear) molecular weights at varying N:P ratios and siRNA concentrations. The HR5-CL11 cell line stably expressing luciferase was used as a model system in vitro.Results Successful siRNA delivery was observed within a very narrow window of conditions, and only with the 25,000 branched PEI at an N:P ratio of 6:1 and 8:1 and with 200 nM siRNA. While the zeta potential and size of PEI:siRNA complexes correlated to transfection efficacy in some cases, complex stability may also affect transfection efficacy.Conclusions The ability of PEI to transfer functionally active siRNA to cells in culture is surprisingly dependent on its biophysical and structural characteristics when compared to its relative success and ease of use for DNA delivery.     

Trends in career choice by US medical school graduates

Context  Trends in career choice among specialties have varied greatly. Most notable is the recent decrease in the percentage of US medical student graduates choosing a primary care career, which has important implications for the US physician workforce. Objective  To review temporal trends in career choice by graduates of allopathic US medical schools, focusing on US medical doctors entering residencies since 1987. Data Sources  Three databases, the Association of American Medical Colleges Graduation Questionnaire (AAMC GQ), the National Resident Matching Program, and the national Graduate Medical Education census, were used to review temporal trends in the number of US medical doctors entering residencies in primary care, general or subspecialty surgical, and non–primary care and nonsurgical specialties from 1987 to 2002. Data Synthesis  In 1987, 49.2% of all medical school graduates matched to one of the generalist residencies (internal medicine, pediatrics, or family medicine). The percentage of students matching to primary care specialties declined in the early 1990s, peaked at 53.2% in 1998, and declined to 44.2% in 2002. Concurrent with the latter decline, AAMC GQ data showed a decrease in medical student interest in primary care careers (35.6% in 1999 to 21.5% in 2002). The total percentage of US medical doctors matching to general or subspecialty surgical residencies remained stable at 11% to 12% from 1987 to 2002. During this same period, emergency medicine and plastic surgery increased as a match choice, while anesthesiology, pathology, and psychiatry were more variable over time. Conclusions  Distribution of medical students' career choices among specialties varied considerably from 1987 to 2002. The debate will continue regarding the appropriate specialty mix within the physician workforce.      

Sleep disruption in young children. The influence of temperament on the sleep patterns of pre-school children

Sleep problems are a common concern of parents with toddlers. Various reasons have been put forward as to the possible causes and maintenance of sleep disruption. These have included neurophysical differences in the child, perinatal differences such as a long labour and depression and anxiety in the parents themselves resulting in adverse effects on the child's sleep patterns. However, recent research has indicated that a child's temperamental style may be a possible causal factor as to whether the child will present its parents with a sleep problem. This study, therefore, sets out to investigate the importance of temperament as a predictor of whether children may or may not have sleep problems. Environmental factors are controlled as far as possible by selecting toddlers with and without sleep problems from very similar environments. Case studies are also introduced to further illuminate other possible associated factors such as parental handling. The results from this study found significant differences in the temperament profiles of children with and without sleep problems. Children with reported sleep problems were more likely to obtain a‘intermediate high to difficult’profile. Various findings from a group of toddlers with and without sleep problems are discussed in this paper together with implications of the findings and recommendations for further research.