RTP801 regulates motor cortex synaptic transmission and learning.

BACKGROUND: RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinson's and Huntington's diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinson's and Huntington's disease mouse models, RTP801 knockdown alleviates motor-learning deficits. RESULTS: We investigated the physiological role of RTP801 in neuronal plasticity and we found RTP801 in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. CONCLUSIONS: Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity and motor learning. They will help to understand its role in neurodegenerative disorders where RTP801 levels are detrimentally upregulated

Adipocyte mitochondrial genes and the forkhead factor FOXC2 are decreased in type 2 diabetes patients and normalized in response to rosiglitazone

<p>Abstract</p> <p>Background</p> <p>FOXC2 has lately been implicated in diabetes and obesity as well as mitochondrial function and biogenesis and also as a regulator of mtTFA/Tfam. In this study, the expression of FOXC2 and selected genes involved in mitochondrial function and biogenesis in healthy subjects and in a matched cohort with type 2 diabetes patients before and after treatment with rosiglitazone was determined. Quantitative real time PCR was used to analyze both RNA and DNA from biopsies from subcutaneous adipose tissue.</p> <p>Methods</p> <p>Blood samples and subcutaneous abdominal fat biopsies were collected from 12 T2D patients, of which 11 concluded the study, pre-treatment and 90 days after initiation of rosiglitazone treatment, and from 19 healthy control subjects on the first and only visit from healthy subjects. Clinical parameters were measured on the blood samples. RNA and DNA were prepared from the fat biopsies and gene expression was measured with real time PCR.</p> <p>Results</p> <p>The expression level of genes in the mitochondrial respiratory complexes I - IV were significantly downregulated in the diabetic patients and restored in response to rosiglitazone treatment. Rosiglitazone treatment also increased the relative number of mitochondria in diabetic patients compared with controls. Furthermore, the transcription factors FOXC2 and mtTFA/Tfam displayed a response pattern identical to the mitochondrial genes.</p> <p>Conclusions</p> <p>FOXC2, mtTFA/Tfam and subunits of the respiratory complexes I - IV show equivalent regulation in gene expression levels in response to TZD treatment. This, together with the knowledge that FOXC2 has a regulatory function of mtTFA/Tfam and mitochondrial biogenesis, suggests that FOXC2 has a possible functional role in the TZD activated mitochondrial response.</p

Norwegian Physicians' Knowledge of and Opinions about Evidence-Based Medicine: Cross-Sectional Study

Objective: To answer five research questions: Do Norwegian physicians know about the three important aspects of EBM? Do they use EBM methods in their clinical practice? What are their attitudes towards EBM? Has EBM in their opinion changed medical practice during the last 10 years? Do they use EBM based information sources? Design: Cross sectional survey in 2006. Setting: Norway. Participants: 966 doctors who responded to a questionnaire (70% response rate). Results: In total 87% of the physicians mentioned the use of randomised clinical trials as a key aspect of EBM, while 53% of them mentioned use of clinical expertise and only 19% patients' values. 40% of the respondents reported that their practice had always been evidence-based. Many respondents experienced difficulties in using EBM principles in their clinical practice because of lack of time and difficulties in searching EBM based literature. 80% agreed that EBM helps physicians towards better practice and 52% that it improves patients' health. As reasons for changes in medical practice 86% of respondents mentioned medical progress, but only 39% EBM. Conclusions: The results of the study indicate that Norwegian physicians have a limited knowledge of the key aspects of EBM but a positive attitude towards the concept. They had limited experience in the practice of EBM and were rather indifferent to the impact of EBM on medical practice. For solving a patient problem, physicians would rather consult a colleague than searching evidence based resources such as the Cochrane Library

Effectiveness of electronic guideline-based implementation systems in ambulatory care settings - a systematic review

<p>Abstract</p> <p>Background</p> <p>Electronic guideline-based decision support systems have been suggested to successfully deliver the knowledge embedded in clinical practice guidelines. A number of studies have already shown positive findings for decision support systems such as drug-dosing systems and computer-generated reminder systems for preventive care services.</p> <p>Methods</p> <p>A systematic literature search (1990 to December 2008) of the English literature indexed in the Medline database, Embase, the Cochrane Central Register of Controlled Trials, and CRD (DARE, HTA and NHS EED databases) was conducted to identify evaluation studies of electronic multi-step guideline implementation systems in ambulatory care settings. Important inclusion criterions were the multidimensionality of the guideline (the guideline needed to consist of several aspects or steps) and real-time interaction with the system during consultation. Clinical decision support systems such as one-time reminders for preventive care for which positive findings were shown in earlier reviews were excluded. Two comparisons were considered: electronic multidimensional guidelines versus usual care (comparison one) and electronic multidimensional guidelines versus other guideline implementation methods (comparison two).</p> <p>Results</p> <p>Twenty-seven publications were selected for analysis in this systematic review. Most designs were cluster randomized controlled trials investigating process outcomes more than patient outcomes. With success defined as at least 50% of the outcome variables being significant, none of the studies were successful in improving patient outcomes. Only seven of seventeen studies that investigated process outcomes showed improvements in process of care variables compared with the usual care group (comparison one). No incremental effect of the electronic implementation over the distribution of paper versions of the guideline was found, neither for the patient outcomes nor for the process outcomes (comparison two).</p> <p>Conclusions</p> <p>There is little evidence at the moment for the effectiveness of an increasingly used and commercialised instrument such as electronic multidimensional guidelines. After more than a decade of development of numerous electronic systems, research on the most effective implementation strategy for this kind of guideline-based decision support systems is still lacking. This conclusion implies a considerable risk towards inappropriate investments in ineffective implementation interventions and in suboptimal care.</p

A structured registration program can be validly used for quality assessment in general practice

ABSTRACT: BACKGROUND: Patient information, medical history, clinical outcomes and demographic information, can be registered in different ways in registration programs. For evaluation of diabetes care, data can easily be extracted from a structured registration program (SRP). The usability of data from this source depends on the agreement of this data with that of the usual data registration in the electronic medical record (EMR). Aim of the study was to determine the comparability of data from an EMR and from an SRP, to determine whether the use of SRP data for quality assessment is justified in general practice. METHODS: We obtained 196 records of diabetes mellitus patients in a sample of general practices in the Netherlands. We compared the agreement between the two programs in terms of laboratory and non-laboratory parameters. Agreement was determined by defining accordance between the programs in absent and present registrations, accordance between values of registrations, and whether the differences found in values were also a clinically relevant difference. RESULTS: No differences were found in the occurrence of registration (absent/present) in the SRP and EMR for all the laboratory parameters. Smoking behaviour, weight and eye examination were registered significantly more often in the SRP than in the EMR. In the EMR, blood pressure was registered significantly more often than in the SRP. Data registered in the EMR and in the SRP had a similar clinical meaning for all parameters (laboratory and non-laboratory). CONCLUSIONS: Laboratory parameters showed good agreement and non-laboratory acceptable agreement of the SRP with the EMR. Data from a structured registration program can be used validly for research purposes and quality assessment in general practice

Outcome based subgroup analysis: a neglected concern

A subgroup of clinical trial subjects identified by baseline characteristics is a proper subgroup while a subgroup determined by post randomization events or measures is an improper subgroup. Both types of subgroups are often analyzed in clinical trial papers. Yet, the extensive scrutiny of subgroup analyses has almost exclusively attended to the former. The analysis of improper subgroups thereby not only flourishes in numerous disguised ways but also does so without a corresponding awareness of its pitfalls. Comparisons of the grade of angina in a heart disease trial, for example, usually include only the survivors. This paper highlights some of the distinct ways in which outcome based subgroup analysis occurs, describes the hazards associated with it, and proposes a simple alternative approach to counter its analytic bias. Data from six published trials show that outcome based subgroup analysis, like proper subgroup analysis, may be performed in a post-hoc fashion, overdone, selectively reported, and over interpreted. Six hypothetical trial scenarios illustrate the forms of hidden bias related to it. That bias can, however, be addressed by assigning clinically appropriate scores to the usually excluded subjects and performing an analysis that includes all the randomized subjects. A greater level of awareness about the practice and pitfalls of outcome based subgroup analysis is needed. When required, such an analysis should maintain the integrity of randomization. This issue needs greater practical and methodologic attention than has been accorded to it thus far

Relevance similarity: an alternative means to monitor information retrieval systems

BACKGROUND: Relevance assessment is a major problem in the evaluation of information retrieval systems. The work presented here introduces a new parameter, "Relevance Similarity", for the measurement of the variation of relevance assessment. In a situation where individual assessment can be compared with a gold standard, this parameter is used to study the effect of such variation on the performance of a medical information retrieval system. In such a setting, Relevance Similarity is the ratio of assessors who rank a given document same as the gold standard over the total number of assessors in the group. METHODS: The study was carried out on a collection of Critically Appraised Topics (CATs). Twelve volunteers were divided into two groups of people according to their domain knowledge. They assessed the relevance of retrieved topics obtained by querying a meta-search engine with ten keywords related to medical science. Their assessments were compared to the gold standard assessment, and Relevance Similarities were calculated as the ratio of positive concordance with the gold standard for each topic. RESULTS: The similarity comparison among groups showed that a higher degree of agreements exists among evaluators with more subject knowledge. The performance of the retrieval system was not significantly different as a result of the variations in relevance assessment in this particular query set. CONCLUSION: In assessment situations where evaluators can be compared to a gold standard, Relevance Similarity provides an alternative evaluation technique to the commonly used kappa scores, which may give paradoxically low scores in highly biased situations such as document repositories containing large quantities of relevant data

Evaluating comorbidities in total hip and knee arthroplasty: available instruments

Each year millions of patients are treated for joint pain with total joint arthroplasty, and the numbers are expected to rise. Comorbid disease is known to influence the outcome of total joint arthroplasty, and its documentation is therefore of utmost importance in clinical evaluation of the individual patient as well as in research. In this paper, we examine the various methods for obtaining and assessing comorbidity information for patients undergoing joint replacement. Multiple instruments are reliable and validated for this purpose, such as the Charlson Index, Index of Coexistent Disease, and the Functional Comorbidity Index. In orthopedic studies, the Charnley classification and the American Society of Anesthesiologists physical function score (ASA) are widely used. We recommend that a well-documented comorbidity index that incorporates some aspect of mental health is used along with other appropriate instruments to objectively assess the preoperative status of the patient

Demographic and biologic influences on survival in whites and blacks: 40 years of follow-up in the Charleston heart study

BACKGROUND: In the United States, life expectancy is significantly lower among blacks than whites. We examined whether socioeconomic status (SES) and cardiovascular disease (CVD) risk factors may help explain this disparity. METHODS: Forty years (1961 through 2000) of all-cause mortality data were obtained on a population-based cohort of 2,283 subjects in the Charleston Heart Study (CHS). We examined the influence of SES and CVD risk factors on all-cause mortality. RESULTS: Complete data were available on 98% of the original sample (647 white men, 728 white women, 423 black men, and 443 black women). After adjusting for SES and CVD risk factors, the hazard ratios (HRs) for white ethnicity were 1.14 (0.98 to 1.32) among men and 0.90 (0.75 to 1.08) among women, indicating that the mortality risk was 14% greater for white men and 10% lower for white women compared to their black counterparts. However the differences were not statistically significant. CONCLUSION: While there are marked contrasts in mortality among blacks and whites in the CHS, the differences can be largely explained by SES and CVD risk factors. Continued focus on improving and controlling cardiovascular disease risk factors may reduce ethnic disparities in survival