State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

The effect of Neuragen PN® on Neuropathic pain: A randomized, double blind, placebo controlled clinical trial

<p>Abstract</p> <p>Background</p> <p>A double blind, randomized, placebo controlled study to evaluate the safety and efficacy of the naturally derived topical oil, "Neuragen PN^®" for the treatment of neuropathic pain.</p> <p>Methods</p> <p>Sixty participants with plantar cutaneous (foot sole) pain due to all cause peripheral neuropathy were recruited from the community. Each subject was randomly assigned to receive one of two treatments (Neuragen PN^®or placebo) per week in a crossover design. The primary outcome measure was acute spontaneous pain level as reported on a visual analog scale.</p> <p>Results</p> <p>There was an overall pain reduction for both treatments from pre to post application. As compared to the placebo, Neuragen PN^®led to significantly (p < .05) greater pain reduction. Fifty six of sixty subjects (93.3%) receiving Neuragen PN^®reported pain reduction within 30 minutes. This reduction within 30 minutes occurred in only twenty one of sixty (35.0%) subjects receiving the placebo. In a break out analysis of the diabetic only subgroup, 94% of subjects in the Neuragen PN^®group achieved pain reduction within 30 minutes vs 11.0% of the placebo group. No adverse events were observed.</p> <p>Conclusions</p> <p>This randomized, placebo controlled, clinical trial with crossover design revealed that the naturally derived oil, Neuragen PN^®, provided significant relief from neuropathic pain in an all cause neuropathy group. Participants with diabetes within this group experienced similar pain relief.</p> <p>Trial registration</p> <p><b>ISRCTN registered: </b>ISRCTN13226601</p

Protocol for a randomised controlled trial of a decision aid for the management of pain in labour and childbirth [ISRCTN52287533]

BACKGROUND: Women report fear of pain in childbirth and often lack complete information on analgesic options prior to labour. Preferences for pain relief should be discussed before labour begins. A woman's antepartum decision to use pain relief is likely influenced by her cultural background, friends, family, the media, literature and her antenatal caregivers. Pregnant women report that information about analgesia was most commonly derived from hearsay and least commonly from health professionals. Decision aids are emerging as a promising tool to assist practitioners and their patients in evidence-based decision making. Decision aids are designed to assist patients and their doctors in making informed decisions using information that is unbiased and based on high quality research evidence. Decision aids are non-directive in the sense that they do not aim to steer the user towards any one option, but rather to support decision making which is informed and consistent with personal values. METHODS/DESIGN: We aim to evaluate the effectiveness of a Pain Relief for Labour decision aid, with and without an audio-component, compared to a pamphlet in a three-arm randomised controlled trial. Approximately 600 women expecting their first baby and planning a vaginal birth will be recruited for the trial. The primary outcomes of the study are decisional conflict (uncertainty about a course of action), knowledge, anxiety and satisfaction with decision-making and will be assessed using self-administered questionnaires. The decision aid is not intended to influence the type of analgesia used during labour, however we will monitor health service utilisation rates and maternal and perinatal outcomes. This study is funded by a competitive peer-reviewed grant from the Australian National Health and Medical Research Council (No. 253635). DISCUSSION: The Pain Relief for Labour decision aid was developed using the Ottawa Decision Support Framework and systematic reviews of the evidence about the benefits and risks of the non-pharmacological and pharmacological methods of pain relief for labour. It comprises a workbook and worksheet and has been developed in two forms – with and without an audio-component (compact disc). The format allows women to take the decision aid home and discuss it with their partner

Clinical inertia in general practice:widespread and related to the outcome of diabetes care

Materials and methods. Baseline and follow-up data of a Dutch randomized controlled trial on the implementation of a locally adapted guideline were used. The study involved 30 general practices and 1283 patients. Treatment targets differed between study groups [HbA1c <8.0% and blood pressure (BP) <140/85% versus HbA1c <8.5% and BP <150/85]. Clinical inertia was defined as the failure to intensify therapy when indicated. A complete medication profile of all participating patients was obtained. Results. In the intervention and control group, the percentages of patients with poor diabetes or lipid control who did not receive treatment intensification were 45% and 90%, approximately. More control group patients with BP levels above target were confronted with inertia (72.7% versus 63.3%, P <0.05). In poorly controlled hypertensive patients, inertia was associated with the height of systolic BP at baseline [adjusted odds ratio (OR) 0.98, 95% confidence interval (CI) 0.98-0.99] and the frequency of BP control (adjusted OR 0.89, 95% CI 0.81-0.99). If a practice nurse managed these patients, clinical inertia was less common (adjusted OR 0.12, 95% CI 0.02-0.91). In both study groups, cholesterol decreased significantly more in patients who received proper treatment intensification. Conclusion. GPs were more inclined to control blood glucose levels than BP or cholesterol levels. Inertia in response to poorly controlled high BP was less common if nurses assisted GPs

Prevalence of macrovascular disease amongst type 2 diabetic patients detected by targeted screening and patients newly diagnosed in general practice: the Hoorn Screening Study

Prevalence of macrovascular disease amongst type 2 diabetic patients detected by targeted screening and patients newly diagnosed in general practice: the Hoorn Screening Study. Spijkerman AM, Henry RM, Dekker JM, Nijpels G, Kostense PJ, Kors JA, Ruwaard D, Stehouwer CD, Bouter LM, Heine RJ. Institutes for Research in Extramural Medicine, VU University Medical Center, Amsterdam, The Netherlands. [email protected] OBJECTIVES: Screening for type 2 diabetes has been recommended and targeted screening might be an efficient way to screen. The aim was to investigate whether diabetic patients identified by a targeted screening procedure differ from newly diagnosed diabetic patients in general practice with regard to the prevalence of macrovascular complications. DESIGN: Cross-sectional population-based study. SETTING: Population study, primary care. SUBJECTS: Diabetic patients identified by a population-based targeted screening procedure (SDM patients), consisting of a screening questionnaire and a fasting capillary glucose measurement followed by diagnostic testing, were compared with newly diagnosed diabetic patients in general practice (GPDM patients). Ischaemic heart disease and prior myocardial infarction were assessed by ECG recording. Peripheral arterial disease was assessed by the ankle-arm index. Intima-media thickness of the right common carotid artery was measured with ultrasound. RESULTS: A total of 195 SDM patients and 60 GPDM patients participated in the medical examination. The prevalence of MI was 13.3% (95% CI 9.3-18.8%) and 3.4% (1.0-11.7%) in SDM patients and GPDM patients respectively. The prevalence of ischaemic heart disease was 39.5% (95% CI 32.9-46.5%) in SDM patients and 24.1% (15.0-36.5%) in GPDM patients. The prevalence of peripheral arterial disease was similar in both groups: 10.6% (95% CI 6.9-15.9%) and 10.2% (4.7-20.5%) respectively. Mean intima-media thickness was 0.85 mm (+/-0.17) in SDM patients and 0.90 mm (+/-0.20) in GPDM patients. The difference in intima-media thickness was not statistically significant. CONCLUSIONS: Targeted screening identified patients with a prevalence of macrovascular complications similar to that of patients detected in general practice, but with a lower degree of hyperglycaemi

Endothelium Derived Nitric Oxide Synthase Negatively Regulates the PDGF-Survivin Pathway during Flow-Dependent Vascular Remodeling

Chronic alterations in blood flow initiate structural changes in vessel lumen caliber to normalize shear stress. The loss of endothelial derived nitric oxide synthase (eNOS) in mice promotes abnormal flow dependent vascular remodeling, thus uncoupling mechanotransduction from adaptive vascular remodeling. However, the mechanisms of how the loss of eNOS promotes abnormal remodeling are not known. Here we show that abnormal flow-dependent remodeling in eNOS knockout mice (eNOS (−/−)) is associated with activation of the platelet derived growth factor (PDGF) signaling pathway leading to the induction of the inhibitor of apoptosis, survivin. Interfering with PDGF signaling or survivin function corrects the abnormal remodeling seen in eNOS (−/−) mice. Moreover, nitric oxide (NO) negatively regulates PDGF driven survivin expression and cellular proliferation in cultured vascular smooth muscle cells. Collectively, our data suggests that eNOS negatively regulates the PDGF-survivin axis to maintain proportional flow-dependent luminal remodeling and vascular quiescence

Pregnant women become insensitive to cold stress

BACKGROUND: The function of the hypothalamic-pituitary-adrenal (HPA) axis is known to be altered during pregnancy, but it has not been tested with a natural stressor. METHODS: A group of pregnant women (n = 10) were tested towards the end of pregnancy (mean 36.8 ± 2.5 weeks gestation) and about 8 weeks postpartum (mean 7.8 ± 1.5 weeks), together with a matched control group, with a one minute cold hand stressor test. Saliva samples were collected before and 10 and 20 minutes after the test, and stored for later radioimmunoassay of cortisol. RESULTS: The control group showed a highly significant response to the test. The pregnant group showed no response, and the postpartum group a variable but non significant one CONCLUSIONS: This shows that the HPA axis becomes hypofunctional to a natural stressor at the end of pregnancy. It is suggested that one possible evolutionary function for this is to protect the fetus from the stress responses of the mother

Comparative Effectiveness Research: An Empirical Study of Trials Registered in ClinicalTrials.gov

Background The $1.1 billion investment in comparative effectiveness research will reshape the evidence-base supporting decisions about treatment effectiveness, safety, and cost. Defining the current prevalence and characteristics of comparative effectiveness (CE) research will enable future assessments of the impact of this program. Methods We conducted an observational study of clinical trials addressing priority research topics defined by the Institute of Medicine and conducted in the US between 2007 and 2010. Trials were identified in ClinicalTrials.gov. Main outcome measures were the prevalence of comparative effectiveness research, nature of comparators selected, funding sources, and impact of these factors on results. Results 231 (22.3%; 95% CI 19.8%–24.9%) studies were CE studies and 804 (77.7%; 95% CI, 75.1%–80.2%) were non-CE studies, with 379 (36.6%; 95% CI, 33.7%–39.6%) employing a placebo control and 425 (41.1%; 95% CI, 38.1%–44.1%) no control. The most common treatments examined in CE studies were drug interventions (37.2%), behavioral interventions (28.6%), and procedures (15.6%). Study findings were favorable for the experimental treatment in 34.8% of CE studies and greater than twice as many (78.6%) non-CE studies (P<0.001). CE studies were more likely to receive government funding (P = 0.003) and less likely to receive industry funding (P = 0.01), with 71.8% of CE studies primarily funded by a noncommercial source. The types of interventions studied differed based on funding source, with 95.4% of industry trials studying a drug or device. In addition, industry-funded CE studies were associated with the fewest pediatric subjects (P<0.001), the largest anticipated sample size (P<0.001), and the shortest study duration (P<0.001). Conclusions In this sample of studies examining high priority areas for CE research, less than a quarter are CE studies and the majority is supported by government and nonprofits. The low prevalence of CE research exists across CE studies with a broad array of interventions and characteristics.National Library of Medicine (U.S.) (5G08LM009778)National Institutes of Health (U.S.