A rearrangement-based approach to secondary difluorophosphonates

[3,3]-Claisen rearrangements allowed the conversion of a readily available allylic difluorophosphonate to nucleic acid and inositol phosphate-related products via epoxide cyclisation or ring closing metathesis respectively

Non-invasive brain stimulation techniques for chronic pain (review)

Background This is an updated version of the original Cochrane review published in 2010, Issue 9. Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES), transcranial direct current stimulation (tDCS) and reduced impedance non-invasive cortical electrostimulation (RINCE). Objectives To evaluate the efficacy of non-invasive brain stimulation techniques in chronic pain. Search methods We searched CENTRAL (2013, Issue 6), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS and clinical trials registers. The original search for the review was run in November 2009 and searched all databases from their inception. To identify studies for inclusion in this update we searched from 2009 to July 2013. Selection criteria Randomised and quasi-randomised studies of rTMS, CES, tDCS or RINCE if they employed a sham stimulation control group, recruited patients over the age of 18 with pain of three months duration or more and measured pain as a primary outcome. Data collection and analysis Two authors independently extracted and verified data. Where possible we entered data into meta-analyses. We excluded studies judged as being at high risk of bias from the analysis. We used the GRADE system to summarise the quality of evidence for core comparisons. Main results We included an additional 23 trials (involving 773 participants randomised) in this update, making a total of 56 trials in the review (involving 1710 participants randomised). This update included a total of 30 rTMS studies, 11 CES, 14 tDCS and one study of RINCE(the original review included 19 rTMS, eight CES and six tDCS studies). We judged only three studies as being at low risk of bias across all criteria. Meta-analysis of studies of rTMS (involving 528 participants) demonstrated significant heterogeneity. Pre-specified subgroup analyses suggest that low-frequency stimulation is ineffective (low-quality evidence) and that rTMS applied to the dorsolateral prefrontal cortex is ineffective (very low-quality evidence). We found a short-term effect on pain of active high-frequency stimulation of the motor cortex in single-dose studies (low-quality evidence, standardised mean difference (SMD) 0.39 (95% confidence interval (CI) -0.27 to -0.51 P \u3c 0.01)). This equates to a 12% (95% CI 8% to 15%) reduction in pain, which does not exceed the pre-established criteria for a minimal clinically important difference (≥ 15%). Evidence for multiple-dose studies was heterogenous but did not demonstrate a significant effect (very low-quality evidence). For CES (six studies, 270 participants) no statistically significant difference was found between active stimulation and sham (low-quality evidence). Analysis of tDCS studies (11 studies, 193 people) demonstrated significant heterogeneity and did not find a significant difference between active and sham stimulation (very low-quality evidence). Pre-specified subgroup analysis of tDCS applied to the motor cortex (n = 183) did not demonstrate a statistically significant effect and this lack of effect was consistent for subgroups of single or multiple-dose studies. One small study (n = 91) at unclear risk of bias suggested a positive effect of RINCE over sham stimulation on pain (very low-quality evidence). Non-invasive brain stimulation appears to be frequently associated with minor and transient side effects, though there were two reported incidences of seizure related to active rTMS in the included studies. Authors\u27 conclusions Single doses of high-frequency rTMS of the motor cortex may have small short-term effects on chronic pain. It is likely that multiple sources of bias may exaggerate this observed effect. The effects do not meet the predetermined threshold of minimal clinical significance and multiple-dose studies do not consistently demonstrate effectiveness. The available evidence suggests that low-frequency rTMS, rTMS applied to the pre-frontal cortex, CES and tDCS are not effective in the treatment of chronic pain. While the broad conclusions for rTMS and CES have not changed substantially, the addition of this new evidence and the application of the GRADE system has modified some of our interpretation and the conclusion regarding the effectiveness of tDCS has changed. We recommend that previous readers should re-read this update. There is a need for larger, rigorously designed studies, particularly of longer courses of stimulation. It is likely that future evidence may substantially impact upon the presented results

Non-invasive brain stimulation techniques for chronic pain

Stimulating the brain without surgery in the management of chronic pain in adults Bottom line: There is a lack of high-quality evidence to support or refute the effectiveness of non-invasive brain stimulation techniques for chronic pain. Background: Electrical stimulation of the brain has been used to address a variety of painful conditions. Various devices are available that can electrically stimulate the brain without the need for surgery or any invasive treatment. There are five main treatment types: repetitive transcranial magnetic stimulation (rTMS) in which the brain is stimulated by a coil applied to the scalp, cranial electrotherapy stimulation (CES) in which electrodes are clipped to the ears or applied to the scalp, transcranial direct current stimulation (tDCS), reduced impedance non-invasive cortical electrostimulation (RINCE) and transcranial random noise stimulation (tRNS) in which electrodes are applied to the scalp. These have been used to try to reduce pain by aiming to alter the activity of the brain. How effective they are is uncertain. Study characteristics: This review update included 94 randomised controlled studies: 42 of rTMS, 11 of CES, 36 of tDCS two of RINCE, two of tRNS and one study which evaluated both tDCS and rTMS. Key findings: rTMS applied to the motor cortex may lead to small, short-term reductions in pain but these effects are not likely to be clinically important. tDCS may reduce pain when compared with sham but for rTMS and tDCS our estimates of benefit are likely to be exaggerated by the small number of participants in each of the studies and limitations in the way the studies were conducted. Low- or very low-quality evidence suggests that low-frequency rTMS and rTMS that is applied to prefrontal areas of the brain are not effective. Low-quality evidence does not suggest that CES is an effective treatment for chronic pain. For all forms of stimulation the evidence is not conclusive and there is substantial uncertainty about the possible benefits and harms of the treatment. Of the studies that clearly reported side effects, short-lived and minor side effects such as headache, nausea and skin irritation were usually reported both with real and sham stimulation. Two cases of seizure were reported following real rTMS. Our conclusions for rTMS, CES, tDCS, and RINCE have not changed substantially in this update. Quality of the evidence: We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low-quality evidence means that we are very uncertain about the results. High-quality evidence means that we are very confident in the results. We considered all of the evidence to be of low or very low quality, mainly because of bias in the studies that can lead to unreliable results and the small size of the studies, which makes them imprecise

Prevalence of drug-herb and drug-supplement interactions in older adults : A cross-sectional survey

© British Journal of General PracticeBackground Polypharmacy is common among older adults, with increasing numbers also using prescription drugs with herbal medicinal products (HMPs) and dietary supplements. There is no reliable evidence from the UK on concurrent use of HMPs and dietary supplements with prescription drugs in older adults. Aim To establish prevalence of concurrent prescription drugs, HMPs, and dietary supplements among UK community-dwelling older adults and identify potential interactions. Design and setting Cross-sectional survey of older adults registered at two general practices in South East England. Method A questionnaire asking about prescription medications, HMPs, and sociodemographic information was posted to 400 older adults aged ≥65 years, identified as taking ≥1 prescription drug. Results In total 155 questionnaires were returned (response rate = 38.8%) and the prevalence of concurrent HMPs and dietary supplements with prescriptions was 33.6%. Females were more likely than males to be concurrent users (43.4% versus 22.5%; P = 0.009). The number of HMPs and dietary supplements ranged from 1 to 8, (mean = 3, median = 1; standard deviation = 1.65). The majority of concurrent users (78.0%) used dietary supplements with prescription drugs. The most commonly used dietary supplements were cod liver oil, glucosamine, multivitamins, and Vitamin D. Others (20.0%) used only HMPs with prescription drugs. Common HMPs were evening primrose oil, valerian, and Nytol Herbal® (a combination of hops, gentian, and passion flower). Sixteen participants (32.6%) were at risk of potential adverse drug interactions. Conclusion GPs should routinely ask questions regarding herbal and supplement use, to identify and manage older adults at potential risk of adverse drug interactions.Peer reviewe

Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction

This work was supported in part by a grant from Alpha MD, London, United Kingdom. Dr Mutch was supported by the British Heart Foundation PG/15/82/31721 and Friends of Anchor. Dr Gorog has received institutional research grants from Bayer, Medtronic, Alpha MD, and Boehringer Ingelheim; has received speaker’s fees from AstraZeneca and Boehringer Ingelheim; and is related through family to a company director in Thromboquest Ltd, but neither she, nor her spouse or children, have financial involvement or equity interest in and they have received no financial assistance, support, or grants from the aforementioned. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.Peer reviewedPublisher PD

Non-invasive brain stimulation techniques for chronic pain. A Cochrane systematic review and meta-analysis

Poster Presentation Non-invasive brain stimulation techniques aim to induce an electrical stimulation of the brain in an attempt to reduce chronic pain by directly altering brain activity. They include repetitive transcranial magnetic stimulation (rTMS), cranial electrotherapy stimulation (CES) and transcranial direct current stimulation (tDCS). These approaches to pain treatment are relatively novel. It is important to assess the existing literature robustly to ascertain the current level of supporting evidence and to inform future research and potential clinical use

SUMO chain-induced dimerization activates RNF4

Dimeric RING E3 ligases interact with protein substrates and conformationally restrain the ubiquitin-E2-conjugating enzyme thioester complex such that it is primed for catalysis. RNF4 is an E3 ligase containing an N-terminal domain that binds its polySUMO substrates and a C-terminal RING domain responsible for dimerization. To investigate how RNF4 activity is controlled, we increased polySUMO substrate concentration by ablating expression of SUMO protease SENP6. Accumulation of SUMO chains in vivo leads to ubiquitin-mediated proteolysis of RNF4. In vitro we demonstrate that at concentrations equivalent to those found in vivo RNF4 is predominantly monomeric and inactive as an ubiquitin E3 ligase. However, in the presence of SUMO chains, RNF4 is activated by dimerization, leading to both substrate ubiquitylation and autoubiquitylation, responsible for degradation of RNF4. Thus the ubiquitin E3 ligase activity of RNF4 is directly linked to the availability of its polySUMO substrates

Socioeconomic Differences and the Potential Role of Tribes in Young People's Food and Drink Purchasing Outside School at Lunchtime

Socioeconomic deprivation has been linked to food consumption practices, but studies investigating the food environment around schools provide mixed findings. Peer influence and marketing cues are considered important influencers of young people's behaviors. This study used a tribal theory lens to investigate the factors affecting pupils' purchasing and consumption of food/drinks outside schools at lunchtime. A survey was conducted with 243 pupils from seven UK secondary schools of differing socioeconomic status (SES). A purchasing recall questionnaire (PRQ) was developed and administered online at the participating schools to capture food and drink purchasing, intake, and expenditure. No significant differences were found in terms of energy and nutrients consumed or food/drink expenditure between pupils from schools of lower and higher SES. Enjoyment of food shopping with friends was linked with higher food energy intake and spend. Higher susceptibility to peer influence was associated with greater influence from food advertising and endorsements. Without ignoring the impact that SES can have on young people's food choices, we suggest that tribal theory can be additionally used to understand pupils' eating behaviors and we present implications for social marketers and policy makers