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    ABSTRACT: The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.-Pryce, G., Visintin, C., Ramagopalan, S. V., Al-Izki, S., De Faveri, L. E., Nuamah, R. A., Mein, C. A., Montpetit, A., Hardcastle, A. J., Kooij, G., de Vries, H. E., Amor, S., Thomas, S. A., Ledent, C., Marsicano, G., Lutz, B., Thompson, A. J., Selwood, D. L., Giovannoni, G., Baker, D. Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
    The FASEB Journal 01/2014; 28(1):117-130.
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    ABSTRACT: Despite compelling evidence of the effect of intelligence on delinquency and violent crime, there is limited data on its impact on population violence. We aimed to determine the association of categories of intelligence with violent behaviors in the general population and the extent of the impact of social class on these associations. A randomly selected sample of 14,738 individuals was derived from 2 British national surveys of adults aged 16 years and older. We measured self-reported violent behavior in the past 5 years, including: repetition, injury, violence while intoxicated, familial and extra-familial victim types and intimate partner violence. We examined the moderating role of social class on all outcomes. The increased risk of violence among persons of below average IQ was explained by social class at population level. High IQ had an overall protective effect on all outcomes except violence towards family members, irrespective of socio-economic circumstances. Social class moderated the association of IQ with violence by decreasing its protective effect among those in the lowest socio-economic positions. Our findings suggest that the association of IQ and violence is not linear but protective on population level. Social class has both an explaining and a moderating role in this association.
    Personality and Individual Differences 01/2014;
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    ABSTRACT: Background and aims Chronic visceral pain is common both in patients with identifiable organic disease and also in those without any structural, biochemical or immunological abnormality such as in the functional gastrointestinal disorders (FGIDs). We aim to provide a contemporaneous summary of pathways involved in visceral nociception and how a variety of mechanisms may influence an individual's experience of visceral pain. Methods In this narrative review, we have brought together evidence through a detailed search of Medline in addition to using our experience and exposure to recent research developments from ourselves and other research groups. Results FGIDs are a heterogeneous group of disorders whose aetiology largely remains an enigma. The germane hypothesis for the genesis and maintenance of chronic visceral pain in FGIDs is the concept of visceral hypersensitivity. A number of peripheral and central mechanisms have been proposed to account for this epiphenomenon. In the periphery, inflammatory mediators activate and sensitize nociceptive afferent nerves by reducing their transduction thresholds and by inducing the expression and recruitment of hitherto silent nociceptors culminating in an increase in pain sensitivity at the site of injury known as primary hyperalgesia. Centrally, secondary hyperalgesia, defined as an increase in pain sensitivity in anatomically distinct sites, occurs at the level of the spinal dorsal horn. Moreover, the stress responsive physiological systems, genetic and psychological factors may modulate the experience of visceral pain. We also address some novel aetiological concepts in FGIDs, namely the gastrointestinal microbiota, connective tissue abnormalities and the gastrointestinal neuromuscular disorders. Firstly, the gastrointestinal microbiota is a diverse and dynamic ecosystem, that safeguards the host from external pathogens, aids in the metabolism of polysaccharides and lipids, modulates intestinal motility, in addition to modulating visceral perception. Secondly, connective tissue disorders, which traditionally have been considered to be confined largely to the musculoskeletal system, have an increasing evidence base demonstrating the presence of visceral manifestations. Since the sensorimotor apparatus of the GI tract is embedded within connective tissue it should not be surprising that such disorder may result in visceral pain and abnormal gut motility. Thirdly, gastrointestinal neuromuscular diseases refer to a heterogeneous group of disorders in which symptoms arise from impaired GI motor activity often manifesting as abnormal transit with or without radiological evidence of transient or persistent dilation of the viscera. Although a number of these are readily recognizable, such as achalasia or Hirschsprung's disease, the cause in a number of patients is not. An international working group has recently addressed this “gap”, providing a comprehensive morphologically based diagnostic criteria. Conclusions/implications Although marked advances have been made in understanding the mechanisms that contribute to the development and maintenance of visceral pain, many interventions have failed to produce tangible improvement in patient outcomes. In the last part of this review we highlight an emerging approach that has allowed the definition and delineation of temporally stable visceral pain clusters, which may improve participant homogeneity in future studies, potentially facilitate stratification of treatment in FGID and lead to improvements in diagnostic criteria and outcomes.
    Scandinavian Journal of Pain 01/2014;
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    ABSTRACT: Trigeminal neuralgia is a sudden, unilateral, brief, stabbing, recurrent pain in the distribution of one or more branches of the fifth cranial nerve. Pain occurs in paroxysms which last from a few seconds to 2 minutes. The frequency of the paroxysms ranges from a few to hundreds of attacks a day. Periods of remission can last for months to years, but tend to shorten over time. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments in people with trigeminal neuralgia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: ablative neurosurgical techniques to the Gasserian ganglion, baclofen, carbamazepine, clonazepam, cryotherapy of peripheral nerves, gabapentin, lamotrigine, microvascular decompression, nerve block, oxcarbazepine, peripheral acupuncture, phenytoin, proparacaine eye drops, sodium valproate, stereotactic radiosurgery, tizanidine, and topiramate.
    BMJ (online) 01/2014; 348:g474.
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    ABSTRACT: Rectal intussusception and external rectal prolapse are uncommon proctographic findings in men reflecting the lack of studies investigating such patients. The aim of this study was to identify the demographic, clinical, and physiological characteristics of this population with a view to appreciate the mechanism of development of this condition. All men, presenting with symptoms of constipation or fecal incontinence, who were diagnosed proctographically with recto-rectal intussusception (RRI)/recto-anal intussusception (RAI) or external rectal prolapse (ERP) between 1994 and 2007 at a tertiary academic colorectal unit were studied. Demographics, relevant comorbidities, distribution and symptom duration, and anorectal physiology results were analyzed retrospectively for each proctographic group and intergroup comparisons performed. Two hundred five men (median age 50 y; range, 13-86) including 155 (75.6%) without any relevant comorbidities were studied. A significant proportion of patients in all proctographic groups reported rectal evacuatory difficulty ([RRI, 46.4%], [RAI, 39.4%], [ERP, 44.8%]; P = 0.38,analysis of variance). Patients also reported a combination of fecal incontinence symptoms (e.g., urge, passive, postdefecatory leakage) that did not differ across the proctographic groups. Anorectal physiological parameters were within normal range and were not found to be statistically different between the proctographic groups with the exception of anal resting pressure, which was lowest in ERP patients (62 cm H2O; range, 14-155) compared with patients with RRI (89 cm H2O; range, 16-250; P = 0.003) and RAI (92 cm H2O; range, 38-175; P = 0.006). Men with rectal intussusception and prolapse present with a combination of symptoms, predominantly defective rectal evacuation. Anorectal physiological assessment has failed to shed light into the mechanism of development of this condition and thus, the need for large observational studies incorporating integrated defecographic and manometric assessments of the evacuation process.
    Journal of Surgical Research 12/2013;
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    ABSTRACT: Poor quality medicines present a serious public health problem, particularly in emerging economies and developing countries, and may have a significant impact on the national clinical and economic burden. Attention has largely focused on the increasing availability of deliberately falsified drugs, but substandard medicines are also reaching patients because of poor manufacturing and quality-control practices in the production of genuine drugs (either branded or generic). Substandard medicines are more wide spread than falsified medications and represent a greater threat to health as they can inadvertently lead to healthcare failures, such as antibiotic resistance and the spread of disease within a community, as well as death or additional illness in individuals. This article will review the different aspects of substandard drug formulation that can occur (for example, pharmacological variability between drug batches or between generic and originator drugs; incorrect drug quantity; and presence of impurities). It will also discuss the possible means of addressing substandard manufacturing practices. A concerted effort is required on the part of governments, drug manufacturers, charities and healthcare providers to ensure that only drugs of acceptable quality reach the patient.
    British Journal of Clinical Pharmacology 11/2013;
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    ABSTRACT: The English National Health Service Constitution states that patients have the right to expect all decisions about access to medicines and treatments to be made 'rationally'. Rationality in health care can be framed as instrumental, institutional or practical. In this article, we present a case example from an ethnographic study of the work of 'Individual Funding Request' panels to explore how rationality is enacted and accounted for in deliberations about the rationing of health care in the National Health Service. Our rhetorical analysis highlights how an embodied, practical rationality emerges as a significant aspect of rationality in practice, but at the same time has a problematic status in formal accounts of decision-making. We suggest that being both 'human' and 'rational' is a 'delicate balance' and creates a dilemma for Individual Funding Request panels. Aristotle's notion of phronesis provides a useful lens for theorising our observation of panel deliberations, and we argue for greater attention to the value of narrative ethics in helping us understand the challenges faced by resource allocators.
    Health 11/2013;
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    ABSTRACT: Multiple sclerosis (MS), typically considered a disease of young adults, is increasingly recognized in early-onset pediatric cases (PMS), with an estimated 3%-5% of patients having onset before age 16 years.(1) Given its rarity, it is challenging to investigate the mechanisms that initiate MS in such young individuals and to assess whether PMS and adult MS share the same risk factors, rather than being 2 separate conditions. Population-based studies investigating the familial aggregation of MS clearly showed genes play a role in adult MS.(2) Most of this genetic risk is mediated by specific risk alleles in the major histocompatibility complex (MHC) class II region. However, genome-wide association studies (GWAS) have provided evidence for more than 50 single nucleotide polymorphisms (SNPs) of more modest effect that also influence the risk of adult MS.(3.)
    Neurology 11/2013;
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    ABSTRACT: We aimed to quantify pharyngeal exposure to gastric contents in patients diagnosed with reflux-related hoarseness and healthy controls using new diagnostic techniques. Hoarseness with typical signs on laryngoscopy is commonly thought to be caused by esophagopharyngeal reflux. New methods are proposed to assess pharyngeal exposure to gastric contents. They are suggested to measure: (1) liquid or mixed gas-liquid acid and nonacid reflux with impedance pH, (2) aerosolized acid reflux (Dx-pH measuring system), and (3) pepsin in the saliva. Twenty-one patients with hoarseness and positive laryngoscopy and 10 controls underwent simultaneous impedance pH, Dx-pH monitoring, and saliva pepsin sampling (5 samples in 24 h). Of the 21 patients, 10 had impedance pH-detected reflux plus at least 1 other test positive. These patients were more likely to have symptomatic relief after proton pump inhibitor therapy. Three of the 21 patients had all 3 tests positive and 4 had all tests negative. None of the controls had impedance pH-detected reflux. Two controls had a positive Dx-pH "RYAN score" and 1 control had >1 saliva sample positive for pepsin. Only 11% of Dx-pH drops to pH<4, 15% pH drops to pH<5, and 10% of pH drops to pH<5.5 coincided with impedance pH-detected reflux in the esophageal body. Positive pepsin saliva samples were preceded by more reflux events [3 (range, 0 to 10)] in the previous 60 minutes than negative samples [0 (range, 0 to 7)] (P<0.0001). A subgroup of patients with hoarseness (10/21) had objective detection of the esophagopharyngeal reflux. We propose that these patients are more likely to benefit from further intense antireflux therapy. Detection of pepsin in the saliva may be a useful screening tool in these patients.
    Journal of clinical gastroenterology 10/2013;
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    ABSTRACT: /st>Current approaches to risk assessment before major surgery have important limitations. The aim of this pilot study was to compare predictive accuracy of preoperative scoring systems, plasma biomarkers, and cardiopulmonary exercise testing (CPET) for complications after major non-cardiac surgery. /st>Single-centre, observational study of patients aged ≥40 yr undergoing major elective non-cardiac surgery. Before surgery, risk scores were calculated and blood samples collected for measurement of plasma biomarkers. Patients underwent CPET for measurement of anaerobic threshold (AT) and peak oxygen consumption ( peak). After surgery, patients were followed for 28 days to evaluate complications and major adverse cardiac events (MACE). Data are presented as area under the receiver operating characteristic curve (AUROC) with 95% confidence intervals. /st>A total of 100 patients were recruited between April 2009 and October 2010; 17 of whom did not proceed to surgery. CPET variables suggested good predictive accuracy for MACE [AT: AUROC 0.83 (0.69-0.96); peak AUROC 0.81 (0.69-0.96)] and poor predictive accuracy for all complications [AT: AUROC 0.64 (0.52-0.77); peak AUROC 0.64 (0.52-0.77)]. There was a trend towards predictive accuracy of the plasma biomarkers B-type natriuretic peptide and estimated glomerular filtration rate (calculated from serum creatinine) for MACE but not all complications. C-reactive protein, ASA score, and revised cardiac risk index had little or no predictive value. /st>These pilot data suggest that CPET and plasma biomarkers may improve risk assessment before surgery. Only large clinical studies can confirm this observation and define the optimal use of these tests in clinical practice.
    BJA British Journal of Anaesthesia 10/2013;
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