Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS. Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population. Expert opinion: There is cautious optimism for the successful treatment of the core behavioral and cognitive symptoms of FXS based on preclinical data in animal models and early studies in humans. However, the association between mGluR5-heightened responsiveness and the clinical phenotype in humans remains to be demonstrated. Many questions regarding the optimal treatment and outcome measures of FXS remain unanswered.

Nearer to Sraffa than Marx: Adam Smith on Productive and Unproductive Labour

This paper supercedes an earlier attempt I made to pin down the meaning and significance of Adam Smith’s theory of productive and unproductive labour. (Strathclyde Discussion Papers in Economics, No.08-05) My conclusion then was that while Smith’s understanding of what was needed to achieve economic growth was sound, his discussion was marred by apparently conflicting definitions of productive labour. That (essentially conventional) interpretation does not, I now believe, do justice to Smith. Revision is therefore called for: hence the present paper.

The effectiveness of tipi in the treatment of hip and knee osteoarthritis: a preliminary report

Osteoarthritis (OA) is a common painful inflammatory condition occurring mainly in the later half of life. Hipe and knee are the joints mostly affected. Petiveria alliacea (tipi) popularly known as an anti-rheumatic medicine, has been used by OA patients to relief pain. This one-week cross-over double-blind trial has preliminary evaluated the analgesic effect of tipi tea in 14 patients with hip and knee OA. Imperata exaltata (sape) was used as the Placebo tea. The pain assessments that were made at baseline and before the start of the second treatment period by treatment groups were comparable. While taking tipi or placebo tea patients experienced a statistically significant improvement in pain on motion and pain at night. The comparison between the improvements reported while on tipi and placebo tea, however, did not disclose any statistically significant difference. At the conclusion of the study 7 patients preferred tipi tea and 6 preferred placebo tea (NS). Two patients reported insomnia, one durign placebo treatment and the other during tipi treatment. In this preliminary report both teas succeeded in the aim of relieving pain.

Reversibility of muscle and heart lesions in chronic Trypanosoma cruzi infected mice after late trypanomicidal treatment

The effect of trypanomicidal treatment upon established histopathological Trypanosoma cruzi induced lesions was studied in Swiss mice. The animals were inoculated with 50 trypomastigotes and infection was allowed to progress without treatment for 99 days. After this period, the animals were divided in three groups, treated for 30 days with either placebo, benznidazole (200 mg/kg/day) or nifurtimox (100 mg/kg/day). These treatments induced 94 and 100 (per cent) cure rates respectively as detected by xenodiagnosis and reduction of antibody levels. Autopsies and histopathological studies of heart, urinary bladderand skeletal muscle performed on day 312 after infection showed almost complete healing without residual lesions. As long periods were allowed between infection, treatment and autopsy, the results indicate that tissue lesions depend, up to advances stages, on the continuous presence of the parasite.

Zinc Sulphate in the Treatment of Cutaneous Leishmaniasis: an in Vitro and Animal Study

This study was designed to evaluate the effectiveness of zinc sulphate both in vitro and in an animal model against both strains of old world cutaneous leishmaniasis. The in vitro sensitivities of promastigotes and axenic amastigotes of both Leishmania major and L. tropica to zinc sulphate was determined, the LD50 calculated and compared to the standard treatment for cutaneous leishmaniasis pentavalent antimony compounds. The results show that the two forms of both strains were sensitive to zinc sulphate and their respective LD50 were lower compared to the pentavalent antimony compound. Furthermore the sensitivities of the forms of both strains were tested using a simple slide method and compared to results of the standard method. To confirm this result, zinc sulphate was administered orally to mice infected with cutaneous leishmaniasis both therapeutically and prophylactically. Results showed that oral zinc sulphate was effective in both treatment and prophylaxis for cutaneous leishmaniasis. These results encourage the use of oral zinc sulphate in the treatment of cutaneous leishmaniasis clinically.

Neues aus Diagnostik und Therapie der spinalen Erkrankungen [Novel aspects of diagnostics and therapy of spinal cord diseases].

BACKGROUND: Both non-traumatic and traumatic spinal cord injuries have in common that a relatively minor structural lesion can cause profound sensorimotor and autonomous dysfunction. Besides treating the cause of the spinal cord injury the main goal is to restore lost function as far as possible. AIM: This article provides an overview of current innovative diagnostic (imaging) and therapeutic approaches (neurorehabilitation and neuroregeneration) aiming for recovery of function after non-traumatic and traumatic spinal cord injuries. MATERIAL AND METHODS: An analysis of the current scientific literature regarding imaging, rehabilitation and rehabilitation strategies in spinal cord disease was carried out. RESULTS: Novel magnetic resonance imaging (MRI) based techniques (e.g. diffusion-weighted MRI and functional MRI) allow visualization of structural reorganization and specific neural activity in the spinal cord. Robotics-driven rehabilitative measures provide training of sensorimotor function in a targeted fashion, which can even be continued in the homecare setting. From a preclinical point of view, defined stem cell transplantation approaches allow for the first time robust structural repair of the injured spinal cord. CONCLUSION: Besides well-established neurological and functional scores, MRI techniques offer the unique opportunity to provide robust and reliable "biomarkers" for restorative therapeutic interventions. Function-oriented robotics-based rehabilitative interventions alone or in combination with stem cell based therapies represent promising approaches to achieve substantial functional recovery, which go beyond current rehabilitative treatment efforts.

The longitudinal association between social functioning and theory of mind in first episode psychosis

Introduction. There is some cross-sectional evidence that theory of mind ability is associated with social functioning in those with psychosis but the direction of this relationship is unknown. This study investigates the longitudinal association between both theory of mind and psychotic symptoms and social functioning outcome in first-episode psychosis. Methods. Fifty-four people with first-episode psychosis were followed up at 6 and 12 months. Random effects regression models were used to estimate the stability of theory of mind over time and the association between baseline theory of mind and psychotic symptoms and social functioning outcome. Results. Neither baseline theory of mind ability (regression coefficients: Hinting test 1.07 95% CI 0.74, 2.88; Visual Cartoon test 2.91 95% CI 7.32, 1.51) nor baseline symptoms (regression coefficients: positive symptoms 0.04 95% CI 1.24, 1.16; selected negative symptoms 0.15 95% CI 2.63, 2.32) were associated with social functioning outcome. There was evidence that theory of mind ability was stable over time, (regression coefficients: Hinting test 5.92 95% CI 6.66, 8.92; Visual Cartoon test score 0.13 95% CI 0.17, 0.44). Conclusions. Neither baseline theory of mind ability nor psychotic symptoms are associated with social functioning outcome. Further longitudinal work is needed to understand the origin of social functioning deficits in psychosis.

Predictors of nonresponse in a questionnaire-based outcome study of vocational rehabilitation patients.

OBJECTIVE: To identify predictors of nonresponse to a self-report study of patients with orthopedic trauma hospitalized for vocational rehabilitation between November 15, 2003, and December 31, 2005. The role of biopsychosocial complexity, assessed using the INTERMED, was of particular interest. DESIGN: Cohort study. Questionnaires with quality of life, sociodemographic, and job-related questions were given to patients at hospitalization and 1 year after discharge. Sociodemographic data, biopsychosocial complexity, and presence of comorbidity were available at hospitalization (baseline) for all eligible patients. Logistic regression models were used to test a number of baseline variables as potential predictors of nonresponse to the questionnaires at each of the 2 time points. SETTING: Rehabilitation clinic. PARTICIPANTS: Patients (N=990) hospitalized for vocational rehabilitation over a period of 2 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Nonresponse to the questionnaires was the binary dependent variable. RESULTS: Patients with high biopsychosocial complexity, foreign native language, or low educational level were less likely to respond at both time points. Younger patients were less likely to respond at 1 year. Those living in a stable partnership were less likely than singles to respond at hospitalization. Sex, psychiatric, and somatic comorbidity and alcoholism were never associated with nonresponse. CONCLUSIONS: We stress the importance of assessing biopsychosocial complexity to predict nonresponse. Furthermore, the factors we found to be predictive of nonresponse are also known to influence treatment outcome and vocational rehabilitation. Therefore, it is important to increase the response rate of the groups of concern in order to reduce selection bias in epidemiologic investigations.

The role of ceramide trihexoside (globotriaosylceramide) in the diagnosis and follow-up of the efficacy of treatment of Fabry disease: a review of the literature.

Fabry disease is caused by a deficiency of a-galactosidase A which leads to the progressive intra-lysosomal accumulation of ceramide trihexoside (CTH), also known as globotriaosylceramide (Gb3), in different cell types and body fluids. The clinical manifestations are multisystemic and predominantly affect the heart, kidney and central nervous system. The role of CTH in the pathophysiological process of Fabry disease is not established, and the link between the degree of accumulation and disease manifestations is not systematic. The use of CTH as a diagnostic tool has been proposed for several decades. The recent introduction of a specific treatment for Fabry disease in the form of enzyme replacement therapy (ERT) has led to the need for a biological marker, in place of a clinical sign, for evaluating the efficacy of treatment and also as a tool for following the long term effects of treatment. The ideal biomarker must adhere to strict criteria, and there should be a correlation between the degree of clinical efficacy of treatment and a change in its concentration. This review of the literature assesses the utility of CTH as a diagnostic tool and as a marker of the efficacy of ERT in patients with Fabry disease. Several techniques have been developed for measuring CTH; the principles and the sensitivity thresholds of these methods and the units used to express the results should be taken into consideration when interpreting data. The use of CTH measurement in Fabry disease should be re-evaluated in light of recent published data.

Female asylum seekers with musculoskeletal pain: the importance of diagnosis and treatment of hypovitaminosis D.

BACKGROUND: Hypovitaminosis D is well known in different populations, but may be under diagnosed in certain populations. We aim to determine the first diagnosis considered, the duration and resolution of symptoms, and the predictors of response to treatment in female asylum seekers suffering from hypovitaminosis D. METHODS: Design: A pre- and post-intervention observational study. Setting: A network comprising an academic primary care centre and nurse practitioners. Participants: Consecutive records of 33 female asylum seekers with complaints compatible with osteomalacia and with hypovitaminosis D (serum 25-(OH) vitamin D < 21 nmol/l). Treatment intervention: The patients received either two doses of 300,000 IU intramuscular cholecalciferol as well as 800 IU of cholecalciferol with 1000 mg of calcium orally, or the oral treatment only. Main outcome measures: We recorded the first diagnosis made by the physicians before the correct diagnosis of hypovitaminosis D, the duration of symptoms before diagnosis, the responders and non-responders to treatment, the duration of symptoms after treatment, and the number of medical visits and analgesic drugs prescribed 6 months before and 6 months after diagnosis. Tests: Two-sample t-tests, chi-squared tests, and logistic regression analyses were performed. Analyses were performed using SPSS 10.0. RESULTS: Prior to the discovery of hypovitaminosis D, diagnoses related to somatisation were evoked in 30 patients (90.9%). The mean duration of symptoms before diagnosis was 2.53 years (SD 3.20). Twenty-two patients (66.7%) responded completely to treatment; the remaining patients were considered to be non-responders. After treatment was initiated, the responders' symptoms disappeared completely after 2.84 months. The mean number of emergency medical visits fell from 0.88 (SD 1.08) six months before diagnosis to 0.39 (SD 0.83) after (P = 0.027). The mean number of analgesic drugs that were prescribed also decreased from 1.67 (SD 1.5) to 0.85 (SD 1) (P = 0.001). CONCLUSION: Hypovitaminosis D in female asylum seekers may remain undiagnosed, with a prolonged duration of chronic symptoms. The potential pitfall is a diagnosis of somatisation. Treatment leads to a rapid resolution of symptoms, a reduction in the use of medical services, and the prescription of analgesic drugs in this vulnerable population.

Hemispheric asymmetry and theory of mind: Is there an association?

Introduction. In autism and schizophrenia attenuated/atypical functional hemispheric asymmetry and theory of mind impairments have been reported, suggesting common underlying neuroscientific correlates. We here investigated whether impaired theory of mind performance is associated with attenuated/atypical hemispheric asymmetry. An association may explain the co-occurrence of both dysfunctions in psychiatric populations. Methods. Healthy participants (n 129) performed a left hemisphere (lateralised lexical decision task) and right hemisphere (lateralised face decision task) dominant task as well as a visual cartoon task to assess theory of mind performance. Results. Linear regression analyses revealed inconsistent associations between theory of mind performance and functional hemisphere asymmetry: enhanced theory of mind performance was only associated with (1) faster right hemisphere language processing, and (2) reduced right hemisphere dominance for face processing (men only). Conclusions. The majority of non-significant findings suggest that theory of mind and functional hemispheric asymmetry are unrelated. Instead of ''overinterpreting'' the two significant results, discrepancies in the previous literature relating to the problem of the theory of mind concept, the variety of tasks, and the lack of normative data are discussed. We also suggest how future studies could explore a possible link between hemispheric asymmetry and theory of mind.

Traitement non chirurgical des rectites postactiniques ou radiques chroniques [Non-surgical treatment of acute and late radiation proctitis]

Pelvic external radiotherapy with or without brachytherapy plays an important role in the management of pelvic cancers. Despite recent technical innovations including conformal three-dimensional (3D) external beam radiotherapy and more recently intensity modulated radiotherapy (IMRT), local side effects can occur secondary to normal tissue damage caused by ionising radiation. Morbidity depends on the anatomic position of the rectum within the pelvis and the fast turnover rate of the mucosa, as well as the characteristics of the radiation treatment and patient co-morbidities. Medical management is sometimes complex and merits herein a short review.

Replacement of (R)-methadone by a double dose of (R,S)-methadone in addicts: interindividual variability of the (R)/(S) ratios and evidence of adaptive changes in methadone pharmacokinetics.

METHODS: Twenty-two patients receiving (R)-methadone maintenance treatment were switched to a double dose of (R,S)-methadone: blood samples were collected before and after the change, and the concentrations of the enantiomers were measured. In the second period, during racemic methadone treatment, important interindividual variability in the stereoselective disposition of the enantiomers of methadone was measured, with (R)/(S) ratios ranging from 0.63 to 2.40. This point should be taken into account particularly with respect to therapeutic drug monitoring of racemic methadone. RESULTS: A significant decrease P < 0.005 in the mean serum concentration/dose ratios of the active (R)-enantiomer before and after the change was measured (mean 3.97 and 3.33). CONCLUSION: Although of small amplitude (16%), this decrease confirms previously described adaptive changes in methadone pharmacokinetics during racemic methadone maintenance treatment and may necessitate, in some patients, a dose adjustment.

A re-focused and re-energised National Drugs Strategy, Issue 14, Summer 2005

The Mid-Term Review1 of the National Drugs Strategy 2001–2008, published on 2 June 2005, recommends a number of additions and amendments to the existing Strategy, including making rehabilitation a new, ‘fifth’ pillar of the Strategy. The Steering Group that oversaw the Review, and the extensive consultation process on which it is based, found that the aims and objectives of the Strategy are fundamentally sound. While what has been achieved varies from action to action, progress has been made across the four pillars of supply reduction, prevention, treatment and research, and in the co-ordination of the institutional structures of the Strategy. The Review recommends the addition of eight new actions, the replacement of nine of the existing actions and amendments to a further eight. It also recommends revisions to the Strategy’s key performance indicators, reflecting new developments and data availability. The recommendations serve to ‘re-focus and re-energise’ the Strategy in the remaining period up to 2008.This resource was contributed by The National Documentation Centre on Drug Use.