Corollary discharge dysfunction in schizophrenia: can it explain auditory hallucinations?

Failure of corollary discharge, a mechanism for distinguishing self-generated from externally generated percepts, has been posited to underlie certain positive symptoms of schizophrenia, including auditory hallucinations. Although originally described in the visual system, corollary discharge may exist in the auditory system, whereby signals from motor speech commands prepare auditory cortex for self-generated speech. While associated with sensorimotor systems, it might also apply to inner speech or thought, regarded as our most complex motor act. In this paper, we describe the results of a series of studies in which we have shown that: (1) event-related brain potentials (ERPs) can be used to demonstrate the corollary discharge phenomenon during talking, (2) corollary discharge is abnormal in patients with schizophrenia, (3) EEG gamma band coherence between frontal and temporal lobes is greater during talking than listening and is disrupted by distorted feedback during talking in normals, and (4) patients with schizophrenia do not show this pattern for EEG gamma coherence. While these studies have identified ERPs and EEG gamma coherence indices of the efference copy/corollary discharge system and documented abnormalities in these systems in patients with schizophrenia, we have so far had limited success in establishing a relationship between these neurobiologic indicators of corollary discharge abnormality and reports of hallucinations in patients.     

Recent Advances in Structure-Based Virtual Screening of G-Protein Coupled Receptors

In addition to the rhodopsin crystal structure, high-resolution crystal structures of ligand-mediated G-protein-coupled receptors (GPCRs) have recently become available, and these have become attractive templates for developing homology models of several GPCRs of therapeutic interest. These crystal structures and the homology models derived from them have provided significant insights into ligand–receptor interactions. Moreover, several studies have demonstrated that the structural models are indeed suitable for virtual screening of compound databases to identify new ligands for various GPCRs. Recent examples of such virtual screening against GPCRs are discussed in this review.     

High-quality controlled trials on preventing episodes of back problems: systematic literature review in working-age adults

Background contextBack problems (BPs), with their cost and disability, are a substantial burden for individuals, employers, and society.PurposeThis systematic review of controlled trials evaluates the effectiveness of interventions to prevent BP episodes in working age adults.Data sourcesWe searched MEDLINE/EMBASE through May 2007, and COCHRANE/Trials Registry through August 22, 2008 using search terms of back pain, back injuries or sciatica, linked to prevention, control, workplace interventions, or ergonomics and searched article bibliographies.Study selectionFor systematic review inclusion, articles had to describe prospective controlled trials of interventions to prevent BPs in working-age adults, with intervention assignment either to individual participants or preexisting groups. Of 185 articles identified as potentially relevant, 20 trials (11%) met inclusion criteria.Data extractionResearchers extracted relevant information from controlled trials and graded methodological quality. Because of heterogeneity of trials, meta-analysis was not performed.ResultsOnly exercise was found effective for preventing self-reported BPs in seven of eight trials (effect size 0.39 to >0.69). Other interventions were not found to reduce either incidence or severity of BP episodes compared with controls. Negative trials included five trials of education, four of lumbar supports, two of shoe inserts, and four of reduced lifting programs.ConclusionsTwenty high-quality controlled trials found strong, consistent evidence to guide prevention of BP episodes in working-age adults. Trials found exercise interventions effective and other interventions not effective, including stress management, shoe inserts, back supports, ergonomic/back education, and reduced lifting programs. The varied successful exercise approaches suggest possible benefits beyond their intended physiologic goals.Level of evidenceSystematic review Level I evidence.     

Americans' Awareness, Knowledge, and Behaviors Regarding Fats: 2006-2007

In recent years, epidemiologic and clinical studies, public and regulatory policy activity, and media coverage have focused on issues related to trans fats. To help increase awareness and understanding of trans fats and other fats, the American Heart Association (AHA) launched the “Face the Fats” national consumer education campaign in April 2007. The AHA commissioned a quantitative tracking survey between 2006 and 2007 to measure changes in consumer awareness, knowledge, and behaviors related fats and oils and their perceived impact on heart disease. The survey was conducted by Cogent Research. Data were collected during March 2006 and May 2007. At both time points, the survey included a representative sample of the American population age 18 to 65 years (n=1,000). The sampling plan for the survey was designed based on the 2000 and 2003 US Census. The margin of error was ±3.10 percentage points. Awareness of trans fats increased during the 1-year study period. In 2007, 92% of respondents were aware of trans fats, an increase from 84% in 2006 (P<0.05). The 2007 level was similar to the awareness of saturated fats (93%). Perceptions that certain fats and oils heighten the risk of heart disease increased for trans fats (73% in 2007 vs 63% in 2006; P<0.05), saturated fats (77% in 2007 vs 73% in 2006; P<0.05), and partially hydrogenated oils (56% in 2007 vs 49% in 2006; P<0.05). Knowledge about food sources of different fats remained low. On an unaided basis, 21% could name three food sources of trans fats in 2007, up from 17% in 2006 (P<0.05). Knowledge of food sources of saturated fat remained unchanged at 30% in 2007. Significantly more respondents in 2007 reported behavioral changes related to trans fat information, such as buying food products because they show “zero trans fat” on labels or packages (37% in 2007 vs. 32% in 2006; P<0.05). Between 2006 and 2007, consumer awareness about trans fats increased and attained awareness levels similar to saturated fats. The increased awareness is associated with improved self-reported behaviors in grocery shopping. Nonetheless, overall knowledge, especially regarding food sources of saturated and trans fats, remains relatively low, underscoring the need for heightened consumer education activities. The positive change in consumer awareness about trans fats is likely attributable to the wide range of messages available to them, including the AHA “Face the Fats” national consumer education campaign.     

Retrolisthesis and lumbar disc herniation: a preoperative assessment of patient function.

BACKGROUND CONTEXT: Retrolisthesis is relatively rare but when present has been associated with increased back pain and impaired back function. Neither the prevalence of this condition in individuals with lumbar disc herniations nor its possible relation to preoperative back pain and dysfunction has been well studied. PURPOSE: The purposes of this study were as follows: (1) to determine the prevalence of retrolisthesis (alone or in combination with other degenerative conditions) in individuals with confirmed L5-S1 disc herniation who later underwent lumbar discectomy; (2) to determine if there is any association between retrolisthesis and degenerative changes within the same vertebral motion segment; and (3) to determine the relation between retrolisthesis (alone or in combination with other degenerative conditions) and preoperative low back pain, physical function, and quality of life. STUDY DESIGN/SETTING: Cross-sectional study. PATIENT SAMPLE: A total of 125 individuals were identified for incorporation into this study. All patients had confirmed L5-S1 disc herniation on magnetic resonance imaging (MRI) and later underwent L5-S1 discectomy. All patients were enrolled in the Spine Patient Outcomes Research Trial (SPORT) study; data were obtained from the multi-institutional database comprised of SPORT patients from across the United States. OUTCOME MEASURES: Retrolisthesis, degenerative change on MRI, and Modic changes. METHODS: MRI scans of the lumbar spine were assessed at spinal level L5-S1 for all 125 patients. Retrolisthesis was defined as posterior subluxation of 8% or more. Disc degeneration was defined as any loss of disc signal on T2 imaging. Modic changes were graded 1 to 3 and collectively classified as vertebral endplate degenerative changes. The presence of facet arthropathy and ligamentum flavum hypertrophy was classified jointly as posterior degenerative changes. RESULTS: The overall incidence of retrolisthesis at L5-S1 in our study was 23.2%. Retrolisthesis combined with posterior degenerative changes, degenerative disc disease, or vertebral endplate changes had incidences of 4.8%, 16%, and 4.8% respectively. The prevalence of retrolisthesis did not vary by sex, age, race, smoking status, or education level when compared with individuals with normal sagittal alignment. However, individuals with retrolisthesis were more likely to be receiving workers' compensation than those without retrolisthesis. Increased age was found to be associated with individuals having vertebral endplate degenerative changes (both alone and in conjunction with retrolisthesis) and degenerative disc disease. Individuals who had retrolisthesis with concomitant vertebral endplate degenerative changes were more often smokers and had no insurance. The presence of retrolisthesis was not associated with an increased incidence of having degenerative disc disease, posterior degenerative changes, or vertebral endplate changes. No statistical significance was found between the presence of retrolisthesis on the degree of patient preoperative low back pain and physical function. Patients with degenerative disc disease were found to have increased leg pain compared with those patients without degenerative disc changes. CONCLUSIONS: We found no significant relationship between retrolisthesis in patients with L5-S1 disc herniation and worse baseline pain or function. It is possible that the contribution of pain or dysfunction related to retrolisthesis was far overshadowed by the presence of symptoms caused by the concomitant disc herniation. It remains to be seen whether retrolisthesis will affect outcome after discectomy in these patients.     

Effectiveness of needle and syringe programmes for preventing HIV transmission

Objective: To examine the effectiveness of needle and syringe programmes (NSPs) in preventing HIV transmission among injecting drug users (IDUs).Methods: An ecological study design was used to determine change in HIV prevalence among injecting drug users between cities with and without NSPs. Several data sources, such as electronic journal databases, surveillance reports, websites, and index review of relevant journals, were used to identify studies of HIV seroprevalence among IDUs, and presence of NSPs. The rate of change in HIV prevalence was estimated by regression analysis.Results: There were 778 years of data from 99 cities globally included in the analysis. HIV prevalence decreased by 18.6% per annum in cities that introduce NSPs, and increased by 8.1% in cities that had never introduced NSPs (mean difference −24.7% [95% CI: −43.8, 0.5%], P=0.06). The mean difference was –33% when comparison was weighted to one over the variance of the regression estimator (29% decrease in cities with NSPs and 5% increase in cities without NSPs, P<0.001). When analysis was restricted to cities with first HIV seroprevalence less than 10%, the average annual change in seroprevalence was 18% lower in cities with NSPs (P=0.03).Conclusions: Despite the inherent limitations within an ecological study design, the study provides additional evidence that NSPs reduce transmission of HIV infection. The rapid spread of HIV among IDU populations and increasing rates of injecting in many countries calls for scaling up of NSPs as well as other harm reduction strategies.     

Work-related recovery opportunities: testing scale properties and validity in relation to health

Objectives  

Recovery opportunities allow employees to recuperate from work and diminish load effects. The aims of this study are to present a scale for measuring recovery opportunities, study its psychometric properties and its relationship with health.     

Reactive arthritis and internal derangement of the temporomandibular joint.

OBJECTIVE: The objective of this study was to determine if temporomandibular joint (TMJ) samples positive for Chlamydia trachomatis have a greater presence of tumor necrosis factor-alpha (TNFalpha) or interleukin-6 (IL-6) when compared with Chlamydia-negative samples. STUDY DESIGN: Posterior bilaminar tissue samples removed during TMJ surgery from 70 patients were evaluated. Cryosections were stained using monoclonal antibody that identifies C. trachomatis. The presence of IL-6 and TNFalpha were evaluated by immunostaining in 15 samples positive and in 25 samples negative for the presence of C. trachomatis. RESULTS: Of the 70 TMJ samples, 32 (46%) were positive for C. trachomatis. In 15 samples positive for C. trachomatis, 10 (67%) were positive for TNFalpha and 7 (47%) for IL-6. In 25 samples negative for C. trachomatis, only 4 (16%) were positive for TNFalpha and only 2 (8%) for IL-6. Differences in C. trachomatis-positive samples versus negative were significant for both TNFalpha (P < .002) and IL-6 (P < .008). CONCLUSION: The presence of C. trachomatis in the TMJ is associated with a significantly increased presence of TNFalpha and IL-6.     

The Specific Endothelin A Receptor Antagonist ZD4054: Preclinical and Clinical Results

ContextZD4054 is a specific endothelin A (ET_A) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer (HRPC). ZD4054 binds specifically to the ET_A receptor, with no detectable activity at the ET_B receptor. In preclinical studies, ZD4054 inhibited endothelin (ET-1)-mediated changes in cellular invasiveness in vitro, and inhibited angiogenesis and growth of tumour xenografts in vivo. Consistent with its specific binding profile, ZD4054 inhibited ET_A-receptor-mediated antiapoptotic events while allowing ET_B-receptor-mediated proapoptotic signalling.Evidence acquisitionThe preclinical and clinical activity of ZD4054 is reviewed.Evidence synthesisIn the clinical setting, stable levels of circulating ET-1 following single ZD4054 doses up to 240 mg demonstrated the absence of ZD4054 activity at the ET_B receptor. ZD4054 is cleared principally via the urine, with a terminal elimination half-life of approximately 8–12 hours and with little accumulation after once-daily oral dosing.In a Phase 2 trial, patients with metastatic HRPC who were pain free or mildly symptomatic for pain were randomized to once-daily oral tablets of ZD4054 10 mg (n = 107), or 15 mg (n = 98), or matched placebo (n = 107). ZD4054 was generally well tolerated in this population, with an adverse effect profile consistent with its known pharmacological activity. The most common adverse effects were headache, peripheral oedema and nasal congestion. At the primary analysis there was no statistically significant difference in time to progression between the ZD4054-treated groups and placebo (hazard ratio [HR]: ZD4054 10 mg, 0.88 [80% CI 0.71, 1.09]; ZD4054 15 mg, 0.83 [0.66, 1.03]). However, a promising signal for prolonged overall survival was observed, which was sustained at a subsequent analysis (HR versus placebo: ZD4054 10 mg, 0.55 [80% CI 0.41, 0.73]; ZD4054 15 mg, 0.65 [0.49, 0.86]).ConclusionsThese results support the strategy of targeting the ET_A receptor in prostate cancer, and mandate further investigation of ZD4054 in Phase 3 clinical trials.