The contribution of AMPA receptors to neuropathic pain

Neuropathic pain is defined as pain arising as a result of damage to or dysfunction of the nervous system and is often resistant to opiate analgesics, making it difficult to treat using conventional therapies. Underlying the development of this chronic pathological pain state is a process of neuronal plasticity termed central sensitisation, involving changes from the spinal to the cortical levels of the central nervous system. Central sensitisation may result in thermal hyperalgesia and mechanical and cold allodynia which are commonly found in this condition. Neurons in the dorsal horn undergo plastic changes during central sensitisation, markedly altering their response profile to sensory stimulation. Glutamate is the major excitatory neurotransmitter at synapses between primary afferents and spinal dorsal horn neurons and plays a vital role in the generation of neuronal plasticity. Several key receptors are involved in altering the sensitivity of these neurons, including ionotropic and metabotropic glutamate receptors and peptidergic receptors.This study was designed to investigate the role of AMPA, NMDA, mGlu group I and VPAC₂ receptors (Rs) in the generation of neuropathic pain. Firstly, the behavioural reflex responses of naive rats to intrathecal administration of low doses of these receptor agonists, singly or in combinations were investigated. Combinations of two or more agonists caused increased behavioural responses to thermal and mechanical stimuli. The combination of AMPA with mGluR group I and VPAC₂ R agonists, showed a synergistic effect whereas other combinations were less than additiveExpression of AMPA R GluRl and GluR2 subunits in the superficial dorsal horn was studied using confocal immunofluorescence. In the chronic constriction injury (CCI) model of neuropathic pain both the number of GluRl-immunopositive cell bodies and the level of GluRl expression within cells decreased significantly in lamina II of the dorsal horn, ipsilateral to the injury. In contrast, there was no change in GluR2 expression or the degree of colocalisation of GluRl and GluR2 subtypes within individual cells following CCI.The subcellular distribution of GluRl subunits was also noted to change significantly as a result of CCI. GluRl subunits were found to redistribute distally into neuronal processes in lamina II cells ipsilateral to CCI and also in response to acute intrathecal AMPA treatment. This redistribution may reflect an increase in the number of GluRl-containing receptors associated with synaptic sites.The relationship between the presynaptic marker protein, Bassoon and GluRl - immunopositive cells was investigated, showing a significant increase in the number of Bassoon immunopositive puncta associated with each GluRl-immunopositive cell ipsilateral to nerve injury. The subcellular redistribution of GluRl subunits caused by CCI was reversed upon behavioural recovery and also by intrathecal administration of a combination of antagonists to NMDA R, mGluRl/5 and VPAC₂ R, whereas an AMPA R antagonist alone had no effect.These results suggest that AMPA Rs are important in the central sensitisation underlying neuropathic pain. However, it is clear that several receptors are involved in triggering maximal behavioural responses, and potential therapeutic interventions may be more effective if designed to target more than one receptor type. There is also evidence to suggest that AMPA Rs may have differing roles dependant upon their subtype composition, so subtype-specific antagonists may potentially be useful in treatment of neuropathic pain

PAin SoluTions In the Emergency Setting (PASTIES)—patientcontrolled analgesia versus routine care in emergency department patients with pain from traumatic injuries: Randomised trial

Objective To determine whether patient controlled analgesia (PCA) is better than routine care in patients presenting to emergency departments with moderate to severe pain from traumatic injuries.Design Pragmatic, multicentre, parallel group, randomised controlled trial.Setting Five English hospitals.Participants 200 adults (71% (n=142) male), aged 18 to 75 years, who presented to the emergency department requiring intravenous opioid analgesia for the treatment of moderate to severe pain from traumatic injuries and were expected to be admitted to hospital for at least 12 hours.Interventions PCA (n=99) or nurse titrated analgesia (treatment as usual; n=101).Main outcome measures The primary outcome was total pain experienced over the 12 hour study period, derived by standardised area under the curve (scaled from 0 to 100) of each participant’s hourly pain scores, captured using a visual analogue scale. Pre-specified secondary outcomes included total morphine use, percentage of study period in moderate/severe pain, percentage of study period asleep, length of hospital stay, and satisfaction with pain management.Results 200 participants were included in the primary analyses. Mean total pain experienced was 47.2 (SD 21.9) for the treatment as usual group and 44.0 (24.0) for the PCA group. Adjusted analyses indicated slightly (but not statistically significantly) lower total pain experienced in the PCA group than in the routine care group (mean difference 2.7, 95% confidence interval −2.4 to 7.8). Participants allocated to PCA used more morphine in total than did participants in the treatment as usual group (mean 44.3 (23.2) v 27.2 (18.2) mg; mean difference 17.0, 11.3 to 22.7). PCA participants spent, on average, less time in moderate/severe pain (36.2% (31.0) v 44.1% (31.6)), but the difference was not statistically significant. A higher proportion of PCA participants reported being perfectly or very satisfied compared with the treatment as usual group (86% (78/91) v 76% (74/98)), but this was also not statistically significant.Conclusions PCA provided no statistically significant reduction in pain compared with routine care for emergency department patients with traumatic injuries.Trial registration European Clinical Trials Database EudraCT2011-000194-31; Current Controlled Trials ISRCTN25343280

Discerning suicide in drug intoxication deaths: Paucity and primacy of suicide notes and psychiatric history

Objective A paucity of corroborative psychological and psychiatric evidence may be inhibiting detection of drug intoxication suicides in the United States. We evaluated the relative importance of suicide notes and psychiatric history in the classification of suicide by drug intoxication versus firearm (gunshot wound) plus hanging/suffocation—the other two major, but overtly violent methods. Methods This observational multilevel (individual/county), multivariable study employed a generalized linear mixed model (GLMM) to analyze pooled suicides and undetermined intent deaths, as possible suicides, among the population aged 15 years and older in the 17 states participating in the National Violent Death Reporting System throughout 2011–2013. The outcome measure was relative odds of suicide versus undetermined classification, adjusted for demographics, precipitating circumstances, and investigation characteristics. Results A suicide note, prior suicide attempt, or affective disorder was documented in less than one-third of suicides and one-quarter of undetermined deaths. The prevalence gaps were larger among drug intoxication cases than gunshot/hanging cases. The latter were more likely than intoxication cases to be classified as suicide versus undetermined manner of death (adjusted odds ratio [OR], 41.14; 95% CI, 34.43–49.15), as were cases documenting a suicide note (OR, 33.90; 95% CI, 26.11–44.05), prior suicide attempt (OR, 2.42; 95% CI, 2.11–2.77), or depression (OR, 1.61; 95% CI, 1.38 to 1.88), or bipolar disorder (OR, 1.41; 95% CI, 1.10–1.81). Stratification by mechanism/cause intensified the association between a note and suicide classification for intoxication cases (OR, 45.43; 95% CI, 31.06–66.58). Prior suicide attempt (OR, 2.64; 95% CI, 2.19–3.18) and depression (OR, 1.48; 95% CI, 1.17–1.87) were associated with suicide classification in intoxication but not gunshot/hanging cases. Conclusions Without psychological/psychiatric evidence contributing to manner of death classification, suicide by drug intoxication in the US is likely profoundly under-reported. Findings harbor adverse implications for surveillance, etiologic understanding, and prevention of suicides and drug deaths

Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study.

Chlamydia trachomatis causes both trachoma and sexually transmitted infections. These diseases have similar pathology and potentially similar genetic predisposing factors. We aimed to identify polymorphisms and pathways associated with pathological sequelae of ocular Chlamydia trachomatis infections in The Gambia. We report a discovery phase genome-wide association study (GWAS) of scarring trachoma (1090 cases, 1531 controls) that identified 27 SNPs with strong, but not genome-wide significant, association with disease (5 × 10(-6) > P > 5 × 10(-8)). The most strongly associated SNP (rs111513399, P = 5.38 × 10(-7)) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell. Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways. New analyses of published transcriptome data sets from Gambia, Tanzania and Ethiopia also revealed that the same cell cycle and immune response pathways were enriched at the transcriptional level in various disease states. Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling

Resistance to First-Line Anti-TB Drugs Is Associated with Reduced Nitric Oxide Susceptibility in Mycobacterium tuberculosis

Background and objective: The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug resistance and clinical outcome is not known. Methods: In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO. Results: Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters, but a tendency towards lower rate of weight gain after two months of treatment. Conclusion: There is a correlation between resistance to first-line anti-TB drugs and reduced NO susceptibility in clinical strains of M. tuberculosis. Further studies including the mechanisms of reduced NO susceptibility are warranted and could identify targets for new therapeutic interventions

Adult attention deficit hyperactivity disorder symptom profiles and concurrent problems with alcohol and cannabis: Sex differences in a representative, population survey

Background: Adult attention deficit hyperactivity disorder (ADHD) shows a robust association with alcohol and cannabis misuse, and these relationships are expressed differently in males and females. Manifestation of specific ADHD symptom profiles, even in the absence of the full disorder, may also be related to problems with alcohol and cannabis, although these relationships have not been investigated in epidemiological studies. To address this question, we studied the sex-specific associations of ADHD symptomatology with problematic alcohol and cannabis use in a representative sample of adults aged 18 years and older residing in Ontario, Canada. Methods: Data were obtained from the Centre for Addiction and Mental Health Monitor, an ongoing cross-sectional telephone survey, between January 2011 and December 2013. Respondents (n = 5080) reported on current ADHD symptomatology, measured using the Adult ADHD Self-Report Version 1.1 Screener (ASRS-V1.1) and four additional items, and alcohol and cannabis use, which were measured using the Alcohol Use Disorders Identification Test (AUDIT) and the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST), respectively. Logistic regression analyses were conducted in men and women to test the association of each ADHD symptom cluster (hyperactivity, inattentiveness, impulsivity) with problematic alcohol and cannabis use. Results: After controlling for age, education, and comorbid internalizing and externalizing psychopathology, hyperactive symptoms were associated with problematic alcohol use in both men and women and with problematic cannabis use in men. Impulsive symptoms were independently associated with problematic cannabis use in men. By contrast, inattentive symptomatology predicted problems with alcohol and cannabis only in women. In all models, age was negatively associated with substance misuse and externalizing behavior was positively correlated and the strongest predictor of hazardous alcohol and cannabis use. Conclusions: ADHD symptom expression in adulthood is related to concurrent hazardous use of alcohol and cannabis. Distinctive ADHD symptom profiles may confer increased risk for substance misuse in a sex-specific manner

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Effectiveness of cognitive-behavioral therapy on nutrition improvement and weight of overweight and obese adolescents: a randomized controlled trial

Aim: To assess the effectiveness of a cognitive-behavioral treatment (CBT) program on weight reduction among Iranian adolescents who are overweight. Methods: Using a randomized controlled trial design, 55 adolescents who were overweight (mean [SD] age=14.64 [1.69] years; zBMI=2.18 [0.65]) were recruited in the CBT program and 55 in the treatment as usual (TAU; mean age=14.88 [1.50]; zBMI=2.09 [0.57]) group. All the participants completed several questionnaires (Child Dietary Self-Efficacy Scale; Weight Efficacy Lifestyle questionnaire; Physical Exercise Self-Efficacy Scale; Pediatric Quality of Life Inventory; and self-reported physical activity and diet) and had their anthropometrics measured (height, weight, waist and hip circumferences, and body fat). Results: The CBT group consumed significantly more fruits and juice, vegetables, and dairy in the 6-month follow- up as compared with the TAU group (p-values <0.001). The CBT group consumed significantly less sweet snacks, salty snacks, sweet drinks, sausages/processed meat, and oils in the six-month follow-up compared with the TAU group (p-values<0.001). Additionally, the waist circumference, BMI, waist-hip ratio, and fat mass were significantly decreased in the CBT group in the six-month follow-up compared with the TAU group (p-values<0.005). The CBT group significantly improved their psychosocial health, physical activity, and health-related quality of life (p-values<0.001). Conclusion: The CBT program showed its effectiveness in reducing weight among Iranian adolescents who were overweight. Healthcare providers may want to adopt this program to treat excess weight problems for adolescents