The four-plates test–retest paradigm to discriminate anxiolytic effects

Rationale Animal models of anxiety such as the four-plates test (FPT) enable the detection of an anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZD anxiolytic compounds such as the antidepressants paroxetine and venlafaxine. Retesting mice in animal models of anxiety markedly alters the behavioural profile of various drugs.Objectives The aim of this study was first to investigate the function of GABA_A/BZD receptor and passive avoidance acquisition in the FPT test–retest. The second aim of this study was to evaluate the capacity of the FPT to discriminate BZDs from other non-BZD anxiolytics in experienced mice.Methods The FPT was performed in naive and experienced mice (submitted to the test 24 h previously). The drugs studied were two BZDs, diazepam (1 mg/kg) and alprazolam (0.25 mg/kg); flumazenil, a GABA_A receptor antagonist (8 mg/kg); atropine sulphate, a muscarinic cholinergic receptor antagonist (4 mg/kg) known for its amnesic properties; paroxetine, a selective serotonin reuptake inhibitor (4 and 8 mg/kg); venlafaxine, a serotonin and noradrenalin reuptake inhibitor (4 and 16 mg/kg); and DOI, a 5-HT_2A agonist (1 mg/kg).Results Our results reveal an increase of anxiety (decrease of punished passages) in saline-experienced mice. Diazepam, alprazolam, paroxetine and venlafaxine did not prevent the increase in anxiety during retest, revealing a passive avoidance acquisition. Flumazenil did not modify the anxiogenic-like behaviour of experienced mice. In contrast, atropine seems to oppose the increase of anxiety; however, its effect is weak and disputable. DOI was the only anxiolytic compound able to oppose the decrease of punished passages of experienced mice.Conclusion Anxiogenic behaviour on retesting indicates aversive learning. The protocol test–retest is unable to discriminate between the anxiolytic effect of BZDs from that of paroxetine or venlafaxine. However, this modified model may constitute a new tool to investigate other neural pathways implicated in anxiety.     

A comparison of plates with and without locking screws in a calcaneal fracture model

BACKGROUND: We compared different plates in an experimental calcaneal fracture model under biocompatible loading. METHODS: Four plates were tested: a plate without locked screws (Synthes), and three different plates with locked screws (Newdeal, Darco, Synthes). Synthetic calcanei (Sawbone) were osteotomized to create a fracture model, and the plates were fixed onto them. Seven specimens for each plate model were subjected to cyclic loading (preload 20 N, 1,000 cycles with 800 N, 0.75 mm/s), and load to failure (0.75 mm/s). Motion, forces, plastic deformation of the plate, and consequent depression of the posterior joint facet were analyzed. RESULTS: During cyclic loading, all plates with locked screws showed statistically significant lower displacement in the primary loading direction than the plates without locked screws. Mean values (mm) of maximal displacements for each plate during cyclic loading were as follows: Synthes, 3.5; Darco, 4.5; Newdeal, 5.0; Synthes without locked screws, 7.5; (p < 0.001). No statistically significant differences between the plates were found in relation to loads to failure and corresponding displacement. CONCLUSION: This is the first biomechanical study to assess the stability of different plates currently in use in our practice for the fixation of calcaneal fractures. Our results showed that plates with locked screws provided greater stability during cyclic loading than the plate without locked screws.     

Bullying and symptoms among school-aged children: international comparative cross sectional study in 28 countries

BACKGROUND: There have been no large-scale international comparisons on bullying and health among adolescents. This study examined the association between bullying and physical and psychological symptoms among adolescents in 28 countries. METHODS: This international cross-sectional survey included 123,227 students 11, 13 and 15 years of age from a nationally representative sample of schools in 28 countries in Europe and North America in 1997-98.The main outcome measures were physical and psychological symptoms. RESULTS: The proportion of students being bullied varied enormously across countries. The lowest prevalence was observed among girls in Sweden (6.3%, 95% CI: 5.2-7.4), the highest among boys in Lithuania (41.4%, 95% CI 39.4-43.5). The risk of high symptom load increased with increasing exposure to bullying in all countries. In pooled analyses, with sex stratified multilevel logistic models adjusted for age, family affluence and country the odds ratios for symptoms among students who were bullied weekly ranged from 1.83 (95% CI 1.70-1.97) to 2.11 (95% CI 1.95-2.29) for physical symptoms (headache, stomach ache, backache, dizziness) and from 1.67 (95% CI 1.55-1.78) to 7.47 (95% CI 6.87-8.13) for psychological symptoms (bad temper, feeling nervous, feeling low, difficulties in getting to sleep, morning tiredness, feeling left out, loneliness, helplessness). CONCLUSION: There was a consistent, strong and graded association between bullying and each of 12 physical and psychological symptoms among adolescents in all 28 countries.     

Binding characteristics of the 5-HT2A receptor antagonists altanserin and MDL 100907

To study the 5-HT(2A) receptors in the living human brain, using positron emission tomography (PET), two selective radiotracers are currently in use: [(18)F]altanserin and [(11)C]MDL 100907. It is, however, currently unknown to what extent data obtained with either tracer are directly comparable. The aim of this study was to compare binding characteristics of these two radiotracers in rat brain with respect to affinity (K(d)), receptor binding density (B(max)), binding potential (BP), and nonspecific binding. Further, binding kinetics, sensitivity towards competition with the endogenous transmitter serotonin, and the competitive/noncompetitive interaction between the two radioligands were evaluated. In addition, the selectivity of [(18)F]altanserin for the 5-HT(2A) receptor was assessed.The K(d) value of [(18)F]altanserin and [(3)H]MDL 100907 was in the order of 0.3 nM. B(max) in frontal cortex was 523 and 527 fmol/mg protein, respectively. The binding of [(18)F]altanserin was not influenced by blocking either the 5-HT(2B/2C) or the alpha(1)-adrenergic receptors. At 37 degrees C the association t(1/2) was 2.8 and 2.7 min and the dissociation t(1/2) was 11 and 13.5 min for [(18)F]altanserin and [(3)H]MDL 100907, respectively.Both radioligands were displaced by 5-HT, only at high concentrations; the K(i) value of 5-HT ranging between 650 and 3,300 nM. This indicates that binding of both radioligands in PET studies is not directly influenced by changes in endogenous 5-HT.Overall, the binding of [(18)F]altanserin and [(3)H]MDL 100907 to the 5-HT(2A) receptor was very comparable, showing selective high affinity binding in the subnanomolar range.     

Influence of sociodemographic and neighbourhood factors on self rated health and quality of life in rural communities: findings from the Agriproject in the Republic of Ireland

OBJECTIVE: To examine the influence of sociodemographic and neighbourhood factors on self rated health, quality of life, and perceived opportunities for change (as one measure of empowerment) in rural Irish communities. DESIGN: Pooled data from cross sectional surveys two years apart. SETTING: Respondents in four randomly selected rural district electoral divisions with a population size of between 750 and 2000. PARTICIPANTS: 1738 rural dwellers aged 15-93, 40.5% men, interviewed at two time points. MAIN OUTCOME MEASURES: Determinants of self rated health (SRH), quality of life (QOL), and perceived opportunities for change, rated on a closed option Likert scale and assessed in multivariate logistic regression models. MAIN RESULTS: Overall 23.8% of the sample reported poor SRH, 22.2% poor QOL, and 50.1% low perceived opportunities for change. Low financial security and dissatisfaction with work were each significantly associated with poor SRH (OR = 1.96 (1.50 to 2.56) and 1.54 (1.11 to 2.14)), with poor QOL (OR = 2.04 (1.56 to 2.68) and 1.87 (1.34 to 2.61). Concern about access to public services was significantly predictive of SRH (OR = 1.47 (1.11 to 1.94)) rather than access to health care (that is, hospital and GP services). There were distinct sex specific patterns and a generational effect for educational status in men. Variables associated with social networks and social support were less strongly predictive of SRH and QOL when economic measures were accounted for. CONCLUSION: Inter-relations between indicators of health status, wellbeing, and deprivation are not well studied in rural communities. Material deprivation has a direct influence on both health status and quality of life, although immediate sources of support are relatively well preserved.     

The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a cyclin D homolog, K cyclin, that is thought to promote viral oncogenesis. However, expression of K cyclin in cultured cells not only triggers cell cycle progression but also engages the p53 tumor suppressor pathway, which probably restricts the oncogenic potential of K cyclin. Therefore, to assess the tumorigenic properties of K cyclin in vivo, we transgenically targeted expression of K cyclin to the B and T lymphocyte compartments via the E micro promoter/enhancer. Around 17% of E micro -K cyclin animals develop lymphoma by 9 months of age, and all such lymphomas exhibit loss of p53. A critical role of p53 in suppressing K cyclin-induced lymphomagenesis was confirmed by the greatly accelerated onset of B and T lymphomagenesis in all E micro -K cyclin/p53(-/-) mice. However, absence of p53 did not appear to accelerate K cyclin-induced lymphomagenesis by averting apoptosis: E micro -K cyclin/p53(-/-) end-stage lymphomas contained abundant apoptotic cells, and transgenic E micro -K cyclin/p53(-/-) lymphocytes in vitro were not measurably protected from DNA damage-induced apoptosis compared with E micro -K cyclin/p53(wt) cells. Notably, whereas aneuploidy was frequently evident in pre-lymphomatous tissues, end-stage E micro -K cyclin/p53(-/-) tumors showed a near-diploid DNA content with no aberrant centrosome numbers. Nonetheless, such tumor cells did harbor more restricted genomic alterations, such as single-copy chromosome losses or gains or high-level amplifications. Together, our data support a model in which K cyclin-induced genome instability arises early in the pre-tumorigenic lymphocyte population and that loss of p53 licenses subsequent expansion of tumorigenic clones.