Income level and antibiotic misuse: a systematic review and dose–response meta-analysis

The European Journal of Health Economics - To quantify the association between income and antibiotic misuse including unprescribed use, storage of antibiotics and non-adherence. We identified...     

Psychotropic medications and the risk of fracture: a meta-analysis.

BACKGROUND: Older adults throughout the developed world are at significant risk of osteoporotic fractures. Many studies have examined the relationship between the use of psychotropic medications and the risk of fractures, but these studies have reported conflicting results. PURPOSE: To resolve discrepancies, we carried out a meta-analysis to assess the risk of fractures among users of several classes of psychotropic drugs. DATA SOURCES: We retrieved studies published in any language by systematically searching MEDLINE, LILACS, EMBASE and ISI Proceedings databases and by manually examining the bibliographies of the articles retrieved electronically as well as those of recent reviews. STUDY SELECTION: We included 98 cohort and case-control studies, published in 46 different articles, that reported relative risk (RR) estimates and confidence intervals (CIs) or sufficient data to calculate these values. DATA SYNTHESIS: Study-specific RRs were weighted by the inverse of their variance to obtain fixed- and random effects pooled estimates. The random effects RR of fractures was 1.34 (95% CI 1.24, 1.45) for benzodiazepines (23 studies), 1.60 (95% CI 1.38, 1.86) for antidepressants (16 studies), 1.54 (95% CI 1.24, 1.93) for non-barbiturate antiepileptic drugs (13 studies), 2.17 (95% CI 1.35, 3.50) for barbiturate antiepileptic drugs (five studies), 1.59 (1.27, 1.98) for antipsychotics (12 studies), 1.15 (95% CI 0.94, 1.39) for hypnotics (13 studies) and 1.38 (95% CI 1.15, 1.66) for opioids (six studies). For non-specified psychotropic drugs (10 studies), the pooled RR was 1.48 (95% CI 1.41, 1.59). LIMITATIONS: Main concerns were the potential for residual confounding and for publication bias. CONCLUSION: Globally, the increase in the risk of fractures among psychotropic drug users is moderate. Further research is needed, especially to examine high-risk populations and newer medications. Future studies should be prospective and emphasise control of confounding bias.     

Doublecortin interacts with the ubiquitin protease DFFRX, which associates with microtubules in neuronal processes

Doublecortin (DCX) is a microtubule-associated protein involved in neuronal migration, which causes X-linked lissencephaly and subcortical laminar heterotopia (SCLH) when mutated. Here we show that DCX interacts with the ubiquitin-specific protease Drosophila fat facets related on X chromosome (DFFRX). This interaction was confirmed by targeted mutagenesis, colocalization, and immunoprecipitation studies. DFFRX is thought to deubiquitinate specific substrates including beta-catenin, preventing their degradation by the proteasome. Interestingly, unlike beta-catenin, no ubiquitinated forms of DCX could be detected, and indeed we show that DCX interacts with a novel recognition domain in DFFRX, located outside of its catalytic site. We also show that DFFRX associates with microtubules at specific subcellular compartments, including those enriched in DCX. These results thus suggest that in addition to vesicular trafficking, DCX may play a role in the regulation of cell adhesion via its interaction with DFFRX in migrating and differentiating neurons.     

CD81-induced behavioural changes during chronic cocaine administration: in vivo gene delivery with regulatable lentivirus

CD81, a tetraspanin transmembrane protein involved in cell adhesion, is up-regulated in the mesolimbic dopaminergic pathway 24 h following acute administration of high doses of cocaine [Brenz-Verca et al., (2001) Mol. Cell. Neurosci., 17, 303-316]. Further evidence consecutive with this observation and based on microarray analysis are presented here. In addition, a regulatable lentivirus was developed bearing the rat CD81 gene under the control of a tetracycline inducible system. This lentivirus vector was stereotaxically injected into the ventral tegmental area (VTA) of two groups of animals, one fed water (expressing CD81) and the other Doxycycline solution (which down-regulates CD81 expression) and locomotor activity after chronic cocaine administration (10 mg/kg daily) was monitored. After 2 weeks, the groups were inverted, animals receiving water were placed on Doxycycline and the second group was placed on water. In all cases highly a significant increase (3.2-fold) in locomotor activity was observed in animals expressing CD81 in the VTA vs. animals placed on Doxycycline. Similar studies where CD81 was delivered into the nucleus accumbens (NAcc) resulted in significantly higher effects (30%), in accordance with microarray data and our previous reports, yielding a 4.2-fold increase in locomotor activity. No change was observed under similar conditions in control animals, which were injected a regulatable lentivirus expressing GFP. These findings suggest that CD81 expression in the mesolimbic dopaminergic pathway contributes to behavioural changes associated with cocaine sensitization. This study provides a powerful approach for evaluating a gene function in vivo in a single animal under various paradigms, even on gene candidates, which display small changes of expression.     

Distribution of alpha- and gamma-synucleins in the adult rat brain and their modification by high-dose cocaine treatment

Synucleins have attracted much attention because of their involvement in several neurodegenerative disorders. In a screening for genes differentially expressed after high-dose cocaine exposure, we found gamma-synuclein as a major upregulated candidate in the tegmentum. Overexpression of both alpha- and gamma-synuclein after drug treatment was confirmed by means of microarrays, yielding an increase in the hippocampus, the striatum and the tegmentum (2.65 x, 1.96 x and 3.5 x, respectively, for alpha-synuclein vs. 2.7 x, 1.96 x and 7.16 x for gamma-synuclein), but no change in the nucleus accumbens. Investigation of the distribution of mRNA (by in situ hybridization) and of the proteins (by immunocytochemistry) shows in both cases a clearly distinct pattern of expression for alpha- and gamma-synuclein. alpha-synuclein displays a very characteristic distribution, confined to specific nuclei, whereas gamma-synuclein is more widely expressed throughout the brain. mRNA of both alpha- and gamma-synucleins display a complementary pattern of expression all over the cortex. In contrast to gamma-synuclein, alpha-synuclein is neuronal, being only found in NeuN-expressing cells, and is expressed in the basal ganglia (faintly) and in the substantia nigra compacta where it is highly correlated with tyrosine hydroxylase. Immunocytochemistry shows that gamma-synuclein generally colocalizes with glial fibrillary acidic protein-expressing cells and is abundant in the red nucleus, the substantia nigra reticulata and the anterior commissure, while gamma-synuclein mRNA labels the matrix compartments of the caudate-putamen. The role of synucleins in relation to cocaine-induced plasticity or neurotoxicity is discussed.