Cell death: tipping the balance of autoimmunity and tissue repair

Inflammation is a key homeostatic process elicited by microbial components and by tissue damage. Increasing evidence indicates that the outcomes either tissue repair or persistent inflammatory damage and degeneration tightly depend on the pattern of cell death in situ and on infiltrating leukocytes and antigen presenting cells. Defects in the initiation and execution steps of programmed cell death such as in the clearance of cell debris are indeed often associated to inflammation defective repair and autoimmunity. Here we report recent developments on the control of apoptosis induction and execution discussing how cell death may be exploited for therapeutic purposes and the links between cell death persisting inflammation and stem cell recruitment and activation in experimental models of complex human diseases such as muscular dystrophy and cancer.     

A critical evaluation of adenosine A2A receptors as potentially "druggable" targets in Huntington's disease

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A(2A) receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A(2A) receptors might play a pathogenetic role in HD. In agreement, changes in A(2A) receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A(2A) receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A(2A) receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A(2A) receptors may represent a suitable target to develop drugs against HD.     

Neurobehavioral assessment of rats exposed to low doses of PCB126 and methyl mercury during development

Epidemiological and laboratory studies have suggested that polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) may have additive or synergistic effects on CNS function. Aim of this study was to characterize the effects of exposure to low levels of MeHg (0.5mg/kgday in drinking water) and PCB126 (100ng/kgday in food), alone and in combination, on neurobehavioral development in Wistar rats. Dams were treated from gestational day 7 to post-natal day (PND) 21. Animals were tested for developmental landmarks and reflexes (PND1-21), attention deficits (PND40), locomotor activity (PND30, 110), spatial learning (PND75), coordination and balance (PND90), object discrimination (PND80), anxiety (PND100), and conditioned learning (PND110). Parameters related to pregnancy, sex ratio at birth, and physical development (at weaning) did not differ among groups, though PCB126 decreased number of pups at birth. A slight delay in negative geotaxis was found in female rats in all treatment groups. No significant effects were seen in attention, coordination and balance, object discrimination, and spatial and conditioned learning. Increased motor activity was present in PCB126-treated male and in MeHg+PCB-treated female rats in the elevated plus maze test, and in PCB126-treated male rats in the open field test (PND110). The results do not support the hypothesis that co-exposure to MeHg and PCB126 results in additive or synergistic effects. This finding is in agreement with more recent in vitro and in vivo studies.     

Anti-tumor-Promoting activity of tibolone and its metabolites

The aim of this study was to evaluate the cancer chemopreventive potential of the widely prescribed drug tibolone (17alpha-ethynyl-7alpha-methyl-5(10)-estren-3-one, CAS 5630-53-5) and its main metabolites, 17alpha-ethynyl-7alpha-methyl-4-estren-3-one (CAS 1162-60-3), 17alpha-ethynyl-7alpha-methyl-5(10)-estrene-3alpha,17beta-diol (CAS 100239-44-9) and 17alpha-ethynyl-7alpha-methyl-5(10)-estrene-3beta,17beta-diol (CAS 100239-45-0), by studying their anti-tumor-promoting activity. To this aim the test compounds were submitted to the short term in vitro assay for the inhibition of Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) as a primary screening for anti-tumor promoters. All the compounds showed high inhibitory activity and low cytotoxicity as compared to literature data. To extend the study to an animal model, tibolone and its 3alpha-hydroxy metabolite (CAS 100239-44-9) were also assayed in the in vivo two-stage on mouse skin carcinogenesis test, exhibiting significant inhibitory effects on TPA promoted mouse skin papillomas formation. A comparison with literature data indicated them as more potent compounds than other steroids previously studied such as digitoxigenin, cortisone, hydrocortisone, and prednisolone.     

Behavioural and neurochemical characterization of the adenosine A2A receptor antagonist ST1535

ST1535 (2-butyl-9-methyl-8-(2H-1,2,3-triazol 2-yl)-9 H-purin-6-ylamine) is a novel compound showing a preferential adenosine A(2A) receptor antagonist profile. To explore the potential neuroprotective profile of this compound, we evaluated whether ST1535 prevented quinolinic acid (QA)-induced glutamate outflow in the rat striatum (a reliable index of neuroprotective activity in vivo). Microdialysis experiments were performed in naive Wistar rats. In these experiments, a behaviourally active and inactive doses of ST1535 were used. Both doses significantly prevented QA-induced glutamate outflow in the striatum. These results show that ST1535 protects towards striatal excitotoxicity, even though its reduced A(2A)/A(1) selectivity might limit its actual neuroprotective potential.     

Buprenorphine sniffing as a response to inadequate care in substituted patients: results from the Subazur survey in south-eastern France

Background

Despite the safety profile of buprenorphine, which makes this treatment highly acceptable for many countries, the risk of its diversion raises several public health and drug policy concerns. Although buprenorphine injection has been investigated quite extensively, diversion by sniffing has been overlooked. The Subazur survey gave us the opportunity to identify factors associated with buprenorphine sniffing in patients receiving buprenorphine in primary care.

Methods

We studied a population of 111 stabilized patients receiving office-based buprenorphine in south-eastern France. The design of the study consisted of two longitudinal assessments by phone interviews (at enrolment and 6 months later) detailing patients' socio-demographic characteristics, addictive behaviors, treatment experience and general health status. We used a logistic regression based on generalized estimating equations (GEE) to identify factors associated with buprenorphine sniffing at any interview.

Results

Among the 111 interviewed subjects, 33 (30%) patients reported sniffing buprenorphine after having initiated treatment. After multivariate analysis, 4 variables remained significantly associated with buprenorphine sniffing: not living in a stable relationship, having had only one or no parents during childhood, a history of drug sniffing and dissatisfaction with buprenorphine treatment.

Conclusions

Our findings underline the need to address these patients to appropriate social and mental services as well as diversifying therapeutic options, in order to provide them with adequate care and minimize diversion. The issues highlighted in the study reflect the need for recommendations for physicians prescribing OST in primary care to consider buprenorphine diversion during treatment more as non-adherence behavior than an abuse.     

High seroprevalence of HCV in the Abruzzo Region,Italy: results on a large sample from opt-out pre-surgical screening

Purpose

Available estimates of the prevalence of chronic HCV infection in Italy are quite conflicting, varying from 1.5 to 22.5 %, with an apparent north to south gradient. As Direct Acting Antivirals are expensive, both National and local governmental Agencies are in urgent need of detailed and reliable estimates of HCV patients to be treated, nationwide and in each district. We investigated the prevalence of anti-HCV antibodies in a large unselected sample of surgical patients providing consent to in-hospital opt-out pre-surgical HCV screening, at two hospitals from the Abruzzo Region, Italy.

Methods

Data were retrieved for 55,533 screened patients (4.1 % of the total population in the Abruzzo Region), admitted in the Orthopedic and General Surgery wards of Pescara and Teramo Hospitals from 1999 to 2014.

Results

The prevalence of anti-HCV antibodies was 4.4 % in the total sample. HCV-positive patients had a mean age of 63.8 ± 19.9 years; 49.2 % were males. From 1999 to 2014, the prevalence of HCV antibodies decreased from 5.4 % to 4.1 %; at both sites, however, two age-related-peaks were evidenced, the first among patients aged 30–49 years, the second among those older than 70 years. Statistical analyses confirmed a significant trend to decrease over time and a higher prevalence in Pescara and among males (all p < 0.01).

Conclusions

Data retrieved from opt-out pre-surgical screening programs may allow inexpensive and easy-to-perform estimates of HCV seroprevalence from large samples of unselected patients with a well-defined provenience, which may turn useful for future treatment resource allocation.