Effective Gene Therapy in a Mouse Model of Prion Diseases

Classical drug therapies against prion diseases have encountered serious difficulties. It has become urgent to develop radically different therapeutic strategies. Previously, we showed that VSV-G pseudotyped FIV derived vectors carrying dominant negative mutants of the PrP gene are efficient to inhibit prion replication in chronically prion-infected cells. Besides, they can transduce neurons and cells of the lymphoreticular system, highlighting their potential use in gene therapy approaches. Here, we used lentiviral gene transfer to deliver PrPQ167R virions possessing anti-prion properties to analyse their efficiency in vivo. Since treatment for prion diseases is initiated belatedly in human patients, we focused on the development of a curative therapeutic protocol targeting the late stage of the disease, either at 35 or 105 days post-infection (d.p.i.) with prions. We observed a prolongation in the lifespan of the treated mice that prompted us to develop a system of cannula implantation into the brain of prion-infected mice. Chronic injections of PrPQ167R virions were done at 80 and 95 d.p.i. After only two injections, survival of the treated mice was extended by 30 days (20%), accompanied by substantial improvement in behaviour. This delay was correlated with: (i) a strong reduction of spongiosis in the ipsilateral side of the brain by comparison with the contralateral side; and (ii) a remarkable decrease in astrocytic gliosis in the whole brain. These results suggest that chronic injections of dominant negative lentiviral vectors into the brain, may be a promising approach for a curative treatment of prion diseases

Sexual behaviour of men that consulted in medical outpatient clinics in Western Switzerland from 2005-2006: risk levels unknown to doctors?

<p>Abstract</p> <p>Background</p> <p>To determine male outpatient attenders' sexual behaviours, expectations and experience of talking about their sexuality and sexual health needs with a doctor.</p> <p>Methods</p> <p>A survey was conducted among all male patients aged 18-70, recruited from the two main medical outpatient clinics in Lausanne, Switzerland, in 2005-2006. The anonymous self-administered questionnaire included questions on sexual behaviour, HIV/STI information needs, expectations and experiences regarding discussion of sexual matters with a doctor.</p> <p>Results</p> <p>The response rate was 53.0% (N = 1452). The mean age was 37.7 years. Overall, 13.4% of patients were defined as at STI risk - i.e. having not consistently used condoms with casual partners in the last 6 months, or with a paid partner during the last intercourse - regarding their sexual behaviour in the last year. 90.9% would have liked their physician to ask them questions concerning their sexual life; only 61.4% had ever had such a discussion. The multivariate analysis showed that patients at risk tended to have the following characteristics: recruited from the HIV testing clinic, lived alone, declared no religion, had a low level of education, felt uninformed about HIV/AIDS, were younger, had had concurrent sexual partners in the last 12 months. However they were not more likely to have discussed sexual matters with their doctor than patients not at risk.</p> <p>Conclusion</p> <p>Recording the sexual history and advice on the prevention of the risks of STI should become routine practice for primary health care doctors.</p

Polyaniline and its derivatives doped with Lewis acids (synthesis and spectroscopic properites)

The presented research is devoted to the studies of the doping of polyaniline and its ring substituted derivatives (polyanisidine, poly(2-ethylaniline)) with AlCl3 and FeCl3 as well as with their derivatives containing mixed chloride - acetylacetonate ligands (AlCl2(acac) and (FeCl(acac)2). AlCl3 and FeCl3 doped polymers are conductive and show the electronic type conductivity of the order 10-3 S/cm. Complementary spectroscopic studies involving UV-Vis-NIR, IR, EPR, 27Al NMR (in the case of AlCl3 doping) and 57Fe Mössbauer effect (in the case of FeCl3 doping), combined with elemental analysis, enabled us to elucidate the doping reaction mechanism, which in both cases is the same. The doping involves, in the first step, the self-dissociation of the dopant molecule. The cationic product of this self-dissociation is the complexed on imine nitrogen sites of the polymer chain, whereas the anionic part is incorporated into the polymer matrix to neutralise the positive charge imposed on the polymer chain. The coordination sphere of the cationic complex is completed by solvation with a nitromethane molecule. Charge rearrangement accompanying the doping process produces mobile radical cations on the polymer chain, which assure electronic conductivity of the doped polymer. This mechanism clearly explains the presence of charge carriers and the radical cation structure of the doped polymer chain detected by EPR and UV-Vis-NIR spectroscopies. FeCl3 doped polyaniline shows poor mechanical properties, which can however, be improved by post-treatment with hexafluoroacetylacetone (HFAA). This treatment results in the transformation of FeCl3 (Lewis acid) doped polyaniline into HFeCl4 (Brönsted acid) doped polymer, simultaneously plasticized with HFAA. Doping with mixed ligands (AlCl2(acac) and (FeCl(acac)2.), although being inactive with respect to polyaniline doping, readily dope polyanisidine and poly(2-ethylaniline). The chains of doped polymers adopt the radical cation structure as evidenced by UV-Vis-NIR spectroscopy, however the doping mechanism is more complex than in the case of reaction with AlCl3 or FeCl3. The doping with AlCl2(acac) results in the AlCl3 doped polymer with Al(acac)3 incorporated to the polymer matrix as a side reaction product. Doping with FeCl(acac)2 produces more than expected non-equivalent iron sites of the chemical constitution not easily identifiable by Mössbauer spectroscopy.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF