A sure house studies on the dynastic promise to David in the books of Samuel

The dissertation studies the texts mentioning or alluding to the dynastic promise to David in the books of Samuel; in the concluding further perspectives it also overviews the occurrences of the promise in the books of Kings; in the appendix, it comments on the "Law of the King" in Deut 17,14-20, the last verse of which may contain an allusion to the Davidic promise. The study engages with recent discussion on the history of the text of 2 Sam 7. In a detailed textual commentary, it treats with all the differences between the main textual witnesses of the chapter, and apart from the evaluation of the individual variants, it attempts to answer the question whether the differences are due exclusively to the process of transmission, or they are of literary character. Special attention is paid to the value of 1 Chr 17 for the reconstruction of the oldest text of 2 Sam 7; the author hopes that the conclusions of this part of the dissertation may prove to be of some importance for a more general study of the reception of Samuel in Chronicles. The subsequent literary analysis of 2 Sam 7 and the other passages referring to the dynastic promise to David leads to two alternative datings of Nathan's oracle and consequently two alternative redactional hypotheses trying to give account of the emergence of the examined passages. In the concluding perspectives, the function of the promise in Samuel is compared with the occurrences of the motif in Kings; this comparison leads to tentative conclusions concerning the development of the relation of the two books.

Le(s) récit(s) dit de l'instauration de la monarchie en 1 Samuel

(Résumé de l'ouvrage) The present debate on the so-called "Deuteronomistic History" has become quite confusing and in recent years more and more scholars are inclined to deny the existence of a Deuteronomistic History as elaborated by Martin Noth or at least to modify this thesis radically. The contributions in this volume reflect the present state of discussion about the Deuteronomistic History. With one exception they have all been presented and discussed in three special sessions dedicated to "Deuteronomism" during the SBL International Meeting in Lausanne (July 1997). Three topics were treated: "The Future of the Deuteronomistic History", "Identity and Literary Strategies of the Deuteronomists", "Deuteronomism and the Hebrew Bible". The contributors are: R. Albertz, A.G. Auld, M. Bauks, W. Dietrich, D. Edelman, F. Garcia Lopez, E.A. Knauf, G. Knoppers, S.K. McKenzie, C. Nihan, T.C. Römer, N.H. Rösel, J. Van Seters and J. Vermeylen. Each contribution offers a valuable entry into one of the most important discussions of Old Testament scholarship at the end of the twentieth century.

Placebo effect characteristics observed in a single, international, longitudinal study in Huntington's disease.

BACKGROUND: Classically, clinical trials are based on the placebo-control design. Our aim was to analyze the placebo effect in Huntington's disease. METHODS: Placebo data were obtained from an international, longitudinal, placebo-controlled trial for Huntington's disease (European Huntington's Disease Initiative Study Group). One-hundred and eighty patients were evaluated using the Unified Huntington Disease Rating Scale over 36 months. A placebo effect was defined as an improvement of at least 50% over baseline scores in the Unified Huntington Disease Rating Scale, and clinically relevant when at least 10% of the population met it. RESULTS: Only behavior showed a significant placebo effect, and the proportion of the patients with placebo effect ranged from 16% (first visit) to 41% (last visit). Nondepressed patients with better functional status were most likely to be placebo-responders over time. CONCLUSIONS: In Huntington's disease, behavior seems to be more vulnerable to placebo than overall motor function, cognition, and function

Lentiviral-mediated gene transfer of siRNAs for the treatment of Huntington's disease.

This chapter describes the potential use of viral-mediated gene transfer in the central nervous system for the silencing of gene expression using RNA interference in the context of Huntington's disease (HD). Protocols provided here describe the design of small interfering RNAs, their encoding in lentiviral vectors (LVs) and viral production, as well as procedures for their stereotaxic injection in the rodent brain.

Neuroprotective gene therapy for Huntington's disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: results of a phase I study.

Huntington's disease (HD) is a monogenic neurodegenerative disease that affects the efferent neurons of the striatum. The protracted evolution of the pathology over 15 to 20 years, after clinical onset in adulthood, underscores the potential of therapeutic tools that would aim at protecting striatal neurons. Proteins with neuroprotective effects in the adult brain have been identified, among them ciliary neurotrophic factor (CNTF), which protected striatal neurons in animal models of HD. Accordingly, we have carried out a phase I study evaluating the safety of intracerebral administration of this protein in subjects with HD, using a device formed by a semipermeable membrane encapsulating a BHK cell line engineered to synthesize CNTF. Six subjects with stage 1 or 2 HD had one capsule implanted into the right lateral ventricle; the capsule was retrieved and exchanged for a new one every 6 months, over a total period of 2 years. No sign of CNTF-induced toxicity was observed; however, depression occurred in three subjects after removal of the last capsule, which may have correlated with the lack of any future therapeutic option. All retrieved capsules were intact but contained variable numbers of surviving cells, and CNTF release was low in 13 of 24 cases. Improvements in electrophysiological results were observed, and were correlated with capsules releasing the largest amount of CNTF. This phase I study shows the safety, feasibility, and tolerability of this gene therapy procedure. Heterogeneous cell survival, however, stresses the need for improving the technique.

Downregulation of cannabinoid receptor 1 from neuropeptide Y interneurons in the basal ganglia of patients with Huntington's disease and mouse models.

Cannabinoid receptor 1 (CB(1) receptor) controls several neuronal functions, including neurotransmitter release, synaptic plasticity, gene expression and neuronal viability. Downregulation of CB(1) expression in the basal ganglia of patients with Huntington's disease (HD) and animal models represents one of the earliest molecular events induced by mutant huntingtin (mHtt). This early disruption of neuronal CB(1) signaling is thought to contribute to HD symptoms and neurodegeneration. Here we determined whether CB(1) downregulation measured in patients with HD and mouse models was ubiquitous or restricted to specific striatal neuronal subpopulations. Using unbiased semi-quantitative immunohistochemistry, we confirmed previous studies showing that CB(1) expression is downregulated in medium spiny neurons of the indirect pathway, and found that CB(1) is also downregulated in neuropeptide Y (NPY)/neuronal nitric oxide synthase (nNOS)-expressing interneurons while remaining unchanged in parvalbumin- and calretinin-expressing interneurons. CB(1) downregulation in striatal NPY/nNOS-expressing interneurons occurs in R6/2 mice, Hdh(Q150/Q150) mice and the caudate nucleus of patients with HD. In R6/2 mice, CB(1) downregulation in NPY/nNOS-expressing interneurons correlates with diffuse expression of mHtt in the soma. This downregulation also occludes the ability of cannabinoid agonists to activate the pro-survival signaling molecule cAMP response element-binding protein in NPY/nNOS-expressing interneurons. Loss of CB(1) signaling in NPY/nNOS-expressing interneurons could contribute to the impairment of basal ganglia functions linked to HD.

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.