Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. International AIDS Society-USA

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included.     

Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer

Fas ligand (FasL) is produced by activated T cells and natural killer cells and it induces apoptosis (programmed cell death) in target cells through the death receptor Fas/Apol/CD95. One important role of FasL and Fas is to mediate immune-cytotoxic killing of cells that are potentially harmful to the organism, such as virus-infected or tumour cells. Here we report the discovery of a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds to FasL and inhibits FasL-induced apoptosis. The DcR3 gene was amplified in about half of 35 primary lung and colon tumours studied, and DcR3 messenger RNA was expressed in malignant tissue. Thus, certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing a decoy receptor that blocks FasL.     

Inhibition of vascular smooth muscle cell proliferation by ribozymes that cleave c-myb mRNA

Proliferation of injured smooth muscle cells contributes to the reocclusion or restenosis of coronary arteries that often occurs following angioplasty procedures. We have identified and optimized nuclease-resistant ribozymes that efficiently cleave c-myb RNA. Three ribozymes targeting different sites in the c-myb mRNA were synthesized chemically and delivered to rat aortic smooth muscle cells with cationic lipids; all three inhibited serum-stimulated cell proliferation significantly. RNA molecules with two base substitutions in the catalytic core that render the ribozyme catalytically inactive had little effect on smooth muscle cell proliferation. Ribozymes with scrambled binding arm sequences also failed to affect cell cycle progression of vascular smooth muscle cells. Furthermore, inhibition of rat smooth muscle cell proliferation correlated with a reduction in intact c-myb mRNA. Efficacy of the chemically-modified ribozyme was compared directly to phosphorothioate antisense oligodeoxynucleotides targeting the same site in the c-myb RNA; the ribozyme had superior efficacy and showed greater specificity than the antisense molecules. Exogenously delivered ribozymes also inhibited porcine and human smooth muscle cell proliferation effectively. Ribozymes targeting c-myb or other regulators of smooth muscle cell proliferation may represent novel therapeutics for the treatment of restenosis after coronary angioplasty.     

The hydrophilic domain of Tic110, an inner envelope membrane component of the chloroplastic protein translocation apparatus, faces the stromal compartment

It has previously been found that Tic110, an integral protein of the chloroplast inner envelope membrane, is a component of the chloroplastic protein import apparatus. However, conflicting reports exist concerning the topology of this protein within the inner envelope membrane. In this report, we provide evidence that indicates that the large (>90-kDa) hydrophilic domain of Tic110 is localized within the chloroplast stroma. Trypsin, a protease that cannot penetrate the permeability barrier of the inner envelope membrane, degrades neither Tic110 nor other proteins exposed to the stromal compartment but is able to digest proteins exposed to the intermembrane space between the two envelope membranes. Previous reports indicating that trypsin is able to degrade Tic110 were influenced by incomplete quenching of protease activity. When trypsin is not sufficiently quenched, it is able to digest Tic110, but only after chloroplasts have been ruptured. It is therefore necessary to employ adequate quenching protocols, such as the one reported here, whenever trypsin is utilized as an analytical tool. Based on a stromal localization for the majority of Tic110, we propose that this protein may be involved in the recruitment of stromal factors, possibly molecular chaperones, to the translocation apparatus during protein import.     

Grouped random effects models for Bayesian meta-analysis

Meta-analysis refers to quantitative methods to combine results from independent studies so as to draw overall conclusions. Frequently, results from dissimilar studies are inappropriately combined, resulting in suspect inferential synthesis. We present a straightforward method to identify and address this problem through the development of grouped random effect models for meta-analysis. We examine 15 comparative studies that investigate the efficacy of a new anti-epileptic drug, progabide. The flexibility of this modelling scheme is exemplified by the result that the open studies support the efficacy of progabide while the closed studies support the reverse hypothesis. Bayesian approaches for meta-analysis are preferable because of the small number of studies prevalent in meta-analysis. We specify diffuse proper prior and hyperprior distributions to assure posterior propriety. We investigate sensitivity of the posterior to choice of prior. We use Gibbs sampling and the Metropolis algorithm to generate samples from the relevant posteriors. We analyse posterior summaries and plots of model parameters to suggest solutions to questions of interest.