Retinal degeneration in the rd mouse in the absence of c-fos

PURPOSE: Apoptosis is the final common death pathway of photoreceptors in light-induced retinal degeneration and in several animal models for retinal dystrophy. To date, little is known about gene regulation of apoptosis in the retina. The expression of the immediate early gene c-fos is upregulated concomitant with apoptosis in light-induced photoreceptor degeneration and in the rd mouse, an animal model for inherited retinal degeneration. In a recent study it was shown that c-Fos is essential for light-induced apoptosis of photoreceptors in vivo. To determine whether c-Fos is also involved in the apoptotic pathway of inherited retinal degeneration, rd/rd, c-fos -/- double-mutant mice have been generated. METHODS: Double-mutant mice (rd/rd, c-fos -/-) were crossbred from c-fos+/- mice and rd/rd mice. Their genotype was determined by polymerase chain reaction analysis of genomic DNA. Wild-type control mice and homozygous rd mice were killed at 2-day intervals from postnatal day (P)9 through P21. Double-mutant mice were killed at postnatal days P9, P11, P13, P15, and P21. To determine levels of apoptosis in the retina, eyes were enucleated and processed for light microscopy and in situ nick-end labeling. Total retinal DNA was extracted from isolated retinas for DNA fragmentation analysis. RESULTS: Morphologic, histochemical, and biochemical analyses showed that the time course of apoptosis and the outcome of photoreceptor degeneration in rd/rd, c-fos-/- double-mutant mice was indistinguishable from that in rd mice carrying functional c-fos. CONCLUSIONS: These data suggest that in contrast to its role in light-induced photoreceptor degeneration, c-Fos is not essential for apoptosis in the rd mouse.     

Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication

Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease. It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication (IC). Cilostazol has been shown to improve walking distance in patients with IC. In addition to its reported vasodilator and antiplatelet effects, cilostazol has been proposed to have beneficial effects on plasma lipoproteins. We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC. After 12 weeks of therapy with 100 mg cilostazol BID, plasma triglycerides decreased 15% (P<0.001). Cilostazol also increased plasma high density lipoprotein cholesterol (HDL-C) (10%) and apolipoprotein (apo) A1 (5.7%) significantly (P<0.001 and P<0.01, respectively). Both HDL3 and HDL2 subfractions were increased by cilostazol; however, the greatest percentage increase was observed in HDL2. Individuals with baseline hypertriglyceridemia (>140 mg/dL) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment. In that subset of patients, HDL-C was increased 12.2% and triglycerides were decreased 23%. With cilostazol, there was a trend (3%) toward decreased apoB as well as increased apoA1, resulting in a significant (9.8%, P<0.002) increase in the apoA1 to apoB ratio. Low density lipoprotein cholesterol and lipoprotein(a) concentrations were unaffected. Cilostazol treatment resulted in a 35% increase in treadmill walking time (P=0.0015) and a 9.03% increase in ankle-brachial index (P<0.001). These results indicate that in addition to improving the symptoms of IC, cilostazol also favorably modifies plasma lipoproteins in patients with peripheral arterial disease. The mechanism of this effect is currently unknown.     

Alpha interferons--new therapeutic modalities

Interferons are naturally occurring substances. In fact, interferons are intercellular signalling proteins produced by cells in response to various biological and synthetic stimuli. Three major classes of interferons have been identified: interferons alpha, beta and gamma. Interferons originate from natural sources and are products of recombinant technology. Two forms of recombinant alpha-interferons, 2a and 2b, are available. Alpha-interferons are secreted and synthetised by leucocytes and lymphoblasts. The objective herein is to review the current therapeutic implications of alpha-interferons. Interferons alpha have antiviral, anticancer and immunomodulatory activities. Clinical trials have proved interferons alpha to be of special value as adjuvant therapy (first line drugs) for hairy cell leukemia, virus hepatitis B and C and condylomata acuminata. The efficacy of interferons alpha is now also being evaluated in other malignancies and virus diseases. For instance, interferons alpha are an important advanced modality in the management of chronic myelogenous leukemia and can be considered a first-line therapy option in patients who cannot receive or relapse following allogenic bone marrow transplant. Of course, further research is also required to evaluate combination therapies with interferons alpha and other agents. Presently malignancies have the broadest potential in application of interferons alpha therapy. Hairy cell leukemia responds to interferons alpha in up to 90% of patients, Kaposi's sarcoma, which occurs primarily in association with AIDS, benefit in up to 40% of patents, lymphomas respond in about 65% of patients whereas chronic myelogeneous leukemia in more than 80% of patients in early cases. The uses of interferons alpha in infectious diseases (condylomaty acuminata, rhinovirus infection, protozoal, parasitic and fungal intracellular infections) may also be significant. However, the cost of interferons alpha is too high. This makes interferons alpha a second line therapy, but not in patients where it is more effective than alternative treatment. Interferons alpha are cytokines (intercellular signalling proteins) which have antiviral, anticancer and immunomodulatory activities. Interferons alpha therapy represents an important advanced modality in the management of patients with hematological diseases, malignancies, lymphomas, solid malignant tumours and viral infections. Clinical trials have proved interferons alpha to be of special value as first line drugs for hairy cell leukemia, virus hepatitis B and C and condylomata accuminata. Interferons alpha are used as single primary therapy, adjuvant therapy and maintenance therapy. The limiting factor for the application of interferons alpha is the cost of treatment.     

Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects

We calculated the mean energy required to produce an ion pair (W) in methane-, propane- and butane-based tissue-equivalent (TE) gas mixtures from W values in pure constituent gases according to various models for energy partition among gas components. We found an agreement between the experimental and calculated W values in the methane-based TE gas regardless of the model concept. In contrast, only those models which take into account differences in the stopping powers, total ionization cross sections and model constants of gas components give acceptable results for the propane-based TE gas. The calculated W value for high-energy electrons in the isobutane-based TE gas mixture is 25.2 eV for high-energy electrons and 28.0 eV for approximately 5 MeV alpha particles.     

Pathogenicity of human anti-platelet factor 4 (PF4)/heparin in vivo: generation of mouse anti-PF4/heparin and induction of thrombocytopenia by heparin

Acinetobacter baumannii strain A148, a clinical isolate resistant to imipenem (MIC = 32 mg l-1), synthesized two beta-lactamases with pIs 6.3 and > 9.2. The pI 6.3 enzyme hydrolyzed the penicillins, including isoxazoylpenicillins, first-, second- and, to a lesser extent, third-generation cephalosporins. It was inhibited by chloride ions and by the penem beta-lactamase inhibitor BRL 42715. Clavulanate was a weak inhibitor and EDTA did not affect the beta-lactamase activity. This enzyme also hydrolyzed imipenem with a catalytic efficiency (Kcat/Km) of 1500 mM-1 s-1. Moreover, this purified beta-lactamase produced a positive microbiological clover-leaf test with imipenem. Therefore, the pI 6.3 beta-lactamase was considered to be involved in the imipenem resistance of A. baumannii strain A148.