Rapid and selective depletion of CD4+ T lymphocytes and preferential loss of memory cells on interaction of mononuclear cells with HIV-1 glycoprotein-expressing cells

Apigenin is a plant flavonoid that has been shown to significantly inhibit ultraviolet-induced mouse skin tumorigenesis when applied topically and may be an alternative sunscreen agent for humans. A long-term goal of our laboratory is to elucidate the molecular mechanism or mechanism by which apigenin inhibits skin tumorigenesis. In a previous publication, we characterized the mechanism by which apigenin induced G2/M arrest in keratinocytes. More recent studies in our laboratory have provided evidence that apigenin can induce G1 arrest in addition to arresting cells at G2/M. Here we describe the mechanism of the apigenin-induced G1 arrest in human diploid fibroblasts (HDF). Treatment of asynchronous HDF for 24 h with 10-50 microM apigenin resulted in dose-dependent cell-cycle arrest at both the G0/G1 and G2/M phases as measured by flow cytometry. The G0/G1 arrest was more clearly defined by using HDF that were synchronized in G0 and then released from quiescence by replating at subconfluent densities in medium containing 10-70 microM apigenin. The cells were analyzed for cell-cycle progression or cyclin D1 expression 24 h later. A dose of apigenin as low as 10 microM reduced the percentage of cells in S phase by 20% compared with control cultures treated with solvent alone. Western blot analysis of apigenin-treated HDF indicated that cyclin D1 was expressed at higher levels than in untreated cells, which signifies that they were arrested in G1 phase rather than in a G0 quiescent state. The G1 arrest was further studied by cyclin-dependent kinase 2 (cdk2) immune complex-kinase assays of apigenin-treated asynchronous HDF, which demonstrated a dose-dependent inhibition of cdk2 by apigenin. Inhibition of cdk2 kinase activity in apigenin-treated cells was associated with the accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein as measured by western blot analysis. The cdk inhibitor p21/WAF1 was also induced in a dose-dependent manner, with a 22-fold induction of p21/WAF1 in 70 microM apigenin-treated cells. In conclusion, apigenin treatment produced a G1 cell-cycle arrest by inhibiting cdk2 kinase activity and the phosphorylation of Rb and inducing the cdk inhibitor p21/WAF1, all of which may mediate its chemopreventive activities in vivo. To our knowledge this is the first report of a chemopreventive agent inducing p21/WAF1, a known downstream effector of the p53 tumor suppressor protein.     

Recent patterns of alcohol consumption in the Russian elderly, 1992-1996

We present data on patterns of alcohol consumption in the Russian elderly aged > or = 60 y (< or = 100 y) between 1992 and 1996. These results come from nationally representative data collected as part of the Russian Longitudinal Monitoring Survey (RLMS), based on three-stage stratified cluster probability samples of the Russian population. The data showed a decreasing prevalence of drinking during this period, but an increase in the amount of alcohol consumed by some members of this population. There were significant differences within the group, with 60-69-y-old men having both the highest prevalence and the highest amounts of alcohol consumption compared with older men and women. Although the decrease in drinking prevalence is reassuring, the increase in the absolute amount of alcohol consumption by drinkers is of concern.     

An experimental pilot study of tacalcitol activities during modulation of parakeratotic skin features

Establishing guidelines and experimental models preclinical and clinical evaluations of new agents for treatment, and/or prevention of human diseases has become a task of crucial importance. Psoriasis is such one disease holding great interest for dermatology owing to its high rate of incidence and complexity of treatment. However the absence of psoriatic lesions in animals and the inability to induce them, calls for experimental techniques both in vitro and in vivo. The purpose of this study was to evaluate experimentally the effects of tacalcitol on cell proliferation and differentiation process. Thereafter a human pilot study on psoriatic patients has been developed.     

Clock stability characterization and measurement intelecommunications

Clock stability characterization and measurement for telecommunications pose peculiar issues and requirements. This paper aims to provide an overview on this subject. After briefly recalling the background work, the key features and issues of clock stability characterization and measurement in telecommunications are described. The timing signal reference model and the stability quantities adopted in the new international standards are introduced and the impact of the measurement configuration and of the time error sampling period on their behavior are elucidated. The measurement of clock stability in telecommunications is then addressed, and a standard practical measurement procedure is outlined. Several measurement results are provided to support the concepts expounded with experimental evidence. The results shown have been chosen among those obtained throughout the last three years by testing clerks of digital switching exchanges, clocks for synchronous digital hierarchy (SDH) equipment, and state-of-the-art stand-alone slave clocks for synchronization networks. They thus represent a survey of the actual performance of clocks currently deployed in telecommunications networks     

Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia

PURPOSE: Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed. PATIENTS AND METHODS: Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0. RESULTS: Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum. CONCLUSION: We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.     

Chicken acidic leucine-rich EGF-like domain containing brain protein (CALEB), a neural member of the EGF family of differentiation factors, is implicated in neurite formation

Chicken acidic leucine-rich EGF-like domain containing brain protein (CALEB) was identified by combining binding assays with immunological screens in the chicken nervous system as a novel member of the EGF family of differentiation factors. cDNA cloning indicates that CALEB is a multidomain protein that consists of an NH2-terminal glycosylation region, a leucine-proline-rich segment, an acidic box, a single EGF-like domain, a transmembrane, and a short cytoplasmic stretch. In the developing nervous system, CALEB is associated with glial and neuronal surfaces. CALEB is composed of a 140/130-kD doublet, an 80-kD band, and a chondroitinsulfate-containing 200-kD component. The latter two components are expressed in the embryonic nervous system and are downregulated in the adult nervous system. CALEB binds to the extracellular matrix glycoproteins tenascin-C and -R. In vitro antibody perturbation experiments reveal a participation of CALEB in neurite formation in a permissive environment.     

Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship.     

Protective effects of CD-832 on organ damage in stroke-prone spontaneously hypertensive rats

Effects of a newly developed Ca2+ channel antagonist, (4R)-(-)-2-(nicotinoylamino)ethyl 3 nitrooxypropyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) 3,5-pyridine-dicarboxylate (CD-832), on hypertensive complications in stroke-prone spontaneously hypertensive rats (SHRSPs) were compared with effects of diltiazem. We examined changes in histological and hematological parameters in SHRSPs given the following treatments at 8 to 20 weeks of age: (a) CD-832; (b) diltiazem; (c) no treatment. CD-832 and diltiazem were added to the diet, in doses of 0.05 and 0.15% (approximately 30 and 100 mg/kg per day), respectively, throughout the experimental period. In untreated control SHRSPs, systolic blood pressure increased and severe renal lesions such as fibrinoid necrosis, smooth muscle proliferation, glomerular and tubular lesions and some cardiac fibrosis were observed at age 20 weeks. 12-week repeated-administration of CD-832 and diltiazem led to a comparable hypotension and decreased heart rate. CD-832 and diltiazem decreased the ratios of weights of kidney and heart to body weight and the concentration of blood urea nitrogen and creatinine in serum, compared to values in controls. In SHRSPs treated with CD-832 and diltiazem, the incidence of renal lesions and myocardial fibrosis was significantly reduced when compared with control SHRSPs. These results suggest that 12-week repeated-administration of CD-832 prevents the development of hypertension and the incidence of organ damage in SHRSPs. CD-832 and diltiazem were equally efficacious in preventing organ damage but this organ-protective effect was obtained at a lower dose for CD-832 (30 mg/kg per day) than that of diltiazem (100 mg/kg per day).     

Nuclear waste management in the US: The Nuclear Waste Technical Review Board's perspective

The US program for the management and disposal of commercial spent nuclear fuel and high level waste is in a period of potential programmatic, regulatory, and legislative change. Proposals currently being considered by the US Congress would authorize the development of a storage facility as soon as possible adjacent to the potential repository site at Yucca Mountain. The legislation also would establish regulatory requirements for a permanent repository at an individual dose limit of 1 mSv year⁻¹ (100 mrem year⁻¹) for the average person living near the repository. Concurrently, the fiscal year 1996 appropriation to characterize the Yucca Mountain site has been reduced by approximately 40%. These initiatives portend possible changes in the focus of the US program, including a fundamental shift in priority from permanent disposal to temporary storage, and a change in the approach to licensing a potential repository at the Yucca Mountain site. This paper provides the perspective of the members of the Nuclear Waste Technical Review Board on the impact these developments could have on the future of the US program. It discusses the Board's opinion on how to address the issues these and other developments raise in a way which moves the US civilian radioactive waste management program forward.     

Biochemical alterations of the tunica albuginea in impotence

PURPOSE: The objectives of this study were to quantify the immunohistochemical stainings of collagen types I, III and IV, and investigate the value of glycohistochemical staining with 3 lectin types specific to a particular glycan structure, Arachis hypogaea, Triticum vulgare and concanavalin A, as a method of defining possible changes in the collagen structure of the tunica albuginea in potent and impotent patients. MATERIALS AND METHODS: The study involved 4 normal men, 4 with pure venous leakage and 4 with pure arterial disease. Collagen types I, III and IV, and lectins Arachis hypogaea, Triticum vulgare and concanavalin A were studied using a cell image processor. The labeling index relates to the percentage of staining and mean optical density relates to the staining intensity. RESULTS: Mean labeling index values for the 3 types of collagen and lectins were similar (p > 0.05). Mean optical density value relating to collagen type I was significantly higher in the arteriogenic group than in the other groups (p < 0.05), while mean optical density value of collagen type IV was significantly higher in the venogenic group than in the 2 other groups (p < 0.05). Mean optical density values relating to the 3 lectin types were similar in the 3 clinical groups (p > 0.05). CONCLUSIONS: An alteration in the distribution and structure of the various collagen types and lectins in the tunica albuginea of impotent patients has been shown that may interfere with normal function and lead to impotence.