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Biomedical subjects

A Rubinstein

Publications and source records attributed to A Rubinstein.

At least 19 recordsLinked to original sources
PubMed1997

The use of scintigraphy to provide "proof of concept" for novel polysaccharide preparations designed for colonic drug delivery.

PURPOSE: The aim of the present study was to provide "proof of concept" data in man for novel polysaccharide preparations designed for colonic drug delivery using gamma scintigraphy. METHODS: Two placebo calcium pectinate matrix tablet formulations were studied: one contained calcium pectinate and pectin (CaP/P) and was designed to rapidly disintegrate in the ascending colon, the other contained calcium pectinate and guar gum (CaP/GG) and was designed to disintegrate more slowly, releasing its contents throughout the ascending and transverse colon. Both formulations were enteric coated in order to protect them from the stomach. Ten healthy volunteers received either a CaP/P or CaP/GG tablet, in a randomised cross-over study. Transit and disintegration of the radiolabelled formulations was followed by gamma scintigraphy. Rat studies were conducted in order to verify that the expected colonic degradation of the polysaccharide formulations was as a consequence of bacterial enzyme attack. RESULTS: The in vivo clinical study confirmed the results obtained in the rat and bench in vitro fermentation models; complete tablet disintegration for Formulation CaP/GG appeared to be slower than that of Formulation CaP/P and the time and the location of complete tablet disintegration was more reproducible with Formulation CaP/P compared to Formulation CaP/GG. CONCLUSIONS: These results provide "proof of concept" data for the use of calcium pectinate preparations for drug delivery to the colon and highlight the value of scintigraphy in focusing the development strategy for colonic targeting preparations.

Adult↗
PubMed1996

CD4 confers susceptibility to human immunodeficiency virus type 1 infection in a rat fibroblast cell line.

A new model system is delineated that will enable study of CD4 cofactors and gp120 binding proteins other than CD4. We have previously described a nontransformed rat fibroblast cell line that can efficiently produce HIV-1 upon transfection with an HIV-1 infectious clone, in contrast to other nonhuman mammalian cell lines tested. In the present study we analyzed the susceptibility to HIV-1 infection of Rat2 cells expressing the human CD4 protein. We have used the mammalian expression vector pKS286, in which HIV-1 LTR drives the expression of the CD4 gene. We show that the Rat2 cell line, expressing the human CD4 (Rat2/CD4), is susceptible to fusion with and infection by HIV-1. The virus produced by the Rat2/CD4 cells was infectious. CD4 expression in the Rat2/CD4 was down-regulated over time, similarly to HIV-1 expression in HIV-1-transfected Rat2 cells. Transfection of the Rat2/CD4 cells with a tat expression vector reestablished the CD4 expression on the surface of those cells, as expected. We conclude that the expression of a gp120 binding protein on the Rat2 cells' surface suffices to render the Rat2 cells susceptible to HIV-1 infection.

Animals↗
PubMed1996

Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: case control study over three years.

OBJECTIVE: To test the hypothesis that subjects who clear chylomicron remnants slowly from plasma may be at higher risk of coronary artery disease than indicated by their fasting plasma lipid concentrations. DESIGN: Case control study over three years. SETTING: An 800 bed general municipal hospital. SUBJECTS: 85 normolipidaemic patients with coronary artery disease selected prospectively and matched with 85 normolipidaemic subjects with normal coronary arteries on angiography. INTERVENTIONS: All subjects were given a vitamin A fat loading test which specifically labels intestinal lipoproteins with retinyl palmitate. MAIN OUTCOME MEASURE: Postprandial lipoprotein metabolism. RESULTS: The area below the chylomicron remnant retinyl palmitate curve was significantly increased in the coronary artery disease group as compared with the controls (mean 23.4 (SD 15.0) v 15.3 (8.9) mumol/l.h; 95% confidence interval of difference 4.37 to 11.82). CONCLUSION: Normolipidaemic patients with coronary artery disease had significantly higher concentrations of chylomicron remnants in plasma than normolipidaemic subjects with normal coronary vessels. This may explain the mechanism underlying the susceptibility to atherosclerosis of coronary artery disease patients with normal fasting lipid values. As diet and drugs can ameliorate the accumulation of postprandial lipoproteins in plasma, the concentration of chylomicron remnants should be measured in patients at high risk of coronary artery disease.

Adult↗
PubMed1996

Inhibition of acute in vivo human immunodeficiency virus infection by human interleukin 10 treatment of SCID mice implanted with human fetal thymus and liver.

To improve the usefulness of in vivo mode for the investigation of the pathophysiology of human immunodeficiency virus (HIV) infection, we modified the construction of SCID mice implanted with human fetal thymus and liver (thy/liv-SCID-hu mice) so that the peripheral blood of the mice contained significant numbers of human monocytes and T cells. After inoculation with HIV-1(59), a primary patient isolate capable of infecting monocytes and T cells, the modified thy/liv-SCID-hu mice developed disseminated HIV infection that was associated with plasma viremia. The development of plasma viremia and HIV infection in thy/liv-SCID-hu mice inoculated with HIV-1(59) was inhibited by acute treatment with human interleukin (IL) 10 but not with human IL-12. The human peripheral blood mononuclear cells in these modified thy/liv-SCID-hu mice were responsive to in vivo treatment with exogenous cytokines. Human interferon gamma expression in the circulating human peripheral blood mononuclear cells was induced by treatment with IL-12 and inhibited by treatment with IL-10. Thus, these modified thy/liv-SCID-hu mice should prove to be a valuable in vivo model for examining the role of immunomodulatory therapy in modifying HIV infection. Furthermore, our demonstration of the vivo inhibitory effect of IL-10 on acute HIV infection suggests that further studies may be warranted to evaluate whether there is a role for IL-10 therapy in preventing HIV infection in individuals soon after exposure to HIV such as for children born to HIV-infected mothers.

Animals↗
PubMed1996

L-cycloserine, an inhibitor of sphingolipid biosynthesis, inhibits HIV-1 cytopathic effects, replication, and infectivity.

Drugs that reduce viral production or prevent viral spread by interference with the host's cellular components are unlikely to induce resistance, in contrast to treatment modalities that interact with the HIV-1 life cycle. Two features make L-cycloserine (L-CS) a candidate drug of this kind: (a) L-CS is a potent inhibitor of the sphingolipid pathway (b) sphingolipids, galactocerebrosides, and sulfatides have been shown, by others, to bind gp120. In a feasibility and efficacy study, we have found that L-CS inhibits HIV-1 replication in a CD4+ lymphoid cell line (CEM) as documented by the reduction of syncytium formation, the number of HIV-1 infected cells, and p24 protein production. This observation may lead to a new strategy for the treatment of HIV-1 infection.

Antimetabolites↗
PubMed1996

Changes in CD4+ and CD8+ cell levels during pregnancy and post partum in women seropositive and seronegative for human immunodeficiency virus-1.

OBJECTIVE: Our objective was to examine changes in CD4+ and CD8+ cell levels during pregnancy and post partum and to determine whether they differ for human immunodeficiency virus-1-seropositive and seronegative women. STUDY DESIGN: A total of 192 human immunodeficiency virus-1-seropositive and 148 seronegative women enrolled in a study of mother-to-child transmission of human immunodeficiency virus-1 who had at least two lymphocyte subset measurements performed during pregnancy or post partum were included in this analysis. Mixed effects repeated-measures models were developed to examine changes in CD4+ and CD8+ cell levels during this period. RESULTS: Consistent with prior reports that CD4+ cell levels decline during pregnancy and return to normal post partum, percent levels increased between the third trimester and 12 months post partum among human immunodeficiency virus-seronegative women (1.98%, p = 0.04). However, CD4+ levels declined steadily during pregnancy and post partum among seropositive women (-1.57%, p = 0.02 between the third trimester and 12 months post partum; =2.65%, p = 0.0004 between 2 and 24 months post partum). The percent CD8+ cell levels increased at or near delivery and declined to baseline between 2 and 6 months post partum in both seronegative and seropositive women, although only the declines were statistically significant in both groups (-2.66%, p = 0.004; and -2.02%, p = 0.02, respectively). CONCLUSIONS: The percent CD4+ cell levels declined steadily during pregnancy and post partum among human immunodeficiency virus-seropositive women, indicating that human immunodeficiency virus disease continues to progress during this period. The percent CD8+ cell levels increased at or near delivery and declined to baseline post partum in both seronegative and seropositive women. These findings may have important clinical implications for both human immunodeficiency virus-infected and uninfected pregnant women.

Adult↗
PubMed1996

Analysis of genetic heterogeneity, antigenicity, and biological characteristics of HIV-1 in a maternal transmitter and nontransmitter patient pair.

To obtain insight into the factors involved in vertical transmission, we compared the sequence diversity, seroreactivity, and biological characteristics of human immunodeficiency virus type 1 (HIV-1) derived from a transmitter and nontransmitter mother pair. Forty-two clones from the transmitter and 20 from the nontransmitter, spanning the principal neutralization determinant (PND) of the env gene, were sequenced and analyzed. The intrapatient sequence variation in transmitter and nontransmitter viruses was 12% and 36%, respectively, and the interpatient variation was 38%. In an effort to correlate immune responses to viral genetics, we analyzed the sera from these patients against a number of V3 peptides from known HIV-1 isolates. We observed that (i) both the transmitter and nontransmitter sera demonstrated higher binding to V3 peptides based on SF-2 and MN sequences than to IIIB and Z6 isolates; (ii) the vertical transmission of HIV-1 is correlated with the absence of high maternal antibody responses to the PND; and (iii) the high-affinity binding of the sera to SF-2 and MN V3 peptides correlated with the sequence analysis, indicating that the V3 sequences from both patients are more closely related to ADA, SF-162, and MN than to IIIB or Z6. Biological analysis of the viruses from these patients demonstrate that the transmitters' viruses infect a number of T-cell lines in vitro, whereas the nontransmitter viruses do not infect cell lines or the primary lymphocytes.

Amino Acid Sequence↗
PubMed1996

Randomized study of the tolerance and efficacy of high- versus low-dose zidovudine in human immunodeficiency virus-infected children with mild to moderate symptoms (AIDS Clinical Trials Group 128). Pediatric AIDS Clinical Trials Group.

The current dosage of zidovudine for children is 180 mg/m2 every 6 h. To investigate whether a lower dosage was equally effective, human immunodeficiency virus (HIV)-infected children (3 months to 12 years) with mild to moderate symptoms were randomly assigned to receive either high-dose (180 mg/m2/dose) or low-dose (90 mg/m2/dose) zidovudine (double-blind). Treatments were compared with respect to neuropsychologic function, survival, clinical and laboratory evidence of disease progression, and safety and tolerance. Four hundred twenty-six HIV-infected children were enrolled; median time for receipt of study drug was 35 months. Zidovudine in either dose was well tolerated, with no difference in efficacy or tolerance by treatment group using any clinical or laboratory parameter. In children with mild to moderate disease, a reduction of zidovudine to 90 mg/m2/dose will result in substantial cost savings and should be the recommended dose.

AIDS Dementia Complex↗
PubMed1996

Neurologic status of human immunodeficiency virus 1-infected infants and their controls: a prospective study from birth to 2 years. Mothers and Infants Cohort Study.

OBJECTIVE: To determine the timing, extent, severity, and persistence of neurologic abnormalities in children with perinatally acquired human immunodeficiency virus 1 (HIV-1) infection compared with similar uninfected children of HIV-1-infected women and control children. METHODS: Serial neurologic examinations and head circumference measurements were performed on a cohort of HIV-1-infected children born to HIV-1-infected women, seroreverting children born to HIV-1-infected women, and control children born to uninfected women. Examination data from 32 HIV-1-infected children, 99 reverters, and 116 control children were summarized by eight neurologic domains. Data were analyzed by longitudinal analysis. RESULTS: Reverter children were not different from control children in neurologic function for any of the eight domains or head circumference. HIV-1-infected children had significantly more neurologic problems than the control and reverter children for seven of the eight domains. The HIV-1-infected children were further classified by whether they had acquired immunodeficiency syndrome (AIDS)-defining clinical conditions (other than lymphoid interstitial pneumonitis) in the first 24 months of life (the AIDS-opportunistic infection group) or did not (the infected-other group). Neurologic abnormalities were early, severe, pervasive, and persistent in the AIDS-opportunistic infection group, and nearly all in this group had head circumference measurements below the 10th percentile. The infected-other group had no statistically significant differences from the uninfected children, although individual children in the infected-other group had some abnormalities. CONCLUSIONS: In utero exposure to HIV-1 without infection seems to have no negative impact on neurologic function in children in the first 2 years of life. Among children with perinatally acquired HIV-1 infection, the most severe and pervasive neurologic problems occur in those children who have early serious HIV-1 clinical disease. Most children without serious AIDS-defining clinical conditions in the first 2 years of life are also free from serious neurologic problems during that period.

AIDS-Related Opportunistic Infections↗
PubMed1995

Escape phenomenon of low-density lipoprotein cholesterol during lovastatin treatment.

The main issue is whether briefly stopping treatment of the hypercholesterolemic patient will accelerate the atherosclerotic process. This is possible, but such a strategy is preferable only in a subgroup of patients who cannot bear the economic burden of increasing the dosage of statins. In addition, stopping and restarting the drug at different stages lessens the likelihood of more adverse effects occurring when the dosage is increased.

Adult↗
PubMed1995

Divergent effects of chronic HIV-1 infection on human thymocyte maturation in SCID-hu mice.

We have recently developed a modified SCID-hu mouse model in which the implanted human thymus and liver (hu-thy/liv) and human peripheral T cells become infected with HIV-1 after i.p. inoculation. By using this model, we evaluated the effect of HIV-1 infection on thymic maturation and observed that different HIV-1 strains had divergent effects of thymic maturation. Although minimal effects on continued thymopoiesis in the hu-thy/liv implant were observed after chronic infection with two primary patient isolates, HIV-1(28) and HIV-1(59), and with HIV-1ADA, HIV-1Ba-L, HIV-1JR-CSF, HIV-1JR-FL, and HIV-1SF162, significant thymocyte depletion was detected after infection with HIV-1IIIB and HIV-1RF. Thus, the effect of HIV-1 infection on thymocyte maturation may depend upon the strain of HIV-1 infecting the thymus. Despite the minimal effects on thymopoiesis observed in the hu-thy/liv implanted in SCID-hu mice 6 mo after infection with HIV-1(28), significant changes were seen in the human T cell population circulating in the peripheral blood of these mice. These changes ranged from an inversion of the CD4/CD8 ratio of peripheral human T cells in some SCID-hu mice to the almost complete depletion of peripheral human T cells observed in other SCID-hu mice. Because these effects were associated with the detection of HIV-1 infection of the peripheral human T cells, these modified SCID-hu mice should prove to be a valuable model for investigating the effects of chronic HIV-1 infection on the peripheral human T cell population.

Animals↗
PubMed1995

Bezafibrate therapy in patients with isolated low high-density lipoprotein cholesterol levels may have a beneficial effect in prevention of atherosclerosis.

Although a low plasma high-density lipoprotein cholesterol (HDL-C) level is a well-accepted risk factor for coronary artery disease (CAD), it is unclear whether pharmacologic agents can effectively increase HDL-C levels and/or reduce the incidence of CAD in patients with isolated low HDL-C levels. An important determinant of HDL levels is the efficiency of postprandial lipoprotein catabolism. The purpose of the present study was to evaluate the efficacy of bezafibrate therapy in increasing HDL-C levels in these patients and to examine its effect on postprandial lipoprotein levels. Fasting and postprandial lipid and lipoprotein levels were studied in 23 patients with isolated low HDL-C levels before and during 3 and 6 months of bezafibrate treatment. Postprandial lipoprotein levels were evaluated using the vitamin A-fat loading test, in which these intestinally derived lipoproteins are specifically labeled with retinyl palmitate (RP). Patients with isolated low HDL had significantly higher levels of chylomicron RP than a control group of 19 normolipidemic subjects. The area below the chylomicron RP curve was 17,773 +/- 6,821 versus 13,936 +/- 6,217 micrograms/L.h, respectively (P < .005). No differences were found in chylomicron remnant levels between the groups. Bezafibrate therapy reduced the chylomicron RP area by 27%, from 17,773 +/- 6,821 to 12,895 +/- 2,576, and the nonchylomicron RP area by 25%, from 6,059 +/- 3,310 to 4,430 +/- 1,963 (P < .0001). It increased fasting HDL-C levels from 35 +/- 3 to 38 +/- 1.4 mg/dL after 3 months (P < .001) and to 40 +/- 2.2 mg/dL after 6 months (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗