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Biomedical subjects

R Horowitz

Publications and source records attributed to R Horowitz.

At least 19 recordsLinked to original sources
PubMed1998

Effects of perturbations of pools of deoxyribonucleoside triphosphates on expression of ribonucleotide reductase, a G1/S transition state enzyme, in p53-mutated cells.

Effects of drug treatment with antimetabolites on a human colon cancer cell line, SW480, were studied. Cells were treated with 10 microM of 5-fluorouracil (5FU), an inhibitor of pyrimidine synthesis, or 1000 microM of hydroxyurea (HU), an inhibitor of both purine and pyrimidine syntheses, or the combination. Recombinant alpha-2a-interferon (IFN), 500 U/mL, also was employed, as this augments the effects of both antimetabolites in vitro and in vivo. The predominant effect of this combination was to block cells in early S phase as measured by 5-bromo-2'-deoxyuridine (BrdUrd) incorporation. By 24 hr, 86% of the cells had accumulated in S phase, but failed to progress to G2/M. This was accompanied by an early, rapid decline in all four deoxyribonucleoside triphosphates (dNTPs) by 38-86% at 4-24 hr. Despite these effects, expression of the G1/S transition state enzyme, ribonucleotide reductase (RR), increased at 24 hr as measured by a 3 to 5-fold increase in mRNA levels for the M2 subunit, in the absence of a measurable effect on protein levels. The rise in levels of RR mRNA and the continued progression of cells into S phase were associated with a synergistic inhibition of cell cycle proliferation resulting from treatment with the three-drug combination. This suggests that in the presence of antimetabolite-induced depletion of dNTPs, SW480 cells, which lack a normal p53 gene, will proceed into S phase, and that this is associated with a rise in expression of the G1/S transition state enzyme, RR. Cells arrested in S phase by a p53-independent mechanism will undergo a synergistic enhancement of cell death.

Cell Cycle↗
PubMed1998

Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes?

BACKGROUND: Despite use of lower doses of corticosteroid hormones after renal allotransplantation in the era of cyclosporine and tacrolimus, posttransplant diabetes mellitus remains a common clinical problem. METHODS: We prospectively investigated the effect of posttransplant diabetes on long-term (mean follow-up, 9.3+/-1.5 years) graft and patient survival in the 11.8% of our renal transplant population (n = 40) who developed diabetes after kidney transplantation, and we compared outcome in 38 randomly chosen nondiabetic control patients who had received transplants concurrently. RESULTS: Twelve-year graft survival in diabetic patients was 48%, compared with 70% in control patients (P = 0.04), and Cox's regression analysis revealed diabetes to be a significant predictor of graft loss (P = 0.04, relative risk = 3.72) independent of age, sex, and race. Renal function at 5 years as assessed by serum creatinine level was inferior in diabetic patients compared to control patients (2.9+/-2.6 vs. 2.0+/-0.07 mg/dl, P = 0.05). Two diabetic patient who experienced graft loss had a clinical course and histological features consistent with diabetic nephropathy; other diabetes-related morbidity in patients with posttransplant diabetes included ketoacidosis, hyperosmolar coma or precoma, and sensorimotor peripheral neuropathy. Patient survival at 12 years was similar in diabetic and control patients (71% vs. 74%). CONCLUSIONS: Posttransplant diabetes mellitus is associated with impaired long-term renal allograft survival and function, complications similar to those in non-transplant-associated diabetes may occur in posttransplant diabetes, and, hence, as in non-transplant-associated diabetes, tight glycemic control may also be warranted in patients with posttransplant diabetes.

Acute Disease↗
PubMed1996

Nucleosome positioning properties of the albumin transcriptional enhancer.

Considering the importance of nucleosome position with regard to how regulatory factors recognize their binding sites in chromatin, we have investigated the inherent nucleosome positioning properties of a transcriptional enhancer of the albumin gene. In the liver, where the albumin gene is highly expressed, the enhancer exists in an array of precisely positioned, nucleosome-like particles with transcription factors bound. In the absence of specific binding factors, such as in non-liver tissues or in polynucleosome arrays assembled in vitro, nucleosomes are randomly positioned over the enhancer. Herein we investigate the intrinsic nucleosome positioning properties of the central enhancer sequence assembled into mononucleosome core particles in vitro. We find that the enhancer DNA prefers three translational positions, each of which utilizes different rotational settings on the nucleosome core. We conclude that DNA binding factors that position nucleosomes may do so by stabilizing one configuration out of several that can be adopted by the underlying DNA, and that the potential exists for different positions to be stabilized at different stages of development.

Albumins↗
PubMed1996

Interferon augments the cytotoxicity of hydroxyurea without enhancing its activity against the M2 subunit of ribonucleotide reductase: effects in wild-type and resistant human colon cancer cells.

The effects of prolonged exposure to the ribonucleotide reductase (RR) inhibitor, hydroxyurea (HU), were assessed in the presence or absence of recombinant interferon alfa-2a (IFN) in wild-type human colon cancer cells (HT-29) and variants expressing low-level resistance to HU (R200). IFN at nontoxic concentrations decreased the IC50 of HU from 368 microM to 215 microM (P < 0.01) in wild-type cells, but not in the resistant variants. Potential cellular targets for the HU/IFN interaction were examined. In wild-type, but not resistant cells, treatment with HU at clinically achievable concentrations (1000 microM) resulted in rapid early inhibition of RR activity between 4 and 24 h after treatment with a maximal decrease of 65% at 12 h, decreases in cellular levels of dATP, dCTP and dGTP by 50-90% over the same time course, and a two- to fourfold increase in the level of mRNA for both the M1 and M2 subunits of RR, at 24, but not between 1 and 4 h, which probably represents a response to the earlier decrease in RR activity. IFN at a clinically achievable concentration (500 U/ml) failed to augment the effects of HU on RR protein, RR mRNA levels or RR enzyme activity in either the wild-type or resistant cells, suggesting that the mechanism by which IFN augments the effects of HU in the wild-type cells is independent of the effects of HU on M2.

Base Sequence↗
PubMed1996

Effect of interferon on 5-fluorouracil-induced perturbations in pools of deoxynucleotide triphosphates and DNA strand breaks.

Interferon (IFN) augments the anabolism of 5-fluorouracil (5FU) to its active metabolite, fluorodeoxyuridylate (FdUMP), which inhibits thymidylate synthase (TS). We sought to determine whether this resulted in greater perturbations of nucleotide pools and if so, whether this was associated with an increase in cell lethality, specifically focussing on the lethal cellular lesion, DNA double strand breaks (dsb). To determine whether combination therapy with 5FU + IFN resulted in greater depletion of thymidine nucleotide pools than 5FU alone, a highly sensitive DNA polymerase assay was used. In two human colon cancer cell lines, treatment with 5FU + IFN resulted in a rapid decrease in levels of dTTP by 95%. The addition of IFN to 5FU resulted in greater depletion of dTTP levels over treatment with 5FU alone by up to fourfold, and markedly augmented the dATP/dTTP ratio. The addition of IFN to 5FU had no effect on 5FU-induced perturbations in dCTP, dGTP or dATP pools at 8 and 12 h. Measurement of DNA dsb demonstrated that treatment of HT-29 cells with 10 microM 5FU for 24 h did not increase DNA dsb versus control. The combination of 5FU + 500 U/ml IFN, however, resulted in an increased number of dsb versus both 5FU and untreated control cells (P < 0.01), equivalent to 0.74 +/- 0.12 Gy. The addition of IFN to 5FU resulted in a selective further depletion of pools of dTTP and an increase in the number of DNA dsb versus 5FU treatment alone.

Antineoplastic Agents↗
PubMed1995

Toward understanding the structure and interactions of microtubules and motor proteins.

To obtain an overall three-dimensional picture of the interaction between microtubules and the motor proteins of the kinesin family it will be necessary to take account of both atomic resolution structures obtained by X-ray crystallography and medium resolution reconstructions obtained by electron cryomicroscopy. We examine the problems associated with obtaining the required structural information from electron micrographs of vitreous ice-embedded microtubules decorated with motor domains. We find that the minus-end directed motor, ncd, decorates microtubules with an 80 A periodicity as for kinesin. Our theoretical analysis and experiments with ncd illustrate the difficulty in determining unambiguously the surface lattice organization by diffraction analysis of micrographs. 3D reconstructions of decorated microtubules are required to accurately locate the motor domains. Helical diffraction theory is not usually applicable because microtubules are cylindrical structures that rarely have complete helical symmetry. We propose using a back-projection method based on the long pitch helices formed by individual protofilaments. Model reconstructions show that this approach is feasible.

Computer Simulation↗
PubMed1995

Modulation of 5-FU/alpha-interferon with high-dose continuous infusion hydroxyurea.

Biochemically modulated 5-fluorouracil (5-FU) regimens are active against several gastrointestinal malignancies. Hydroxyurea is an inhibitor of the enzyme ribonucleotide reductase. Despite successful in vitro studies, studies combining oral hydroxyurea with 5-FU based regimens have failed to demonstrate clinical synergy. Based on the pharmacokinetic properties of hydroxyurea, continuous exposure to the drug may be required to reproduce the synergy observed in vitro. We will review the pharmacology of hydroxyurea and the rationale for the modulation of 5-FU/alpha-interferon (IFN) with high-dose continuous infusion hydroxyurea.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

The location of a disease-associated polymorphism and genomic structure of the human 52-kDa Ro/SSA locus (SSA1).

Sera from approximately 30% of patients with systemic lupus erythematosus (SLE) contain high titers of autoantibodies that bind to the 52-kDa Ro/SSA protein. We previously detected polymorphisms in the 52-kDa Ro/SSA gene (SSA1) with restriction enzymes, one of which is strongly associated with the presence of SLE (P < 0.0005) in African Americans. A higher disease frequency and more severe forms of the disease are commonly noted among these female patients. To determine the location and nature of this polymorphism, we obtained two clones that span 8.5 kb of the 52-kDa Ro/SSA locus including its upstream regulatory region. Six exons were identified, and their nucleotide sequences plus adjacent noncoding regions were determined. No differences were found between these exons and the coding region of one of the reported cDNAs. The disease-associated polymorphic site suggested by a restriction enzyme map and confirmed by DNA amplification and nucleotide sequencing was present upstream of exon 1. This polymorphism may be a genetic marker for a disease-related variation in the coding region for the protein or in the upstream regulatory region of this gene. Although this RFLP is present in Japanese, it is not associated with lupus in this race.

Amino Acid Sequence↗
PubMed1993

Psychiatric hospitalization of immigrants to Israel from the former USSR: assessment of demand in future waves of immigration.

In the years 1970-1990 approximately half a million immigrants from the former USSR arrived in Israel. Experts predict that new waves of immigration are likely to happen. This paper presents an attempt to forecast the need for appropriate psychiatric services in future waves of immigration. The study compares hospitalization patterns of immigrants arriving in Israel between 1972-1980 with those arriving in 1990. The rates of admission were compared to the rates for Israelis in the specified periods and an estimate for the future need for psychiatric services was calculated. The central finding in this study was that former Soviet immigrants were admitted to psychiatric hospitals within the first year of their arrival at a higher rate than Israelis in the 1970s and in 1990. In the 1970s the admission rate for immigrants was 33 per 10,000, while the rate for Israelis was 20 per 10,000. In 1990 the admission rate for immigrants was 31 per 10,000, while the rate for Israelis was 20 per 10,000. The forecast for the next years is for 320 first admissions within a year after arrival for every 100,000 immigrants. Planning for new waves of immigrations from the former USSR should therefore include a serious consideration of the provision of appropriate psychiatric services.

Adult↗
PubMed1991

Reflections on the casework relationship: beyond empiricism.

This article examines the dynamics of the casework relationship from a holistic perspective. The significance of the interplay between caseworker and client often evades efforts at objective evaluation. Too often emphasis is placed on concrete indications of progress. Staff who look solely at these measures may become frustrated and lose sight of internal change not easily revealed in empirical studies. This article looks at how long-term casework relationships revolve around existential issues that lie at the heart of psychiatric rehabilitation. These relationships, however resistant to stringent measurement, enjoy value apart from specific achievements and merit recognition in their own right. The ordeal of change that both parties endure leaves them heir to a legacy of struggle and renewal.

Attitude of Health Personnel↗
PubMed1987

Iliofemoral venous obstruction without thrombosis.

Nonthrombotic iliofemoral venous obstruction, masquerading as deep vein thrombosis, was diagnosed in four patients. In each instance the patient was hospitalized and intravenous heparin therapy was started. Phlebography demonstrated venous outflow obstruction without thrombosis; subsequent CT scanning revealed an obstructing lesion in each case. At surgical exploration, (1) endoaneurysmorrhaphy of a hypogastric artery aneurysm decompressed an obstructed right iliac vein; (2) a primary iliac vein leiomyosarcoma was extirpated; (3) a synovial cyst arising from the right hip joint, which obstructed the femoral vein, was excised; and, (4) a postherniorrhaphy inflammatory mass obstructing the left iliofemoral vein junction was confirmed with biopsy results. Improved diagnostic accuracy with its attendant specific therapy is achieved in suspected cases of iliofemoral vein thrombosis if, in addition to noninvasive venous studies or phlebography, CT scanning of the abdomen and pelvis is performed.

Adult↗
PubMed1987

Injury patterns in motor vehicle fatalities.

A retrospective pilot study of motor vehicle incident fatalities was conducted to determine what relationships exist between injuries received by deceased drivers, passengers, and a control population of pedestrians, and some of the environmental factors existing at the time of the incident. A number of correlations were established between the types and locations of injuries received, seat belt use, position of the injured party, and so forth. A study of this type, if performed on a large enough population, could lead to predictive models for the determination of position of the victims within a motor vehicle at the time of a fatal crash, based on a unique clustering of injuries.

Abdominal Injuries↗
PubMed1986

Left atrial myxoma in the elderly. Report of four patients over the age of 70 and review of the literature.

Myxoma of the atrium presents distinctive clinical profile, yet precise diagnosis of the tumor on the basis of clinical findings is often not made in the elderly patient as the symptoms are often attributed to "generalized arteriosclerosis of the elderly." The authors report the clinical findings in four elderly patients with left atrial myxoma in whom the diagnosis had not been clinically suspected before echocardiographic evaluation.

Aged↗
PubMed1985

Effect of human syncytiotrophoblast extract on in vitro proliferative responses.

The authors studied the effects of soluble syncytiotrophoblast extract (STE) on the proliferative responses of lymphocytes to different lectins (PHA and Con A) and to allogeneic cells in one-way mixed lymphocyte cultures. STE suppressed lymphocyte reactivity to lectins and to allogeneic cell cultures. The inhibitory effect was dose dependent. Increased concentrations of lectins failed to overcome the inhibitory effect of STE. Lymphocytes preincubated with STE for 18 hr, then washed and exposed to lectins still exhibited an inhibition of cellular proliferation. STE added to lymphocyte cultures at various times in the presence of both mitogens or of allogeneic cells continued to inhibit lymphoproliferative responses even when it was added after 43 hr of cell culture. Furthermore, STE was able to reduce the spontaneous proliferation of tumor cell lines K562 and LHN13 maintained in vitro culture prior to testing. In all cases, the inhibition observed was not due to lymphocytotoxicity or to tumor cell mortality. The inhibitory effect of STE on the proliferative responses of lymphocytes to stimulants may be due to a cytostatic effect that may represent a contributing factor in the nonrejection of the fetus by a competent immune system.

Cell Survival↗
PubMed1984

Correlation of plasma hormone levels and peripheral circulating lymphocyte subpopulations during human pregnancy.

Using monoclonal antibodies (OKT3, OKT4, OKT8) peripheral blood lymphocyte subsets were determined in 40 normal primiparous pregnant women and compared with those of 31 nonpregnant controls. In pregnant women plasma concentrations of estradiol, progesterone, human placental lactogen (HPL), beta subunit of human chorionic gonadotropin (beta HCG), and alpha-fetoprotein were measured by means of radioimmunoassay. We studied if correlations between peripheral lymphocyte subsets and plasma hormone levels might exist. We observed in pregnant women from 10 to 40 wk of amenorrhea a decrease in the percentage of OKT3 and OKT8 cells, and during the course of pregnancy an increase in the percentage of OKT4 cells. This increase inversely correlated with plasma beta HCG levels and directly correlated with plasma HPL levels.

Adult↗