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Biomedical subjects

J Rubin

Publications and source records attributed to J Rubin.

At least 109 records · Page 6Linked to original sources
PubMed1994

Health insurance coverage among the elderly.

The research reported in this paper examines the decision to have private health insurance by elderly Medicare enrollees. Models allowing both stimultaneity and a joint error structure between health insurance and use of medical care are considered. We find that common unobserved variables underlying the joint errors are important determinants in the decision to purchase private health insurance. Simultaneity is present only between the decision to have private health insurance and the probability of visiting a doctor. Health status and functional limitations are important determinants of the decision to have private health insurance in addition to Medicare coverage. Other personal characteristics (age, sex, race and education), as well as household income, Medicaid enrollment, and the employment of a family member are also found to be related to the decision to have private health insurance.

Activities of Daily Living↗
PubMed1994

Carotid brachial bypass for treating proximal upper-extremity arterial occlusive disease.

Symptomatic occlusive disease of the subclavian arteries, not associated with thoracic outlet syndrome, is an uncommon problem with a paucity of literature related to the appropriateness of bypass graft selection and long-term patency for revascularization. Between 1985 and 1993, 9 patients (3 men and 6 women) underwent 13 carotid brachial bypasses for chronic severe upper-extremity ischemia. Ages ranged from 47 to 75 years (mean 65). Three patients had documented collagen vascular disease, 1 had radiation arteritis, and 4 had bilateral disease requiring staged arterial reconstruction. Indications for operation included severe exercise-induced ischemia in two limbs (15%), rest pain in eight (62%), and gangrene or infection, or both, in three (23%). Two bypasses were performed for failed prior reconstructions. Inflow originated from the carotid artery (4 proximal and 9 bifurcation), and distal anastomoses were made to a disease-free section of brachial artery. Reinforced 6 mm thin-wall polytetrafluoroethylene (PTFE) grafts were used in all operations. No operative mortality or major upper-extremity amputation was associated with the procedure, although digital amputations were performed in four instances. Follow-up ranged from 4 to 83 months with a mean of 38 months. The 5-year primary patency rate, by life-table analysis, was 92%. Our results showed excellent long-term patency when prosthetic grafts were used for carotid brachial bypass, because of excellent runoff and the relatively short graft length required.

Aged↗
PubMed1994

A model to study the transport function of the intestinal viscera during peritoneal dialysis.

A preparation was developed to selectively study the transport properties of the intestinal viscera. A rat was positioned prone on a 100-mL beaker (reservoir) and the viscera were completely immersed and suspended without tension in dialysate solution maintained at 37 degrees C. A volume of 11.6 +/- 0.9 mL was ultrafiltered over a period of 180 minutes with a 5.6% glucose dialysate solution (n = 5) versus 0.5 +/- 0.5 mL for a 1.5% hydrous glucose dialysate solution (n = 4). The suspended viscera were able to absorb glucose from the beaker. The viscera absorbed more glucose when they were suspended in a higher glucose concentration: 922 +/- 46 mg for the 5.6% solution (54% of the initial glucose present) and 151 +/- 13 mg for the 1.5% solution (39% of the initial glucose present). Protein was found to leak from the viscera, and the amount found in dialysate was not related to the concentration of glucose used as dialysate (75 +/- 25 mg for the 5.6% solution and 41 +/- 3 mg for the 1.5% solution; P = NS). Studies also demonstrated transport from blood into the dialysate and that transport into dialysate could be altered by altering visceral blood supply (intravenous infusion of antidiuretic hormone, 800 micrograms/hr). Urea and glucose clearances were greater in the absence of antidiuretic hormone, whereas creatinine and inulin clearances were not different in both groups. This model offers the potential to selectively study the responses of the visceral peritoneum.

Animals↗
PubMed1994

A combination of anti-CD15 monoclonal antibody PM-81 and 4-hydroperoxycyclophosphamide augments tumor cytotoxicity while sparing normal progenitor cells.

A cyclophosphamide congener, 4-hydroperoxycyclophosphamide (4HC), has been used to purge bone marrow (BM) of residual leukemia cells ex vivo for use in support of high-dose chemotherapy for patients with acute myeloid leukemia (AML) undergoing autologous BM transplantation (ABMT). The efficacy and toxicity of 4HC are dose-related. The maximally tolerated concentration, 60-100 micrograms/ml, is toxic to tumor cells but also to normal committed hematopoietic progenitor cells. The anti-CD15 monoclonal antibody (mAb) PM-81 has also been employed for purging BM in patients with AML. In some patients, all tumor cells may not be lysed due to antigenic heterogeneity. Because the two agents used individually are associated with potential limitations in terms of toxicity to normal cells and efficacy of tumor cell purging, using these agents together might have advantages. In fact, in this study the use of these two agents together in subtherapeutic concentration ranges as single agents revealed killing of cells from the HL60 and NB4 promyelocytic leukemia cell lines in addition to cells from patients with AML while sparing normal progenitor cells. Surprisingly, not only did the combination enhance killing of tumor cells, but the order of addition of the two agents was important in maximizing toxicity to tumor cells. Adding mAb+complement (C') first or simultaneously to 4HC was less effective than adding 4HC first followed by mAb + C'. This combination regimen was toxic to HL60 and NB4 leukemia cells that may not be killed by the mAb alone due to antigen-negative tumor cells or by low concentrations of 4HC.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

A single up-stream element confers responsiveness to 1,25-dihydroxyvitamin D3 and tumor necrosis factor-alpha in the rat osteocalcin gene.

Tumor necrosis factor-alpha (TNF alpha) is one of several autocrine/paracrine factors known to exert potent inhibitory effects on bone. We have shown that TNF alpha inhibition of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-stimulated synthesis of the bone-specific protein osteocalcin (OC) occurs by decreasing steady state levels of OC mRNA, suggesting a pretranslational mechanism. In many genes, TNF alpha action is mediated by the transcription factor NF kappa B. Analysis of OC 5'-flanking DNA revealed a sequence structurally homologous to the previously described NF kappa B-binding site and, thus, a potential TNF alpha response element. Deletion analysis was performed to identify the sequences mediating the response to TNF alpha in osteoblastic ROS 17/2.8 cells by transient transfection with reporter constructs containing rat OC 5'-flanking DNA [chloramphenicol acetyltransferase (CAT)] that retained or deleted homologous NF kappa B sites or a previously defined 1,25-(OH)2D3 response element (VDRE). Transfection with all reporter constructs resulted in low basal CAT activity, measured 72 h after transfection. 1,25-(OH)2D3 stimulated CAT activity 2.8- to 4.5-fold in cells transfected with constructs that included the VDRE. TNF alpha inhibited 1,25-(OH)2D3-stimulated, but not basal, CAT activity. Deletion analysis localized the effect of TNF alpha to a sequence between -522 and -306 relative to the OC transcription start site, an area that included the VDRE but deleted a homologous NF kappa B element. Transfection of cells with a heterologous reporter containing one copy of the OC VDRE inserted in correct orientation or two copies in inverse orientation was sufficient to confer a response to TNF alpha. Gel mobility shift analysis of DNA-nuclear protein interaction revealed that 1,25-(OH)2D3 stimulated an increase in binding of nuclear proteins to an OC 32P-VDRE probe. Preincubation of nuclear extract with specific monoclonal antibodies confirmed that the proteins binding the VDRE included the vitamin D receptor and retinoid-X receptor. TNF alpha treatment of cells inhibited the 1,25-(OH)2D3-stimulated increase in nuclear protein binding to the VDRE. These results suggest 1) the VDRE is sufficient to confer a response to the inhibitory effect of TNF alpha on 1,25-(OH)2D3-stimulated rat OC gene transcription; 2) the action of TNF alpha does not require homologous NF kappa B response elements; and 3) the mechanism of TNF alpha inhibition of 1,25-(OH)2D3-stimulated OC gene expression includes modulation of binding of the vitamin D receptor/retinoid-X receptor heterodimer to the VDRE.

Animals↗
PubMed1994

Increased expression of tissue plasminogen activator messenger ribonucleic acid is an immediate response to parathyroid hormone in neonatal rat osteoblasts.

Osteoblasts have been reported to produce tissue-type (t) plasminogen activator (PA), which may be involved in the initiation of bone resorption via plasmin-metalloproteinase degradation of adjacent extracellular matrix. To investigate this cAMP-activated gene, we characterized the PTH regulation of tPA messenger RNA (mRNA) in neonatal rat osteoblast cultures before and after differentiation in vitro. RNA was purified from cultures at confluence or after treatment with glucocorticoid for 1 week and BGJ/ascorbic acid/beta-glycerophosphate for a second week. Northern blots of total or poly(A)+ RNA were hybridized simultaneously with an oligonucleotide or complementary RNA probe for rat tPA and an oligomeric DNA probe for cyclophilin (CYP), an abundant control gene. Differentiation was monitored by expression of rat osteocalcin mRNA and protein. Both bovine PTH1-34 and forskolin caused an increase in tPA/CYP ratio in the presence of phosphodiesterase inhibitor (IBMX) and cycloheximide (CHX). The effect was maximal (16- to 21-fold increase in tPA mRNA and 6- to 8-fold increase in tPA/CYP ratio) with 25 nM hormone for 6 h and was half-maximally stimulated by 0.75-2.5 nM PTH. The tPA response to PTH was present in first passage osteoblast cultures at confluence and after 1 to 2 weeks of glucocorticoid treatment. Exposure of the differentiated cultures of 1,25-dihydroxyvitamin D (10 nM) for 2 days markedly stimulated osteocalcin mRNA while having no effect on tPA. In Northern blots of poly(A)+ RNA from cultures not treated with CHX, IBMX and PTH (2.5 h) independently stimulated tPA mRNA with no significant effect on CYP mRNA levels. The tPA/CYP ratio increased in five consecutive experiments and the effect of IBMX and PTH were additive. These data indicate that PTH acts via cAMP to stimulate tPA expression by a mechanism that is independent of protein synthesis. The enhancement of PTH action by CHX is compatible with feedback inhibition of tPA transcription by a hormone-activated repressor (which has been proposed to occur in granulosa cells) but effects of CHX on tPA mRNA stability may also occur. Expression of tPA mRNA before and after differentiation may indicate that the enzyme has more than one function.

Animals↗
PubMed1994

1,25-Dihydroxyvitamin D3 and phorbol myristate acetate synergistically increase carbonic anhydrase-II expression in a human myelomonocytic cell line.

Expression of carbonic anhydrase-II (CA-II), an enzyme important to osteoclast function, distinguishes osteoclasts from other cells of monocytic lineage. A cell's selection of terminal osteoclast phenotype is controlled by many different factors, which are not well understood and which may also control the expression of CA-II. We studied the control of CA-II expression in the human HL-60 cell to better understand the signal transduction systems involved in progression to the osteoclast phenotype. Both 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3; 10 nM] and phorbol myristate acetate (10 ng/ml), doses that cause monocytic differentiation of the HL-60 cell, induced small increases in CA-II mRNA and CA-II protein, as measured by Northern analysis and Western immunoblotting, respectively. The maximal response was seen at 3 days. Treatment of HL-60 cells with both agents resulted in synergistic increases in CA-II mRNA (80-fold) and protein. The large increase in CA-II mRNA allowed assessment of the dose dependence of both agents, with ED50 values of 1 nM for 1,25-(OH)2D3 and 1 ng/ml for phorbol myristate acetate. In addition, we have shown that this synergistic response was completely inhibited by a potent inhibitor of protein kinase-C activity, staurosporine (0.1 microM), which has not previously been demonstrated in other cell systems. Staurosporine did not inhibit 1,25-(OH)2D3 induction of nonspecific esterase. Thus, 1,25-(OH)2D3 synergistically interacts with protein kinase-C-activated systems to cause a myelomonocytic precursor to express CA-II a marker of the osteoclast phenotype.

Alkaloids↗
PubMed1994

Positive nitrogen balance after intraperitoneal administration of amino acids in 3 patients.

OBJECTIVE: To determine whether intraperitoneal (IP) administration of amino acids improves nitrogen balance during continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Nitrogen balance studies of CAPD patients comparing periods of peritoneal dialysis using dialysate with nitrogen added from a commercial amino acid solution, versus standard dialysate. SETTING: Clinical research center in a tertiary facility. PATIENTS: Patients on CAPD who volunteered. INTERVENTIONS: One 4-day balance period was carried out with conventional dialysate and one 4-day period with conventional dialysate to which amino acids were added. The study periods were separated by a 3-day washout period. MAIN OUTCOME MEASURES: Nitrogen accumulation or loss during each period. RESULTS: The mean (SD) daily control period balances (grams per day) were 0.2, 1.9, and -3.4; during the amino acid period the balances were 5.4, 2.7, -0.7. The mean daily control effluent dialysate volumes (milliliters) were 11,350 +/- 443, 10,052 +/- 449, and 10,165 +/- 154; during the amino acid period the volumes were 10,345 +/- 50, 12,325 +/- 1021, and 10,220 +/- 655. CONCLUSIONS: The IP addition of amino acids diminishes the amount of nitrogen lost from dialysate while maintaining effluent dialysate volume. Nitrogen balances improved in all 3 patients during the period with IP amino acids, compared to control.

Adult↗
PubMed1993

Variability in the oral bioavailability of all-trans-retinoic acid.

BACKGROUND: Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies. PURPOSE: This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy. METHODS: Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography. RESULTS: Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase. CONCLUSION: The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.

Adenocarcinoma↗
PubMed1993

Carbamazepine and its metabolites in neuralgias: concentration-effect relations.

The aim of this study was to investigate the use of carbamazepine in the treatment of neuralgic pain and to determine a therapeutic plasma concentration range for carbamazepine in neuralgias. The relation between plasma concentration and the response to treatment (reduction in pain) was examined by logistic regression analysis of carbamazepine and its metabolites, the epoxide, the diol, and 2-hydroxycarbamazepine. The plasma concentrations of carbamazepine, the epoxide, and the diol were significantly related to the probability of a 25% reduction in pain. Only carbamazepine was significantly related to the probability of 50% and 75% pain reduction. However, multiple regression analysis with backward elimination of the data showed a significant correlation between both carbamazepine and the epoxide with regard to the probability of 50% and 75% reductions in pain. This confirms the previous finding that the epoxide has antineuralgic properties [Tomson and Bertilsson 1984]. The therapeutic plasma concentration range for carbamazepine in neuralgias, defined as the range of concentrations that would be expected to provide a 25-75% reduction in pain in 50% of patients, was 2-7 micrograms.ml-1 (HPLC) or 5-17 micrograms.ml-1 (EMIT).

Adult↗
PubMed1993

Ascending afferent regulation of rat midbrain dopamine neurons.

Standard, extracellular single-unit recording techniques were used to examine the electrophysiological and pharmacological responsiveness of midbrain dopamine (DA) neurons to selected, ascending afferent inputs. Sciatic nerve stimulation-induced inhibition of nigrostriatal DA (NSDA) neurons was blocked by both PCPA (5-HT synthesis inhibitor) and 5,7-DHT (5-HT neurotoxin), suggesting mediation by a serotonergic (5-HT) system. Direct stimulation of the dorsal raphe (which utilizes 5-HT as a neurotransmitter and inhibits slowly firing NSDA neurons) inhibited all mesoaccumbens DA (MADA) neurons tested. Paradoxically, DPAT, a 5-HT1A agonist which inhibits 5-HT cell firing, enhanced sciatic nerve stimulation-induced inhibition of NSDA neurons. MADA neurons were not inhibited by sciatic nerve stimulation and, therefore, could not be tested in this paradigm. In contrast to the dorsal raphe, electrical stimulation of the pedunculopontine tegmental nucleus preferentially excited slowly firing NSDA and MADA neurons. Thus, both excitatory and inhibitory ascending afferents influence the activity of midbrain DA neurons, and intact 5-HT systems are necessary for sciatic nerve stimulation to alter DA cell activity. However, the role that 5-HT plays in mediating peripheral sensory input remains unclear.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Rat osteoblasts and ROS 17/2.8 cells contain a similar protein tyrosine phosphatase.

Tyrosine phosphorylation plays a central role in intracellular signaling by many hormones and growth factors. Termination of the signal is thought to involve dephosphorylation of target proteins by phosphotyrosine phosphatases (PTPase). Soluble protein PTPases from neonatal rat osteoblasts (ROBs) and rat osteosarcoma (ROS 17/2.8) cells were chromatographically distinguished and characterized using 32P-labelled glutamate/tyrosine co-polymer as substrate. Two activities from both cell types were chromatographically separable. The dominant PTPase activity in the presence of 60-125 mM salt (E1), was eluted from phosphocellulose by 180-280 mM NaCl, bound weakly to a strong anion exchange column (QAE-trisacryl), had an apparent Km for [32P]glutamate/tyrosine copolymer of 52 micrograms/ml, was enhanced (5-10-fold, ROS; 1.5-3-fold, ROB) by assay in 125 mM NaCl, had no significant alkaline, acid, or serine phosphatase activity and had an M(r) of 53,000. A second activity (E2) was not retained by phosphocellulose but eluted from QAE-trisacryl in a single peak at 90-130 mM NaCl. It had an apparent Km for [32P]glutamate/tyrosine copolymer of 30 micrograms/ml (ROS) and its activity was not enhanced by NaCl in the assay. Activity E1 from both cells was 50% inhibited by 0.05 microM Na3VO4, 20 microM ZnCl2, or 5-10 microM CoCl2, but not by 1 mM NaF; activity E2 had a similar inhibition profile, but was more sensitive to ZnCl2 (IC50, 5 microM). Co2+ is a relatively non-toxic metal which may be a useful tool for investigating the role of phosphotyrosine in osteoblast proliferation and function. The similarity between the E1 activity from ROS cells and ROBs suggests that ROS cells may be useful in studying PTPase regulation by hormones, but molecular approaches will be required to establish the identity of PTPases in ROBs and ROS cells.

Animals↗
PubMed1993

1,25-Dihydroxyvitamin D3 and phorbol myristate acetate produce divergent phenotypes in a monomyelocytic cell line.

The human monomyelocytic HL-60 cell line differentiates along a monocytic lineage when cultured in the presence of phorbol myristate acetate (PMA) or 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. The protooncogene c-fms, coding for the macrophage colony-stimulating factor (M-CSF) receptor, is characteristically expressed in cells of monocytic lineage, but is not present in HL-60 cells. Since M-CSF has an undefined role in osteoclast development, we wished to examine the effect of 1,25-(OH)2D3, a strong promoter of osteoclast development, on the induction of M-CSF receptor. Treatment of HL-60 cells with 10-50 ng/ml PMA for 3 days stimulated expression of c-fms, as measured by steady state mRNA levels. Treatment with 10 nM 1,25-(OH)2D3 for 4-72 h did not promote c-fms expression. In fact, 1,25-(OH)2D3 attenuated PMA-stimulated c-fms expression in a dose-dependent manner (ED50, 1 nM). Along with attenuation of c-fms expression, 1,25-(OH)2D3 induced expression of mRNA for the osteoclastic enzyme carbonic anhydrase-II (CA II) almost 2-fold over the level expressed in untreated HL-60 cells. The addition of PMA to the culture diminished the basal expression of CA II mRNA, but did not affect 1,25-(OH)2D3-stimulated CA II induction. PMA and 1,25-(OH)2D3, thus, promote divergent phenotype development in the HL-60 cell. Induction of c-fms mRNA by PMA should ensure further macrophage development. The effect of 1,25-(OH)2D3 to attenuate expression of c-fms mRNA and stimulate CA II mRNA suggests that 1,25-(OH)2D3 activates osteoclast, rather than macrophage, development. 1,25-(OH)2D3-induced phenotypic changes may, therefore, involve modulation of the M-CSF effect.

Base Sequence↗