Biomedical subjects

R Stein

Publications and source records attributed to R Stein.

At least 19 recordsLinked to original sources

PubMed1992

Dissociation between release and gene expression of gonadotropin alpha-subunit in gonadotropin-releasing hormone-stimulated alpha T3-1 cell line.

The alpha T3-1 cell line which was derived by targeted tumorigenesis in transgenic mice [Windle et al. (1990) Mol. Endocrinol. 4, 597-603] possesses high-affinity binding sites for GnRH analogs coupled to enhanced phosphoinositide turnover and phospholipase D activity. Incubation of alpha T3-1 cells with [D-Trp6]-GnRH analog (GnRH-A) resulted in a rapid increase in gonadotropin alpha-subunit mRNA levels which was detected already at 30 min of incubation (0.1 nM GnRH-A, 3-fold, p < 0.01). The effect diminished with time to reach basal levels at about 12 h of incubation, with a secondary rise in alpha mRNA levels between 12 and 24 h of incubation. Addition of the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 ng/mL) or the Ca2+ ionophore ionomycin (1 microM) to alpha T3-1 cells also resulted in a rapid increase in alpha-subunit mRNA levels. Surprisingly, GnRH-induced alpha-subunit release was detected only after a lag of 4 h of incubation. Thus, dissociation between exocytosis and gene expression can be demonstrated in GnRH-stimulated alpha T3-1 cell line.

Animals↗

PubMed1992

A double-blind study of the efficacy of metronidazole gel in the treatment of malodorous fungating tumours.

A double-blind placebo-controlled trial was undertaken to assess the value of topical metronidazole gel preparation in the palliation of the offensive odour of fungating tumours. This 5 day trial was followed by a 6 day period during which all patients received the active gel. Subjective odour assessments were performed by both patients and medical staff. 11 patients were entered and the randomisation was then halted because of an obvious overall benefit over the whole 11 days. There was a non-significant trend in favour of the active treatment during the initial double-blind placebo-controlled phase of the trial, and no side-effects were observed.

Administration, Topical↗

PubMed1992

Conservative surgery of renal cell tumors in 140 patients: 21 years of experience.

Operative method, course and complications were analyzed retrospectively in 140 patients who underwent a conservative operation for renal tumor between June 1969 and December 1990. In 53 patients (20 women and 33 men, mean age 61.2 years, range 38 to 77 years, with 49 renal cell carcinomas and 4 benign renal tumors) there was an imperative indication for an organ preserving operation because nephrectomy would have made dialysis obligatory. In 87 patients (29 women and 58 men, mean age 53.7 years, range 27 to 74 years, with 72 renal cell carcinomas and 15 benign renal tumors) the tumor was conservatively resected in the presence of a normal contralateral unit (elective indication) and 68 of these patients (78%) were symptom-free. In the imperative group 32 of 49 patients (65.3%) with renal cell carcinoma had no evidence of disease after a mean followup of 4.6 years. Known metastases were present in 4 of 7 patients who died of the tumors in this group. In 3 patients with an imperative indication for conservative surgery a second tumor occurred in the kidney: 2 were treated with further parenchyma sparing operations, while in 1 with poor physical condition no further measures were possible. Of 72 patients with renal cell carcinoma who underwent an elective operation 68 (94.4%) had no signs of tumor progression after a mean followup of 3.3 years. One patient died of tumor metastases, and 2 (2.7%) had tumor recurrence in the kidney requiring nephrectomy and enucleation, respectively. The 5-year cause-specific survival rates for the imperative and elective groups were 84% and 96%, respectively. Patients with a local stage T3 tumor were characterized by a significantly worse survival curve than those with a stage T1 or T2 tumor but no significant difference was noted among the various grades of differentiation.

Adult↗

PubMed1992

Haematological effects of radioimmunotherapy in cancer patients.

The haematologic effects of radioimmunotherapy (RAIT) in cancer patients have been studied in order to better understand the aetiology of RAIT-associated myelosuppression. Evaluations were performed on patients treated with 131I-anti-carcinoembryonic antigen (CEA) and 131I-LL2, a monoclonal antibody (MAb) reactive with non-Hodgkin's B-cell lymphoma. Both groups of patients experienced decreases in WBC and platelets. Nadirs were observed 42-51 d post first injection in the lymphoma patients, and 49-66 d post first injection (30-43 d post high-dose therapeutic injection) in the carcinoma patients. Within the WBC population, B cells were the most radiosensitive. The evaluations of the binding of these MAbs to peripheral blood cells and the effect of RAIT on lymphocyte subpopulations indicated a drop of 26-92% in the percentage of B lymphocytes within 1 week following treatment with both 131I-LL2 and 131I-anti-CEA MAbs even though only LL2 binds to B cells. The percentage of T lymphocytes was not affected by the 131I-antibody treatments. These observations suggest that the marked drop in circulating B lymphocytes and platelets after the administration of radioiodinated antibodies is a nonspecific radiation effect, and not necessarily related to the binding of MAb to normal B cells. Thus, among WBCs, B cells are uniquely radiosensitive, and will be unusually affected by antibody-directed internal radiation.

Adult↗

PubMed1992

Growth factor-like effects mediated by muscarinic receptors in PC12M1 cells.

Rat pheochromocytoma (PC12) cells stably expressing cloned m1 muscarinic acetylcholine receptors (PC12M1) undergo morphological changes when stimulated by muscarinic agonists. These changes, which include the outgrowth of neurite-like processes, are blocked by the muscarinic antagonist atropine and are not observed in PC12 cells. The observed morphological changes, which are independent of RNA and protein synthesis, are blocked by the methylation inhibitor 5'-deoxy-5'-methylthioadenosine, suggesting that methylation plays a role in this process. Analysis of cyclic AMP accumulation and phosphoinositide turnover reveals that both processes are enhanced on activation by muscarinic agonist. Our data suggest, however, that the muscarinic-dependent neurite-like outgrowth processes are not mediated by cyclic AMP, Ca2+, or protein kinase C pathways. The muscarinic-dependent neurite outgrowth effect is enhanced by nerve growth factor, with a resulting increase in both the number of neurite-extending cells and the length of the neurite. In addition, activation of muscarinic receptors in PC12M1 cells stimulates the induction of marker genes for neuronal differentiation. Muscarinic receptors may therefore mediate growth factor-like effects in these cells.

Adenylyl Cyclases↗

PubMed1992

Cardiovascular responses of patients with cardiac disease to talking and exercise stress testing.

The blood pressure (BP), heart rate (HR), and premature ventricular contraction responses of patients with cardiac disease during talking were compared with those during exercise stress testing (EST). BPs, HR, and heart rhythm were recorded in 52 patients with cardiac disease before and during talking about an intentionally neutral topic and compared with changes during EST. The systolic and diastolic BP and HR increased significantly during talking. Diastolic BP increased significantly more during talking than during EST stages 1 and 2. The increase in diastolic BP during EST stage 3 did not differ from the increase during talking. HR and systolic BP increased more during EST than during talking. Nine patients had premature ventricular contractions during both EST and talking, two during EST only, and one while talking only. The verbalization protocol provides information about changes in diastolic BP that are not seen with EST. It also may be of value for evaluating heart rhythm, HR, and systolic BP changes for patients whose disabilities preclude EST.

Adult↗

PubMed1991

Normal tissue reactivity of four anti-tumor monoclonal antibodies of clinical interest.

Normal tissue reactivity on frozen sections was examined with 4 monoclonal antibodies (MAbs) that were reported previously to be negative or weakly reactive with normal tissues, and strongly reactive with some types of carcinoma. All 4 antibodies reacted strongly with certain normal epithelial cells. The antibodies tested include 2 antibodies to ovarian cancer, MOv18 and MOv19, one antibody to breast cancer, H23, and one antibody reactive with a range of carcinomas, B72.3. MOv18, MOv19 and H23 reacted with many normal glandular and ductal epithelial cells, while B72.3 reacted most strongly with secretions of the small intestine epithelium and the suprabasal squamous epithelial cells of the esophagus. Since the tissue distribution of MOv19 was very similar to that of another antibody described previously, MW207, these two antibodies were compared by competitive binding inhibition, and found to recognize the same epitope. Our data emphasize the importance of repeated, independent tests of antibody specificity.

Antibodies, Monoclonal↗

PubMed1991

Autonomic nervous control of the heart rate response to dynamic incremental exercise: evaluation of the Rosenblueth-Simeone model.

To evaluate the validity of the Rosenblueth-Simeone model for the heart rate response to incremental dynamic exercise, 11 healthy men performed maximal exercise tests on a cycle ergometer after administration of placebo, propranolol, atropine or both propranolol and atropine. The model showed that the influence of sympathetic activity on heart rate increased at intensities up to those which resulted in a heart rate 70% maximal heart rate on placebo, and levelled off at higher intensities, while there was a progressive withdrawal of the parasympathetic activity. The ratio between heart rate predicted by the model and the recorded heart rate following placebo treatment tended to be less than 1.0 at lower exercise intensities, and approached the unit at intensities above those which resulted in a heart rate higher than 70% of maximal heart rate on placebo. There was a strong correlation (r = 0.94, P less than 0.01) between the heart rate on placebo and the heart rate estimated by the model. Nevertheless, there was some scattering of the data around the identity line, with a standard error of the estimate for the regression line of 11 beats.min-1. Thus, during incremental exercise, the influence of sympathetic activity on heart rate does not become progressively more important at higher exercise intensities. The application of the Rosenblueth-Simeone model shows limitations during incremental exercise, particularly at low exercise intensities.

Adult↗

PubMed1991

Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer.

The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3-4 days, oestradiol levels fell to 31.1% +/- 6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 micrograms/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates for Co (21.7 +/- 1.82 micrograms/ml), Km (2.66 +/- 0.68 micrograms/ml) and Vmax (0.86 +/- 0.06 micrograms ml-1 h-1). On subsequent repeated dosing with PyG, both the Km (4.31 +/- 0.48 micrograms/ml) and the Vmax (1.83 +/- 0.13 micrograms ml-1 h-1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.

Aminoglutethimide↗

PubMed1991

Transplantation of beta cells from transgenic mice into nude athymic diabetic rats restores glucose regulation.

We have shown that elevated plasma D-glucose levels in experimentally-induced diabetic nude athymic rats can be reduced by intraperitoneal transplantation of microcarrier-attached insulin producing beta cells from the mouse pancreatic beta cell line, beta TC-1. The reduction in the level of hyperglycemia was observed as early as two days following cell transplantation and was associated with a concomitant increase in plasma insulin levels. beta TC-1 cell transplanted diabetic rats had plasma D-glucose levels similar to those found in non-diabetic control animals and remained normoglycemic throughout the 39 day experimental period. The beta TC-1 cell transplanted diabetic rats also had near normalization of body weight, food and water intake and of urine output when compared to control diabetic and non-diabetic rats. Similarly, they exhibited improved blood glucose clearance following intravenous D-glucose administration. These results suggest that beta TC-1 cells regulate D-glucose homeostasis following transplantation into diabetic rat recipients in a manner similar to that of endogenous pancreatic beta cells.

Animals↗

PubMed1991

Core biopsy instrument in the diagnosis of prostate cancer: superior accuracy to fine needle aspiration.

The recent availability of an automated core biopsy gun has made the performance of core biopsies of the prostate easier and better tolerated. A prospective study was conducted to compare the efficacy of fine needle aspiration to core biopsy with the gun. Among 94 patients subjected to both biopsy techniques at the same visit 30 (32%) had a positive diagnosis of prostate cancer. Core biopsy was positive in these 30 patients (100%), while fine needle aspiration was positive in 21 (70%). This study suggests that core biopsy with the gun is superior to fine needle aspiration in the diagnosis of prostate cancer.

Biopsy, Needle↗

PubMed1991

A new murine monoclonal antibody against human hepatoma.

A murine monoclonal antibody (MAb 336) reactive with human hepatocellular carcinoma has been raised after immunizing BALB/c mice with whole HepG2 cells. MAb 336 (IgG1) was reactive with HepG2 (whole cells and membrane fractions), but not normal liver or peripheral blood cells. Immunohistological studies indicated that 12/16 hepatocellular carcinoma and 6/11 cirrhotic livers expressed MAb 336-associated antigen, and most normal human tissues and tissues derived from other cancers were unstained. Direct and competitive binding assays ruled out the possibility that this MAb reacts with alpha-fetoprotein, carcinoembryonic antigen, or ferritin. Western blot analysis indicated that MAb 336 reacts with an antigen of approximately 30,000 daltons. This MAb may be potentially useful for studying antigenic expression in hepatocellular carcinoma and as a targeting agent for radioimmunodetection and immunoconjugate therapy.

Animals↗

PubMed1991

Contamination and radiation exposure from 201Tl in patients undergoing dialysis after a nuclear medicine study.

Our institution is a major kidney research and transplant center. Hemodialysis patients that are scheduled for renal transplant are given a 201Tl stress test. Possible radiation exposure and contamination are of concern to attending personnel. We investigated this situation and found measurable activity in the effluent of patients receiving dialysis but no significant contamination of equipment. We determined that dialysis personnel received minimal radiation exposure.

Equipment Contamination↗

PubMed1991

CD5+ B cells and naturally occurring autoantibodies in cancer patients.

We have determined the percentage of CD5+ B lymphocytes in the peripheral blood of cancer patients and healthy controls, using antibodies directed at the CD5 and CD19 (pan-B) markers. The frequencies of CD5+ B cells, expressed as a percentage of total B cells, ranged from 14.3 to 57.5% in the controls and from 14.8 to 82.8% in the patient population. One-third of the cancer patients had frequencies greater than 2 s.d. above the mean of the control population. The CD5+ B cell fraction expressed as a percentage of total lymphocytes was also significantly elevated in this group of cancer patients. These results suggest that the CD5+ B cell compartment may be affected by the malignant process or by the therapy modality employed. The plasma levels of several naturally occurring autoantibodies, the products of the CD5+ B cells, were also assessed in cancer patients and controls. No significant differences were observed when reactivity to several autoantigens was measured. These included nuclear components and phospholipids.

Adolescent↗

PubMed1991

Pancreatic beta-cell-type-specific transcription of the insulin gene is mediated by basic helix-loop-helix DNA-binding proteins.

The pancreatic beta-cell-specific expression of the insulin gene is mediated, at least in part, by the interaction of unique trans-acting beta-cell factors with a cis-acting DNA element found within the insulin enhancer (5'-GC CATCTG-3'; referred to as the insulin control element [ICE]) present in the rat insulin II gene between positions -100 and -91. This sequence element contains the consensus binding site for a group of DNA-binding transcription factors called basic helix-loop-helix proteins (B-HLH). As a consequence of the similarity of the ICE with the DNA sequence motif associated with the cis-acting elements of the B-HLH class of binding proteins (CANNTG), the ability of this class of proteins to regulate cell-type-specific expression of the insulin gene was addressed. Cotransfection experiments indicated that overexpression of Id, a negative regulator of B-HLH protein function, inhibits ICE-mediated activity. Antibody to the E12/E47 B-HLH proteins attenuated the formation, in vitro, of a previously described (J. Whelan, S. R. Cordle, E. Henderson, P. A. Weil, and R. Stein, Mol. Cell. Biol. 10:1564-1572, 1990) beta-cell-specific activator factor(s)-ICE DNA complex. Both of these B-HLH proteins (E12 and E47) bound efficiently and specifically to the ICE sequences. The role of B-HLH proteins in mediating pancreatic beta-cell-specific transcription of the insulin gene is discussed.

Animals↗

PubMed1991

Insulin gene expression in nonexpressing cells appears to be regulated by multiple distinct negative-acting control elements.

Selective transcription of the insulin gene in pancreatic beta cells is regulated by its enhancer, located between nucleotides -340 and -91 relative to the transcription start site. Transcription from the enhancer is controlled by both positive- and negative-acting cellular factors. Cell-type-specific expression is mediated principally by a single cis-acting enhancer element located between -100 and -91 in the rat insulin II gene (referred to as the insulin control element [ICE]), which is acted upon by both of these cellular activities. Analysis of the effect of 5' deletions within the insulin enhancer has identified a region between nucleotides -217 and -197 that is also a site of negative control. Deletion of these sequences from the 5' end of the enhancer leads to transcription of the enhancer in non-insulin-producing cells, even though the ICE is intact. Derepression of this ICE-mediated effect was shown to be due to the binding of a ubiquitously distributed cellular factor to a sequence element which resides just upstream of the ICE (i.e., between nucleotides -110 and -100). We discuss the possible relationship of these results to cell-type-specific regulation of the insulin gene.

Animals↗

PubMed1991

Lymphocytic pneumonitis following bone marrow transplantation in severe combined immunodeficiency.

Lung disease in patients with severe combined immune deficiency (SCID) undergoing bone marrow transplantation (BMT) is most commonly caused by infection. Noninfectious episodes of pulmonary disease following BMT are more frequently encountered in patients with hematologic disorders or malignancy and are probably related to ablation therapy or graft-versus-host disease (GVHD). In contrast, patients with SCID do not receive chemotherapy before an HLA-identical allogeneic BMT and they do not suffer significant GVHD. We report a patient who developed severe lung disease during the period of rapid engraftment following an HLA-identical allogeneic bone marrow transplantation. Lung biopsy showed dense lymphocytic infiltrates in the alveolar septae and no evidence of infection. Following the idea that the acute recruitment of engrafted lymphocytes may have contributed to or caused the pulmonary disease, we have attempted to suppress cellular immunity by administering high-dose methylprednisolone. The patient's lung disease rapidly improved and eventually completely resolved.

Bone Marrow↗

PubMed1991

Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody.

Sixteen patients with non-Hodgkin's lymphoma were infused with 6.2 to 58.2 mCi (0.2 to 3.9 mg) doses of radioactive iodine (131I)-labeled LL2 immunoglobulin G (IgG) or F(ab')2, in order to study antibody distribution, pharmacokinetics, dosimetry, toxicity, tumor targeting, and therapy. LL2 is a murine IgG2a monoclonal antibody (MAb) reactive with B cells and non-Hodgkin's B-cell lymphoma. In a series of five assessable therapy patients, doses as small as 30 mCi 131I-LL2 IgG or F(ab')2 resulted in tumor responses (two partial remissions, two mixed and minor responses, and one no response), while one patient receiving diagnostic doses as low as 6.2 mCi showed a partial remission for 1 year and a complete remission after a second low radiation dose. No acute toxicities were noted, and only myelotoxicity accompanied therapeutic doses, with grade IV marrow toxicity seen in three of seven patients receiving total doses of about 50 mCi. Dosimetry calculations showed spleen and tumor dose rules of about 4.6 cGy/mCi, which was three to four times the dose to other organs. Despite the administration of relatively low doses of LL2 (0.2 to 3.9 mg), 82% of 60 known extrasplenic lymphoma sites were imaged. Serum clearance showed an average distribution half-life (T1/2) of 2.1 hours and an elimination T1/2 of 32.0 hours. The average total-body clearance T1/2 was 43 to 45 hours. LL2's antigenic target does not appear to be shed in high amounts into the circulation. Three of eight patients having at least two injections showed a human antimouse antibody response. These patients may have been presensitized to animal protein. An interesting observation in this study was the marked drop in circulating B lymphocytes after the administration of radioiodinated LL2 or anticarcinoembryonic antigen MAbs, suggesting that this is a nonspecific radiation effect and not necessarily related to the binding of MAb to normal B cells.

Adult↗