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Biomedical subjects

D Rosen

Publications and source records attributed to D Rosen.

At least 73 records · Page 4Linked to original sources
PubMed1994

Calcium channel blockers modify electrophysiological effects induced by lytic granules from cytotoxic T lymphocytes in guinea pig ventricular myocytes.

Damage to myocytes by infiltrating cytotoxic lymphocytes, containing lytic granules and the pore-forming protein, perforin, thereof, probably contribute to the immunological rejection of the transplanted heart, to autoimmune diseases and possibly to congestive heart failure associated with myocarditis. In the present study we investigated whether electrophysiological and morphological changes induced in guinea pig ventricular myocytes by lytic granules extracted from cytotoxic T lymphocytes, are modified by L-type Ca++ channel blockers. The organic blockers, verapamil (2 microM) and nisoldipine (500 microM) were unable to prevent or inhibit any of the deleterious effects of lytic granule on action potential and myocyte morphology, and the granule-induced increase in the membrane current measured at the end of 300-msec clamp pulse. In contrast, the inorganic blockers CoCl2 (3 mM) and NiCl2 (4 mM) provided considerable protection against the granule actions mentioned above, but an equally potent Ca++ blocker, CdCl2 (3 mM) was ineffective. The protective efficacy of CoCl2 (and probably that of NiCl2) was most likely due to its capacity to reduce or block the generation by lytic granules/perforin of large-conductance (approximately 1400 pS) channels responsible for inducing Ca++ overload and cell destruction. We consider these studies of importance because they direct further studies aimed at developing effective means for attenuating cytotoxic T lymphocyte-induced tissue damage, for example during transplant rejection or in autoimmune diseases.

Action Potentials↗
PubMed1993

A genetic linkage map of chromosome 21: a look at meiotic phenomena.

We have developed a genetic linkage map of chromosome 21 using 17 microsatellite marker polymorphisms. The markers span virtually the entire length of 21q, and define a sex-equal map of 56 cM. Extensive error checking has been used to provide an accurate map. All recombination events have been identified, allowing us to place within a small interval any new markers by genotyping only a few critical individuals. The resulting segregation data has been examined for several meiotic phenomena, including sex differences in recombination, age differences in recombination, interference, and segregation distortion.

Alzheimer Disease↗
PubMed1993

Mechanism of lymphocyte-mediated cytolysis: functional cytolytic T cells lacking perforin and granzymes.

Involvement of the lytic protein perforin (c. 65,000 MW) and of granule proteases (granzymes) in cell lysis induced by cytolytic T lymphocytes (CTL) has been suggested, but is still controversial. For example, in vivo-primed peritoneal exudate CTL (PEL) have been found to express perforin and granzyme activity in amounts comparable to those found in non-lytic lymphocytes, although PEL are the most potent of all CTL. Exploiting several cloned CTL hybridomas developed in this laboratory and newly available molecular probes for detecting perforin, granzymes, protein and mRNA, we now directly demonstrate killer T lymphocytes which kill effectively and specifically, but are free from perforin, lytic granules and granzymes, all three of which have been postulated to be involved in lymphocyte-mediated killing. The CTL hybridomas are completely devoid of perforin and granzymes prior to, during, and after activation by antigen, mitogen or interleukin-2 (IL-2). The induction of lytic granules, perforin, and granzymes in the in vivo-primed PEL, but not in the cloned CTL hybridomas, upon cultivation in IL-2, further suggests the involvement of these constituents in antigen/lymphokine-induced CTL activation and differentiation rather than directly in their cytocidal activity. Together, these findings support a perforin- and granzyme-independent CTL lytic mechanism.

Animals↗
PubMed1992

Irradiation of Langmuir-Blodgett multilayer preparations of phospholipids and a fatty acid. 1: Effect of UV radiation.

Langmuir-Blodgett (LB) preparations containing stacked monolayers of phospholipids or stearic acid were irradiated with UV light and the electric conductance perpendicular to the planes of the monolayers was measured. There was no observable change of conductance when LB preparations of stearic acid were irradiated. For LB preparations of phospholipids, a rise of conductance, dependent on dose rate, was observed, reaching an equilibrium level after a few hours. After irradiation the conductance fell with a temperature-dependent time constant, and eventually reached a final level a little above the initial value. A three-state model is proposed for the LB phospholipid preparations. This suggests that the absorption of one photon raises a molecule from the ground to an excited state; and the absorption of a second photon carries it into a damaged but repairable or metastable state.

Cell Membrane↗
PubMed1992

Irradiation of Langmuir-Blodgett multilayer preparations of phospholipids and a fatty acid. 2: Effect of X-radiation.

X-irradiation of Langmuir-Blodgett (LB) preparations of stearic acid with doses up to a few thousand Gy produced no change of measured electrical conductance in the direction perpendicular to the stacked monolayers. However, irradiation of LB preparations of phospholipids resulted in increased conductance. The effect depended on dose, but not on dose rate and, unlike the corresponding effect of UV-radiation, did not reverse at room temperature. For doses up to about 2 kGy the increased conductance fell away over some tens of minutes if the temperature was raised above 45 degrees C. For doses between 2 and 60 kGy the conductance increased linearly, but less rapidly than the initial rise and the increase was only partly reversible by heating. The rate of increase of conductance rose again for doses above about 60 kGy and for these doses the increase could not be reversed on heating. It is suggested that X-irradiation left molecules in a damaged but reversible state similar to that found after UV irradiation; and that subsequent excitation and ionization damaged the molecules irreversibly.

Cell Membrane↗
PubMed1992

Spinal cord compression in prostate cancer. A 10-year experience.

Of 478 patients treated at a single institution for prostate cancer, 29 developed spinal cord or cauda equina compression. In 5 patients, spinal cord compression was the first evidence of malignancy. Clinical features were predominantly pain, weakness, sensory and sphincter disturbance. The median duration of symptoms was 2 weeks, although the diagnosis was made rapidly at presentation. Clinical diagnosis correlated well with myelographic findings. Only 1 patient suffered neurological deterioration as a consequence of myelography. The functional outcome was dependent on the ability to walk prior to treatment. The median survival in those who were bedridden following treatment was 6 weeks (range 3.5-13) and 21 weeks (range 7-110+) in those who were ambulant following therapy.

Cauda Equina↗
PubMed1992

Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study.

PURPOSE: The Pediatric Oncology Group (POG) designed a randomized two-arm protocol (8304) to improve the survival of children with acute lymphoblastic leukemia (ALL) who experience an isolated testicular relapse and to evaluate the efficacy of teniposide (VM-26) and doxorubicin as intensification agents during second remission. The outcome and toxicity observed in 80 patients with isolated testicular leukemia treated on POG 8304 are presented. PATIENTS AND METHODS: The following are common features of POG 8304: (1) remission reinduction therapy with vincristine, prednisone, and doxorubicin; (2) bilateral testicular irradiation (2,600 cGy) during reinduction therapy; (3) CNS prophylaxis with intrathecal hydrocortisone, methotrexate (MTX), and cytarabine (Ara-C); and (4) continuation therapy (for 80 weeks) with alternating 6-week cycles of oral mercaptopurine (6-MP)/MTX and intravenous vincristine and cyclophosphamide. Treatment differences consisted of pulses (administered every 7 weeks) of either prednisone and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2) during continuation therapy and a 4-week late intensification phase with either vincristine, prednisone, and doxorubicin (arm 1) or VM-26 and Ara-C (arm 2). RESULTS: Fifty-five boys with ALL had isolated microscopic testicular leukemia detected by an elective biopsy at completion of initial treatment, and 25 had a late (greater than or equal to 6 months off-therapy) isolated overt testicular relapse. All patients with overt testicular leukemia attained a second clinical remission, and no patient with microscopic testicular leukemia progressed during reinduction. Of 42 patients on arm 1, 11 have relapsed compared with 18 of 38 patients on arm 2 (log-rank analysis, P = .22), indicating no significant difference between an anthracycline and an epipodophyllotoxin-Ara-C combination in the treatment of testicular leukemia. The overall 4-year event-free survival (EFS) among boys with occult testicular relapse was 53% +/- 8%. Age greater than 10 years at initial diagnosis, a WBC count greater than 50,000/microL at diagnosis, and black race were associated with a worse outcome. The 4-year EFS for boys with a late overt testicular relapse was 84% +/- 10%, and these patients fared significantly better than patients with occult disease (P = .007). CONCLUSION: The treatment approach reported here can secure a prolonged second remission in many patients with occult or late overt testicular leukemia.

Adolescent↗
PubMed1991

Phase II trial of mitoxantrone in acute lymphocytic leukemia of childhood. A Pediatric Oncology Group study.

Thirty children with refractory acute lymphocytic leukemia (ALL) were treated with mitoxantrone, 8 mg/m2/day, for 5 days. Three children received a second course of the drug 3 to 4 weeks later. All but two patients had received prior anthracycline therapy. There were 2 complete responses, 4 early deaths, and 24 patients with persistent leukemia. Of the 21 patients with circulating blasts at the start of mitoxantrone who did not achieve remission, 16 (76%) had complete clearance of their peripheral blood blasts. Although all patients developed profound neutropenia (less than 100 per mm-3), mucosal and hepatic toxicities were uncommon and mild. Mitoxantrone has moderate activity in childhood ALL and should be considered for further trials in less heavily pretreated patients.

Adolescent↗
PubMed1991

Conversion of the electrohydraulic electrode to an electromechanical stone impactor: basic studies and a case report.

A 3.3F electrohydraulic electrode (Wolf 2137.23) has been confined within a spring with a metal end cap, irrigated with water and covered with a 0.003-inch metal sheath (outside diameter 5F). The electrohydraulic lithotripsy discharge (Wolf Generator 2137.50) at E1 causes the metal cap to extend 3 mm. at 1,500 cm. per second and creates an impact pressure of 600 to 800 bar. Stone fragmentation efficiency of the electromechanical impactor was equivalent to unshielded electrohydraulic lithotripsy (gallstone 2.83 mg. per pulse, struvite/apatite 1.41 mg. per pulse, cystine 0.41 mg. per pulse, uric acid 1.48 mg. per pulse and 100% calcium oxalate monohydrate 0.10 mg. per pulse). Studies of the discharge of the electromechanical impactor within the pig ureter showed that minimal ureteral submucosal edema and hemorrhage occurred at 300 shocks discharged at a single point, and disruption of the mucosa and partial injury to the muscle layer occurred after 600 shocks given at the site of a pinched pig ureter. Pushing the electromechanical impactor perpendicular to the wall of the pig bladder will create a mechanical perforation within 35 shocks (electrohydraulic lithotripsy within 2 shocks). One patient had excellent fragmentation of a lower ureteral mixed monohydrate and dihydrate stone under direct vision performed with the electromechanical impactor passed via a 9.5F ureteroscope. There was no evidence of mucosal injury with 500 shocks. The electromechanical impactor has been developed to provide a safe and inexpensive method of ureteral stone fragmentation or disimpaction. These studies were performed to establish limits of safety that may allow use of the electromechanical impactor for stone fragmentation in the ureter without the need for ureteroscopy.

Adult↗
PubMed1991

Morphometry of bladder carcinoma: morphometry and grading complement each other.

Subjective grading of bladder carcinoma is a good predictor of the clinical outcome in those patients whose tumours are grade 1 or grade 3. However, in grade 2 tumours, which account for 45% of cases, grading has little predictive value in an individual patient. We have complemented the use of subjective grading with measurement of nuclear area and used a calculation of the distribution of nuclear sizes as a predictor of the clinical course. When subjective grading was complemented by morphometry the outcome was correctly predicted in 55 of 58 cases and all cases with poor clinical outcome were identified.

Carcinoma, Transitional Cell↗
PubMed1990

Osteoinductive factor inhibits formation of human osteoclast-like cells.

Osteoinductive factor (OIF) is a glycoprotein in bone that induces ectopic bone formation. Implantation of OIF plus transforming growth factor beta (TGF-beta) type 1 or 2 into subcutaneous tissues of rats induces formation of bone at the implantation site. Since TGF-beta is also present in bone matrix and inhibits formation of multinucleated cells that express an osteoclast phenotype in long-term human marrow cultures, we tested the effects of OIF on formation of these osteoclast-like cells to determine the effects of OIF on cells in the osteoclast lineage. We found that OIF inhibited total multinucleated cell (MNC) formation in a dose-dependent fashion and preferentially inhibited formation of MNCs that react with monoclonal antibody 23c6 (23c6-positive MNCs), an antibody that identifies osteoclasts. In addition, low concentrations of OIF in combination with low concentrations of TGF-beta acted synergistically to inhibit 23c6-positive MNC formation. The inhibition of 23c6-positive MNC formation by OIF was not mediated by prostaglandin synthesis. These data suggest that regulatory growth factors, such as OIF or TGF-beta, that are stored within the bone matrix and released when bone is resorbed can serve as natural inhibitors of osteoclast activity by inhibiting osteoclast formation.

Alprostadil↗
PubMed1990

Molecular cloning of a novel bone-forming compound: osteoinductive factor.

cDNA clones encoding osteoinductive factor (OIF) have been isolated from a bovine osteoblast library. Sequence analysis of these clones indicated that the 105-amino-acid OIF is synthesized as a larger 299-amino-acid precursor, the carboxyl terminus of which is cleaved to yield the mature protein. Northern blot analysis of bovine osteoblast mRNA revealed two OIF-specific transcripts of 1.9 and 2.4 kb. The polymerase chain reaction was used to obtain clones coding for human OIF from the osteosarcoma cell line, MG-63. The human OIF cDNA encodes a precursor of 298 amino acids that exhibits 94% identity to the bovine protein. Northern blot analysis of various cell lines and tissues indicated that expression of OIF transcripts is limited and may be restricted to cells of bone lineage.

Amino Acid Sequence↗
PubMed1990

Inhibitory effects of the bone-derived growth factors osteoinductive factor and transforming growth factor-beta on isolated osteoclasts.

Demineralized bone matrix contains a number of growth factors for osteoblast-like cells. Two of these, the novel glycoprotein osteoinductive factor (OIF) and transforming growth factor-beta (TGF beta), act together to cause ectopic bone formation in vivo. Since OIF, like TGF beta, is likely released from bone when the matrix is resorbed, we examined the effects of homogeneous OIF and TGF beta on osteoclast function. Osteoclast function was tested in isolated avian osteoclasts and was measured in terms of tartrate-resistant acid phosphatase (TRAP) activity, oxygen-derived free radical production, and formation of characteristic resorption lacunae on slices of sperm whale dentine. OIF (50-100 ng/ml) inhibited the capacity of these osteoclasts to form lacunae whether assessed by the number of excavations per slice or by the total area resorbed. OIF (10-100 ng/ml) or TGF beta (10-20 ng/ml) caused a decrease in TRAP activity as well as a reduction in oxygen-derived free radical generation detected by nitroblue tetrazolium staining. TGF beta had no effect on the resorption capacity of isolated osteoclasts in concentrations that inhibited TRAP activity and nitroblue tetrazolium staining. These results suggest that growth regulatory factors, such as OIF and TGF beta, released during the resorption of bone may be endogenous inhibitors of continued osteoclastic activity. This cessation of osteoclast activity may be an essential preliminary step to the new bone formation that occurs at resorption sites during bone remodeling.

Acid Phosphatase↗