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Biomedical subjects

J Rosenthal

Publications and source records attributed to J Rosenthal.

At least 19 recordsLinked to original sources
PubMed1996

Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease.

To reduce the morbidity and mortality associated with unrelated donor bone marrow (BM) transplantation and potentially extend the pool of suitable donors, cryopreserved unrelated donor umbilical cord blood was considered as an alternate source of hematopoietic stem cells for transplantation. Patients with leukemia, BM failure syndrome, or inborn error of metabolism were eligible for a phase I clinical trial designed to estimate the risk of graft failure and severe acute graft-versus-host disease after transplantation of umbilical cord blood from unrelated donors. As of December 21, 1995, unrelated donor umbilical cord blood was used to reconstitute hematopoiesis in eighteen patients aged 0.1 to 21.3 years weighing 3.3 to 78.8 kg with acquired or congenital lympho-hematopoietic disorders or metabolic disease. Patients received either HLA-matched (n = 7) or HLA-1 to 3 antigen disparate (n = 11) grafts collected and evaluated by the New York Blood Center (New York, NY). The probability of engraftment after unrelated donor umbilical cord blood transplantation was 100% with no patient having late graft failure to date. The probability of grade III-IV acute graft-versus-host disease at 100 days was 11%. With a median follow-up of 6 months (range, 1.6 to 17 months); the probability of survival at 6 months is 65% in this high risk patient population. We conclude that cryopreserved umbilical cord blood from HLA-matched and mismatched unrelated donors is a sufficient source of transplantable hematopoietic stem cells with high probability of donor derived engraftment and low risk of refractory severe acute graft-versus-host disease. Limitations with regard to recipient size and degree of donor HLA disparity remain to be determined.

Actuarial Analysis↗
PubMed1996

Adrenocortical activation by herpes virus: involvement of IL-1 beta and central noradrenergic system.

We investigated the involvement of brain cytokines and central monoamines in mediating the effect of the neurotropic herpes simplex virus-1 (HSV-1) on adrenocortical activity in rats. Corneal inoculation with a neurovirulent HSV-1 strain, but not with an avirulent strain, induced interleukin-1 beta (IL-1 beta) gene expression mainly in the pons and hypothalamus, and caused an elevation in serum corticosterone levels. Infectious virus was isolated in low titres only from the trigeminal ganglia and pons. Viral DNA was detected by PCR in these tissues and in other brain regions. Virus-induced adrenocortical activation was abolished in rats in which hypothalamic norepinephrine (NE) was depleted by 6-hydroxydopamine. Depletion of hypothalamic serotonin by 5,7-dihydroxytryptamine did not prevent adrenocortical activation. These results suggest that central IL-1 and NE are involved in HSV-1 induced adrenocortical activation.

5,7-Dihydroxytryptamine↗
PubMed1996

Effect of acidic phospholipids on sphingosine kinase.

Sphingosine-1-phosphate (SPP) is a unique sphingolipid metabolite involved in cell growth regulation and signal transduction. SPP is formed from sphingosine in cells by the action of sphingosine kinase, an enzyme whose activity can be stimulated by growth factors. Little is known of the mechanisms by which sphingosine kinase is regulated. We found that acidic phospholipids, particularly phosphatidylserine, induced a dose-dependent increase in sphingosine kinase activity due to an increase in the apparent Vmax of the enzyme. Other acidic phospholipids, such as phosphatidylinositol, phosphatidic acid, phosphatidylinositol bisphosphate, and cardiolipin stimulated sphingosine kinase activity to a lesser extent than phosphatidylserine, whereas neutral phospholipids had no effect. Diacylglycerol, a structurally similar molecule which differs from phosphatidic acid in the absence of the phosphate group, failed to induce any changes in sphingosine kinase activity. Our results suggest that the presence of negative charges on the lipid molecules is important for the potentiation of sphingosine kinase activity, but the effect does not directly correlate with the number of negative charges. These results also support the notion that the polar group confers specificity in the stimulation of sphingosine kinase by acidic glycerophospholipids. The presence of a fatty acid chain in position 2 of the glycerol backbone was not critical since lysophosphatidylserine also stimulated sphingosine kinase, although it was somewhat less potent. Dioleoylphosphatidylserine was the most potent species, including a fourfold stimulation, whereas distearoyl phosphatidylserine was completely inactive. Thus, the degree of saturation of the fatty acid chain of the phospholipids may also play a role in the activation of sphingosine kinase.

3T3 Cells↗
PubMed1996

Pranidipine, a novel calcium antagonist, once daily, for the treatment of hypertension: a multicenter, double-blind, placebo-controlled dose-finding study.

The antihypertensive effects and tolerance of once-daily (od), pranidipine, a novel dihydropyridine derivative with a long duration of action, were evaluated in a double-blind, placebo-controlled, parallel-group dose-finding study. A total of 199 patients, with a diastolic blood pressure (BP) of 95-115 mmHg, were included in the trial. After 4 weeks on placebo, patients were randomly assigned to either placebo or pranidipine at 1, 2, 4, or 8 mg od for a further 4 weeks. A dose response was seen in the reduction (delta) of diastolic BP: placebo, delta 1.7 mm Hg; 1 mg, delta 6.4 mmHg; 2 mg, delta 7.5 mmHg, p < 0.01; 4 mg, delta 11.5 mmHg, p < 0.01; and 8 mg, delta 10.6 mmHg, p < 0.01. There were no meaningful changes in heart rate. The number of responders (decrease of diastolic blood pressure to < 90 mmHg and by 10 mmHg or more from baseline value) in each group also revealed a dose-response relationship: placebo = 9%; 1 mg = 25%, n.s.; 2 mg = 27%, n.s.; 4 mg = 41.5%, p < 0.01; and 8 mg = 41%, p < 0.01 (compared with placebo). Plasma concentrations of pranidipine also demonstrated linear dose-response relationships. An increase in adverse events was observed within the 8 mg group. The degree of reduction in BP and the number of responders were not greater in the 8 mg group compared with the 4 mg group, although the plasma concentration (mean values, ng/dl) of pranidine in the 8 mg group was higher (2.2 on day 42; 2.3 on day 56) compared with the 4 mg group (1.4 on day 42; 1.6 on day 56). In conclusion, pranidipine is a well-tolerated and 24-hour effective novel calcium antagonist that reduces BP in a dose-related manner up to 4 mg od.

Adult↗
PubMed1996

Follow-up assessment of medication-treated dysthymia.

1. The objective was to assess long-term efficacy of antidepressant medications in dysthymia. 2. In a naturalistic study, patients with DSMIII-R dysthymia who had participated in previous antidepressant trials with fluoxetine and trazodone were evaluated at a mean of 40.0 weeks of follow-up to assess whether medication response persisted over time. A multivariate analysis was performed for patients on vs. off medication. Relapse rates (with relapse defined as HDRS score > 13) were also compared for these two groups. 3. Of 40 patients, the 24 still on medication showed significantly lower scores on most rating scales (HDRS, Cornell Dysthymia Rating Scale, and CGI, but not on the SCL-58) than the heterogeneous group of 16 patients not taking medication. Relapse was low (17.4%) among patients remaining on medication. 4. These preliminary findings suggest that dysthymia patients who remain on medication maintain improvement over time.

Adult↗
PubMed1996

A two-year follow-up of neonates with presumed sepsis treated with recombinant human granulocyte colony-stimulating factor during the first week of life.

We have previously reported that recombinant human granulocyte colony-stimulating factor was well tolerated and resulted in sustained neutrophilia and improvement of neutrophil functions in newborn infants with presumed sepsis. We now report a 2-year follow-up on 21 of the initial cohort of 28 patients. Treatment with recombinant human granulocyte colony-stimulating factor in neonates with presumed sepsis was not associated with any long-term adverse hematologic, immunologic, or developmental effects.

Blood Cell Count↗
PubMed1996

Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol.

PURPOSE: Patients with stage D2 prostate carcinoma are often treated initially with hormones to decrease endogenous testosterone. Therapy with diethylstilbestrol (DES), leuprolide, or bilateral orchiectomy has been reported to be equivalent. DES is the cheapest preparation, but has the potential for serious cardiovascular or thromboembolic complications. Flutamide is a novel antiandrogen with fewer side effects. PATIENTS AND METHODS: The Eastern Cooperative Oncology Group (ECOG) conducted a double-blind, randomized study to compare the efficacy of flutamide (250 mg three times daily) to DES (1 mg three times daily) as the primary hormonal therapy for patients with stage D2 prostate cancer. Patients were stratified by performance status, disease sites, and history of cardiovascular disease at randomization. RESULTS: Forty-eight patients received DES and 44 flutamide. Patient characteristics were evenly distributed between the two treatments. The overall response rate was similar (DES, 62%; flutamide, 50%). Grade III or worse cardiovascular or thromboembolic toxicity developed in 33.3% of patients on DES and in 17.6% on flutamide (P = .051). Other toxicities were similar between the two treatment arms. However, DES produced significantly longer time to treatment failure (26.4 v 9.7 months, P = .016) and longer survival than flutamide (43.2 v 28.5 months, P = .040). CONCLUSION: As the primary hormonal therapy for stage D2 prostate cancer, DES caused more serious cardiovascular or thromboembolic complications than flutamide. Despite this, flutamide was not as active an initial agent as DES. However, the effectiveness of flutamide in conjunction with other agents compared with DES remains undetermined, and the optimal initial hormone therapy of stage D2 prostate cancer requires further studies.

Administration, Oral↗
PubMed1996

Rescue of HSV-1 neurovirulence is associated with induction of brain interleukin-1 expression, prostaglandin synthesis and neuroendocrine responses.

Several HSV-1 neurovirulence genes have been mapped but the mechanisms by which they affect host-virus interactions are not known. We have previously mapped HSV-1 neurovirulence to the UL53 gene region of the viral DNA by transfer of this gene from the neurovirulent R-19 strain to the non-neurovirulent R-15 strain in the generation of the p-71 recombinant, in which neurovirulence was rescued. In the present study we inoculated these strains into the paraventricular nucleus (PVN) of the hypothalamus of rats. We examined: (1) Clinical course of encephalitis. (2) Hypothalamic-pituitary-adrenocortical (HPA) axis function. (3) Brain cytokine gene mRNA expression and prostaglandin E2 (PGE2) production. (4) The relation of these parameters to viral replication and to cellular inflammation. In R-15 infected rats no signs of disease were observed. There was a temporary inflammatory reaction and IL-1 beta transcription in the PVN area. The function of the HPA axis was similar to control rats. Only slight increase in brain PGE2 production was found. In R-19 and p-71 infected rats, overt clinical signs of encephalitis and cellular inflammation in the PVN area were observed within 3 days post-infection (p.i). All rats died between 4-7 days p.i. These strains induced IL-1 beta transcription in the hypothalamus as well as in extra-hypothalamic brain regions in which no cellular inflammation was found. Basal serum ACTH and' CS were markedly elevated and hypothalamic CRF-41 content was significantly reduced as compared to R-15 infected rats. Both strains markedly increased brain PGE2 production. HSV-1 brain titers at 3 days p.i. were 100-fold lower than the inoculum titer although clinical signs of encephalitis were prominent. The results suggest that rescue of HSV-1 neurovirulence by the UL53 gene region of the viral genome is associated with enhancement of viral-induced brain IL-1 beta gene expression, increased brain PGE2 synthesis and hypersecretion of HPA axis hormones. Viral-induced brain derived cytokines and prostaglandins may contribute to the clinical syndrome of acute herpetic encephalitis in particular at early stages of the disease when virus load in the brain is low and cellular infiltrates are not widespread.

Adrenocorticotropic Hormone↗
PubMed1995

Results of a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in very low birthweight neonates: significant induction of circulatory neutrophils, monocytes, platelets, and bone marrow neutrophils.

Neonates, especially those of very low birthweight (VLBW), have an increased risk of nosocomial infections secondary to deficiencies in development. We previously demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) production and mRNA expression from stimulated neonatal mononuclear cells are significantly less than that from adult cells. Recombinant murine GM-CSF administration to neonatal rats has resulted in neutrophilia, increased neutrophil production, and increased survival of pups during experimental Staphylococcus aureus sepsis. In the present study, we sought to determine the safety and biologic response of recombinant human (rhu) GM-CSF in VLBW neonates. Twenty VLBW neonates (500 to 1,500 g), aged < 72 hours, were randomized to receive either placebo (n = 5) or rhuGM-CSF at 5.0 micrograms/kg once per day (n = 5), 5.0 micrograms/kg twice per day (n = 5), or 10 micrograms/kg once per day (n = 5) given via 2-hour intravenous infusion for 7 days. Complete blood counts, differential, and platelet counts were obtained, and tibial bone marrow aspirate was performed on day 8. Neutrophil C3bi receptor expression was measured at 0 and 24 hours. GM-CSF levels were measured by a sandwich enzyme-linked immunosorbent assay at 2, 4, 6, 12, and 24 hours after the first dose of rhuGM-CSF. At all doses, rhuGM-CSF was well tolerated, and there was no evidence of grade III or IV toxicity. Within 48 hours of administration, there was a significant increase in the circulating absolute neutrophil count (ANC) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day, which continued for at least 24 hours after discontinuation of rhuGM-CSF. When the ANC was normalized for each patient's first ANC, there was a significant increase in the ANC on days 6 and 7 at each dose level. By day 7, all tested doses of rhuGM-CSF resulted in an increase in the absolute monocyte count (AMC) compared with placebo-treated neonates. In those receiving rhuGM-CSF 5.0 micrograms/kg twice per day, there was additionally a significant increase in the day 7 and 8 platelet count. Tibial bone marrow aspirates demonstrated a significant increase in the bone marrow neutrophil storage pool (BM NSP) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day. Neutrophil C3bi receptor expression was significantly increased 24 hours after the first dose of rhuGM-CSF at 5.0 micrograms/kg once per day. The elimination half-life (T1/2) of rhuGM-CSF was 1.4 +/- 0.8 to 3.9 +/- 2.8 hours.(ABSTRACT TRUNCATED AT 400 WORDS)

Birth Weight↗
PubMed1995

The immunization of children enrolled in the Special Supplemental Food Program for Women, Infants, and Children (WIC). The impact of different strategies.

OBJECTIVE: To assess the impact of different interventions to increase measles vaccination coverage among preschool children enrolled in the Special Supplemental Food Program for Women, Infants, and Children (WIC). DESIGN: Public health intervention trial. SETTING: Six volunteer WIC sites in New York City. STUDY PARTICIPANTS: Children aged 12 to 59 months presenting for WIC certification between April 1 and September 30, 1991, who were eligible for measles vaccination. INTERVENTIONS: Two WIC sites were assigned at random to one of three immunization strategies: (1) escort: child was escorted to a nearby pediatric clinic for immunization; (2) voucher incentive: the family returned monthly, rather than every 2 months, to pick up WIC food vouchers until the child was immunized; or (3) referral: the family was passively referred for immunization. MAIN OUTCOME MEASURE: Proportion of eligible children receiving measles vaccination. RESULTS: Of children eligible for measles immunization, 74% (618/836) were immunized. Children at escort sites were 5.5 times (relative risk [RR] = 5.5; 95% confidence interval [CI], 3.7 to 8.1) and those at voucher incentive sites were 2.9 times (RR = 2.9; 95% CI, 1.9 to 4.5) more likely to be immunized than children at referral sites. Children were immunized more rapidly at escort sites (median, 14 days) and voucher incentive sites (median, 26 days) than at referral sites (median, 45 days; P < .001). CONCLUSIONS: Both escort and voucher incentive models resulted in more children being immunized more rapidly than passive referral. Because of ease of administration, voucher incentives may be a more suitable immunization intervention for use at WIC sites, with addition of escort where feasible.

Female↗
PubMed1995

Comparison of the positional cloning methods used to isolate the BRCA1 gene.

A critical step in positional cloning is the identification of candidate genes from a large, genetically defined region. Candidate gene isolation by hybrid selection, genomic sequencing, and direct cDNA library screening identified 45 candidate gene fragments (CGFs) from a 600 kb genomic region that contains the BRCA1 gene. These CGFs define a minimum of 15 genes, six of which are newly localized to the BRCA1 region. We present an analysis of the efficiency and the sequences generated for each of these methods. We also compare our CGF set to those reported for the BRCA1 region by three other groups, revealing a surprising lack of overlap among the sets.

Breast Neoplasms↗
PubMed1994

Localization of the VHR phosphatase gene and its analysis as a candidate for BRCA1.

The VH1-related human protein (VHR) gene was localized to human chromosome 17q21 in a region thought to contain the BRCA1 locus, a locus that confers susceptibility to breast and ovarian cancer. VHR encodes a phosphatase with dual specificity for tyrosine and serine residues. Thus it is a plausible candidate for a tumor suppressor gene such as BRCA1. To test this possibility, the VHR coding sequence was screened in individuals with familial breast cancer and in sporadic breast tumor and breast cancer cell lines. No mutations were detected, suggesting that the VHR gene is not BRCA1.

BRCA1 Protein↗
PubMed1994

[Malignant solid tumors in the first year of life].

The records of all children in Northern Israel under the age of 1 year in whom a malignant solid tumor was diagnosed were analyzed. Between 1973-1990 such tumors were found in 39 boys and 25 girls. The overall annual incidence was 137.1 per million, and the incidence was higher in boys (1.9/1.0), in Jews compared to non-Jews (1.3/1.0), and in Ashkenazic Jews compared to Sephardic Jews (1.2/1.0). Neuroblastoma was the most common (52% of all malignancies), followed by Wilms' tumor (13%), CNS neoplasm (11%), retinoblastoma (8%), soft tissue sarcoma (6%), lymphoma (5%) and all others (6%). The retinoblastomas were all in non-Jews, but Jews had a higher incidence of neuroblastomas. No differences in incidence were observed in other neoplasms.

Central Nervous System Neoplasms↗
PubMed1994

Sphingosine kinase from Swiss 3T3 fibroblasts: a convenient assay for the measurement of intracellular levels of free sphingoid bases.

Sphingoid bases are important for diverse cellular processes. This paper describes the development of a simple and rapid enzymatic method to quantify mass levels of free long-chain sphingoid bases in cellular lipid extracts. The assay is based on the ability of sphingosine kinase from Swiss 3T3 fibroblasts to phosphorylate sphingoid bases, predominantly sphingosine. To quantitatively determine cellular levels of sphingosine or other long-chain sphingoid bases, it was necessary to solubilize cellular lipids by sonication and to generate standard curves in the presence of lipid extracts containing at least 50 nmol of phospholipids. The assay conditions were optimized to allow quantification of sphingosine over a broad range from 25 to 1,000 pmol. Using this method we were able to obtain reproducible measurements of free sphingoid bases in various cell types and to detect increases in intracellular sphingoid base levels after treatment with exogenous sphingosine or stimulation with fetal bovine serum.

3T3 Cells↗
PubMed1994

Phase II clinical trial of didemnin B in previously treated small cell lung cancer.

Didemnin B (NSC 325319), a cyclic depsipeptide isolated from a Carribean sea tunicate, exhibited potent antitumor activity in preclinical studies. After determining the maximum tolerated dose in our previous phase I/II trial, we conducted a phase II study of this drug in patients with previously treated small cell lung cancer; the starting dose was 6.3 mg/m2 intravenously over 30 min every 28 days. The major side effects were in the neuromuscular system and included severe muscle weakness, myopathy and/or myotonia by electromyography, and elevation of creatine phosphokinase and aldolase levels. We also observed modest increases in bilirubin and alkaline phosphatase levels. There were minimal hematologic toxic effects. No response was observed among 15 evaluable patients, leading us to conclude that didemnin B was toxic but inactive in patients with previously treated small cell lung cancer at the stated dose and schedule. A review of the literature revealed no significant antitumor activity in cancers of the colon, breast, ovaries, cervix, or lung (non-small cell) or in renal cell carcinoma. Further clinical trials for didemnin B may not be warranted at the stated dose and schedule.

Adult↗