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Biomedical subjects

J Rosenthal

Publications and source records attributed to J Rosenthal.

At least 73 records · Page 4Linked to original sources
PubMed1995

The role of cytokines in modulating neonatal myelopoiesis and host defense.

Neonatal sepsis is a major cause of morbidity and mortality in newborn infants. Hematopoiesis and host defense in the neonate is developmentally immature compared with the adult. Defects in both the quantitative and qualitative aspects of the phagocytic system contribute significantly to a relative state of immunodeficiency in the neonate. Dysregulation of neonatal hematopoiesis and the immune response is a significant contributing factor to the increased susceptibility of the neonate to infection. A relatively small set of pluripotent stem cells gives rise to large numbers of functionally diverse mature effector cells. Cell proliferation and differentiation are regulated and controlled by highly specific protein factors, affecting single and multiple lineage hematopoiesis. Reduced neonatal rat myeloid progenitor pools, accelerated myeloid progenitor proliferative rates and decreased total body neutrophil storage pools predispose the newborn rat to depletion of mature effector neutrophils and a tendency to develop neutropenia during states of increased demand such as overwhelming bacterial infection. We review here the multifactorial complex biological process involved in the regulation of hematopoietic growth factors. We also review the biological effects of various non-lineage-committed and lineage-committed growth factors as reported in in vitro investigations and in vivo neonatal animal experiments. We also review our results of phase I/II clinical studies utilizing rhuG-CSF in neonates with presumed sepsis, and of rhuGM-CSF in very low birth weight neonates.

Animals↗
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↗
PubMed1994

Long-term treatment of double depression: a preliminary study with serotonergic antidepressants.

1. There is increasing evidence that many patients with major depression also have coexisting dysthymia, and that antidepressant treatment may alleviate both conditions. 2. Open-label study of fluoxetine and trazodone for 18 patients meeting DSM-III-R criteria for concurrent dysthymia and major depression. 3. Fourteen patients completed three-month medication trials, and seven (50%) of completers) responded to treatment. At five months, eight (57.1%) were in remission. Fluoxetine was significantly better tolerated than trazodone, with respective dropout rates of 7.7% and 80%. 4. Findings are consistent with efficacy of serotonergic agents in this condition.

Adult↗
PubMed1994

Isolation of a diverged homeobox gene, MOX1, from the BRCA1 region on 17q21 by solution hybrid capture.

Using the technique of solution hybridization coupled with magnetic bead capture, we have isolated a novel homeobox-containing gene from the BRCA1 region of 17q21. This gene is the human homologue of the mouse Mox1 gene previously localized to a syntenic region of mouse chromosome 11. Multiple overlapping cDNAs of human MOX1 were identified using both a cosmid and a P1 genomic clone containing the microsatellite markers D17S750 and D17S858 which map within the BRCA1 region defined by D17S776 and D17S78. MOX1 expression was observed in a variety of normal tissues examined, including breast and ovary. Given that the gene contains a homeobox domain and has the potential to regulate growth and differentiation, MOX1 represents an attractive candidate for the BRCA1 gene. This possibility was investigated in a series of BRCA1 kindreds and primary sporadic breast tumors. No evidence for mutation was found in the coding sequence, making it unlikely that MOX1 is the BRCA1 gene. However, the widespread expression of MOX1 in non-embryonal tissues suggests a role in normal cell biology which warrants further study.

Amino Acid Sequence↗
PubMed1994

Stretch-mediated activation of cardiac renin gene.

This study was designed to quantitate cardiac mRNA levels encoding components of the local renin-angiotensin system during the development of volume overload-induced cardiac hypertrophy. Changes in cardiac renin mRNA levels were measured in relation to renin activity in the left ventricle (LV) and in plasma after acute passive stretch of the heart caused by an aortovenocaval shunt in the rat. A quantitative reverse-transcriptase polymerase chain reaction method with competitive internal standards was used to measure mRNA levels in total RNA derived from cardiac tissues after shunt. Seven days after shunt surgery, LV weight was increased by 23%. Renin activities were elevated four- and twofold in plasma and LV, respectively. LV angiotensinogen mRNAs were not significantly increased by shunt surgery; they were twofold higher than phosphoglycerate kinase mRNA from the housekeeping gene PGK-1. By day 7, LV levels for renin mRNA were significantly increased from well below 0.25% to approximately 1% of PGK-1 mRNA. Identity between renin polymerase chain reaction products from kidney and heart cDNAs and absence of "reninlike" amplification products were supported by Southern blotting. Volume overload caused increased expression of the renin gene in the stretched myocardium. This finding is consistent with the concept of a myocardial renin-angiotensin system that can be activated by locally produced renin and contributes to the hypertrophy of cardiac muscle.

Animals↗
PubMed1994

Nilvadipine: profile of a new calcium antagonist. An overview.

Nilvadipine is a new calcium antagonist of the the dihydropyridine group. Owing to its high receptor affinity, nilvadipine blocks L-type calcium channels in vascular muscle cells. This leads to prolonged vascular relaxation and lowering of blood pressure. In comparison with nifedipine, the prototype of the dihydropyridines, nilvadipine possesses special pharmacokinetic and pharmacodynamic properties. The duration of action is longer, and the vasodilatory effect is 5-16 times greater. Compared with nifedipine, the cardiodepressive action and the adrenergic counterregulation are less intense for nilvadipine. Nilvadipine's higher vasoselectivity is expressed in a vascular/cardiac efficacy quotient of 251, is 9-10 times higher than that of nifedipine. In therapeutic dosages nilvadipine has no negative inotropic, chronotropic, or dromotropic effects. In various in vitro and animal experiments, nilvadipine demonstrated a good antiatherogenic action. Nilvadipine is absorbed quickly and completely. Owing to a marked first-pass effect, the absolute bioavailability is 14-19%. The final elimination half-life is between 15 and 20 h, probably due to slow redistribution from the tissue. Nilvadipine is mainly excreted via the kidneys in the form of inactive metabolites. The pharmaceutical preparation as a depot form prevents an over-increase of the plasma level, and therefore reduces the typical side effects of dihydropyridine calcium antagonists. The pharmacokinetics of nilvadipine are not affected by reduced renal function. The bioavailability is increased in liver cirrhosis, but with repeated administration no cumulative effect takes place. Because of nilvadipine's long half-life, a once-daily administration is adequate to reduce blood pressure over 24 h in the treatment of arterial hypertension. At a daily dosage of 8-16 mg, the responder rate (RRdiast < 90 mm Hg) is 60-70% in single-drug therapy and up to 80% in combination therapy. Nilvadipine can be used to treat hypertensive patients who are also suffering from diabetes mellitus, lipometabolic disturbances, chronic obstructive respiratory tract disease, or cerebral circulatory disturbances. Owing to its high vascular selectivity, antiatherogenic properties, 24-h action, and good tolerance, nilvadipine fulfills the requirements for a modern antihypertensive agent.

Antihypertensive Agents↗
PubMed1994

Hodgkin's disease in childhood: treatment modalities, outcome and epidemiological aspects. The Northern Israel Cancer Center experience.

PURPOSE: A retrospective analysis of Hodgkin's disease (HD) in children treated at the Northern Israel Cancer Center between 1971 and 1990 was conducted. PATIENTS AND METHODS: Records of 102 patients < 18 years of age at diagnosis were reviewed. Patient characteristics were similar to those previously reported. There were 54 boys and 48 girls (1.1:1 boy:girl ratio), with more boys < 10 years of age. Forty-four patients were of Arab ancestry and 58 were Jewish; incidence rates were similar in both groups. The most common histological types were nodular sclerosing and mixed cellularity, the latter being more commonly diagnosed in the younger age group. RESULTS: The outcome of various treatment modalities in childhood HD were evaluated. Sixty-five patients (64%) had stage I or II and 37 (34%) had stage III or IV at diagnosis. Patients with stage I-II received radiotherapy alone (20 patients), chemotherapy alone (10 patients), or a combined approach of chemotherapy plus radiotherapy (35 patients). Survival rates and median disease-free intervals were statistically similar in all three modalities. However, relapse rates were higher among patients receiving radiotherapy alone or chemotherapy alone (35% and 38%, respectively) compared with patients receiving chemotherapy plus radiotherapy (14%). CONCLUSIONS: We conclude that a combined approach of chemotherapy plus radiotherapy is advantageous over radiotherapy alone or chemotherapy alone.

Adolescent↗
PubMed1993

[Hodgkin's disease in childhood--northern Israel cancer center experience, 1971-1990].

Records of children treated for Hodgkin's disease between 1971-1990 were analyzed retrospectively, and 102 cases of children younger than 18 years when diagnosed were reviewed. There were 54 boys and 48 girls, with male predominance in those younger than 10 years. 44 patients were of Arab ancestry and 58 were Jewish; the incidence was similar in both groups. Most common were the nodular sclerosing and mixed cellularity types, the latter more common in the younger age group. The outcome of various treatments was evaluated. At diagnosis, 64% were in stages I or II and 34% in stages III or IV. 20 of those in stages I-II received radiotherapy (RT) alone, 10 chemotherapy (CT) alone, and 35 combined CT and RT. Survival rates and median disease-free intervals were statistically similar with all 3 modalities. However, relapse rates were higher with either RT or CT alone (35% and 38%, respectively) than with combined therapy (14%). We conclude that combined CT and RT is superior to RT or CT alone.

Adolescent↗
PubMed1993

Role of renal and extrarenal renin-angiotensin system in the mechanism of arterial hypertension and its sequelae.

The role of the renin-angiotensin system in cardiovascular function and disease has long been recognized. The renin-angiotensin system was originally thought to be only active in the plasma as a circulating endocrine system, controlling blood pressure and electrolyte homeostasis. The recent introduction of new biotechnologies to cardiovascular research has demonstrated that the renin-angiotensin system can operate as both an endocrine (circulating) and an autocrine/paracrine (tissue) system. The endocrine component is involved with acute circulating homeostasis, whereas it is believed that the tissue renin-angiotensin system participates in the tonic regulation of cardiovascular function and structure. Multiple lines of evidence support the presence of complete renin-angiotensin systems in the central nervous system, vasculature, adrenal, heart, kidney, and reproductive organs. Although more research is necessary to delineate the role of tissue renin-angiotensin systems in local tissue function, the significant contribution of the renin-angiotensin system in the pathophysiology of cardiovascular disease is increasingly apparent (Table 1).

Adrenal Glands↗
PubMed1993

A fast protein liquid chromatography (FPLC) method for study of thyrotropin-releasing hormone (TRH) and its metabolite histidyl-proline diketopiperazine (CHP) in human blood: degradation in liver and pancreatic diseases.

We have developed a convenient method combining fast protein liquid chromatography (FPLC) with sensitive radioimmunoassay (RIA) for thyrotropin-releasing hormone (TRH) to separate and identify TRH and its metabolite histidyl-proline diketopiperazine (CHP) and applied this to study inactivation of TRH by blood extracts from patients with liver cirrhosis (LC) and acute edematous pancreatitis (AP). Blood samples spiked with TRH and CHP were extracted by cold methanol and injected on a reverse-phase FPLC column. A linear gradient was applied for separation. Subsequent analyses of fractions by RIA for TRH revealed that only fractions 9-10 contained TRH. Separation by retention time (9.9 +/- 0.8 min for TRH, 10.5 +/- 0.6 min for CHP, mean +/- SEM) was highly reproducible. For degradation studies, pooled sera from patients with LC and AP were incubated with TRH and CHP for 60 min. Inactivation of TRH was less rapid in the presence of blood extract from LC patients than that from normal subjects or AP patients. CHP was more stable than TRH. These data suggest that activity of TRH-degrading enzymes is reduced in liver disease, whereas it does not appear to be altered in AP. Degradation of CHP does not closely reflect metabolic processing of its major precursor. This rapid and sensitive method may be applicable for further investigations on the metabolism of TRH in organic fluids.

Acute Disease↗