Amiloride-sensitive sodium channels and salt preference in rats.
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Biomedical subjects
Publications and source records attributed to I Bernstein.
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A modified form of Nathanson and Becker's (1983) Health Belief Model Questionnaire and other measures designed to assess cognitive processing were administered to low-income black adolescent female clients of an inner-city comprehensive health care clinic. The purpose of the study was to explore determinants of sexual activity and contraceptive use. Subjects were classified as not sexually active (n = 50), sexually active/noncontracepting (n = 20), or sexually active/contracepting (n = 72). Not sexually active subjects tended to be younger, more career motivated, to have a father at home, to be more influenced by family values, and to have more conservative attitudes regarding adolescent sexuality than did sexually active subjects. Sexually active/noncontracepting subjects tended to report fewer benefits and more barriers to the use of contraception. Level of cognitive processing did not differ among the three groups, but was at a lower-than-expected level for age. Finally, inconsistent contraceptive use was common to both sexually active groups.
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Pelvic floor muscle thickness was assessed in nine healthy female physiotherapists by perineal sonography. All measurements were performed as triple-measurements. The aims were to assess the reliability of the measurements and to establish a reference material. The muscle thickness at rest and at contraction was 9.4 +/- 0.8 mm and 11.5 +/- 1.1 mm respectively (mean +/- SD). Contraction increased the thickness by 2.2 +/- 0.8 mm or 23 +/- 8%. The intra- and inter observer standard deviation of the estimate was in the range of 4-6%. In conclusion, we find the reliability of the measurements acceptable.
In marrow transplantation, radioisotope-labeled monoclonal antibodies may provide a way to selectively deliver high doses of radiation to target tissues (marrow in the case of myeloid malignancies) without significant toxicity to other normal organs. This paper describes the production and characterization of a novel monoclonal antibody, DM5, that we have developed for use in an animal model of radiotherapy targeted to the marrow. DM5 recognizes three glycosylation variants, gp19,21,23DM5, of a polypeptide core that is expressed on canine cells of the myeloid lineage, but not on lymphoid cells. The antigen recognized by DM5 is not present on most progenitor cells as determined by CFU-GM assays of DM5 positive and negative cell populations.
Despite the use of near maximal doses of chemoradiotherapy, tumor recurrence remains the most frequent cause of treatment failure following marrow transplantation for leukemia. We have previously demonstrated that it is possible to selectively deliver radiation to the marrow space. In that study an initial short half-life of the radionuclide was observed. In this study we attempted to prolong the retention of the radioiodine in marrow through the use of propylthiouracil (PTU). When administered to normal dogs, PTU pretreatment resulted in improved marrow localization of 131I-labeled DM-5. There was no appreciable loss of activity from the marrow during the 2-4 hr postinjection time interval; a finding in contrast to the control animals where marrow activity declined a mean 45 +/- 0.5% over the same time period. Additionally, in contrast to controls, a rise in plasma trichloroacetic acid (TCA) nonprecipitable activity was not demonstrated in the PTU treated group during this 2-4 hr period. These results suggest that PTU's inhibition of deiodinases resulted in longer residence time of the radionuclide in its target tissue without adversely affecting distribution to non-target organs.
Tumor recurrence and regimen-related toxicity remain major obstacles in the successful use of marrow transplantation as therapy for hematologic malignancies. By attaching radionuclides to monoclonal antibodies (MoAbs) targeted at myeloid-associated antigenic determinants, a more effective and directed delivery of therapy may be possible without increasing toxicity. We investigated the biodistribution over time of an anti-myeloid antibody (DM-5) labeled with trace amounts of 131I in normal dogs. This study demonstrates the ability to target marrow with a high degree of selectivity, achieving marrow/blood ratios of 25-30:1 with the greatest concentration in any other organ being a tissue/blood ratio of 1.4:1 for stomach at 48 h. A pretreatment dose of unlabeled antibody effectively reduced early hepatic uptake by 80%, resulting in improved marrow localization with an estimated 58.6% of the injected dose localized in marrow within 2 h following infusion, compared to 32.8% without pretreatment. The marrow concentration clearance curve for the radioimmunoconjugate revealed an initial short half-life (4.75 h), suggesting rapid internalization, digestion, and release of free iodine (dehalogenation). This view was supported by a corresponding rise in trichloroacetic acid-non-precipitable activity during this period. Methods aimed at decreasing dehalogenation may result in longer residence time of the radionuclide within the marrow space, resulting in more effective tumor cell kill. This approach may provide a way to improve upon the current results obtained with marrow transplantation as treatment for patients with leukemia and other hematologic malignancies.
Today approximately 75 per cent of children with ANLL can be induced into a complete remission and approximately 40 per cent will have an event-free survival for more than 3 years, irrespective of whether they received a bone marrow transplantation or chemotherapy after induction. In order to achieve these results very intensive therapy is required. The morbidity and mortality of treatment are high. The length of therapy needed after induction of remission is not known. Whether or not maintenance therapy is required is perhaps related most directly to the intensity of the therapy employed. Similarly, the role of bone marrow transplantation in patients in first remission, treatment of CNS leukemia, and treatment of chloromas are controversial. There is general agreement that WBCs over 100,000, acute monoblastic leukemia in infants less than 2 years of age, and certain chromosomal abnormalities are associated with a poor prognosis. Although there has been a dramatic improvement in the treatment of ANLL over the past 15 years, stratification of therapy based on biologic parameters, and alteration of treatment based on the early responses to treatment may be required before further advances will be made.
Children with ALL diagnosed at less than 2 years of age have a poor prognosis when compared with older children. In an effort to identify biologic features of ALL in children less than 2 that might explain this difference, we performed extensive immunophenotypic and molecular genetic analyses on a series of patients. For comparison purposes patients were divided into four groups: CALLA- (CD10-) infants less than 2 years of age at diagnosis (n = 10), CALLA- children greater than 2 years of age at diagnosis (n = 10), CALLA+ infants (less than 2 years, n = 21) and CALLA+ children (older than 2 years, n = 21). No immunophenotyping differences in CALLA- or CALLA+ subgroups were identified when cases less than 2 were compared with cases greater than 2 years of age at diagnosis. The most interesting results were in the CALLA- group where 94% of the samples expressed the B cell antigen CD19 but 27% co-expressed CD7. Double labeling experiments confirmed leukemic blast cells co-expressed CD19 and CD7. The double-labeled cells represent either leukemic conversion of a precursor cell which has not yet committed to B or T cell lineage or aberrant expression of these antigens. Molecular genetic studies demonstrated that all samples, regardless of the patients' age or immunophenotype, had rearrangement of the Ig heavy chain gene. The most striking molecular results were in CALLA- patients; in patients less than 2 at diagnosis neither the beta- nor the gamma-chain gene of the T cell receptor (TCR) was rearranged, whereas DNA from 5 of 10 patients over the age of 2 demonstrated beta- or gamma-chain TCR gene rearrangements. The percentage of CALLA+ cases under the age of 2 years with rearrangements in TCR genes is less than that found in CALLA+ cases over the age of 2 years. The finding of no TCR rearrangements in CALLA- ALL and a decreased number of gamma-TCR rearrangements in CALLA+ cases under the age of 2 suggest that age may affect TCR gene rearrangements in lymphoblasts. The molecular differences in TCR gene rearrangements do not appear to correlate with the response to therapy.
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Recent advances in immunologic techniques have allowed the generation of monoclonal antibodies against antigens on tumor cells and their normal counterparts. Monoclonal antibodies useful for diagnosing and defining subtypes of acute leukemias and neuroblastoma have been prepared, although the prognostic significance of the subtypes defined by such antibodies remains to be determined. The usefulness of these reagents for therapeutic purposes either ex vivo, in association with autologous bone marrow transplantation, or in vivo, as carriers of cytotoxic agents, is currently under investigation.
Cytogenetic analyses of bone marrow cells were performed in 195 children with acute nonlymphocytic leukemia (ANLL) at diagnosis, as part of Childrens Cancer Study Group Study No. 251. Ninety-six patients (49%) exhibited clonal abnormalities, including trisomy 8 in 18 patients, t(8;21) in 11, t(15;17) in seven, loss of a sex chromosome in seven, monosomy 7 in seven, and the Philadelphia chromosome in four. Clonal abnormalities were found significantly more often in younger patients. Furthermore, recurring cytogenetic abnormalities tended to correlate with specific ages. For example, t(8;21) was associated significantly with children over four years of age, while -7 associated with overall loss of genetic material from the long arm of chromosome 7 (7q) and 11q- were associated significantly with younger children. Recurring chromosome abnormalities also correlated with specific ANLL histologic subtypes, such as t(8;21) with acute myelogenous leukemia and t(15;17) with acute promyelocytic leukemia. Presence or absence of cytogenetic abnormalities was compared with the ability of patients to achieve remission. Individuals exhibiting clonal abnormalities in bone marrow cells had an equally likely chance of achieving remission (74%) as those individuals with normal karyotypes (75%). Nonrandom chromosome abnormalities associated with a high induction success rate included +8 with a 94% induction success rate (P = .13) and t(8;21) with a 91% success rate (P = .46). Patients exhibiting the -7 abnormality associated with overall loss of 7q had a significantly less successful induction outcome, with only 28% achieving remission (P = .02); three of seven patients with t(15;17) died during induction therapy.
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A consecutive series of pseudophakic retinal detachments was statistically compared with a matched group of aphakic retinal detachments. Distribution of breaks, anatomic results, and final visual acuities were tabulated. Success in reattachment was equal in the two groups, but final visual acuities were better in the aphakic group. Emphasis was placed on the intraoperative ophthalmoscopic examination of pseudophakic eyes with compromised peripheral fundus visibility.
The administration of intrapleural bacillus Calmette-Guérin (BCG) alone and intrapleural BCG plus levamisole was compared to placebo in patients with resectable, non-small cell cancer of the lung. This report is based on an interim analysis of 100 eligible patients with a median followup of 245 days. No significant treatment effects are apparent at the present time, although current trends are consistent with an approximate 30% reduction in recurrence rate in patients receiving intrapleural BCG. There is little evidence to suggest that the addition of levamisole will contribute to this effect. A relationship between purified protein derivative conversion and tumor recurrence is apparent. Failure to manifest purified protein derivative conversion following administration of intrapleural BCG is associated with a significantly greater risk of tumor recurrence.
Immune reactions to tumor-specific and tumor-associated antigens have been demonstrated in animals with neoplasms with in vitro and in vovo techniques. Some of the antigens detected in vitro induce transplantation resistance in vivo, while others do not. Human neuroblastoma cells cultivated in vitro have been shown to possess common antigens to which lymphocytes from neuroblastoma patients react. Whether it is possible to augment the immune reactivity of patients with neuroblastoma to these common antigens and, if so, whether this heightened immune reactivity would have clinically beneficial effects are as yet unknown. These reactions are complex, involving both cellular and humoral mechanisms. The fact that one type of immune response can be detected to one type of antigen present in a tumor in vitro does not necessarily mean that the immune response is effective in vivo. Responses to other tumor antigens may be deficient, or the immune response may be depressed. This may be due to active suppression of and/or selective deficiencies in critical cell populations required for an augmented immune response; this possibility may be evaluated with techniques allowing for in vitro sensitization to tumor antigens.