Biomedical subjects
Publications and source records attributed to E Baker.
Multiple drug resistance has been shown to be associated with amplification/increased expression of a gene designated MDR. The localization of one member of the MDR gene family, MDR1, to the long arm of chromosome 7 by in situ hybridization is reported.
UNLABELLED: In a retrospective study on 167 ovarian cancer patients the presenting symptom was defined via anamnesis. This parameter was correlated to others characterising the cancer and the patient: age, parity, menopause, stage, extent of operation, tumor residue, postoperative therapy, induction of remission and several morphological data. The prognostic significance was analysed using Hazard-models (Cox 1972, Carter 1983) and contingency tables. RESULTS: The presenting signs and symptoms were: atypical bleeding in 44 patients, pain in 75 patients and other signs in 48 patients. These signs and symptoms were significantly correlated with tumor residue, and were more frequently seen in mucinous and endometrioid carcinomas. There were no significant correlations to the other examined parameters, but there was a trend for patients with atypical bleedings to be diagnosed at early stages and their survival prognosis was significantly (p less than 0.01) better compared with that for patients with pain or other presenting signs or symptoms.
A simple, reliable method for the induction of folate-sensitive fragile sites, including the fragile X, in fibroblasts is described. The method involves only the addition of 600 mg/l thymidine to cultures 24 hrs before they are harvested.
The hepatocytes form part of the iron storage system of the body. In serving this function they exchange iron bidirectionally with the plasma iron transport protein transferrin (Tf). Iron uptake involves binding of the iron-Tf complex to cell membrane receptors and endocytosis into low-density vesicles, where the iron is released from its carrier protein before the Tf is returned undegraded to the extracellular medium. Two components of the iron uptake process can be distinguished, one saturable at low concentrations of diferric Tf and the other not saturable by increasing the Tf concentration. Both result in net uptake of iron by the cells and both appear to depend on specific binding to the cell membrane and endocytosis. Hepatocytes also obtain some iron from haptoglobin-hemoglobin, heme-hemopexin, and ferritin (Fn), in each case by interaction with membrane receptors and endocytosis. Within the cell iron from all sources enters one or more transit pools, where it is available for exchange with the iron storage protein Fn, and for release from the cell to plasma Tf or to iron chelators administered therapeutically or experimentally. Chelator-mediated iron release occurs to the plasma and/or to the bile, depending on the nature of the chelator and the source of the iron.
Pyridoxal isonicotinoyl hydrazone (PIH) and several analogues were synthesized and assessed in the rat hepatocyte culture for their potential in iron chelation therapy. Pyridoxal isonicotinoyl hydrazone and pyridoxal benzoyl hydrazone were as effective as desferrioxamine (DFO) in reducing both net uptake of rat transferrin-59Fe and incorporation into ferritin by hepatocytes. Dialysis studies showed that this was due to a cellular action and not to the extracellular chelation of transferrin-bound 59Fe. The analogues of PIH were more effective in mobilization studies than PIH and DFO, releasing more 59Fe from ferritin as well as from the stroma-mitochondrial membranes in hepatocytes prelabelled using transferrin-59Fe. Chelator action was dependent on incubation time, concentration, temperature and lipophilicity. Pyridoxal benzoyl hydrazone, the most effective iron chelator, was also the most lipophilic, suggesting that access to cellular iron compartments as well as iron-binding affinity is important in effective iron chelation.
Folate sensitive fragile sites on human chromosomes have been found to be inducible in cultured lymphocytes by high levels of thymidine but not by high levels of BrdU. The biochemical interpretation of events leading to fragile site expression has been revised since it is now clear that low levels of either thymidylate or deoxycytidine triphosphate will result in this phenomenon. A model for the DNA at a fragile site, composed of alternating repeating polypurine/polypyrimidine sequences is proposed.
Two new classes of common fragile site seen in chromosomes from blood lymphocyte cultures are reported. The first class is induced in bands 1q42 and 19q13 by 5-azacytidine (5-AZA). Maximum induction of these fragile sites occurs when the 5-AZA is added 5-8h prior to harvest. The second class is induced in bands 6q13, 9p21, and 10q21 by bromodeoxyuridine (BrdU). In this instance maximum induction occurred if the BrdU was added 4-6h prior to harvest. The known fragile sites, both rare and common, are summarised.
Characteristic computed tomographic, clinical and pathologic features are discussed in two patients with cerebral amyloid angiopathy (CAA) associated with massive intracerebral hemorrhage. Amyloid angiopathy should be considered in any elderly patient in whom intracerebral hemorrhage occurs at an atypical site. Cortical involvement, multiplicity of hemorrhages, bilaterality, and repeated episodes should further arouse diagnostic suspicion. Clinical management is confined to prevention of systemic hypertension.
For 230 patients with common epithelial ovarian cancer, the prognostic impact of age was examined. Statistical analysis was done using proportional hazard models, 3- and 5-year survival rates and median survival of stratified groups, and the Kaplan-Meier mean. Taking the age-adjusted mortality into account, the prognosis of the older patients was significantly worse. This effect depended primarily on early mortality (survival time less than 2 months). A comparative analysis was made of the prognostic factors age, grade, and stage, taking into account the correlation between factors. This analysis showed that, for our series, age was of lesser prognostic significance than grading, and both of these were of much less prognostic importance than staging.
UNLABELLED: Tissue slides of 230 epithelial ovarian cancers were examined by two different pathologic teams to determine the following details: histological pattern, grade of polymorphy, mitotic index, density of chromatin, presence of nuclei and macronuclei, lymphocytic infiltration, psammoma bodies, and necrosis. For statistical evaluations the data were presented together with stage, age and survival times in form of an information vector for each of the 230 patients and analysed using hazard-models (Cox 1972, Carter 1983) and contingency tables. RESULTS: The agreement between the 2 pathologic teams was good. There were many interrelated histological concomitants, such as polymorphy and chromatin density, and as nuclei and macronuclei. Necrosis was relatively independent. Significant effects on prognosis could be demonstrated for polymorphy, chromatin density, mitotic index, histologic pattern, (macro)nuclei. Polymorphy was the best histological prognostic indicator and, together with necrosis, produced the best prognostic grading system.
The regulation of transferrin and iron release from the liver was studied using adult rat hepatocytes in primary monolayer culture. The cells were prelabeled by incubation with rat transferrin doubly labeled with iodine-125 and iron-59. Approximately 50% of the 125I-transferrin but only 10% of the iron-59 taken up by the cells was released during reincubation for 24 h. Less than 10% of the refluxed transferrin was catabolized as indicated by the protein-free iodine-125 values. These results suggest that at least part of iron uptake by hepatocytes is mediated by the reversible binding of transferrin in a manner comparable with erythroid cells and placenta. However, several iron chelators mobilized hepatic iron, in contrast to erythroid cells. Apotransferrin and desferrioxamine released a maximum of about 20% iron-59 with little effect on transferrin binding. A greater proportion of the iron-59 was available for chelation after shorter uptake times (1-2 h) than longer times. Hence, there are at least three iron compartments in hepatocytes in culture: rapidly refluxing iron that may be transferrin bound, a fixed pool, and a chelatable pool that may represent iron in transit between plasma transferrin and ferritin.
The mechanism of action of the hydroxamate iron chelators desferrioxamine (DFO), rhodotorulic acid (RHA) and cholylhydroxamic acid (CHA) was studied using rat hepatocytes in culture. Each chelator affected both the uptake and, to a much smaller extent, the release of transferrin-125I-59Fe from the cells. All chelators reduced the 59Fe uptake and incorporation into ferritin in a concentration-dependent manner. Uptake of 59Fe into the membrane (stromal-mitochondrial) fraction was also decreased by DFO and RHA but increased by CHA. Transferrin-125I binding was reduced slightly by DFO and RHA and increased by CHA. All chelators released 59Fe transferrin-125I from hepatocytes prelabelled by incubation with rat transferrin-125I-59Fe and washed before reincubation in the presence of the chelators. DFO decreased membrane 59Fe but had little effect on ferritin-59Fe. RHA decreased 59Fe in both membrane and ferritin fractions. CHA decreased hepatocyte-59Fe but increased 59Fe in the hepatocyte membrane fraction. Higher concentrations of the chelators had little further effect on 59Fe release but promoted transferrin-125I release from hepatocytes. All chelators appeared to act on kinetically important iron pools of limited size and hence are likely to be most effective when given by continuous infusion rather than bolus injection.
Nicotinates, pantothenates, riboflavin, vitamins B6 and B12' free (acetyl) and total (free and bound) choline, biopterin, thiamin, biotin, methylated and nonmethylated folates in frontal, temporal, precentral, postcentral, and occipital cortex, thalamus, cerebellum, pons, basal ganglia, and substantia nigra were estimated. Nicotinates are significantly more concentrated in basal ganglia and thalamus than pons. Nonmethylated folate content is not significantly varied in brain segments; the pons contains more methylated folate. Riboflavin content is higher in the basal ganglia and temporal cortex than frontal cortex. Biotin is concentrated in pons and basal ganglia. Thiamin concentration is less in the postcentral cortex than the thalamus and substantia nigra. Biopterin is significantly higher in substantia nigra and basal ganglia than the other brain segments. Total choline content is high in substantia nigra, pons, and thalamus; free (acetyl) choline is significantly elevated in basal ganglia. B12 content is less concentrated in the cortex segments. B6 is highly concentrated in the basal ganglia. Pantothenate content is elevated in pons when compared to the various cortex segments and cerebellum.
This study was aimed at evaluating the self-control behaviors of hyperactive (HA) and nonhyperactive ( NHA ) first-grade pupils under conditions of repeated failure on a previously learned concept formation task. Subjects were divided into HA and NHA groups on the basis of their scores on the Conners (1969) Teacher Rating Scale. During the training stage of the experiment the children learned a concept formation task under a schedule of contingent positive reinforcement. In the test stage they performed the same task but under a negative noncontingent reinforcement schedule. The results revealed no differences in initial rate of learning the task between the groups. After the introduction of the negative noncontingent reinforcement schedule, however, the HA group showed a marked decrease in the use of effective problem-solving strategies. The HA children's performance on the concept formation task was accompanied by the emission of negative self-evaluations and solution-irrelevant statements. The NHA group used significantly more statements showing useful goal-directed cognitive mediations than the HA children. The results suggested that HA children may have deficits in self-control skills.
The effectiveness of a 20 session cognitive-behavioral approach to substance abuse prevention was tested on seventh grade students (n = 1,311) from 10 suburban New York junior high schools. The prevention strategy attempted to reduce intrapersonal pressure to smoke, drink excessively, or use marijuana by fostering the development of general life skills as well as teaching students tactics for resisting direct interpersonal pressure to use these substances. Additionally, this study was designed to compare the relative effectiveness of this type of prevention program when implemented by either older peer leaders or regular classroom teachers. Results indicated that the prevention program had a significant impact on cigarette smoking, excessive drinking, and marijuana use when implemented by peer leaders. Furthermore, significant changes were also evident with respect to selected cognitive, attitudinal, and personality predisposing variables in a direction consistent with non-substance use. These results provide further support for the efficacy of a broad-spectrum smoking prevention strategy and tentative support for its applicability to the prevention of other forms of substance abuse.
Hepatic iron and transferrin metabolism was studied using rat transferrin doubly labeled with 59Fe and 125I and adult rat hepatocytes in primary monolayer culture. Iron uptake was linear for 48 h while transferrin uptake was biphasic. Total transferrin and iron uptake increased in a linear manner as the transferrin concentration was raised up to at least 130 microM. This indicates that transferrin and iron are taken up primarily by nonspecific processes, possibly by endocytosis (absorptive or fluid) and by the action of iron chelators. However, some evidence indicated the presence of receptors for diferric transferrin on hepatocytes: the molar ratio of iron to transferrin accumulation increased with incubation time, transferrin and iron uptake was proportional to the iron saturation of the transferrin, apotransferrin displaced bound apotransferrin but had no effect on the binding of diferric transferrin, and the molar ratio of iron to transferrin uptake decreased with increasing transferrin concentrations.
Seventh graders (N = 239) from two New York City junior high schools were involved in a 9-month study testing the efficacy of a broad-spectrum approach to prevention of alcohol misuse. The two schools were randomly assigned to experimental and control conditions. The seventh graders in the treatment school received a 20-session program targeted at the major cognitive, attitudinal, social and personality factors believed to promote the early stages of alcohol misuse. The program contained material on decision making, coping with anxiety, general social skills and assertiveness (including techniques for resisting peer pressure to drink) as well as information about the short- and long-term consequences of alcohol misuse. Complete pretest, posttest 1 and posttest 2 data were collected from 167 students (89 women). A significantly greater proportion of the students in the experimental group reported less frequent drinking (p less than .02), less drinking per occasion (p less than .04), and less frequent episodes of drunkenness (p less than .01) than the students in the control group.