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Biomedical subjects

R Clark

Publications and source records attributed to R Clark.

At least 217 records · Page 12Linked to original sources
PubMed1994

Parent-of-origin effects in multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases arising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in order to determine the parental origin of the mutated RET allele. In all cases the new mutation was of paternal origin. We observe a distortion of the sex ratio in both de novo MEN 2B patients and the affected offspring of MEN 2B transmitting males. These results suggests a differential susceptibility of RET to mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development.

Chromosomes, Human, Pair 10↗
PubMed1994

Lowering cholesterol levels in children and adolescents: a role for the occupational health nurse.

1. The atherosclerotic process begins in childhood and is influenced by genetics, diet, and lifestyle. Abnormal cholesterol levels are not uncommon in children. 2. The NIH Expert Panel on Blood Cholesterol Levels in Children and Adolescents recommends heart healthy eating for all children over the age of 2 years. This eating pattern is nutritionally adequate and lowers amounts of saturated fatty acids and total fat in the diet. 3. Children with a family history of premature coronary heart disease or elevated cholesterol levels should have a lipoprotein analysis to assess for abnormal levels. 4. The occupational health nurse has an important role in assisting families in which parents and children have lipid disorders.

Adolescent↗
PubMed1993

Adjuvant radiotherapy for early breast cancer: patterns of practice in Ontario.

OBJECTIVE: To determine the number of different radiation schedules used in Ontario to treat women with node-negative breast cancer after lumpectomy and axillary dissection. DESIGN: Retrospective survey. SETTING: Princess Margaret Hospital, Toronto, and regional centres of the Ontario Cancer Treatment and Research Foundation (in Hamilton, London, Ottawa, Windsor and Thunder Bay). PATIENTS: A total of 551 of 1624 consecutive patients with node-negative breast cancer having undergone lumpectomy and axillary dissection who were eligible but did not participate in the Ontario Clinical Oncology Group randomized clinical trial and who received adjuvant breast irradiation between April 1984 and February 1989. OUTCOME MEASURES: Schedules of radiotherapy received. RESULTS: Forty-eight different radiotherapy schedules were identified. Total doses ranged from 4000 to 6600 cGy and the number of fractions from 15 to 30. Several different schedules were preferred: 322 patients (58.5%) received 4000 cGy in 15 or 16 fractions to the whole breast over 3 weeks plus a local boost of 1250 cGy to the primary site in 5 fractions over 1 week; 66 patients (12.0%) received 4000 cGy in 15 or 16 fractions over 3 weeks to the whole breast plus a local boost of 1000 cGy to the primary site in 4 or 5 fractions over 1 week; and 63 patients (11.5%) received 5000 cGy in 25 fractions to the whole breast in 5 weeks, without a boost. CONCLUSIONS: The practice of adjuvant radiotherapy for early breast cancer in Ontario varies. The optimal radiation regimen for patients after lumpectomy should be determined through randomized clinical trials.

Breast Neoplasms↗
PubMed1993

Characterization of full-length neurofibromin: tubulin inhibits Ras GAP activity.

Full-length neurofibromin is a GTPase activating protein (GAP) for the Ras proto-oncogene product. Regulation of neurofibromin activity therefore has important implications for cell growth. Neurofibromin co-purifies with tubulin when expressed in insect cells. The interaction between neurofibromin and tubulin is sensitive to the microtubule depolymerizing agent colchicine. Neurofibromin GAP activity is inhibited even at low concentrations of tubulin. However, maximal inhibition of GAP activity is only approximately 70%, suggesting that the neurofibromin-tubulin complex retains residual GAP activity. This decreased activity is reflected by a 4-fold decrease in its affinity for Ras. A truncated mutant of neurofibromin with reduced sensitivity to tubulin localizes some tubulin-binding determinants to an 80 residue segment immediately N-terminal to the GAP-related domain. Since tubulin is an abundant protein in eukaryotic cells, the tubulin-neurofibromin interaction may regulate the Ras signalling pathway.

Amino Acid Sequence↗
PubMed1993

MDMA and memory: the acute and chronic effects of MDMA in pigeons performing under a delayed-matching-to-sample procedure.

The purpose of the present study was to examine the acute and chronic effects of (+/-)3,4-methylenedioxy-methamphetamine (MDMA) in pigeons responding under a delayed-matching-to-sample procedure with 0-, 3-, and 6-s delays. In the absence of drug, accuracy (percent correct responses) was inversely related to delay length. When administered pre-chronically, MDMA (0.32-5.6 mg/kg) generally decreased accuracy and response rates at doses of 3.2 mg/kg and above. Although humans report a distinct "hangover" when exposure to MDMA ends, performance of pigeons in the present study did not deteriorate when the chronic regimen ended, indicating an absence of behavioral dependence on the drug. Tolerance developed following chronic exposure to 3.2 mg/kg. In general, greater tolerance occurred at the 0-s delay than at longer delays. Although MDMA is reported to have neurotoxic effects, it does not inevitably produce long-lasting or cumulative behavioral impairment.

Animals↗
PubMed1993

Analysis of organophosphorus pesticides in rice by supercritical fluid extraction and quantitation using an atomic emission detector.

A rapid and sensitive method for the detection and quantitation of organophosphorus pesticides in rice has been developed. It uses extraction with methanol-modified supercritical carbon dioxide followed by quantitation by a gas chromatograph equipped with an atomic emission detector operating in the phosphorus and sulfur modes. Evaporative displacement of the collection solvent during the supercritical fluid extraction stage allows quantitation of the analyte down to 10 ng/g without any intermediate concentration steps.

Chromatography, Gas↗
PubMed1993

ATLS-based videotape trauma resuscitation review: education and outcome.

Trauma resuscitations (TRs) can be improved with ongoing videotape review. Unrecognized errors, delays, and system problems can be identified and corrected. Previous studies have demonstrated the importance of a short TR on survival and that videotape education can shorten TR time. Trauma resuscitation efficiency depends on details of TR including timing, organization, and appropriateness of care. Videotape education review monitors TR detail and improves TR efficiency by eliminating wasted time and treatment errors. Eight hundred eighty-three patients were evaluated. Group I included a control group prior to the incorporation of an ATLS based videotape review process. Group II included patients who were resuscitated after the educational review process was established. Subgroups based on ISS, direct OR transfer, DPL, and CT scan were also compared. Time and outcome were compared. Videotape educational review based on ATLS guidelines has improved TR efficiency. The benefits of ongoing videotape review include more efficient time utilization, correction of conceptual and technical errors, elimination of "wasted time," and improved survival.

Audiovisual Aids↗
PubMed1993

Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro.

Raf-1 is a serine/threonine kinase which is essential in cell growth and differentiation. Tyrosine kinase oncogenes and receptors and p21ras can activate Raf-1, and recent studies have suggested that Raf-1 functions upstream of MEK (MAP/ERK kinase), which phosphorylates and activates ERK. To determine whether or not Raf-1 directly activates MEK, we developed an in vitro assay with purified recombinant proteins. Epitope-tagged versions of Raf-1 and MEK and kinase-inactive mutants of each protein were expressed in Sf9 cells, and ERK1 was purified as a glutathione S-transferase fusion protein from bacteria. Raf-1 purified from Sf9 cells which had been coinfected with v-src or v-ras was able to phosphorylate kinase-active and kinase-inactive MEK. A kinase-inactive version of Raf-1 purified from cells that had been coinfected with v-src or v-ras was not able to phosphorylate MEK. Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. We conclude that MEK is a direct substrate of Raf-1 and that the activation of MEK by Raf-1 is due to phosphorylation by Raf-1, which is sufficient for MEK activation. We also tested the ability of protein kinase C to activate Raf-1 and found that, although protein kinase C phosphorylation of Raf-1 was able to stimulate its autokinase activity, it did not stimulate its ability to phosphorylate MEK.

Animals↗
PubMed1993

Differential regulation of cellular activities by GTPase-activating protein and NF1.

The regulation of the GTPase activity of the Ras proteins is thought to be a key element of signal transduction. Ras proteins have intrinsic GTPase activity and are active in signal transduction when bound to GTP but not following hydrolysis of GTP to GDP. Three cellular Ras GTPase-activating proteins (Ras-gaps) which increase the GTPase activity of wild-type (wt) Ras but not activated Ras in vitro have been identified: type I and type II GAP and type I NF1. Mutations of wt Ras resulting in lowered intrinsic GTPase activity or loss of response to cellular Ras-gap proteins are thought to be the primary reason for the transforming properties of the Ras proteins. In vitro assays show type I and type II GAP and the GAP-related domain of type I NF1 to have similar biochemical properties with respect to activation of the wt Ras GTPase, and it appears as though both type I GAP and NF1 can modulate the GTPase function of Ras in cells. Here we report the assembling of a full-length coding clone for type I NF1 and the biological effects of microinjection of Ras and Ras-gap proteins into fibroblasts. We have found that type I GAP, type II GAP, and type I NF1 show markedly different biological activities in vivo. Coinjection of type I GAP or type I NF1, but not type II GAP, with wt Ras abolished the ability of wt Ras to induce expression from an AP-1-controlled reporter gene. We also found that serum-stimulated DNA synthesis was reduced by prior injection of cells with type I GAP but not type II GAP or type I NF1. These results suggest that type I GAP, type II GAP, and type I NF1 may have different activities in vivo and support the hypothesis that while type I forms of GAP and NF1 may act as negative regulators of wt Ras, they may do so with differential efficiencies.

Animals↗
PubMed1993

Insulin-like growth factor-1 stimulation of lymphopoiesis.

We show that treatment of adult mice with recombinant human insulin-like growth factor 1 (rhIGF-1) induces striking modifications in lymphocyte number and function. 9-mo-old male mice received rhIGF-1 (4 mg/kg per d) or its excipient by subcutaneous infusion from osmotic minipumps for 7 or 14 d. Mice were weighed daily and bled at sacrifice; the spleen and thymus were harvested and single cell suspensions were made for analysis of cell phenotype and cell number. The responses of splenocytes to mitogens (concanavalin A, lipopolysaccharide, and pokeweed mitogen), alloantigens and dinitrophenyl ovalbumin were measured. After either 7 or 14 d of treatment, rhIGF-1 had an overall whole-body anabolic effect, resulting in increased body and organ weights with prominent increases in the weight of the spleen and thymus. Furthermore, the rhIGF-1 treated mice were normoglycemic but had reduced blood urea nitrogens, again reflecting the anabolic activity of rhIGF-1. The increased spleen and thymus weights were associated with a large increase in the number of lymphocytes in both organs. In addition to an increase in T cells, specifically CD4+ T cells, a dramatic increase in splenic B cells was also observed. This increase was accompanied by an enhanced responsiveness to dinitrophenyl ovalbumin resulting in increased immunoglobulin production. However, despite the increases in cellularity, there was a decrease in the in vitro responses of spleen cells to mitogens after 7 d of rhIGF-1 treatment. In contrast, treatment with rhIGF-1 for 14 d increased both the cell number and mitogenic responses of splenocytes suggesting that some time is required for the cells populating the peripheral organs to gain mitogenic responsiveness. It is clear from these data that rhIGF-1, at doses that have whole-body anabolic activity, can expand cell number in lymphoid tissue in a normal adult mouse. These dual effects of rhIGF-1, of increasing lymphocyte number and activity, indicate that, in a normal adult animal, rhIGF-1 can cause major changes in lymphoid tissues that are of potential benefit to the functioning of the immune system.

Animals↗
PubMed1993

Assessment of cardiovascular reactivity: a methodological overview.

The purpose of this article is to provide an overview of the rationale and methodological procedures for the assessment of cardiovascular reactivity. We hope that this introduction to the field will facilitate studies on cardiovascular reactivity in populations of Africa and encourage American-African collaborative projects.

Africa↗
PubMed1993

Multiple circumferential skin folds and other anomalies: a problem in syndrome delineation.

Three patients with multiple ring creases of the extremities are reported. Evidence to date points to aetiological heterogeneity. The skin folds may occur as an isolated abnormality or together with other patterns of malformation, making-up various syndromes that need to be further delineated. One type is associated with autosomal dominant inheritance. This striking abnormality usually resolves with time.

Abnormalities, Multiple↗
PubMed1993

The medical legal implications of following mammographic breast masses.

Delay in breast cancer diagnosis continues to account for the highest percentage of medical malpractice cases in the United States. A retrospective, computer-aided study was undertaken to investigate a number of parameters used in making medical-legal decisions in missed breast cancer cases. Over a 5-year period, 435 women with invasive breast cancers were registered at the Comprehensive University Breast Cancer Center. A close correlation between mammographic and final histologic size was verified (R = 0.74). In 5-mm increments, starting with a 1.0-mm tumor, there was an increasing percentage of positive nodes identified with increasing size of the tumor. Major percentage increases in frequency of positive nodes were noted at tumor sizes of 11 and 21 mm. This corresponded to an increasing number of recurrences and a decreasing 5-year disease-free survival (DFS) between consecutive 5-mm increments, although the differences were not significant. A multivariate regression analysis confirmed that the most important predictor of DFS was lymph node status (p = 0.0046) and not tumor size. After adjusting for lymph node status, tumor size was not significant. It is concluded that a period of observation, in which a breast cancer may increase in size is not substandard care since tumor size, after accounting for lymph node status is not significant at predicting DFS.

Breast↗