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Biomedical subjects

L Smith

Publications and source records attributed to L Smith.

At least 307 records · Page 17Linked to original sources
PubMed1994

Regulation of sodium-calcium exchanger by glucocorticoids and growth factors in vascular smooth muscle.

The findings presented in this paper indicate that glucocorticoids down-regulate Na(+)-Ca2+ exchanger (NCX) mRNA and activity in aortic myocytes. Serum and purified growth factors reversed NCX down-regulation. Dexamethasone, cortisol, or aldosterone decreased NCX activity by approximately 55% in 24 h. Dexamethasone was > 100 times more potent than aldosterone, indicating that a glucocorticoid receptor mediates the down-regulation of NCX activity. Dexamethasone decreased the NCX transcript to approximately 10% of the control level in 24 h without affecting plasma membrane Ca(2+)-ATPase transcripts. Fetal bovine serum increased NCX mRNA 10-fold in 4 h in dexamethasone-treated cells and restored full NCX activity in 16 h. The increase in NCX mRNA produced by serum required RNA and protein synthesis. Thrombin moderately increased NCX mRNA and partially restored NCX activity in dexamethasone-treated cells. Insulin, platelet-derived growth factor, or epidermal growth factor increased NCX mRNA similarly to thrombin. Tunicamycin, which inhibits N-linked glycosylation, prevented the restoration of NCX activity. These observations suggest that changes in the level of NCX mRNA mediate the opposing influences of glucocorticoids and growth factors on NCX activity. NCX induction by growth stimuli would increase the capacity for Ca2+ efflux and cycling between the cell and the environment.

Animals↗
PubMed1994

Increased injuries on night shift.

Concern over safety has resulted in legislation by, for example, the Commission of the European Union, to limit the number of hours worked at night. There is, however, no direct evidence that injuries are more frequent at night. We analysed all 4645 injury incidents reported for a year on a rotating three-shift system in a large engineering company where the a-priori accident risk appeared to be constant. The relative risk of sustaining an injury was 1.23 (95% CI 1.14-1.31) higher on the night shift than on the morning shift, which showed the lowest incidence. The type of work (machine versus self-paced) affected the pattern and nature of injuries; for self-paced work the relative risk of more serious injury on the night shift compared with the morning shift was 1.82 (1.30-2.34).

Accidents, Occupational↗
PubMed1994

Transfer and expression of the human multiple drug resistance gene in human CD34+ cells.

The human multiple-drug resistance (MDR1) gene has been transferred into human hematopoietic progenitors using retroviral gene transfer. Human bone marrow cells and isolated CD34+ cells isolated from marrow were exposed to growth factors interleukin-3 (IL-3), IL-6, and stem cell factor for 48 hours and then to two changes of MDR retroviral supernatants over the next 24 hours. Progenitor assays in methylcellulose at this time showed that 18% to 70% of BFU-E and 30% to 60% of CFU-GM contain the transferred MDR gene by polymerase chain reaction analysis. Up to 11.2% of the progeny of these cells express increased amounts of MDR glycoprotein on their surface by fluorescence-activated cell sorter (FACS) analysis. In addition, transduced cells are enriched in high MDR-expressing cells after exposure to taxol as assessed by FACS analysis, and by resistance of BFU-E to taxol (Bristol-Myers Squibb, Princeton, NJ). These studies indicate the feasibility of using MDR gene transfer as a means of enriching marrow for MDR-transduced cells. They also provide the basis of a phase 1 clinical protocol in patients with advanced cancers not involving the bone marrow for the use of MDR gene transfer as a means of protecting marrow cells, which normally express low levels of MDR, from the myelosuppressive effects of drugs like taxol.

Antigens, CD↗
PubMed1994

[Premature infants at double risk].

Premature infants risk neurological and neuropsychological sequelae. Usually, however, the outcome bears no strong relation to perinatal medical events. This study examines the outcome for 105 infants with very low birth weights up to age three years. The data suggest that the assessment of processing ability and parental socioeconomic status may provide a better foundation for detecting developmental delay than a medical main-effect model does. Children at "double risk", who had poor processing abilities and came from families with few social resources, were especially vulnerable to sequelae. The results have implications for intervention in the case of infants with low birth weights.

Child Development↗
PubMed1994

The effects of deletion of the amino-terminal helix on troponin C function and stability.

Troponin C has a 14-residue alpha-helix at the extreme amino terminus (the N-helix) which is absent in calmodulin. To learn the significance of this region in troponin C, residues 1-14 were deleted using site-directed mutagenesis. Analysis of the mutant troponin C (delta 14-TnC) showed that deletion of the N-helix did not alter the secondary structure of troponin C. Like wild type troponin C, it exhibited Ca(2+)-dependent conformational changes based on electrophoretic mobility and increases in alpha-helix content. The thermal stability of delta 14-TnC, however, was 20 degrees C lower than wild type troponin C in the presence or absence of divalent cations because of destabilization of the amino-terminal domain. To determine the functional consequences of the deletion, its ability to relieve troponin I and IT inhibition of the actomyosin ATPase was assayed. The results show that the mutant could relieve troponin I inhibition in the presence and absence of Ca2+ but could relieve troponin IT inhibition only to 45-50% of the wild type level, even at high concentrations. Also, the calcium affinity of the low affinity sites is reduced as evidence by the 2.4-2.8-fold increase in Ca2+ concentration required to achieve half-maximal activation of the MgATPase and calcium titration of the metal-induced conformation monitored by far UV circular dichroism measurements. In addition, the N-helix is required for the full conformational change to take place upon the binding of Ca2+, but not Mg2+, to the high affinity sites. The results indicate that the N-helix of troponin C is important for the stability of troponin C and may play a vital role in the Ca(2+)-switching mechanism.

Adenosine Triphosphatases↗
PubMed1994

Tumor activity confirmation and isodose curve display for patients receiving iodine-131-labeled 16.88 human monoclonal antibody.

A study was performed to correlate activity quantitation derived from external imaging with surgical tumor specimens in patients who received radiolabeled monoclonal antibody. Patients were given I-131 labeled 16.88 human antibody and scanned 3-5 times by planar and/or single photon emission computed tomography imaging methods to acquire time-dependent activity data in tumor and normal tissues. A method also was developed to assess the heterogeneous activity distributions in tumor samples. Postsurgical tumor and normal tissue samples were subdivided into volume elements (voxels) of 0.5 cm x 0.5 cm x 0.05 cm thick, which were used to verify the activity quantitation computed by the conjugate view method and to appraise the heterogeneity of radiolabeled antibody uptake. Through the use of the measured voxel activities, along with the time-dependent activity curves available for the entire tumor specimen derived from imaging, the cumulated activity and absorbed dose for each voxel were uniquely determined. The calculated total absorbed dose values were color-coded as isodose curves and overlaid on a correlated computed tomographic image. In two patients, activity quantitation derived from external imaging correlated with surgical tumor resection specimens within +/- 11%. The tumor-absorbed dose heterogeneity ratio was found to be as high as 10:1, with an average tumor to whole body absorbed dose ratio of 4:1. The mapping of activity with a histologic overlay showed a good correlation among activity uptake, the presence of tumor, and antigen expression on a microscopic scale. The resultant isodose curves overlaid on correlative computed tomographic scans represent the first images obtained with actual radiolabeled antibody biodistribution data in patients.

Absorption↗
PubMed1994

A mutant human histocompatibility leukocyte antigen DR molecule associated with invariant chain peptides.

From a human histocompatibility leukocyte antigen (HLA)-DR/DQ hemizygous, B lymphoblastoid progenitor, we isolated a cell line, 10.24.6, with a DR alpha missense mutation (96P-->96S), which results in an N-linked carbohydrate addition at position 94 in the DR alpha 2 domain. Several features of 10.24.6 cells suggest that the mutation disrupts normal intracellular formation of peptide/DR complexes. The mutant HLA-DR dimers, though expressed at the cell surface, lack the conformation of the mature, peptide-loaded class II molecules of the progenitor cell, as assessed by their loss of binding of certain antibodies and by the lack of stability in detergent (sodium dodecyl sulfate) solution. In addition, presentation of endocytosed antigen to HLA-DR-restricted T cells is defective in the mutant, but can be restored by transfection of a wild type DRA gene. Assays with synthetic peptides indicate that the 10.24.6 phenotype is not due to an intrinsic inability of the mutant DR molecules to bind peptides. Therefore, to directly evaluate peptide occupancy of the mutant molecules, we analyzed acid-eluted, HLA-DR-associated peptides. The predominant species from the 10.24.6 mutant is a nested set of invariant chain (Ii)-derived peptides that are undetectable in the DR eluate from progenitor cells. The region of DR alpha altered in the mutant molecules is thus implicated in normal formation of peptide/DR complexes. Further, the same set of Ii peptides associated with the DR molecules is present in the eluate from an antigen presentation mutant with a defect in an major histocompatibility complex (MHC)-linked gene. These results suggest that DR molecules in 10.24.6 and in certain presentation mutants are affected at the same or related steps in class II molecule biosynthesis, raising the possibility that class II molecules interact with an MHC-encoded accessory molecule during antigen presentation.

Amino Acid Sequence↗
PubMed1994

Mortality among fire fighters in metropolitan Toronto.

Fire fighters are exposed to substances which are recognized or suspected causal agents in cancer or heart disease. The purpose of this study was to determine whether or not fire fighters experience increased risk for any specific cause of death. A retrospective cohort study was conducted, with 5,995 subjects recruited from all six fire departments within Metropolitan Toronto. The mortality experience of the cohort was ascertained through computerized record linkage and compared to that of the male Ontario population specific to cause, age, and calendar period from 1950 through 1989. Average duration of follow-up was 21 years, and there were 777 deaths among the 5,414 males included in the analysis, giving an all-cause standardized mortality ratio of 95 (95% confidence interval: 88-102). Three specific causes of death exhibit statistically significant excesses (brain tumors, "other" malignant neoplasms, and aortic aneurysms). There are also slight increases in risk for some other sites of cancer, and for various diseases of the respiratory, circulatory, and digestive systems. This study is consistent with others in demonstrating that fire fighters experience increased risk of death from cancer of the brain, and in suggesting increased risk for various other causes of death.

Adolescent↗
PubMed1994

Mapping of the ACTH, MSH, and neural (MC3 and MC4) melanocortin receptors in the mouse and human.

The melanocortin peptides regulate a wide variety of physiological processes, including pigmentation and glucocorticoid production, and also have several activities in the central and peripheral nervous systems. The melanocortin receptor family includes the melanocyte-stimulating hormone receptor (MSH-R), adrenocorticotropic hormone receptor (ACTH-R), and two neural receptors, MC3-R and MC4-R. In the human these receptors map to 16q24 (MSH-R), 18p11.2 (ACTH-R), 20q13.2 (MC3-R), and 18q22 (MC4-R). The corresponding locations in the mouse are 8, 18, and 2; a variant for mapping MC4-R has not yet been identified. The data reported here also show that the neural MC3 receptor maps close to a disease locus for benign neonatal epilepsy in human and near the E1-2 epilepsy susceptibility locus in the mouse.

Animals↗
PubMed1994

Red cell autoantibody production in utero: a case report.

BACKGROUND: Autoantibody production by the fetus is thought to be extremely unlikely. Only one possible case of in utero autoantibody production against red cells by the fetus has previously been described. STUDY DESIGN AND METHODS: A case of apparent red cell IgG autoantibody production in utero is reported. RESULTS: This was established by a positive direct antiglobulin test in a newborn infant without evidence of maternal alloantibodies or autoantibodies. There was no evidence of clinically significant hemolysis at the infant's birth. After 6 weeks, his direct antiglobulin test remained strongly positive. The infant thrived without evidence of hemolysis, and after 6 months the direct antiglobulin test was negative. CONCLUSION: The production of autoantibodies to red cells in utero is possible, though rare. This did not result in apparent hemolysis in this patient.

ABO Blood-Group System↗
PubMed1994

Phase I and pharmacokinetic studies of topotecan administered as a 72 or 120 h continuous infusion.

Topotecan (SK&F 104864-A, NSC 609699) is a water-soluble, semi-synthetic analog of camptothecin which is an inhibitor of topoisomerase I. Since topoisomerase I is cell specific for S phase, we undertook a phase I study to determine the maximum tolerated dose and toxicities of continuous infusion (CI) topotecan. This phase I trial first explored a 5 day CI every 21 day schedule. Doses of topotecan included 0.17, 0.34 and 0.68 mg/m2/day. Fourteen patients [median age 60; median performance status (PS) of 1] with refractory malignancies received 59 courses of drug. Hematologic toxicities occurred only at the highest dose level; NCI grade 3-4 granulocytopenia and thrombocytopenia occurred in 4/8 and 3/8 patients, respectively. The protocol was amended to a 3 day infusion in an effort to ameliorate toxicity and obtain greater dose intensity (DI). Doses of 0.68, 0.85, 1.05, 1.3 and 1.6 mg/m2/day were evaluated. Thirty-two patients (median age 60; median PS of 1) received a total of 115 courses. The major toxicity seen was hematologic with 9/32 and 5/32 patients demonstrating grade 3-4 granulocytopenia and thrombocytopenia, respectively. Non-hematologic toxicities were mild (grade 1-2) in the two schedules and included nausea, vomiting, fatigue and alopecia. At the maximum tolerated dose (MTD) on the 5 day schedule, patients received 0.87 mg/m2/week, whereas they received 1.08 mg/m2/week at the MTD on the 3 day schedule (24% increase in relative dose intensity). A steady-state plasma lactone concentration of 5.5 mg/ml of topotecan was achieved at the phase II recommended dose of 1.6 ng/m2/day as a 3 day continuous infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Very low birth weight infants (< 1501 g) at double risk.

This study examines the outcome at ages 2 and 3 years of very-low-birth-weight infants (N = 105) at double risk. Double risk was defined with reference to Fagan's model of intelligence. According to this model, cognitive-processing ability and culturally provided information produce knowledge. The Fagan Test of Infant Intelligence was used to assess processing ability, whereas parental socioeconomic status (SES) was used as an indicator of available information. Knowledge was measured by means of well-known psychometric tests of young children's abilities. Children at double risk were consistently delayed with respect to knowledge of intellectual skills and language as compared with children who were not at double risk. The data suggest that the assessment of processing ability and parental SES may provide a better foundation for detecting developmental delay than does a medical main-effect model.

Brain Damage, Chronic↗
PubMed1994

The pitch of electrically presented sinusoids.

A patient who uses the Ineraid cochlear implant, and who has hearing thresholds less than 50 dB HL for frequencies under 500 Hz in his nonimplanted ear, was asked to match the pitch of low-frequency signals presented to his two ears. The patient produced pitch matches, for frequencies of 125, 200, and 300 Hz presented to his most apical electrode, that were slightly higher than the reference frequency. When signals of fixed frequency were presented to electrodes located in successively more basal cochlear locations, pitch increased in an orderly fashion--an average of 57 Hz (range = 31-87 Hz) for each change in electrode location.

Auditory Threshold↗
PubMed1994

Effects on health of a change from a delaying to an advancing shift system.

OBJECTIVES: Shift work can lead to a range of problems for some people that seem to result from the disturbance of the circadian system, and can broadly be classified as: disturbances of sleep, impaired physical and psychological health, and disturbed social and domestic life. The main attempt to try to reduce these problems has focused on the design of the shift system, and the identification of the most problematic features of the shift system. One such feature is believed to be the direction of shift rotation. Systems that advance are thought to be more problematic than those that delay. The present study examines the change in the direction of shift rotation from a delaying to an advancing system on health and wellbeing. METHODS: Self reported measures of tolerance to shift work were taken two months before and six months after the change. These included sleep difficulties, gastrointestinal problems, psychological ill health, chronic fatigue, social and domestic disruption, job satisfaction, and satisfaction with the shift system. RESULTS: The change from a delaying to an advancing system resulted in an increase in sleep difficulties between successive afternoon shifts, but a decrease in social disruption. There was little evidence of impaired health on the advancing compared with the delaying system. CONCLUSIONS: The increase in sleep difficulties was thought to result from the undesired adaptation of the circadian system to night work, as a result of the afternoon shifts now following a series of night shifts, whereas previously they followed a series of morning shifts. The decrease in social disruption was thought to result from the specific sequence of the shifts and the discontinuous nature of the shift system, in particular, the long week-end off every third week. Lack of reported health related differences are explained in terms of the relatively unharmful nature of the shift system in question, and the relatively short time span over which the study was conducted.

Adult↗