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Biomedical subjects

M Smith

Publications and source records attributed to M Smith.

At least 685 records · Page 38Linked to original sources
PubMed1993

Glaucoma in the immediate postoperative period after penetrating keratoplasty.

In a prospective study 155 consecutive patients undergoing penetrating keratoplasty were examined for postoperative increase in intraocular pressure to determine the frequency and duration of intraocular pressure spikes, risk factors, and response to treatment. Patients were maintained on preoperative glaucoma medications except miotics. Additional medications to lower intraocular pressure perioperatively were not given. Intraocular pressure was measured two to five hours, one day, and one week postoperatively. An intraocular pressure of 30 mm Hg or greater was considered an increase in pressure and was treated according to a standardized protocol. The results were analyzed by procedure as well as by variables commonly perceived to be associated with intraocular pressure increase (history of glaucoma, use of hyaluronate, lysis of the synechiae, or vitrectomy at the time of the operation). Overall, intraocular pressure increases in the early postoperative period occurred in 18 of 155 patients (12%). Pressure increases occurred in ten of 48 patients (21%) with a history of glaucoma; five of 24 patients (21%) undergoing combined penetrating keratoplasty, extracapsular cataract extraction, and posterior chamber intraocular lens implantation; and ten of 43 patients (23%) undergoing vitrectomy at the time of penetrating keratoplasty.

Cataract Extraction↗
PubMed1993

pp60src is an endogenous substrate for calpain in human blood platelets.

Calpain is distributed ubiquitously in virtually every tissue (Croall, D. E., and DeMartino, G. N. (1991) Physiol. Rev. 71, 813-846), but its physiological role remains to be determined. The identification of its natural endogenous substrates would be of great interest. Since pp60src, a major tyrosine kinase in platelets, is known to be easily cleaved during purification from cells (Feder, D., and Bishop, J. M. (1990) J. Biol. Chem. 265, 8205-8211), we examined the possibility that it is an endogenous substrate of calpain. In the whole cell lysate from resting platelets, which was analyzed by Western blotting with monoclonal antibody 327, we found pp60src almost exclusively in a 60-kDa form, with a trace of 52-kDa form. Addition of A23187 (a calcium ionophore) or dibucaine, which are known to be activators of platelet calpain (Croall and DeMartino, 1991; Fox, J. E., Reynolds, C., Morrow, J. S., and Phillips, D. R. (1987) Blood 76, 2510-2519; Fox, J. E., Austin, C. D., Boyles, J. K., and Steffen, P. K. (1990b) J. Cell Biol. 111, 483-493), caused dose- and time-dependent cleavage of actin-binding protein and p235 protein (talin). At the same time, loss of the 60-kDa species of pp60src and generation of the 52-kDa (occasionally seen as doublets) and 47-kDa species were detected by the Western blotting. In platelets aggregated by 1 unit/ml thrombin, apparently identical cleavage products were found. The cleavage of pp60src was inhibited by calpeptin (20 microM), an inhibitor of calpain (Tsujinaka, T., Kajiwara, Y., Kambayashi, J., Sakon, M., Higuchi, N., Tanaka, T., and Mori, T. (1988) Biochem. Biophys. Res. Commun. 153, 1201-1208; Tsujinaka, T., Ariyoshi, H., Uemura, Y., Sakon, M., Kambayashi, J., and Mori, T. (1990) Life Sci. 46, 1059-1066; Fox, J. E., Clifford, C. C., and Austin, C. D. (1990) Blood 76, 2510-2519; Fox, J. E., Austin, C. D., Boyles, J. K., and Steffen, P. K. (1990) J. Cell. Biol. 111, 483-493; Fox, J. E., Austin, C. D., Clifford, C. C., and Steffen, P. K. (1991) J. Biol. Chem. 266, 13289-13295). Addition of EGTA (3 mM) to the extracellular media completely inhibited the cleavage of actin-binding protein, talin, and pp60src in response to A23187 (1 microM). Intact pp60src was distributed in both cytosolic and particulate (membrane) fractions. Cleaved species were found exclusively in the cytosolic fraction. pp60src-associated enolase kinase activity was reduced. Thus, pp60src is an endogenous substrate for calpain, the cleavage of which may have regulatory effects on the kinase.

Antibodies, Monoclonal↗
PubMed1993

Redesign of the interior hydrophilic region of mitochondrial cytochrome c by site-directed mutagenesis.

Heme propionate-7 in cytochrome c is an ionizable group located in a region of the protein that is inaccessible to bulk solvent. Electrostatic stabilization of this functional group appears to be achieved through interaction of heme propionate-7 with several amino acid residues that occur within hydrogen-bonding distance of it. To investigate the functional and spectroscopic roles of the amino acid residues that contribute to the immediate environment of heme propionate-7, the following variant forms of yeast (Saccharomyces cerevisiae) cytochrome c have been prepared and characterized by electrochemical and spectrochemical analyses: Arg38Ala, Tyr48Phe, Ala38Phe, Tyr48Phe/Trp59Phe, and Arg38Ala/Tyr48Phe/Trp59Phe. For each protein, the dependence of midpoint reduction potential and NMR spectrum on pH was determined, and the UV (250-450 nm) circular dichroic (CD) spectrum was measured. All of the variant proteins exhibited decreased reduction potentials with the greatest difference (-65 to -70 mV) exhibited by the multiply mutated proteins. The electrostatic properties of the variant proteins as reflected by the oxidation-state dependence of the His-39 pKa value were similar to those of the wild-type protein. Previous indirect assignments of minima in the CD spectrum of cytochrome c at 282 and 289 nm to Trp-59 are confirmed by spectra of the variant cytochromes in which this residue is replaced by Phe. The present results establish that the electrochemical effects of eliminating hydrogen-bonding interactions with heme propionate-7 are not additive and that the functional modulation of cytochrome c through regulation of the heme propionate-7 dielectric environment involves a complex combination of solvation effects and electrostatic or hydrogen-bonding interactions.

Base Sequence↗
PubMed1993

Children and cancer. A perspective from the Cancer Therapy Evaluation Program, National Cancer Institute.

The Cancer Therapy Evaluation Program, National Cancer Institute (CTEP, NCI) strongly supports the role of controlled clinical trials in improving the care of children with cancer, and particularly the central role that the pediatric Cooperative Groups play in this process. Trends that threaten the ability to perform these trials include the increasingly limited financial resources available for clinical investigations and the sentiment within some circles that controlled clinical trials may be inappropriate for ethical reasons. The inherent risks of accepting a new therapy without rigorous comparison to existing therapy strongly support the need for randomized trials with adequate accrual to answer important therapeutic questions in a timely and reliable fashion. Retrospective analysis of multiple clinical trials is one method for identifying compelling hypotheses to be tested prospectively. Using this method, we have demonstrated the association between doxorubicin dose intensity and positive response and outcome for patients with Ewing sarcoma and osteosarcoma, thereby providing direction for the selection of important therapeutic questions to be addressed in future clinical trials for these malignancies.

Antineoplastic Agents↗
PubMed1993

Reductions in turnover, accidents, and absenteeism: the contribution of a pre-employment screening inventory.

This study examined the rates of turnover, work-related accidents, and unauthorized absence among two contrasted groups of employees in a mid-sized manufacturing environment. For the calendar year 1989, comparative rates on each variable were obtained for a group hired prior to the inclusion of a pre-employment inventory in the Company's selection process and a group hired subsequently. Results indicate that rates of turnover, accidents, and unauthorized absence were all significantly lower in the group hired subsequent to inclusion of the pre-employment screening inventory. Some possible design artifacts and cost-benefit implications are discussed.

Absenteeism↗
PubMed1993

Restricter anorexia nervosa in a thirteen-year-old sheltered Muslim girl raised in Lahore, Pakistan: developmental similarities to westernized patients.

An academically perfectionistic and interpersonally compliant 13-year-old girl raised in a traditional, sheltering Muslim home in Lahore, Pakistan developed restricter anorexia nervosa in the context of being teased about her weight by her closest friend and younger brother, and in a context of family weight preoccupation. Similarities to current pathogenetic hypotheses among Western adolescents are discussed.

Adolescent↗
PubMed1993

A sequence pattern for peptides presented to cytotoxic T lymphocytes by HLA B8 revealed by analysis of epitopes and eluted peptides.

HLA B8-restricted cytotoxic T lymphocytes (CTL) specific for influenza A virus were generated and shown to recognize the nucleoprotein (NP). The dominant epitope was mapped using recombinant vaccinia viruses that expressed fragments of the NP and then synthetic peptides based on the NP amino acid sequence. The peptide 380-393 was first identified and further refined; it was shown that the glutamic acid at position 380 was essential for recognition by CTL and that the nonamer 380-388 was the optimum peptide. Six HLA B8-positive influenza immune donors that we have tested respond to this peptide as part of their influenza-specific CTL response. The amino acid sequence of the peptide epitope was compared to six other known virus peptides known to be restricted by HLA B8 and a sequence homology was identified, which predicted nonamer and octamer epitope sequences. Probable anchor residues were identified at peptide residues 3 (lysine/arginine), 5 (lysine/arginine) and 9 (leucine/isoleucine). Support for this pattern came from sequencing peptides eluted from purified HLA B8 molecules, where lysines were predominant at positions 3 and 5. One of the predicted epitope peptides was made and shown to be recognized by specific CTL. These and the two others were shown to compete with NP 380-388 for binding to HLA B8. A model was made of the HLA B8 molecule and negatively charged pockets predicted, which could accommodate the positively charged side chains of the peptide anchor residues.

Amino Acid Sequence↗
PubMed1993

Calpain-catalyzed cleavage and subcellular relocation of protein phosphotyrosine phosphatase 1B (PTP-1B) in human platelets.

The non-transmembrane phosphotyrosine phosphatase 1B (PTP-1B) is an abundant enzyme, normally localized to the cytosolic face of the endoplasmic reticulum via a C-terminal targeting sequence. We have found that agonist-induced platelet activation results in proteolytic cleavage of PTP-1B at a site upstream from this targeting sequence, causing subcellular relocation of its catalytic domain from membranes to the cytosol. PTP-1B cleavage is catalyzed by the calcium-dependent neutral protease calpain and is a general feature of platelet agonist-induced aggregation. Moreover, PTP-1B cleavage correlates with the transition from reversible to irreversible platelet aggregation in platelet-rich plasma. Engagement of gpIIb-IIIa is necessary for inducing PTP-1B cleavage, suggesting that integrins regulate tyrosine phosphatases as well as tyrosine kinases. PTP-1B cleavage is accompanied by a 2-fold stimulation of its enzymatic activity, as measured by immune complex phosphatase assay, and correlates with discrete changes in the pattern of tyrosyl phosphorylation. Cleavage and subcellular relocation of PTP-1B represents a novel mechanism for altering tyrosyl phosphorylation that may have important physiological implications in cell types other than platelets.

Blood Platelets↗
PubMed1993

Fibronectin promotes the elongation of microvessels during angiogenesis in vitro.

Fibronectin is a component of the extracellular matrix of developing microvessels whose role in angiogenesis is poorly understood. This study evaluated the effect of plasma fibronectin on angiogenesis in serum-free collagen gel culture of rat aorta. Aortic explants embedded in collagen gels generated microvascular outgrowths. Fibronectin incorporated in the collagen gel promoted a selective dose-dependent elongation of the newly formed microvessels without stimulating vascular proliferation. The fibronectin-treated microvessels were longer due to a proportional increase in the number of microvascular cells. However, fibronectin had no effect on microvascular DNA synthesis and mitotic activity. Fibronectin stimulated microvascular length also in cultures in which mitotic activity was suppressed and angiogenesis was markedly reduced by pretreating the aortic explants with mitomycin C. The synthetic peptide Gly-Arg-Gly-Asp-Ser (GRGDS), which competes for the binding of fibronectin to its cell receptors and inhibits the adhesion of endothelial cells to substrates, arrested the elongation of developing microvessels causing regression and inhibition of angiogenesis. Conversely, Gly-Arg-Gly-Glu-Ser (GRGES), which lacks the RGD sequence, had no inhibitory effect. These data support the hypothesis that fibronectin promotes angiogenesis and suggest that developing microvessels elongate in response to fibronectin as a result of an adhesion-dependent migratory recruitment of endothelial cells that does not require increased cell proliferation.

Amino Acid Sequence↗
PubMed1993

Dependence of induction of osteocalcin gene expression on the presence of wild-type p53 in a murine osteosarcoma cell line.

The p53 gene undergoes rearrangement in a high percentage of osteosarcomas, resulting in loss of its expression. A p53-null murine osteosarcoma cell line F6 was transfected with either a wild-type or a mutant p53 gene. Stably transfected cell lines were obtained, and their differentiation capabilities were compared in vitro with the parental cell line. Alkaline phosphatase and osteocalcin expression were measured as early and late differentiation markers, respectively. Induction of alkaline phosphatase expression was not affected by the presence of either p53 gene, whereas osteocalcin expression was seen in cells containing the wild-type p53 gene but not in the parental p53-null or mutant-expressing cell lines. That the induction of osteocalcin was intrinsically dependent on the presence of wild-type p53 was also indicated by the use of a temperature-sensitive Val 135 p53 mutant at 32 degrees C; predominant expression of p53 in the wild-type conformation resulted in osteocalcin expression. While the wild-type p53 gene could suppress tumor formation in vivo, the tumors expressing the mutant p53 gene grew two to three times as large as the tumors that did not express p53. Therefore, the absence of end-point differentiation in bone due to p53 rearrangements may contribute to the maintenance of the tumorigenic phenotype in osteosarcomas.

Alkaline Phosphatase↗
PubMed1993

Feast and famine: critical role of glucocorticoids with insulin in daily energy flow.

The hypothesis proposed in this review is that normal diurnal rhythms in the hypothalamic-pituitary-adrenal (HPA) axis are highly regulated by activity in medial hypothalamic nuclei to effect an interaction between corticosteroids and insulin such that optimal metabolism results in response to changes in the fed or fasted state of the animal. There are marked diurnal rhythms in function of the HPA axis under both basal and stress conditions. The HPA axis controls corticosteroid output from the adrenal and, in turn, forward elements of this axis are inhibited by feedback from circulating plasma corticosteroid levels. Basal activity in the HPA axis of mammals fed ad lib peaks about 2 h before the peak of the diurnal feeding rhythm, and is controlled by input from the suprachiasmatic nuclei. The rhythm in stress responsiveness is lowest at the time of the basal peak and highest at the time of the basal trough in the HPA axis activity. There are also diurnal rhythms in corticosteroid feedback sensitivity of basal and stress-induced ACTH secretion which peak at the time of the basal trough. These rhythms are all overridden when feeding, and thus insulin secretion, is disrupted. Corticosteroids interact with insulin on food intake and body composition, and corticosteroids also increase insulin secretion. Corticosteroids stimulate feeding at low doses but inhibit it at high doses; however, it is the high levels of insulin, induced by high levels of corticosteroids, that may inhibit feeding. The effects of corticosteroids on liver, fat, and muscle cell metabolism, with emphasis on their interactions with insulin, are briefly reviewed. Corticosteroids both synergize with and antagonize the effects of insulin. The effects of stress hormones, and their interactions with insulin on lipid and protein metabolism, followed by some of the metabolic effects of injury stress, with or without nutritional support, are evaluated. In the presence of elevated insulin stimulated by glucocorticoids and nutrition, stress causes less severe catabolic effects. In the central nervous system, regulation of function in the HPA axis is clearly affected by the activity of medial hypothalamic nuclei that also alter feeding, metabolism, and obesity in rats. Lesions of the arcuate (ARC) and ventromedial (VMN) paraventricular (PVN) nuclei result in obesity and hyperactivity in the HPA axis. Moreover, adrenalectomy inhibits or prevents development of the lesion-induced obesity. There are interactions among these nuclei; one mode of communication is via inputs of neuropeptide Y (NPY) cells in the ARC to the VMN, dorsomedial nuclei, and PVN.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Precise prediction of a Kk-restricted cytotoxic T cell epitope in the NS1 protein of influenza virus using an MHC allele-specific motif.

The nonstructural protein NS1 of influenza A/PR/8/34 virus has previously been reported to be recognized by murine Kk-restricted cytotoxic T lymphocytes (CTL), although the sequence of the epitope was not defined. A Kk-specific motif has previously been published and consists of a glutamic acid or (less frequently) an aspartic acid at position 2 and an isoleucine at the carboxyl terminus of a peptide eight or nine residues long. This motif was used here to predict the sequence of the NS1 epitope, which was defined as a nonapeptide corresponding to amino acid residues 152-160, sequence EEGAIVGEI. This is the first CTL epitope to be defined within the NS1 protein of the influenza A virus. A model of how this epitope could bind to the Kk molecule was produced by homology modelling from an X-ray crystal structure of a human HLA/peptide complex.

Alleles↗
PubMed1993

Body composition analysis in liver cirrhosis. The measurement of body fat by dual energy X-ray absorptiometry in comparison to skinfold anthropometry, bioelectrical impedance and total body potassium.

In this cross-sectional study of methods to determine total body fat in patients with abnormal body composition secondary to chronic liver disease, we have demonstrated that TBFDXA by four-site skinfold anthropometry was highly correlated to TBFDXA, with small SEE and no bias in patients with ascites, but a small and significant bias in patients without ascites. TBFBIA showed no bias but a weaker correlation with a large SEE. In the presence of fluid retention the correlation coefficient decreased. TBFTBK showed a highly significant bias, and the correlation was not as good as SFA, and decreased in the presence of fluid retention.

Absorptiometry, Photon↗
PubMed1993

Screening for osteoporosis by bone densitometry: a stratified intervention approach.

We have performed computer modelling of the relationship between bone mass, age and hip fracture in a conditional probability model using a national population of 100,000 postmenopausal women aged 50 who have their bone density measured once. The computer model very closely reproduced the actual number of fractures in a Western Australian population. Intervention to bone loss completely in subjects with the lowest bone density (below 1 SD below the mean) would prevent 0.42 of a hip fracture per patient treated if the whole population were treated. Halving the rate of bone loss in the whole population would reduce hip fracture by two-thirds. These data suggest that hormone replacement therapy, which is the most effective therapy for preventing bone loss but which has the most side effects, should be focused on subjects with bone mass below 1 SD below the mean. The remainder of the population could be targeted with a public health campaign based on the lifestyle factors of increased dietary calcium and exercise which have been shown to slow but not stop bone loss.

Bone Density↗
PubMed1993

An administrator's dilemma: keeping the innovative mental health and aging programs alive after the grant funds end.

Too often innovative and successful mental health and aging programs terminate when external funding sources end. This article describes one such project that has survived and even flourished well beyond the grant period. The original program is set forth, and changes in both the type of services offered and in the clientele are reviewed. The rationale for deviations from the original model are highlighted. Expansion, contraction and reexpansion of the range of services offered, as well as factors that impeded and enhanced program survival, are noted. The critical role of administrative leadership, vision and support for geropsychiatric services and staff is emphasized.

Aged↗
PubMed1993

Induction of micronuclei in rat bone marrow and peripheral blood following acute and subchronic administration of azathioprine.

The frequency of micronuclei was assessed in polychromatic erythrocytes of bone marrow and in polychromatic and normochromatic erythrocytes in peripheral blood of rats following exposure to azathioprine for 28 days. This was compared with the incidence of micronuclei in bone-marrow following exposure to a single dose of azathioprine. The incidence of micronuclei in bone-marrow polychromatic erythrocytes at the maximum tolerated dose (10 mg/kg) following exposure for 28 days was 29.5/1000. The incidence of micronucleated polychromatic erythrocytes in the peripheral blood at this dose was 4.4/1000. At the maximum tolerated dose in the single-dose study (40 mg/kg) the incidence obtained at 48 h post-treatment was 15.7/1000. This supports the view that the use of animals in a subchronic toxicity study is at least as sensitive for assessing in vivo clastogenic activity as an acute study and could reduce animal usage in toxicology assessments.

Animals↗
PubMed1993

Diagnostic imagings for primary cardiac fibrosarcoma.

Primary tumors of the heart are rare; primary cardiac fibrosarcoma is even rarer. We report a patient with primary cardiac fibrosarcoma widespread metastases presenting with pulmonary metastases initially. The cardiac lesion was identified by bone-imaging localization on bone scan, by hypodense areas in the cardiac chambers of contrast computed tomography of the chest, and by protruding masses in ventricular cavities causing aortic valve outflow-tract obstruction by echocardiogram. At autopsy, a large tumor invaded the interventricular septum and both ventricular cavities of the heart (880 g in weight), and accounted for these imaging findings. While bone-agent localization in the heart does not differentiate malignant from benign conditions, computed tomography and echocardiography of the interatrial and interventricular septal, and right atrial and biventricular cavitary involvement may differentiate fibrosarcoma from myxoma.

Aged↗