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Biomedical subjects

M L Smith

Publications and source records attributed to M L Smith.

At least 109 records · Page 6Linked to original sources
PubMed1998

Hyperglycemia-exaggerated ischemic brain damage following 30 min of middle cerebral artery occlusion is not due to capillary obstruction.

Transient focal ischemia of brief duration (15-30 min) gives rise to brain damage. In normoglycemic animals this damage usually consists of selective neuronal necrosis (SNN), and is largely confined to the lateral caudoputamen. In hyperglycemic subjects damage occurs more rapidly, involves also neocortical areas, and is often of the pan-necrotic type ('infarction'). Since experiments on forebrain ischemia of 30 min duration suggest that microcirculatory compromise develops during recirculation, we studied whether focal ischemia of the same duration, followed by reperfusion for 1, 2 or 4 h, leads to microcirculatory dysfunction. To test this possibility, we fixed the tissue by perfusion and counted the number of formed elements (leukocytes, macrophages and erythrocytes) in capillaries and postcapillary venules. Furthermore, capillary patency was evaluated following in vivo injection of Evan's blue. Histopathological examination of tissue fixed by perfusion after 1, 2 and 4 h of recirculation showed an increasing density of SNN in the caudoputamen of normoglycemic animals. Hyperglycemic, but not normoglycemic, animals showed pan-necrotic lesions ('infarction') after 4 h of recirculation. As a result, the total volume of tissue damage (SNN plus infarction) was larger in hyper- than in normoglycemic animals at 2 and 4 h of recirculation. In addition, hyperglycemic animals showed involvement of neocortex which increased with the time of reperfusion. In the ischemic hemisphere, between 5 and 10% of counted capillaries contained formed elements. However, since hyperglycemic animals contained an equal (or smaller) amount of cells the results did not suggest that capillary 'plugging' could explain the aggravated damage. Moreover, both normo- and hyperglycemic animals showed close to 100% capillary patency. The results thus fail to support the notion that the aggravation of focal ischemic damage by hyperglycemia is due to obstruction of microvessel by swelling or leukocyte adherence.

Animals↗
PubMed1998

Chromatin relaxation by overexpression of mutant p53, HPV16-E6, or cyclin G transgenes.

In this study, using a cell line that carries endogenous wild-type p53 genes, we show that transfection of cells with mutant p53, HPV16-E6, or cyclin G transgenes results in the disruption of higher-order chromatin structure, as evidenced by enhanced sensitivity to micrococcal nuclease. Multiple mechanisms may contribute to this phenotype, including histone H1 phosphorylation, direct binding of oncoproteins to nuclear matrix attachment sites, and altered expression of component genes of the p53 pathway, whose products may function in maintenance of chromatin structure.

Carcinoma↗
PubMed1998

Preischemic hyperglycemia leads to rapidly developing brain damage with no change in capillary patency.

The present experiments were undertaken to explore whether exaggeration of ischemic brain damage by preischemic hyperglycemia is due to lack of capillary patency in the postischemic period. Normo- and hyperglycemic rats were exposed to 10 min of forebrain ischemia. Histopathological changes were evaluated after 6 and 16-18 h of recovery by light microscopy, and capillary patency was assessed at the same time points by a double-staining technique, depicting perfused and morphologically identifiable capillaries. The results demonstrate that some neuronal damage was detectable after 6 h of recirculation which was aggravated after 16-18 h of recirculation in hyperglycemic rats. In contrast, the degree of capillary patency was similar in normo- and hyperglycemic rats. In both groups the perfusion marker, Evans blue, perfused about 95% of all capillaries when injected 10 s before decapitation. Since preischemic hyperglycemia exaggerates brain damage without cessation of capillary perfusion the primary targets of hyperglycemic brain damage may not be capillaries but neurons or glial cells.

Animals↗
PubMed1998

Influence of hypoglycemic coma on brain water and osmolality.

To study the effects of pronounced hypoglycemia on brain osmolality and brain edema formation, fasted rats were rendered hypoglycemic by injection of insulin, and subjected to 30 min of hypoglycemic coma. Recovery was accomplished by glucose administration. The change in water content in different brain regions was measured as a change in specific gravity after 30 min of hypoglycemic coma, or 30, 60, and 180 min after glucose administration. Plasma and brain tissue osmolality were measured in separate animals. The results show a significant decrease in specific gravity (increase in water content) in all structures measured (caudoputamen, neocortex, hippocampus, and cerebellum) at the end of the period of coma, as well as after 30 min and 60 min of recovery. At 180 min of recovery, brain water was normalized. The edema affected all structures to the same degree regardless of their vulnerability to hypoglycemic damage. Brain tissue osmolality showed a tendency to decrease with decreasing tissue glucose content. The decrease was significant (P<0.01) at 30 min of isoelectric coma. In the recovery phase, normal brain osmolality was restored within 30 min. Measurements of blood-brain barrier (BBB) permeability after 30 min of hypoglycemic coma showed no extravasation of Evan's blue, though a small but significant increase in the permeability for aminoisobutyric acid (AIB) in caudoputamen and in cerebellum was found. To analyze the importance of tissue acidosis for formation of edema, hypoglycemic animals were made acidotic by increasing the CO2 concentration in inspired air to produce an arterial plasma pH of 6.8-6.9. In these animals the edema was of a similar degree to the normocapnic animals, and the permeability for AIB was normal. We conclude that osmolytic mechanisms are not the primary cause of the selective neuronal vulnerability in hypoglycemic coma. Furthermore, the BBB is largely intact during a hypoglycemic insult.

Acidosis↗
PubMed1998

Atypical psychosis.

When one considers the 100 billion or so neurons that constitute the central nervous system, along with the thousands (average of 10,000) of synaptic connections for each neuron, in addition to the growing list of neurotransmitter agents and our growing awareness of the complexity of the glial "support" structures, it is quite remarkable that serious malfunctions in this extremely complex system do not occur more often. Psychosis, in its various forms, is one manifestation of disturbed functioning. It is hoped that practitioners recognize psychosis as a complex symptom of a complex organ system. Patients who present with psychosis ought to receive a thorough evaluation to ensure an accurate diagnosis and appropriate treatment. Failure to accurately determine the cause of a patient's psychosis likely leads to the wrong treatment. Patients who fail to respond as expected should be considered for a thorough reassessment in order to ensure an accurate diagnosis and appropriate treatment. Psychosis is a symptom that is not at all unique to a specific diagnosis. As discussed previously, many pathologic states may result in psychosis, and the presentation of the psychotic symptoms may be further influenced by cultural, social, and psychological factors.

Adolescent↗
PubMed1998

Neurodevelopmental outcomes in children surviving d-transposition of the great arteries.

We investigated the prevalence of neurological abnormalities and learning problems in a population cohort of children with dextro-transposition of the great arteries (d-TGA) born between January 1, 1981 and July 1, 1990. Fifty-seven of the 60 survivors and 35 siblings in the control group underwent neurodevelopmental assessments. As compared with population norms, children with d-TGA were more likely to have abnormal neurological examination findings, learning disabilities, and behavioral disorders. There was no significant difference in IQ or frequency of abnormal neurological examination results between children undergoing atrial as compared with arterial switch procedures. Compared with their siblings, the children with d-TGA had more neurological findings and learning disabilities. The siblings of children with d-TGA had more learning problems than expected. The findings suggest that ongoing surveillance is indicated for children surviving d-TGA. Furthermore, a familial tendency for learning differences should to be taken into consideration when neurodevelopmental outcomes of various perioperative parameters are examined.

Child↗
PubMed1998

Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria.

OBJECTIVE: To test the efficacy of tyrosine supplementation, as an adjunct to dietary treatment, on neuropsychological test performance in individuals with phenylketonuria. DESIGN: A randomised controlled trial of tyrosine supplementation using a double blind crossover procedure with three four week phases. SETTING: The Hospital for Sick Children, Toronto. PARTICIPANTS: 21 individuals with phenylketonuria (ages 6 to 28 years, mean 11.3). INTERVENTION: Participants were given 100 mg/kg body weight/d of L-tyrosine or L-alanine (placebo). RESULTS: At baseline, performance on several of the neuropsychological test measures was correlated with tyrosine levels. Dietary supplements of tyrosine increased plasma tyrosine concentrations; however, no change in test performance was found across the tyrosine and placebo phases of the study. CONCLUSIONS: Tyrosine supplementation of this type does not appear to alter neuropsychological performance in individuals with phenylketonuria.

Administration, Oral↗
PubMed1998

Bioethics education in a clinical pastoral education program.

Notes that contemporary health care delivery and the interface of clinical professionals with patients and families are marked by complexity and pluralism and that within this modern matrix patients, families, professionals, and administrators frequently struggle with difficult ethical issues. Observes that these realities have significant implications for chaplains and for chaplains-in-training, a factor which has received the attention of the Bioethics Committee of the Professional Chaplains Association through its Bioethics Committee and resulting in a set of guidelines for the chaplain's appropriate roles in bioethical issues and for their role on bioethics committees. Describes the establishment of a bioetchics modulate at the Cleveland Clinic Foundation (CCF) in which chaplain residents are enabled to function as professional peers with other healthcare professionals and as competent chaplains with patients and families in bioethical decision making. Reports on the methods and the results of a pilot study based on the model described.

Chaplaincy Service, Hospital↗
PubMed1998

Better training for less money--from outer space.

Agencies that wish to develop innovative, interactive and entertaining inservices for their employees may want to look at the Alabama Department of Public Health's program, which has developed cost-effective inservice training for more than 6,000 employees working at 120 sites across the state. It works by using satellite technology--rocket science to bring the caring touch closer to home.

Alabama↗
PubMed1998

Discovery of ascomycin analogs with potent topical but weak systemic activity for treatment of inflammatory skin diseases.

Drug therapy for the major inflammatory skin diseases, which include atopic dermatitis, psoriasis and allergic contact dermatitis, is often inadequate due to poor efficacy, toxicity, or both. Much research has focused on the macrolactam T cell inhibitors as a promising new class of agents for immunotherapy, and medicinal chemistry efforts to design novel ascomycin analogs have produced clinically promising agents. A synthetic program to modify the ascomycin nucleus to alter its physicochemical properties and promote systemic clearance is described. A biologic screening strategy to identify analogs with reduced systemic activity and rapid pharmacokinetic elimination led to identification of the clinical candidate, ABT-281. A swine contact hypersensitivity model was used as a stringent indicator of skin penetration as human doses of topical corticosteroids produced inhibition only in the 50% range and ED50 values were 100-fold less potent than in rat. Also, cyclosporine was confirmed to be topically inactive in swine, as seen in human. ABT-281 had topical potency equal to tacrolimus (FK506) despite a severalfold lower potency for inhibiting swine T cells in vitro, consistent with superior skin penetration. ABT-281 was found to have a shorter duration of action after i.v. dosing in monkeys using an ex vivo whole blood IL-2 production assay. Systemic potency was reduced by 30-fold or more in rat popliteal lymph node hyperplasia and contact hypersensitivity assays. Following i.v. or i.p. administration in the swine contact hypersensitivity model, ABT-281 was 19- and 61-fold less potent, respectively, than FK506. Pharmacokinetic studies showed that ABT-281 had a shorter half life and higher rate of clearance than FK506 in all three species. The potent topical activity and reduced systemic exposure of ABT-281 may thus provide both efficacy and a greater margin of safety for topical therapy of skin diseases.

Administration, Topical↗
PubMed1998

Human cardiovascular acclimation to microgravity.

This brief review provides an update on recent studies of human cardiovascular responses to spaceflight. This report complements prior reviews of the acute responses and chronic acclimation of the cardiovascular system to actual and simulated microgravity.

Adaptation, Physiological↗
PubMed1998

Reduction mammaplasty: its role in breast conservation surgery for early-stage breast cancer.

Segmental resection and radiotherapy is an accepted alternative over mastectomy for small, staged breast malignancies. However, women with large, pendulous breasts have been documented to have poorer cosmetic outcomes when undergoing irradiation after breast conservative surgery compared with women with small- or medium-size breasts, thought to be caused by dose inhomogeneity. The purpose of this study was to evaluate the efficacy of combining reduction mammaplasty with breast conservative surgery to facilitate postoperative irradiation. Between 1988 and 1996, 10 women have undergone bilateral reduction mammaplasty for breast malignancy followed by radiation therapy at our center. All women wished to avoid mastectomy (average age, 59 years). All lesions were detected preoperatively on mammography. The average amount of tissue removed was 945 g per breast. A variety of reduction techniques were employed to include the malignant lesions. All patients received 50 Gy of radiation therapy delivered in 25 fractions following reduction mammaplasty during a 5-week period. Radiation therapy was usually initiated within 4 weeks following surgery. Follow-up is currently 37 months, with all patients being followed for at least 8 months. No patients have had complications from the surgery or radiation therapy. No local recurrent malignancies have been detected. Cosmesis has been good to excellent in all patients. Despite equivalent survival outcomes for mastectomy for early-stage breast cancer, certain women are not good candidates for breast conservation and radiation therapy. An alternative for women with large, pendulous breasts that combines breast conservation therapy and concurrent bilateral reduction mammaplasty should be considered. This combination, in selected women, provides good functional and cosmetic results, and at the same time minimizes the potential difficulties of radiation therapy.

Breast Neoplasms↗
PubMed1998

Vitamin B2 interference with TDx drugs-of-abuse assays.

Migraine is a headache condition found in significant frequency in the general population. One recent study has shown that riboflavin, Vitamin B2, is an effective prophylactic treatment for this headache condition. One subject in a recent study conducted by the Division of Forensic Toxicology, Armed Forces Institute of Pathology (AFIP) was taking 200 mg of riboflavin twice daily for the prevention of migraine headaches. When that subject's urine was tested using Abbott TDx drugs-of-abuse assays a number of tests resulted in a MX BKG error and all samples had BLK I values greater than those observed with normal urine specimens. The MX BKG error occurs when the BLK I value is greater than the upper limit determined by the manufacturer for a particular assay. High BLK I values may result if the specimen being analyzed contains a fluorophore that will compete with the fluorescein-labeled antibody used in the assay. This error serves as a notification that an interfering substance may be present and the assay is not performing according to manufacturer-specifications. Upon termination of riboflavin therapy the subject's BLK I values began to decrease within 60 h of the last 200 mg dose. A second subject began chronic riboflavin use to confirm this interferent effect. Elevated BLK I values resulted within 3 h of a single 200 mg dose and MX BKG errors occurred 1 h after a second 400 mg dose. No false negative results were noted with either subject (both subjects used butalbital and the first subject also used hydrocodone and diazepam during the study), suggesting that riboflavin is not an adulterant. Riboflavin use, however, does interfere with the TDx DAU assays and may result in quantitative values being determined which are of questionable validity in the face of an elevated BLK I value or may result in only an MX BKG error and no quantitative value reported. It is unclear if the interfering fluorophore is simply riboflavin itself or a combination of riboflavin and its metabolic products. Results obtained on urine samples collected from individuals using prophylactic riboflavin for migraine prevention and analyzed by TDx may be of questionable validity. Such samples may require analysis utilizing another immunoassay technique that does not employ a fluorescein-labeled antibody.

Fluorescence Polarization Immunoassay↗
PubMed1997

Cells lacking CIP1/WAF1 genes exhibit preferential sensitivity to cisplatin and nitrogen mustard.

We have previously shown that p53 disruption sensitizes certain cancer cell types to cisplatin (CDDP) (Fan et al., 1995). In the present study we investigated the role of the p53 downstream effector, p21CIP1/WAF1 (p21), in this sensitization. Studies were performed in human colon cancer HCT-116 cells and murine embryonic fibroblasts (MEF) with intact versus disrupted p21 genes. For comparison, HCT-116 cells lacking p53 function were also prepared through stable transfection with the human papillomavirus type-16 E6 gene. HCT-116/E6 cells were found to be more sensitive than control transfectants to CDDP and another DNA crosslinking agent, nitrogen mustard (HN2). HCT-116 cells with disrupted p21 genes also exhibited greater CDDP and HN2-sensitivity than parental HCT-116 cells. In contrast, the clonogenic survival of HCT-116 cells exposed to ionizing radiation, adriamycin, taxol or vincristine was not affected by p53 or p21 disruption. Sensitization of HCT-116/p21-/- cells to CDDP and HN2 was not limited to the HCT-116 cell background since MEF from p21 knockout mice were also more sensitive to these DNA crosslinking agents. Investigations into a possible cause of this enhanced sensitivity revealed that HCT-116 cells lacking p53 or p21 function exhibited a reduced ability to repair cisplatin-damaged CAT-reporter plasmids transfected into the cells. In addition, we found that HCT-116/p21-/- cells were much more susceptible to HN2-induced cell cycle delay than parental cells. Our results suggest that p21 disruption preferentially sensitizes at least some cell types to DNA crosslinking agents.

Animals↗
PubMed1997

Role of p21Waf1/Cip1/Sdi1 in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells.

Postulated roles for p21(Waf1/Cip1/Sdi1) (p21) in DNA repair and apoptosis remain controversial. Studies suggest both stimulatory and inhibitory effects of p21 in DNA repair. p21 has also been implicated in induction or protection from apoptosis. Using the tetracycline inducible expression system, we studied the role of p21 in DNA repair and apoptosis in wild-type p53 deficient DLD1 colorectal carcinoma cells. These cells displayed marked heterogeneity in their ability to tolerate higher levels of exogenous p21. The majority of the p21 overexpressing cells grew slower and did not exhibit apoptotic phenotype, some cells underwent apoptotic death within 5-8 days following p21 induction while other became giant cells prior to undergoing cell death. Induction of p21 transgene neither sensitized to nor protected from adriamycin-induced acute cell death. p21 also did not alter the clonogenic survival following adriamycin treatment. Clonogenic survival after u.v.-irradiation was, however, increased when p21 expression was transiently induced a few hours before and after u.v.-irradiation. Consistent with its effect on clonogenic survival, p21 also enhanced the cellular capacity to repair three different exogenously introduced u.v.-damaged reporter plasmids. Taken together our results demonstrate that p21 may modulate the nucleotide excision repair process to facilitate the repair of u.v.-type DNA damage even in the absence of wild-type p53.

Cell Death↗
PubMed1997

New protein and PCR markers RAK for diagnosis, prognosis and surgery guidance for breast cancer.

Breast cancer antigens RAK-p120, -p42, -p25 were detected in 100% of breast cancer cases tested (71 cases). Only 10% of adjacent tissue cases tested positive for all three cancer antigens, and 17.5% of the cases tested positive for two antigens only. Eighty-five percent of histologically normal breast tissue samples, isolated either from breast cancer patients or patients with advanced fibrocystic disease, tested RAK-negative, with the exception of low expression of p25, observed in some patients. Polymerase chain reaction (PCR) with HIV-1 gp 41-derived primers revealed cancer-associated DNA fragments of similar size (140 bp) as in HIV-1 genome. Fifty-four percent of cancer adjacent tissues, and 50% of malignancy-free breast tissue samples, tested PCR-negative. It is suggested that genetic predisposition to cancer may be associated with the presence of RAK genes, while expression of RAK antigens marks an already ongoing process of malignant changes.

Biomarkers, Tumor↗