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Biomedical subjects

M L Smith

Publications and source records attributed to M L Smith.

At least 73 records · Page 4Linked to original sources
PubMed2000

Neuropsychological function in mild hyperphenylalaninemia.

Whether specific cognitive deficits related to frontal-lobe dysfunction that have been reported in individuals with phenylketonuria (PKU) are also characteristic of mild hyperphenylalaninemia (MHP) was investigated. Tests of executive function and control tasks not assessing executive function were administered to a group of individuals with MHP and a group without MHP, similar in age, gender, and IQ. Tests of academic skills and behavior-rating questionnaires were also administered to the group with MHP. No group differences were found for any measure, suggesting that the mild elevations of phenylalanine in individuals with MHP are not sufficient to produce behavioral and cognitive impairments characteristic of PKU.

Adolescent↗
PubMed2000

Neuropsychology of childhood epilepsy: pre- and postsurgical assessment.

Childhood epilepsy is one of the most prevalent forms of chronic and disabling childhood disorders. Because it disrupts brain maturation, it has long been thought to produce non-specific consequences such as mental deficiency and behavioral problems. However, advances in medical knowledge have shown that childhood epilepsy should not be considered as a single disorder, and it is now becoming apparent that various clinical entities have different cognitive expressions that yet need to be specified. The purpose of this paper is to provide an up-to-date analysis of this multi-faceted pathology. The first section is devoted to the characterization of the neuropsychological profile that accompanies focal epilepsies, as defined by the site of the epileptic process. We report the first group study of children with frontal lobe epilepsy. The results indicate that frontal lobe epilepsy produces symptoms (deficits of planning, attention and motor dexterity) that are akin to those found in frontal-lesioned adults. Similarly, like in adults, temporal lobe epilepsy produces memory impairment in children as well as behavioral and academic disturbances. Occipito-parietal lobe epilepsy is rare in children and its effects still need to be specified. The second section deals with the neuropsychological techniques used in presurgical evaluation. Finally, the various neurosurgical procedures that are increasingly being used as part of the arsenal of epilepsy treatment are described along with the neuropsychological findings that are associated with these interventions. It can be concluded that the beneficial effects of epilepsy surgery (callosotomy, hemispherectomy, temporal and extra-temporal resections) by far outweigh the few cognitive deficits that are occasionally reported following these interventions.

Adult↗
PubMed2000

NCCN Practice Guidelines for Breast Cancer.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. In many situations, the patient and physician have the responsibility to jointly explore and ultimately select the most appropriate option from among the available alternatives. With rare exception, the evaluation, treatment, and follow-up recommendations contained within these guidelines were based largely on the results of past and present clinical trials. However, there is not a single clinical situation in which the treatment of breast cancer has been optimized with respect to either maximizing cure or minimizing toxicity and disfigurement. Therefore, patient and physician participation in prospective clinical trials allows patients not only to receive state-of-the-art cancer treatment but also to contribute to the improvement of treatment of future patients.

Breast Neoplasms↗
PubMed1999

Screening postmortem blood and tissues for nine classes [correction of cases] of drugs of abuse using automated microplate immunoassay.

A commercially available enzyme-linked immunosorbant assay (ELISA) was evaluated as a screening procedure for the detection of nine classes of abused drugs in postmortem blood and tissue specimens. Specifically, postmortem blood, fluid and/or tissue homogenates were screened for amphetamine (AMP), methamphetamine (MET), barbiturates (BARB), benzodiazepines (BZD), cannabinoids (CNB), cocaine (benzoylecgonine; BE), morphine-specific (MOR), opiates (class; OPI), phencyclidine (PCP) and lysergic acid diethylamide (LSD) by ELISA and by coated tube radioimmunoassay (CTR) (BARB, BE, OPI, PCP, LSD) or double-antibody radioimmunoassay (DAR) (AMP/METH, BZD, CNB). Specimens that screened 'positive' by any method were confirmed and quantitated by gas chromatography/mass spectrometry (GC/MS). The only assay that appeared to perform less optimally than RIA was the MOR assay (five false negatives). However, this assay is very specific for free morphine while the GC/MS confirmation method provided a total morphine value. The OPI assay was more sensitive, producing fewer false negatives, and is recommended for broad class opiate screening. EIA is an adequate alternative to RIA for screening postmortem specimens, including blood and tissue, for nine major classes of drugs.

Amphetamine↗
PubMed1999

Reflex control of sympathetic activity during simulated ventricular tachycardia in humans.

BACKGROUND: Ventricular tachyarrhythmias present a unique set of stimuli to arterial and cardiopulmonary baroreceptors by increasing cardiac filling pressures and decreasing arterial pressure. The net effect on the control of sympathetic nerve activity (SNA) in humans is unknown. The purpose of this study was to determine the relative roles of cardiopulmonary and arterial baroreceptors in controlling SNA and arterial pressure during ventricular pacing in humans. METHODS AND RESULTS: Two experiments were performed in which SNA and hemodynamic responses to ventricular pacing were compared with nitroprusside infusion (NTP) in 12 patients and studied with and without head-up tilt or phenylephrine to normalize the stimuli to either the arterial or cardiopulmonary baroreceptors in 9 patients. In experiment 1, the slope of the relation between SNA and mean arterial pressure was greater during NTP (-4.7+/-1.4 U/mm Hg) than during ventricular pacing (-3.4+/-1.1 U/mm Hg). Comparison of NTP doses and ventricular pacing rates that produced comparable hypotension showed that SNA increased more during NTP (P=0.03). In experiment 2, normalization of arterial pressure during pacing resulted in SNA decreasing below baseline (P<0.05), whereas normalization of cardiac filling pressure resulted in a greater increase in SNA than pacing alone (212+/-35% versus 189+/-37%, P=0. 04). Conclusions--These data demonstrate that in humans arterial baroreflex control predominates in mediating sympathoexcitation during ventricular tachyarrhythmias and that cardiopulmonary baroreceptors contribute significant inhibitory modulation.

Action Potentials↗
PubMed1999

Baroreflex gain predicts blood pressure recovery during simulated ventricular tachycardia in humans.

BACKGROUND: Despite similar degrees of left ventricular dysfunction and similar tachycardia or pacing rate, blood pressure (BP) response and symptoms vary greatly among patients. Sympathetic nerve activity (SNA) increases during sustained ventricular tachycardia (VT), and the magnitude of this sympathoexcitatory response appears to contribute to the net hemodynamic outcome. We hypothesize that the magnitude of sympathoexcitation and thus arterial baroreflex gain is an important determinant of the hemodynamic outcome of VT. METHODS AND RESULTS: We evaluated the relation between arterial baroreflex sympathetic gain and BP recovery during rapid ventricular pacing (VP) in patients referred for electrophysiological study. Efferent postganglionic muscle SNA, BP, and central venous pressure (CVP) were measured in 14 patients during nitroprusside infusion and during VP at 150 (n=12) or 120 (n=2) bpm. Arterial baroreflex gain was defined as the slope of the relationship of change in SNA to change in diastolic BP during nitroprusside infusion. Recovery of mean arterial pressure (MAP) during VP was measured as the increase in MAP from the nadir at the onset of pacing to the steady-state value during sustained VP. Arterial baroreflex gain correlated positively with recovery of MAP (r=0.57, P=0.034). No significant correlation between ejection fraction and baroreflex gain (r=0.48, P=0.08) or BP recovery (r=0.41, P=0.15) was found. When patients were separated into high versus low baroreflex gain, the recovery of MAP during simulated VT was significantly greater in patients with high gain. CONCLUSIONS: These data strongly suggest that arterial baroreflex gain contributes significantly to hemodynamic stability during simulated VT. Knowledge of baroreflex gain in individual patients may help the clinician tailor therapy directed toward sustained VT.

Adult↗
PubMed1999

Post-apneic inhalation reverses apnea-induced sympathoexcitation before restoration of blood oxygen levels.

Sleep apneas acutely increase sympathetic nerve activity (SNA) and thus arterial blood pressure. We hypothesized that after apnea, sympathoexcitation decreases before recovery of blood oxygen levels because of the predominant inhibitory effect respiratory factors exert over sympathetic nervous system activation. Seven healthy subjects were instrumented for arterial oxygen saturation (pulse oximetry, SaO2), leg muscle SNA (microneurography), and arterial pressure (Finapres). Supine subjects breathed 12% oxygen, 3% carbon dioxide, and 85% nitrogen for one min prior to apnea at the end of a normal tidal expiration. We accounted for circulatory delay in SaO2 measurement (5.4 +/- 0.4 s, mean +/- SE) as the time from the termination of apnea to the midpoint of the nadir of SaO2. SaO2 decreased to average 84 +/- 3% over the final 10 seconds of apnea, and recovered only partially to average 87 +/- 3% over the 10 seconds immediately following apnea. End-expiratory apnea increased SNA 14-fold from baseline levels of 217 +/- 37 units/10 seconds to 3063 +/- 442 units/10 seconds. However, SNA decreased to 93 +/- 32 units/10 s during the first 10 seconds after apnea. These findings indicate that sympathoinhibitory effects of respiratory signals, either lung inflation receptors or central respiratory inputs, predominate over sympathoexcitatory inputs from chemoreceptors to produce immediate and complete sympathoinhibition at the termination of a voluntary apnea. Arterial baroreflexes probably also contribute to sympathoinhibition after apnea.

Adult↗
PubMed1999

The effect of alpha-phenyl-N-tert-butyl nitrone on bioenergetic state in substantia nigra following flurothyl-induced status epilepticus in rats.

Status epilepticus (SE), i.e. ongoing seizures of more than 30 min duration, gives rise to bilateral pan-necrotic lesions of the substantia nigra, pars reticulata (SNPR). These are known to be preceded by an initial increase, followed by a depression of metabolic rate, and by failure of the bioenergetic state, suggesting mitochondrial dysfunction. We have previously shown that the spin trap alpha-phenyl-N-tert-butyl nitrone (PBN) prevents the lesions caused by 45 min of SE from occurring, in spite of ongoing seizure activity. In this article, we demonstrate that PBN, given 30 min before seizure induction, reduces or prevents the decrease in ATP concentration and adenylate energy charge, without significantly reducing the amount of lactate accumulated, or the decrease in intracellular pH (pHi). The results suggest that the spin trap nitrone preserves the structural and functional integrity of SNPR neurons by protecting the mitochondria against oxidative damage.

Animals↗
PubMed1999

Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45.

Recently Gadd45, a p53-regulated stress protein, has been implicated in the activation of a G2/M checkpoint after damage by UV radiation and alkylating agents. While inhibitory phosphorylation of Cdc2 and suppression of cyclin B1 levels are known to be involved in G2 delays after genotoxic stress, Gadd45 has now been found to directly inhibit the activity of Cdc2/Cyclin B1 complex, while it had no appreciable effect on Cdk2/ Cyclin E activity even at very high levels of Gadd45. In contrast, p21CiP1/Waf1 is an universal cdk/cyclin inhibitor and inhibited both of the cyclin complexes tested here. Gadd45 was also able to physically interact with Cdc2, but not Cyclin B1. Addition of Gadd45 to immunoprecipitated Cdc2/Cyclin B1 in vitro led to a dissociation of this complex, and thus may represent a new checkpoint mechanism whereby Cdc2/Cyclin B1 can be inhibited. With the use of an antisense approach, reduced Gadd45 expression attenuated the suppression of Cdc2/Cyclin B1 activity in UV-irradiated human cells. Taken together, these results implicate Gadd45 in the control of G2/M cell cycle progression after certain stresses.

Antibodies, Monoclonal↗
PubMed1999

Inhibition of p56(lck) tyrosine kinase by isothiazolones.

Lck encodes a 56-kDa protein-tyrosine kinase, predominantly expressed in T lymphocytes, crucial for initiating T cell antigen receptor (TCR) signal transduction pathways, culminating in T cell cytokine gene expression and effector functions. As a consequence of a high-throughput screen for selective, novel inhibitors of p56(lck), an isothiazolone compound was identified, methyl-3-(N-isothiazolone)-2-thiophenecarboxylate(A-125800), which inhibits p56(lck) kinase activity with IC50 = 1-7 microM. Under similar assay conditions, the isothiazolone compound was equipotent in blocking the ZAP-70 tyrosine kinase activity but was 50 to 100 times less potent against the catalytic activities of p38 MAP kinase and c-Jun N-terminal kinase 2alpha. A-125800 blocked activation-dependent TCR tyrosine phosphorylation and intracellular calcium mobilization in Jurkat T cells (IC50 = 35 microM) and blocked T cell proliferation in response to alloantigen (IC50 = 14 microM) and CD3/CD28-induced IL-2 secretion (IC50 = 2.2 microM) in primary T cell cultures. Inhibition of p56(lck )by A-125800 was dose- and time-dependent and was irreversible. A substitution of methylene for the sulfur atom in the isothiazolone ring of the compound completely abrogated the ability to inhibit p56(lck) kinase activity and TCR-dependent signal transduction. Incubation with thiols such as beta-ME or DTT also blocked the ability of the isothiazolone to inhibit p56(lck) kinase activity. LC/MS analysis established the covalent modification of p56(lck) at cysteine residues 378, 465, and 476. Together these data support an inhibitory mechanism, whereby cysteine -SH groups within the p56(lck) catalytic domain react with the isothiazolone ring, leading to ring opening and disulfide bond formation with the p56(lck) enzyme. Loss of p56(lck) activity due to -SH oxidation has been suggested to play a role in the pathology of AIDS. Consequently, a similar mechanism of sulfhydryl oxidation leading to p56(lck) inhibition, described in this report, may occur in the intact T cell and may underlie certain T cell pathologies.

Adenosine Triphosphate↗
PubMed1999

Regulation of the c-met proto-oncogene promoter by p53.

In the present study, we have investigated the possible involvement of p53 in the transcriptional regulation of the c-met gene. Cotransfection of various c-met promoter reporter vectors with p53 expression plasmids demonstrated that only wild-type p53 but not tumor-derived mutant forms of p53 resulted in a significant enhancement of c-met promoter activity. Functional assays revealed that the p53 responsive element in the c-met promoter region is located at position -278 to -216 and confers p53 responsiveness not only in the context of the c-met promoter but also in the context of a heterologous promoter. Electrophoretic mobility shift assays using purified recombinant p53 protein showed that the p53 binding element identified within the c-met promoter specifically binds to p53 protein. Induction of p53 by UV irradiation in RKO cells that express wild-type p53 increased the level of the endogenous c-met gene product and p21(WAF1/CIP1), a known target of p53 regulation. On the other hand, in RKO cells in which the function of p53 is impaired either by stable transfection of a dominant negative form of p53 or by HPV-E6 viral protein, no induction of the endogenous c-met gene or p21(WAF1/CIP1) was noted by UV irradiation. These results suggest that the c-met gene is also a target of p53 gene regulation.

Base Sequence↗
PubMed1999

Electron ionization mass fragmentometric detection of urinary ecgonidine, a hydrolytic product of methylecgonidine, as an indicator of smoking cocaine.

When cocaine is smoked, methylecgonidine (anhydroecgonine methyl ester) is also consumed as a pyrolytic product. Methylecgonidine, on incubation with human liver homogenate, was metabolized to a stable compound, ecgonidine. The compound was also formed when methylecgonidine was exposed to a urine pH > or = 8.0. Ecgonidine is a zwitterion and highly water soluble. A method was developed to identify ecgonidine quantitatively in urine. After removal of cocaine, benzoylecgonine and methylecgonidine from urine at pH 5.5 +/- 0.5 using a solid-phase extraction (SPE) technique, the pH of the solution was readjusted to 2.0-3.0. The acidic solution reduced the dissociation of the carboxylic acid and improved the lipophilic and cationic character of ecgonidine. The compound was extracted from the solution with the SPE technique with an 89-99% yield. Ecgonidine was then detected as a tert-butyldimethylsilyl derivative by a gas chromatographic/electron ionization mass spectrometric method. Quantitation was linear over the concentration range 7-2000 ng ml-1. Concentrations as low as 7 ng ml-1 can be detected by this procedure. Ecgonidine was detected in > 95% of benzoylecgonine-positive urine specimens from a random drug testing program, indicating smoking as the major route of cocaine administration.

Cocaine↗
PubMed1999

Ex vivo assessment of immunosuppression in undiluted whole blood from pigs dosed with tacrolimus (FK506).

To assess the duration of immunosuppression in FK506-dosed pigs, an undiluted whole blood assay was established to measure reactivities of T cells in their physiological milieu. PMA and ionomycin were shown to induce IL-2 production in swine blood. The IC50 of FK506 in inhibiting IL-2 production in whole blood and isolated PBMC stimulated with PMA and ionomycin measured 1.2 and 0.04 nM, respectively. These data underscore the influence of red blood cells and plasma proteins on drug potency. IL-2 levels were determined in blood drawn immediately before and 1, 24, 48, and 72 h after iv dosing. For pigs dosed with 0.05 mg/kg, 50% recovery of IL-2 production was observed at 16 h and 100% at 35 h after dosing. For pigs dosed with 0.15 mg/kg, 50% recovery was observed at 38 h and 100% at 72 h. Blood concentrations of FK506 at 50 and 100% recovery of IL-2 production measured 10.8 and 2.2 nM for pigs dosed with 0.05 mg/kg and 6.1 and 1.1 nM for pigs dosed with 0.15 mg/kg, respectively. These concentrations are severalfold higher than predicted from the IC50 of FK506 for inhibiting IL-2 production in the whole blood assay. These data suggest that the true potency of FK506 in blood after dosing is influenced by additional factors, which could include plasma protein binding, the presence of active or interfering metabolites, serum interfering factors, and sequestration of drug in blood cells. Our results demonstrate the utility of an undiluted whole blood assay for assessing the duration of immunosuppression in drug-dosed animals and emphasize the importance of assessing drug potency in the whole blood environment ex vivo.

Animals↗
PubMed1999

Mdm2 sensitizes MCF7 breast cancer cells to cisplatin or carboplatin.

Overexpression of Mdm2 in cancer cells with otherwise wild-type p53 is believed to be an alternative mechanism for p53 inactivation during carcinogenesis. Because a number of genetic alterations that inactivate p53, including mutation, homozygous deletion, or viral oncoprotein expression (e.g. HPV16-E6), inhibit DNA repair, we tested the hypothesis that Mdm2 would likewise inhibit DNA repair. Repair of cisplatin-induced DNA damage was reduced in MCF7 cells overexpressing Mdm2, compared to MCF7 cells in which wild-type p53 function was intact. MCF7-Mdm2 cells exhibited preferential sensitivity to cisplatin and carboplatin. MCF7-Mdm2 cells showed a pronounced S-phase arrest after cisplatin treatment, similar to that observed in mutant-p53 cells in the present and prior studies. MCF7 cells with intact wild-type p53, on the other hand, arrested primarily in G2/M phase after cisplatin treatment. These findings indicate that Mdm2 overexpression can recapitulate the effect of p53 mutations on DNA repair of cisplatin lesions.

Antineoplastic Agents↗
PubMed1999

Systemic candidiasis with candida vasculitis due to Candida kruzei in a patient with acute myeloid leukaemia.

Candida kruzei-related systemic infections are increasing in frequency, particularly in patients receiving prophylaxis with antifungal triazoles. A Caucasian male with newly diagnosed acute myeloid leukaemia (AML M1) developed severe and persistent fever associated with a micropustular eruption scattered over the trunk and limbs during induction chemotherapy. Blood cultures grew Candida kruzei, and biopsies of the skin lesions revealed a candida vasculitis. He responded to high doses of liposomal amphotericin B and was discharged well from hospital.

Acute Disease↗
PubMed1999

A macrolactam inhibitor of T helper type 1 and T helper type 2 cytokine biosynthesis for topical treatment of inflammatory skin diseases.

T lymphocytes play a critical part in inflammatory skin diseases but are targeted by available therapies that have only partial efficacy, significant side-effects, or both. Because psoriasis, atopic dermatitis, and allergic contact hypersensitivity are associated with T helper type 1 (Th1), T helper type 2 (Th2), or mixed Th1-Th2 cell subsets and cytokine types, respectively, there is a need for a better broad-based inhibitor. The macrolactam ascomycin analog, ABT-281, was found to inhibit potently T cell function across species and to inhibit expression of multiple cytokines in human peripheral blood leukocytes which have been found in human skin disease cells and tissues. These included immunoregulatory Th1 (interleukin-2 and interferon-gamma) and Th2 (interleukin-4 and interleukin-5) cytokines. ABT-281 was shown to have potent topical activity (ED50 = 0.6% in acetone/olive oil) in a stringent swine model of allergic contact hypersensitivity, but its potency was markedly reduced compared with ascomycin when administered systemically due to more rapid clearance. Topical application of 3% ABT-281 in acetone/olive oil over 25% of the body surface in swine resulted in undetectable blood levels. Compared with a wide potency range of topical corticosteroids in clinical formulations, 0.3% and 1% ABT-281 ointments profoundly inhibited dinitrochlorobenzene-induced contact hypersensitivity in the pig by 78% and 90%, respectively, whereas super-potent steroids such as clobetasol propionate only inhibited in the 50% range and mild to moderate potency steroids such as fluocinolone acetonide were inactive. The potent topical activity of ABT-281 in swine, its superior efficacy, its rapid systemic clearance following uptake into the bloodstream, and its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in inflammatory skin diseases, including psoriasis, atopic dermatitis, and allergic contact dermatitis.

Administration, Topical↗
PubMed1999

Tissue distribution of mirtazapine (Remeron) in postmortem cases.

Mirtazapine (Remeron) is a member of the relatively new class of tetracyclic antidepressants. There are published cases of mirtazapine's detection as an incidental finding in postmortem cases; however, case reports with associated tissue concentrations and interpretations are not available. This report documents the tissue distribution of mirtazapine in eight postmortem cases in which it was identified but did not contribute to the cause or manner of death. The following mean mirtazapine concentrations (milligrams per liter or milligrams per kilogram) were found: heart blood 0.12 (range, < 0.01-0.33, n = 7); peripheral blood 0.09 (< 0.01-0.14, n = 4); urine 0.61 (0.01-3.2, n = 7); liver 0.88 (0.04-3.6, n = 6), kidney 0.21 (0.02-0.48, n = 5); and bile 0.62 (0.11-1.6, n = 6). In each case, the mirtazapine concentration in heart blood was approximately equal to that of peripheral blood, indicating that postmortem redistribution was not a factor in evaluating postmortem blood concentrations in these cases. However, because the liver mirtazapine concentrations were 5-30 times the blood concentrations, the potential for postmortem redistribution cannot be excluded. Additionally, because urine concentrations of the parent compound were consistently greater than the blood concentrations, urine is an adequate screening specimen for mirtazapine.

Antidepressive Agents, Tricyclic↗