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Biomedical subjects

S M Fleming

Publications and source records attributed to S M Fleming.

At least 19 recordsLinked to original sources
PubMed2006

Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein.

Overexpression of alpha-synuclein causes familial Parkinson's disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. Male Thy1-aSyn and wild-type mice received vehicle, benserazide/L-DOPA (25 mg/kg, i.p.), high (2 mg/kg, s.c.) and low doses (0.125, 0.25, 0.5 mg/kg, s.c.) of apomorphine, and amphetamine (5 mg/kg, i.p.), beginning at 3 months of age, and were tested on the challenging beam, spontaneous activity, pole test, and gait. l-DOPA had a paradoxical effect and worsened the deficits in Thy1-aSyn mice compared with controls, whereas the high dose of apomorphine only produced few deficits above those already present in Thy1-aSyn. In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of alpha-synuclein led to abnormal pharmacological responses in mice.

Amphetamine↗
PubMed2001

Amino-terminal pro-brain natriuretic peptide in normal and hypertensive pregnancy.

OBJECTIVES: To investigate serum levels of amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) as an index of left-ventricular function in normal pregnancy and pregnancies complicated by hypertension and also to investigate levels in both primigravid and multigravid women. METHODS: Women with hypertension in pregnancy (at least two readings of systolic blood pressure > 140 mm Hg and diastolic blood pressure > 90 mm Hg) (n = 24) and normotensive women (n = 42) were included in the study. Serum Nt pro-BNP was measured using an enzyme-linked immunosorbent assay technique. RESULTS: The median serum Nt pro-BNP level in pregnancies complicated by hypertension was 420 fmol/L, which was significantly greater than that measured in samples obtained from normotensive women in pregnancy (340 fmol/L) (p = 0.03). There was a nonsignificant trend toward increased levels in proteinuric as compared to nonproteinuric hypertension in pregnancy. Multigravida had higher Nt pro-BNP levels (n = 26; median Nt pro-BNP = 358 fmol/L) than primigravida (n = 16; median Nt pro-BNP = 278 fmol/L) (p = 0.01) in association with normal pregnancy. Multigravida also demonstrated a dramatic rise in serum Nt pro-BNP levels in association with hypertension in pregnancy (n = 13; median Nt pro-BNP = 572 fmol/L) as compared to normal pregnancy (n = 26; median Nt pro-BNP = 358 fmol/L) (p = 0.009). CONCLUSION: Serum Nt pro-BNP is elevated in women with hypertensive disorders of pregnancy, indicating elevated left-ventricular filling pressures. Measured serum levels in both normal and hypertensive pregnancy are higher in multigravida than in primigravida.

Adult↗
PubMed2001

Cardiac troponins in suspected acute coronary syndrome: a meta-analysis of published trials.

We performed a meta-analysis of published trials to determine the predictive value of cardiac troponin I (cTnI) and T (cTnT) levels for adverse events (death and myocardial infarction) in acute coronary syndrome without ST elevation (ACS). The accumulated odds ratio (OR) for adverse events (30 days) in ACS with elevated cTnI (n = 5,759) and cTnT (n = 5,483) was 4.9 (95% confidence interval, CI, 3.9-6.2) and 4.6 (95% CI 3.8-5.5), respectively. Trials that mandated timed serum sampling (6 or more hours after symptom onset) had an improved predictive value for elevated cTnI (n = 2,807, OR 8.8; 95% CI 5.9-13.2) and cTnT (n = 1,990, OR 8.5; 95% CI 5.9-12.5). In conclusion, cTnI and cTnT provide similar information in ACS. The risk of adverse events is 4-fold higher in patients with suspected ACS and elevated serum cTn. For patients with an elevated timed (6-hour) sample the risk is over 8-fold higher.

Biomarkers↗
PubMed2000

CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury.

We have reviewed a battery of useful tests for evaluating sensorimotor function and plasticity acutely and chronically in unilateral rat models of central nervous system injury. These tests include forelimb use for weight shifting during vertical exploration in a cylindrical enclosure, an adhesive removal test of sensory function, and forelimb placing. These tests monitor recovery of sensorimotor function independent of the extent of test experience. Data are presented for four models, including permanent focal ischemia, focal injury to the forelimb area of sensorimotor cortex, dopaminergic neurodegeneration of the nigrostriatal system, and cervical spinal cord injury. The effect of the dendrite growth promoting factor, Osteogenic Protein-1 (OP-1) on outcome following permanent middle cerebral artery (MCA) occlusion was used as an example to illustrate how the tests can be applied preclinically. OP-1 showed a beneficial effect on limb use asymmetry in the cylinder test.

Animals↗
PubMed2000

Catalytic mechanism of a C-C hydrolase enzyme: evidence for a gem-diol intermediate, not an acyl enzyme.

2-Hydroxy-6-keto-nona-2,4-diene 1,9-dioic acid 5,6-hydrolase (MhpC) from Escherichia coli catalyses the hydrolytic cleavage of the extradiol ring fission product on the phenylpropionate catabolic pathway and is a member of the alpha/beta hydrolase family. The catalytic mechanism of this enzyme has previously been shown to proceed via initial ketonization of the dienol substrate (Henderson, I. M. J., and Bugg, T. D. H. (1997) Biochemistry 36, 12252-12258), followed by stereospecific fragmentation. Despite the implication of an active site serine residue in the alpha/beta hydrolase family, attempts to verify a putative acyl enzyme intermediate by radiochemical trapping methods using a (14)C-labeled substrate yielded a stoichiometry of <1% covalent intermediate, which could be accounted for by nonenzymatic processes. In contrast, incorporation of 5-6% of two atoms of (18)O from H(2)(18)O into succinic acid was observed using the natural substrate, consistent with the reversible formation of a gem-diol intermediate. Furthermore, time-dependent incorporation of (18)O from H(2)(18)O into the carbonyl group of a nonhydrolysable analogue 4-keto-nona-1,9-dioic acid was observed in the presence of MhpC, consistent with enzyme-catalyzed attack of water at the ketone carbonyl. These results favor a catalytic mechanism involving base-catalyzed attack of water, rather than nucleophilic attack of an active site serine. The implication of this work is that the putative active site serine in this enzyme may have an alternative function, for example, as a base.

Carbon Radioisotopes↗
PubMed2000

Cardiac troponin I in pre-eclampsia and gestational hypertension.

OBJECTIVE: To investigate serum cardiac troponin I, a sensitive marker of cardiac myocyte damage, in normal pregnancy and pregnancies complicated by hypertension with and without significant proteinuria. DESIGN: Prospective cross sectional study. SETTING: University hospital delivery suite. SAMPLE: Serum samples obtained from women in normal pregnancy and in pregnancies complicated by hypertension with and without significant proteinuria. METHOD: Women with hypertension in pregnancy (at least two readings of systolic blood pressure > 140 mmHg and diastolic blood pressure > 90 mmHg) (n = 26) and normotensive women (n = 43) were included in the study. Serum cardiac troponin I was measured using Beckman Access immunoassay. MAIN OUTCOME MEASURE: Serum cardiac troponin I level in the pregnancies complicated by hypertension (with and without significant proteinuria) compared with the levels measured in normotensive women. RESULTS: The median serum cardiac troponin I level in pregnancies complicated by hypertension was 0.118 ng/mL (n = 26) which was significantly greater than that measured in samples obtained from normotensive women in pregnancy (0.03 ng/mL; n = 43) (P < 0.0001). There were higher median serum cardiac troponin I levels in hypertensive women with significant proteinuria (0.155 ng/mL; n = 6), compared with those without proteinuria (0.089 ng/mL; n = 20; P = 0.03). CONCLUSION: Serum cardiac troponin I is elevated in women with hypertensive disorders of pregnancy indicating some degree of cardiac myofibrillary damage in these disorders.

Adult↗
PubMed1998

Prefrontal cortex infusions of SCH 23390 cause immediate and delayed effects on ventral tegmental area stimulation reward.

A reward-relevant relationship between dopamine projection regions of the ventral tegmental area (VTA) was investigated through the use of brain stimulation reward (BSR) thresholds. Using a rate-free method, changes in VTA BSR thresholds were determined after intracranial injections of the dopamine D1 antagonist, SCH 23390 into the prefrontal cortex (PFC), or the nucleus accumbens (NAcc). Reward thresholds assessed immediately after the infusion of SCH 23390 into the NAcc (0.5 microgram/0.5 microliter/side) were significantly higher than those assessed just after saline infusions, indicating a drug-induced attenuation of the rewarding effects of the brain stimulation. The effects of this dose subsided when tested 24 h later. Conversely, intra-PFC infusions of SCH 23390 at the same dose (0.5 microgram/0.5 microliter/side) resulted in lowered BSR thresholds when rats were tested immediately after infusion. In addition, animals tested 24 h after receiving the lowest dose (0.125 microgram/0.5 microliter/side) demonstrated a robust delayed threshold-lowering effect. These immediate and delayed effects of the intra-PFC dopamine antagonist demonstrate a facilitation of VTA BSR and are consistent with the view that PFC dopamine serves a modulatory role over important reward elements within the NAcc. The deferred effects of intra-prefrontal cortex DA receptor blockade on brain stimulation reward thresholds may reflect adaptive responses of subcortical structures to changes in PFC dopamine neurotransmission. It has been suggested that neural adjustments of this type may underlie long term changes in central nervous system functioning brought about by disease, drug use or behavioral conditioning.

Analysis of Variance↗
PubMed1998

The effect of hypothalamic peptide YY on hippocampal acetylcholine release in vivo: implications for limbic function in binge-eating behavior.

Central injection of peptide YY (PYY) in sated rats produces the most powerful stimulating effect of food intake known to date. The neural mechanisms by which PYY regulates appetite are not clear but may be important because abnormal levels of PYY have been implicated in the neurobiology of bulimia nervosa. Interactions between brain acetylcholine (ACh) and PYY had not been studied. Therefore, the present experiments were designed to explore the in vivo release of ACh from the hippocampus (HPC) of rats in response to hypothalamic infusion of PYY. Hippocampal ACh release was found to increase 400% in response to 10 microg PYY. In a separate experiment, blockade of the same area of the HPC with bilateral intracerebral injections of 3.5 microg scopolamine did not affect intake stimulated by intrahypothalamic injection of 4 microg PYY. Furthermore, a third experiment showed, for the first time, that PYY (2.5-10.0 microg) can elicit robust feeding when infused directly into the HPC. The significance of these findings to the activation of limbic functions such as memory, reinforcement, and obsessional processes that accompany human binge-eating syndromes is discussed.

Acetylcholine↗
PubMed1997

DAMGO and DPDPE facilitation of brain stimulation reward thresholds is blocked by the dopamine antagonist cis-flupenthixol.

The role of dopamine neurotransmission in opioid reward was investigated using a rate-independent measure for determining brain stimulation reward (BSR) thresholds. Intra-accumbens infusions of the mu- and delta-specific peptides, D-Ala2, N-Me-Phe4, Gly-ol5-Enkephalin and D-Pen2, D-Pen5-Enkephalin caused significant lowering of BSR thresholds. The dopamine D1/D2 antagonist, cis-flupenthixol, blocked these effects at a dose that did not significantly alter thresholds when given alone. These data suggest both mu- and delta-opioid potentiation of BSR is dopamine dependent.

Animals↗
PubMed1996

Involvement of delta- and mu-opioid receptors in the potentiation of brain-stimulation reward.

A rate-free method of determining brain-stimulation reward thresholds was used to identify the rewarding effects of the delta-opioid receptor and mu-opioid receptor agonist peptides, [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2-MePhe4-Gly(o1)5]enkephalin (DAMGO). The nucleus accumbens-delivered opioid receptor agonists produced marked lowering of the threshold for ventral tegmental area brain-stimulation reward. No change in baseline thresholds was seen after peripheral administration of the nonpeptide delta-opioid receptor antagonist, naltrindole. However, an unexpected finding was that naltrindole blocked the threshold-lowering effects of both DPDPE and DAMGO. These data demonstrate nucleus accumbens activation of delta- and mu-opioid receptors and ventral tegmental area brain-stimulation reward share common brain substrates. In addition, the interference of both delta- and mu-opioid receptor mediated reward by naltrindole may have implications for therapeutic use.

Analgesics↗
PubMed1996

Acute stress causes mucin release from rat colon: role of corticotropin releasing factor and mast cells.

We determined the effects of immobilization stress on rat colonic mucus release and mast cell degranulation and examined whether corticotropin releasing factor (CRF) was involved in these responses. After 30-min immobilization, rats were killed, colonic mucosal explants were cultured, and levels of rat mast cell protease II (RMCP II) and prostaglandin E2 (PGE2) were measured. Mucin release from explants was assayed by incorporation of [3H]glucosamine into colonic mucin and by histological evaluation of goblet cell depletion. Stress caused significant increases of colonic RMCP II, PGE2, and mucin release and fecal pellet output and caused an approximately 10-fold increase in colonic mucosal levels of cyclooxygenase-2 (COX-2) mRNA. These stress-associated changes were reproduced by intravenous or intracerebral injection of CRF in conscious, nonstressed rats. Pretreatment of rats with the CRF antagonist alpha-helical-CRF9-41, hexamethonium, atropine, or bretylium, or the mast cell stabilizer lodoxamide inhibited stress-induced release of RMCP II, PGE2, and mucin, whereas indomethacin prevented mucin release but not mast cell degranulation. Hexamethonium and CP-96,345, a substance P antagonist, inhibited fecal pellet output caused by stress. We conclude that CRF released during immobilization stress increases colonic transit via a neuronal pathway and stimulates colonic mucin secretion via activation of neurons and mast cells.

Animals↗
PubMed1992

Sounds of swallowing following total laryngectomy.

Accelerometer transduced sounds of swallowing in total laryngectomees did not show acoustical differences for liquid vs paste swallows, as are found in normals. Compared with normal swallows, tongue propulsion of the bolus in laryngectomee swallows occurred closer in time to a distinctive spectral change associated with bolus flow into the esophagus. Interpretation stressed the lack of mechanical traction from laryngeal elevation contributing to pharyngoesophageal sphincter opening, and the increased role of tongue propulsion in laryngectomee swallows.

Adult↗
PubMed1983

Ototoxicity associated with cis-platinum in three chemotherapy multi-drug regimens.

Hearing threshold differences postcis-platinum, relative to precis-platinum levels, were studied in 21 men from a Veterans Administration Medical Center. These patients had previously untreated advanced epidermoid cancers of the head and neck. Each patient received one of three drug combinations: (1) cis-platinum, Oncovin, and bleomycin (n = 9); (2) cis-platinum and 5-fluorouracil (n = 7); or (3) cis-platinum and bleomycin (n = 5). Wide variations in prechemotherapy hearing thresholds prevented analysis among various drug combinations. Therefore, the three groups were pooled to compare the thresholds by frequency. The frequencies tested and analyzed were: 250 Hz, 500 Hz, 1000 Hz, 2000 Hz, 4000 Hz, and 8000 Hz. Significant differences were found at 2000 Hz (P less than 0.01) and 8000 Hz (P less than 0.05). Any existing ototoxic effects of cis-platinum may have been overridden by already high prechemotherapy hearing thresholds at 4000 Hz. Since 2000 Hz was most sensitive to the ototoxic effects of cis-platinum it is suggested that this frequency be monitored routinely as a part of standard chemotherapy assessment.

Aged↗
PubMed1983

Feeding device for glossectomy patients.

Instructions are provided for making a feeding spoon from a plastic syringe for use by patients who have had a glossectomy. This adaptation may be accomplished using only a hacksaw blade and sandpaper. Such a device may be indicated for patients who have had at least 60% of their tongue resected, but who are not at significant risk of aspiration.

Eating↗
PubMed1979

Mouthwash and oral cancer: carcinogen or coincidence?

Among 200 patients with squamous cell cancer of the head and neck, 11 persons abstained from all alcoholic beverages and tobacco. All but one of these 11 patients had used mouthwash many times daily for more than 20 years. Most of them used a brand of mouthwash that contained 25% alcohol. This evidence, along with information from other patients, may be used to confirm or refute the theory that mouthwash may be carcinogenic for susceptible persons.

Aged↗
PubMed1979

Triple endoscopy: a neglected essential in head and neck cancer.

Surgeons are sometimes embarrassed to discover a second unanticipated cancer while focusing attention on an already evident cancer in the head and neck area, the bronchus, or the esophagus. we began in October, 1976, to do direct laryngoscopy, esophagoscopy, and bronchoscopy on each of the 134 cases admitted to our unit with suspected head and neck cancer. In 10 of the 134 patients in whom triple endoscopy was done, no malignancy was found. Of 24 of 124 (20%) patients with head and neck cancer, 16 patients (13%) had synchronous carcinoma and eight patients (7%) had metachronous carcinoma in this 2-year period. The incidence can be expected to rise steadily with time and mandates "triple endoscopy" on all patients with a suspected cancer in the head and neck area, the bronchus, or the esophagus, as these structures form a closely related unstable field. The discovery of several patients with dysplastic mucosal changes, carcinoma in situ, or very early invasive cancer, not only of the head and neck but also of the esophagus and bronchus, presents new problems of management.

Bronchial Neoplasms↗