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Biomedical subjects

D Lyons

Publications and source records attributed to D Lyons.

At least 37 records · Page 2Linked to original sources
PubMed1997

Identification and characterization of a pro-tumor necrosis factor-alpha-processing enzyme from the ADAM family of zinc metalloproteases.

Tumor necrosis factor-alpha (TNF) is initially expressed as a 26-kDa membrane-bound precusor protein (pro-TNF) that is shed proteolytically from the cell surface, releasing soluble 17-kDa TNF. We have identified human ADAM 10 (HuAD10) from THP-1 membrane extracts as a metalloprotease that specifically clips a peptide substrate spanning the authentic cleavage site between Ala76 and Val77 in pro-TNF. To confirm that HuAD10 has TNF processing activity, we cloned, expressed, and purified an active, truncated form of HuAD10. Characterization of recombinant HuAD10 (rHuAD10) suggests that this enzyme has many of the properties (i.e. substrate specificity, metalloprotease activity, cellular location) expected for a physiologically relevant TNF-processing enzyme.

ADAM Proteins↗
PubMed1997

ACE inhibition: postsynaptic adrenergic sympatholytic action in men.

BACKGROUND: The mechanisms by which ACE inhibitors produce a sustained clinical benefit are not entirely clear but may involve the sympathetic nervous system. We compared the effect of local brachial artery infusions of an ACE inhibitor (perindoprilat) with the effect of placebo (0.9% NaCl) on endogenously mediated (lower body negative pressure [LBNP]) and exogenously mediated (brachial artery infusions of norepinephrine) sympathetic vasoconstriction. METHODS AND RESULTS: Eight healthy, normotensive male volunteers (20 to 32 years) were studied on one occasion. Forearm blood flow (FABF; mL x dL forearm(-1) x min(-1)) responses to LBNP (-20 cm H2O) and increasing increments of norepinephrine (60, 120, and 240 pmol/min) were compared when coinfused with placebo and perindoprilat (5 nmol/mL). FABF was measured simultaneously in both arms by venous occlusion plethysmography with mercury-in-Silastic strain gauges with drugs infused locally at the left brachial artery. The right arm served as a control. Baseline FABFs did not differ between the infused and control arms (3.04+/-0.52 versus 3.05+/-0.42 mL x dL forearm(-1) x min(-1); P=.98). Perindoprilat did not alter FABF when infused alone, but the FABF response to LBNP in the infused arm was attenuated during the perindoprilat infusion compared with placebo (-17.8+/-4.3% versus -33.8+/-3.1%, respectively; P=.015). The FABF response to the maximum dose of norepinephrine was also attenuated during the perindoprilat infusion compared with placebo (-28.3+/-1.4% versus -36.9+/-2.8%, respectively; P=.015). The mean slope of the FABF (log transformed) versus norepinephrine dose-response curve was significantly attenuated by perindoprilat compared with placebo (-0.11+/-0.019 versus -0.02+/-0.02; P=.001). CONCLUSIONS: We conclude that ACE inhibition has a significant postsynaptic sympatholytic effect in the forearm circulation of men.

Adult↗
PubMed1997

Dopamine depletion in the rostral nucleus accumbens alters the cerebral metabolic response to cocaine in the rat.

The functional consequences of dopamine depletion in the rostral nucleus accumbens were examined using the quantitative 2-[14C]deoxyglucose method for determining rates of local cerebral glucose utilization. Cerebral metabolism was determined in 35 brain structures of Sprague-Dawley rats with unilateral 6-hydroxydopamine or sham lesions of the rostral accumbens. The effect of the lesion was assessed in cocaine-naive animals treated systemically with cocaine or saline. In saline-treated animals, the lesion increased cerebral metabolism in typical basal ganglia regions, such as the globus pallidus and entopeduncular nucleus, as well as portions of the extended amygdala that included the bed nucleus of the stria terminalis and the hypothalamic preoptic area. Cerebral metabolism was affected bilaterally in a subset of all affected structures which demonstrated that the functional consequences of the lesion extended beyond the primary monosynaptic output zones of the rostral accumbens. The lesion also changed the topography of the normal cocaine response such that cocaine effects were blunted in the shell of the nucleus accumbens, globus pallidus and the medial ventral pallidum. Thus, the present study describes functional evidence of the link between the rostral accumbens and the extended amygdala and demonstrates that dopamine in the rostral accumbens plays an important role in the central response to cocaine.

Animals↗
PubMed1997

Partnership nursing home care for dementia: the Glasgow experience--one-year follow-up.

The outcome of the transfer of 60 elderly patients suffering from dementia from hospital to nursing home care under a partnership contract was reviewed at 6 and 12 months following transfer. The nursing home population had fared badly compared with patients remaining in hospital during the first 3 months. This difference was less evident at 6 months follow-up and had disappeared at 12 months follow-up. It seems that a partnership agreement such as this can deliver a quality of health care at least as good as hospital treatment as long as the transfer is handled carefully.

Aged↗
PubMed1997

Partnership nursing home care for dementia: the Glasgow experience--one-year follow-up.

The outcome of the transfer of 60 elderly patients suffering from dementia from hospital to nursing home care under a partnership contract was reviewed at 6 and 12 months following transfer. The nursing home population had fared badly compared with patients remaining in hospital during the first 3 months. This difference was less evident at 6 months follow-up and had disappeared at 12 months follow-up. It seems that a partnership agreement such as this can deliver a quality of health care at least as good as hospital treatment as long the transfer is handled carefully.

Aged↗
PubMed1997

Effect of enalapril and quinapril on forearm vascular ACE in man.

OBJECTIVE: Different ACE inhibitors can be distinguished in vitro by their affinity for converting enzyme in vascular and other tissues. Quinapril appears to be amongst the more effective inhibitors of vascular tissue ACE in vitro. This study assesses the in vivo effect of single oral doses of quinapril and enalapril, in attenuating the vasoconstrictive action of angiotensin I (AI) (which we have previously shown depends on its conversion to angiotensin II (AII) by vascular ACE) in the forearm resistance vessels of man. METHODS: The design was of randomized, open, placebo controlled, two way crossover type, Forearm blood flow (FABF) was measured simultaneously in both forearms by mercury in silastic strain gauge plethysmography. AI infusion were via a fine bore cannula in the left brachial artery with the right arm serving as a control. RESULTS: Mean plasma ACE on placebo was 34.3 U.l-1. Both quinapril and enalapril produced a similar degree of plasma ACE inhibition reducing concentrations to 2.8 U.l-1 and 2.6 U.l-1 respectively. Quinapril caused a significantly greater inhibition of AI induced vasoconstriction with a 30.0% reduction compared with 67.0% and 85.0% for enalapril and placebo respectively. Enalapril attenuated AI induced vasoconstriction to a greater degree than placebo but the difference was not significantly different. CONCLUSION: These results indicate that when quinapril and enalapril are administered as single 20 mg doses, each of which produces the same degree of plasma ACE inhibition and blood pressure reduction- quinapril inhibits vascular ACE to a greater degree than both enalapril and placebo.

Adult↗
PubMed1997

Impaired nitric oxide-mediated vasodilatation and total body nitric oxide production in healthy old age.

1. Basal release of nitric oxide from the vascular endothelium maintains a constant vasodilating tone. Impaired nitric oxide-mediated vasodilatation has been described in hypertension and atheromatous disease. Circulatory diseases account for considerable morbidity and almost half of all deaths in people over the age of 75 years. 2. We have therefore compared nitric oxide-dependent vasorelaxation in 12 healthy elderly subjects with 12 young volunteers matched for blood pressure, cholesterol and glucose, using forearm occlusion venous plethysmography combined with brachial artery infusions of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 1, 2 and 4 mumol/min) with noradrenaline (60, 120 and 240 pmol/min) as a control vasoconstrictor. We also measured urinary nitrate excretion after a controlled 48 h low nitrate diet as an index of total body nitric oxide production and correlated these changes with forearm blood flow responses to L-NMMA and noradrenaline in both groups. 3. The mean age and blood pressure of the elderly subjects was 76 (range 66-82) years and 132/76 (SEM 4/3) mmHg respectively, while in the young these were 27 (20-35) years and 131/72 (4/3) mmHg respectively. L-NMMA and noradrenaline produced dose-dependent reductions in forearm blood flow in both groups. L-NMMA (4 mumol/min) produced less vasoconstriction in the elderly than in the young (-37.7 +/- 2.6 versus -48.3 +/- 4.2%; P = 0.017). The mean slope of the L-NMMA dose-response curves in the elderly was significantly less than the younger group (-35.2 +/- 3.1 versus -63.7 +/- 10.6; P = 0.041). Noradrenaline, 240 pmol/min, also produced less vasoconstriction in the elderly compared with the young (-22.8 +/- 2.9 versus -35.3 +/- 5.0%; P = 0.029) although the slopes of the dose-response curves did not differ significantly. 4. Urinary nitrate adjusted for creatinine clearance was also significantly higher in the younger group (460.6 +/- 97.7 versus 205.9 +/- 64.8 mumol/day; P = 0.042) and showed a significant correlation with the percentage change in forearm blood flow in response to the maximum dose of L-NMMA (r = 0.5, P = 0.046). 5. We conclude that nitric oxide-mediated vasodilatation in the forearm vascular bed is diminished in old age and this reflects a more generalized reduction in nitric oxide production (as measured by urinary nitrate) in the circulation of older people. The blunted response to noradrenaline points to a more generalized reduction in vascular reactivity in the elderly.

Adult↗
PubMed1997

Do trandolapril and indomethacin influence renal function and renal functional reserve in hypertensive patients?

AIMS: To assess the effect of trandolapril (2 mg once daily) and indomethacin (25 mg three times daily), alone and in combination, on renal function and renal functional reserve in hypertensive patients (DBP 95-115 mmHg) requiring regular non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: Randomized, double-blind, placebo-controlled, four way crossover design. After 3 weeks treatment renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured using the p-aminohippurate (PAH) and inulin methods. Renal functional reserve was estimated by measuring RPF and GFR at the end of an intravenous infusion of dopamine 2 microg kg(-1) and 10% amino acid solution. RESULTS: There was no significant difference in RPF between treatments: -22.79 ml min(-1) (95% CI -54.82, 9.24) for placebo and trandolapril, -10.37 ml min(-1) (95% CI -30.7, 9.96) for placebo and indomethacin, -14.78 ml min(-1) (95% CI -50.33, 20.77) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve RPF between treatments: -34.96 ml min(-1) (95% CI -119.8, 49.88) for placebo and trandolapril, 29.78 ml min(-1), -15.18, 74.74) for placebo and indomethacin, and -25.84 ml min(-1) (95% CI -87.62, 35.94) for placebo and trandolapril with indomethacin. There was no significant difference in GFR between treatments: -1.01 ml min(-1) (95% CI -7.45, 5.42) for placebo and trandolapril, -7.88 ml min(-1) (95% CI -15.08, -0.68) for placebo and indomethacin, and -0.36 ml min(-1) (95% CI -7.58, 6.86) for placebo and trandolapril with indomethacin. There was no significant difference in functional reserve GFR between treatments: 5.13 ml min(-1) (95% CI -4.97, 15.23) for placebo and trandolapril, 6.31 ml min(-1) (95% CI -1.88, 14.5) for placebo and indomethacin, 7.21 ml min(-1) (95% CI 1.26, 13.16) for placebo and trandolapril with indomethacin. CONCLUSION: In hypertensives chronic treatment with NSAIDs or ACEI alone or in combination did not change RPF or GFR and did not change renal functional reserve capacity of RPF or GFR.

Adult↗
PubMed1997

The contractile properties of the elderly human diaphragm.

It has previously been reported that aging is associated with a substantial decrease in diaphragm strength. To test this hypothesis we studied 15 (10 male, 5 female) subjects with a mean age of 29 (range 21 to 40) and 15 elderly (10 male, 5 female) subjects, mean age 73 (range 67 to 81). We measured transdiaphragmatic pressure (Pdi) during a maximal sniff (Sniff Pdi) and during bilateral cervical magnetic stimulation (CMS) of the phrenic nerve roots (Tw Pdi). Additionally in 17 subjects (9 elderly and 8 young) the Pdi elicited by paired CMS (pTw Pdi) was obtained at interstimulus intervals ranging from 10 to 999 ms (1 to 100 Hz). There was considerable overlap between groups. Mean Sniff Pdi in the elderly was 119 cm H2O compared with 136 cm H2O for the young subjects; this represented a median reduction of 18 cm H2O or 13% (p = 0.05, 95% Cl of difference 0 to 33 cm H2O). Mean Twitch Pdi in the elderly was 26.8 cm H2O compared with 35.2 cm H2O, a median reduction of 8 cm H2O or 23% (p = 0.004, 95% Cl 3 to 13 cm H2O). At 10 Hz the elderly tended to generate a higher fraction of the Pdi obtained at 100 Hz than the young, but this trend did not achieve statistical significance (p = 0.11). We conclude that aging is associated with a reduction in diaphragm strength. However the magnitude of the reduction is small and may be offset by a leftward shift of the force-frequency relationship.

Adult↗
PubMed1997

Effect of the non peptide angiotensin II antagonist, GR117289C on the vasoconstrictor actions of angiotensin II in the human forearm.

AIMS: GR117289C is a non peptide, selective angiotensin (AT1) receptor antagonist. The purpose of this study was to determine whether this agent, given orally, could attenuate the vasoconstrictor effects of angiotensin II(AII) infused locally into the forearm circulation in man. METHODS: Eight healthy male subjects were studied on four occasions in a randomized, double-blind, placebo controlled, crossover study. Five hours (approximate time of peak dynamic effect) following dosing with GR117289C (300 mg, 100 mg, 10 mg or placebo), A II was infused in incremental doses (0, 0.1, 0.4, 1.6, 6.2, 25 and 100 pmol min-1) into the left brachial artery, each for 10 min. Forearm blood flow was measured using venous occlusion plethysmography. RESULTS: GR117289C inhibits the vasoconstrictor effects of A II in a dose dependent manner. The active treatment: placebo ratios of forearm blood flow in the infused arm during the highest dose of AII (100 pmol min-1) were: GR117289C 10 mg, 1.12 (95% C.I. 0.81-1.55; P = 0.478), 100 mg, 1.43 (95% C.I. 1.01-2.01; P = 0.042) and 300 mg, 1.62 (95% C.I. 1.17-2.24; P = 0.006). There was no significant difference in blood pressure between each of the treatment groups and placebo. CONCLUSIONS: GR117289C is a pharmacologically active, oral A II antagonist in healthy men.

Administration, Oral↗
PubMed1996

Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys.

The functional consequences of acute cocaine administration in nonhuman primates were assessed using the quantitative 2-[14C]deoxyglucose method. Local rates of cerebral metabolism were determined after an intravenous infusion of 1.0 mg/kg cocaine or vehicle in six awake cynomolgus monkeys (Macaca fascicularis) trained to sit calmly in a primate chair. Cocaine administration decreased glucose utilization in a discrete set of structures that included both cortical and subcortical portions of the limbic system. Glucose metabolism in the core and shell of the nucleus accumbens was decreased markedly, and smaller decrements were observed in the caudate and anterior putamen. In addition, cocaine administration produced significant decreases in limbic cortex. Metabolism was decreased in orbitofrontal cortex (areas 11, 12o, 13, 13a, 13b), portions of the gyrus rectus including area 25, entorhinal cortex, and parts of the hippocampal formation. The cortical regions in which functional activity was altered provide dense projections to the nucleus accumbens, and the decreased activity in these projections may be responsible in part of the large alterations in functional activity within the ventral striatum. Decreased metabolism also was evident in the anterior nuclear group of the thalamus, raphe nuclei, and locus ceruleus. The acute cerebral metabolic effects of cocaine in the conscious macaque, therefore, were contained primarily within a set of interconnected limbic regions, including ventral prefrontal cortex, medial temporal regions, the ventral striatal complex, and anterior thalamus. The decreased rates of glucose metabolism reported here resemble decrements found using positron emission tomography in humans. In the rat, by contrast, metabolic activity increased and changes were focused in subcortical regions. The present results represent an important expansion of the neural circuitry on which cocaine acts in the monkey as compared with the rat, and this in turn implies that cocaine affects a broader spectra of behaviors in primates than in rodents.

Animals↗
PubMed1996

Comparison of two fluorine-18 labeled benzamide derivatives that bind reversibly to dopamine D2 receptors: in vitro binding studies and positron emission tomography.

The purpose of the present set of studies was to characterize, in vitro and in vivo, two benzamide analogues, 2,3-dimethoxy-N-[1-(4-fluorobenzyl)piperidin4yl]benzamide (MBP) and 4'-fluoroclebopride (FCP), for studying dopamine D2 receptors with Positron Emission Tomography (PET). In vitro binding studies were conducted to determine the affinities of MBP and FCP to the three subtypes of dopamine D2 receptors: D2(long), D3, and D4 receptors. MBP was found to have a high affinity (Ki = 1-8 nM) for all three subtypes of the D2 receptor, whereas FCP had nanomolar affinity (Ki approximately 5.5 nM) for D2(long) and D3 receptors, and a lower affinity for D4 receptors (Ki = 144 nM). In vitro binding studies also revealed that MBP had a relatively high affinity for rho1 receptors (Ki = 11 nM) compared to FCP (Ki = 340 nM). PET imaging studies were conducted in rhesus monkeys with the fluorine-18 labeled analogues of each compound. Both [18F]MBP and [18F]FCP displayed reversible binding kinetics during the 3 h time course of PET. [18F]FCP was found to have a higher basal ganglia:cerebellum ratio and lower variability in the rate of washout from D2 receptors in vivo relative to [18F]MBP. Neither radiotracer was found to produce radiolabeled metabolites capable of crossing the blood-brain barrier. The high rho1 binding affinity and low basal ganglia:cerebellum ratio of [18F]MBP indicate that this ligand may not be suitable for quantitative studies of D2 receptors. The results from the in vitro and in vivo studies indicate that [18F]FCP is a promising ligand for studying D2 receptors with PET.

Animals↗
PubMed1996

Isolation and characterization of human tissue kallikrein produced in Escherichia coli: biochemical comparison to the enzymatically inactive prokallikrein and methionyl kallikrein.

This report describes bacterial expression, isolation, and characterization of human tissue kallikrein recombinantly produced in Escherichia coli. Successful production of enzymatically active recombinant human kallikrein requires the following processes: expression, solubilization and refolding of prokallikrein, thermolysin activation, and chromatographic separation. All experimental data confirmed that bacterially derived human kallikrein is properly folded and exhibits expected biochemical functions. As confirmed by SDS-PAGE and reverse-phase HPLC, recombinant kallikrein is apparently pure and is devoid of reduced or other partially folded kallikrein forms. Recombinant kallikrein behaves as a monomeric molecule in solution and exhibits full enzymatic activity in hydrolyzing peptide substrates. The molecule can bind to aprotinin to form kallikrein-inhibitor complex at a 1:1 molar ratio. Peptide mapping analysis derived from pepsin digestion of recombinant kallikrein assigned five disulfide bonds which match those of porcine kallikrein predicted from X-ray structure. Peptides containing unpaired cysteines or mispaired disulfide bonds were not detected. Both properly folded prokallikrein and methionyl kallikrein, containing a propeptide and an initiator methionine at their N-termini, respectively, were also produced and isolated. These two molecules are structurally similar to recombinant kallikrein, but are not enzymatically active.

Amino Acid Sequence↗
PubMed1996

Indomethacin does not attenuate the hypotensive effect of trandolapril.

This is a randomised, double-blind, placebo-controlled, four-way crossover study to determine if indomethacin attenuates the hypotensive effect of trandolapril. Twenty-three hypertensive patients (diastolic blood pressure (DBP) 95-115) requiring NSAID were recruited. Seventeen completed the study. Three week treatment periods: trandolapril 2 mg od and indomethacin 25 mg tds, trandolapril 2 mg and placebo, indomethacin and placebo, placebo and placebo. Clinic and ambulatory BP after 3 weeks of each treatment. Study had 85% power to detect a 5 mm Hg difference in BP (s.d. 7 mm Hg). End of treatment clinic BPs were: 152.9/98 mm Hg (95% CI 147.2, 158.6/95.8, 101.4) with placebo and placebo; 150.4/94.9 mm Hg (95% CI 144.7, 156.1/92.1, 97.7) with trandolapril and indomethacin; 148.2/96.5 mm Hg (95% CI 142.5, 153.9/93.7, 99.3) with trandolapril and placebo; and 156.6/97.4 mm Hg (95% CI 150.9, 162.3/94.6, 100.2) with indomethacin and placebo. There were no significant interactions between trandolapril and indomethacin for clinic systolic BP (SBP) (P = 0.79) or clinic DBP (P = 0.87). When trandolapril treatments (placebo or with indomethacin) were compared to treatments without trandolapril (placebo or indomethacin), trandolapril lowered clinic SBP by 5.4 mm Hg (P = 0.047) and DBP by 2.3 mm Hg (P = 0.08). Mean ambulatory BP was: 140.6/88.2 mm Hg (trandolapril and placebo); 142.8/89.7 mm Hg (trandolapril and indomethacin); 149.6/95.0 mm Hg, (indomethacin and placebo); 147.7/94.0 mm Hg (placebo and placebo). Compared with placebo, trandolapril and placebo lowered BP by 6.5/7.5 mm Hg (P < 0.001, SBP; P < 0.001, DBP). Compared with indomethacin, trandolapril and indomethacin lowered BP by 5.0/5.5 mm Hg (P = 0.001, SBP; P < 0.001, DBP). In the present study trandolapril 2 mg lowered clinic SBP and ambulatory BP, but indomethacin did not attenuate this. Indomethacin had no significant effect on either clinic or ambulatory BP. The antihypertensive effects of trandolapril in this study were modest. Patient selection factors may have contributed to the observed responses, but it seems unlikely from these data that a clinically important drug interaction has occurred.

Adult↗
PubMed1995

Benefits of placebos.

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Clinical Trials as Topic↗
PubMed1995

Angiotensin II. Adrenergic sympathetic constrictor action in humans.

BACKGROUND: Angiotensin II (Ang II) facilitates adrenergic neurotransmission in normotensive and hypertensive subjects, whereas angiotensin-converting enzyme inhibitors have been shown to depress circulating catecholamine concentrations in some studies. We investigated the effect of local intra-arterial infusion of Ang II into the brachial artery of healthy volunteers during blockade of postsynaptic alpha-receptors with phentolamine. The response was compared with that seen with Ang II infused during nitroprusside administration at a dose designed to give a dilator response similar to that with phentolamine. METHODS AND RESULTS: Ang II (6.25, 25, and 100 pmol/min) was infused alone and then together with sodium nitroprusside (4 micrograms/min) and phentolamine (40 micrograms/min) in eight healthy volunteers. Forearm blood flow was measured by strain-gauge plethysmography. The percentage reduction in forearm blood flow produced by Ang II 100 pmol/min in the phentolamine-predilated vascular bed was significantly lower than that seen in the sodium nitroprusside-predilated forearm bed (28.1 +/- 2.9% versus 52.9 +/- 4.2%; P = .006). Comparison of the rate of change of blood flow in response to quadrupling doses of Ang II during blockade of alpha-receptors with phentolamine and during nitroprusside administration was calculated from the mean slope of the regression line of log-transformed blood flow versus dose of Ang II. The mean slope during nitroprusside administration (-0.16 +/- 0.025) was significantly greater than that during blockade with phentolamine (-0.098 +/- 0.020) (P = .046). CONCLUSIONS: We conclude that a significant part of the vasoconstrictive action of exogenous Ang II on forearm resistance vessels in humans is sympathetically mediated.

Adult↗
PubMed1995

Conflict of interest in academia.

Conflict of interest in academia has been increasingly recognized over the past decade. Yet, comparatively little is written in respect to this problem. The authors provide an overview of conflict of interest as it applies to nursing research and addresses how it can also affect practice and education. Resources for the development of guidelines to prevent conflicts of interest are presented.

Biomedical Research↗