The move towards evidence-based medicine.
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Humans↗
Biomedical subjects
M F O'Rourke
Publications and source records attributed to M F O'Rourke.
Comparative PET studies of the distribution of (-)-3,4-methylenedioxy-N-[11C]methamphetamine and (-)-[11C]methamphetamine in a monkey brain.
Carbon-11 labeled (-)-methamphetamine and (-)-3,4-methylenedioxy-N-methamphetamine were synthesized by methylation of the corresponding desmethyl precursors with [11C]H3I in 40-60% yield in a synthesis time of 30 min from EOB with a specific activity of 0.5-1.2 Ci/microM. PET studies in a Rhesus monkey revealed that the uptakes of both compounds in different brain regions were similar, and the retention of radioactivity in these brain regions remained constant throughout the study for the former while it was washed out slowly for the latter. The half-life of (-)-3,4-methylenedioxy-N-methamphetamine in monkey brain was approximately 70 min. Analyses of arterial plasma by HPLC revealed that 50% of radioactivity in the plasma remained as (-)-methamphetamine while only 3% remained as (-)-3,4-methylenedioxy-N-methamphetamine at 60 min post-injection. These results suggest that the uptakes of both compounds in monkey brain are probably not receptor mediated. Rather, blood flow, lipophilicity of the compounds or other transport mechanisms may play a role in their uptakes.
3,4-Methylenedioxyamphetamine↗
PET study of the distribution of [11C]fluoxetine in a monkey brain.
No-carrier-added [11C]fluoxetine (2) was synthesized by methylation of norfluoxetine (1) with [11C]H3I in 20% radiochemical yield in a synthesis time of 40 min from EOB with a specific activity of 0.48 Ci/microM (EOB). In vivo study in mouse indicated that the uptake of 2 in mouse tissues was high and the radioactivity remained constant throughout the study. The uptake of 2 in mouse brain was 4%/g. PET study in a Rhesus monkey also showed that the uptakes of 2 in different brain regions were similar and the retention of radioactivity in these regions remained constant throughout the study (80 min). Analysis of arterial plasma by HPLC showed that only 20% of radioactivity in the plasma remained as 2 at 30 min post-injection. These results suggest that the uptake of fluoxetine in monkey brain is probably not receptor mediated. Rather, blood flow, lipophilicity or other transport mechanisms may play a role in its uptake.
Animals↗
Pressure wave propagation in a multibranched model of the human upper limb.
The influence of the large arteries and the peripheral load on pressure wave propagation in the human upper limb was investigated in an anatomically realistic multibranched model based on linear transmission theory. To mimic vascular changes seen in life, the viscoelastic properties of large arteries and the peripheral load properties (represented as modified windkessels) were altered as follows: Young's modulus (from 10.9 x 10(6) to 15.3 x 10(6) dyn/cm2) and phase (from 0 to 15 degrees) of the complex elastance, windkessel time constant (from 0 to 0.6 s), and peripheral reflection coefficient (from 0 to 0.95). The relationship between the central aortic and peripheral radial pressure waveforms was analyzed in the time and the frequency domain. Results indicate that the large arterial properties have less influence (peak systolic pressure changed by 3% and peak of transfer function changed by 29%) than the properties of the peripheral load (systolic pressure changed by 14% and peak of transfer function changed by 74%) on the pressure wave propagation in the upper limb.
Arm↗
Characterization of [3H]RX821002 binding to alpha-2 adrenergic receptor subtypes.
Alpha-2 adrenergic receptors have been divided into four pharmacological subtypes based on their differences in affinity for several drugs. Previous studies showed that [3H]RX821002 has a high affinity for the alpha-2A subtype. The current study characterized the binding properties of [3H]RX821002 [2-(2-methoxy-1,4- benzodioxan-2yl)-2-imidazoline] to the alpha-2A receptor in CHO-C10 cells, alpha-2B in neonatal rat lung, alpha-2C in OK cells and alpha-2D in bovine pineal gland. Membrane binding studies of [3H]RX821002 were done in 25 mM glycylglycine buffer at room temperature. The nonspecific binding rates at the KD concentration were 4.9%, 20%, 14% and 8.3% of the total for CHO-C10, neonatal rat lung, OK cells and bovine pineal, respectively, which were determined by adding 100 microM norepinephrine. Saturation curves indicate that [3H]RX821002 has a high affinity for all alpha-2 adrenergic subtypes. The KD values were 0.29, 1.05, 0.37 and 0.19 nM for CHO-C10, neonatal rat lung, OK cells and bovine pineal, respectively. [3H]Rauwolscine has affinities of 0.34, 0.55 and 0.24 nM for the alpha-2A, -2B and -2C subtypes. By contrast, [3H]rauwolscine has a much lower affinity for alpha-2D subtype with a KD value of 5.2 nM. The binding site density for [3H]RX821002 was significantly lower in the neonatal rat lung compared with [3H]rauwolscine. The correlation coefficients of pKi values of adrenergic compounds against [3H]RX821002 versus [3H]rauwolscine were close to unity for each tissue. These data clearly show that the two ligands label the same alpha-2 adrenergic receptor population.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic alpha-Antagonists↗
Pulse wave mechanics revisited: relevance to therapy of cardiovascular disease with calcium antagonists.
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Calcium Channel Blockers↗
Continuous noninvasive recording of arterial pressure.
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Blood Pressure↗
Arterial mechanics and wave reflection with antihypertensive therapy.
PURPOSE: To describe a logical therapy for hypertension, based on functional elements of structural changes. EFFECTS OF STRUCTURAL CHANGES: Structural changes to large blood vessels in hypertension include medial degenerative changes, which stiffen arteries and increase pulse wave velocity, and intimal atherosclerotic changes, which narrow arterial segments. The former cause early wave reflection with increased systolic pressure in central arteries and the left ventricle. The latter compromise blood flow to vital organs. LOGIC OF VASODILATOR THERAPY: Vasodilator drugs with arterial dilating properties are the most logical and effective therapy. These agents decrease wave reflection from peripheral sites and so reduce systolic pressure in the left ventricle and central arteries; this effect is achieved both by decreasing the stiffness of peripheral arteries and by a differential effect on arterial calibre at branching sites. Arterial vasodilators also tend to dilate stenoses and collateral vessels and thereby minimize vascular 'steal', whereas arterial vasodilators (such as dipyridamole, hydralazine, prazosin) have little or no significant effect on wave reflection, and so fail to reduce the ill-effects of early wave reflection on the left ventricle and central arteries. Furthermore, by dilating arterioles in normal tissue, arteriolar vasodilators can cause vascular 'steal' in the heart or brain. CONCLUSIONS: The most effective vasodilators are those with both arterial- and arteriolar-dilating properties. Differential effects of vasodilators on arteries and arterioles can explain some differing effects of antihypertensive agents in clinical trials, as well as differing clinical responses in individual patients.
Arteries↗
Accuracy of a portable interpretive ECG machine in diagnosis of acute evolving myocardial infarction.
From a study of 526 patients having automatic ECG analysis, criteria were established which diagnosed acute evolving Q wave myocardial infarction with 71% sensitivity and 98% specificity. Specificity was 100% when patients with known previous Q wave infarction were excluded. In pre-hospital practice the high sensitivity and specificity were maintained. This method appears appropriate, when other criteria are met, for paramedic-initiated pre-hospital thrombolysis with remote supervision of a cardiologist by telephone.
Adult↗
Frederick Akbar Mahomed.
Frederick Akbar Mahomed was an Englishman of mixed Indian and Irish descent who made substantial contributions to the study of high blood pressure in a short professional life from 1872 to 1884. He was strongly influenced by the previous work of Richard Bright on kidney disease at his own hospital (Guy's Hospital in London) and by the contemporary pathological studies of Gull and Sutton on arteriolar changes in persons with high blood pressure. In detailed clinical studies, he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. He described the constitutional basis and natural history of essential hypertension and pointed out that this disease could terminate with nephrosclerosis and renal failure. His clinical studies were done without the benefit of a sphygmomanometer but with the aid of a quantitative sphygmogram that he had initially developed while a medical student. He described characteristic features of the pressure pulse in patients with high blood pressure and in persons with arteriosclerosis consequent on aging. These pressure wave changes have recently been verified and explained. He contributed to a number of other advances in medical care, including blood transfusion and appendectomy for appendicitis. He initiated the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials. Mahomed died from typhoid fever, almost certainly contracted from one of his patients, at age 35 at the height of his career.
Blood Pressure Determination↗
Introduction to arterial compliance and function.
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Arteries↗
Determinants of recurrent ischaemia and revascularisation procedures after thrombolysis with recombinant tissue plasminogen activator in primary coronary occlusion.
This paper reports the immediate effects of thrombolysis and their subsequent influence on revascularisation procedures and clinical outcome over the subsequent twelve months. Coronary arteriography was performed at 21 days on 131 of 145 patients who received recombinant tissue plasminogen activator (n = 68) or placebo (n = 63) within 2.5 hours of symptom onset after primary coronary occlusion. Patency rates (TIMI grades 2 and 3) of the infarct-related artery were 81% with plasminogen activator and 63% with placebo (P = 0.02). Early (within 21 days) angiography for recurrent ischaemia was necessary in 31 (21%) patients (20 plasminogen activator, 11 placebo NS) and definite reinfarction occurred in 8 (5%) patients (4 plasminogen activator, 4 placebo). During one year follow-up without planned secondary intervention, coronary artery bypass grafting was more frequent in patients who had received thrombolytic therapy (23% plasminogen activator, 4% placebo P = 0.001); coronary angioplasty procedures were similar in both groups (12% plasminogen activator, 11% placebo NS). Mortality at 21 days was 5% (4 plasminogen activator, 4 placebo) and at one year was 7% (5 plasminogen activator, 5 placebo). Logistic regression analysis identified models comprising characteristics predictive of subsequent bypass grafting (plasminogen activator, multivessel disease, occluded infarct-related artery) and coronary angioplasty (non-q wave infarction, severe (91-99%) residual stenosis, left anterior descending infarct-related artery). Initial non-q wave infarction was the only predictor of early recurrent ischemia (odds ratio 4, P = 0.02) irrespective of residual stenosis severity.
Angioplasty, Balloon, Coronary↗
Effects of atropine on pancreatic response to bethanechol, cholecystokinin, and food intake in rats.
Atropine was used to examine the role of cholinergic mechanisms in the pancreatic secretory response to food intake. Unanesthetized rats with gastric, jugular vein, bile-pancreatic, and duodenal cannulas were used; bile-pancreatic juice was recirculated. The maximal response to bethanechol (4 mg.kg-1.h-1) was similar to cholecystokinin (CCK)-8-induced maximal secretion. Atropine (25-200 micrograms.kg-1.h-1) markedly inhibited basal amylase output and caused dose-related inhibition of the incremental response to a maximal dose of bethanechol. Atropine (50 micrograms.kg-1.h-1) shifted the dose-response curve to bethanechol (1-32 mg.kg-1.h-1) to the right but did not alter maximal amylase output. L 364718 (0.5 mg/kg), a CCK receptor antagonist, had no effect on bethanechol-stimulated pancreatic secretion. Atropine (50 micrograms.kg-1.h-1) did not affect the incremental responses to low doses of CCK-8; the maximal response occurred at a higher CCK-8 dose because atropine decreased basal secretion. Atropine (50 or 200 micrograms.kg-1.h-1) did not decrease the amylase response to ingestion of a liquid meal. We conclude that 1) bethanechol is a full agonist for stimulation of pancreatic enzyme secretion and its effects are not mediated by CCK release; 2) atropine is a competitive antagonist of bethanechol-induced pancreatic secretion in vivo but does not directly affect responses to CCK-8; 3) cholinergic mechanisms do not mediate the pancreatic enzyme response to a liquid meal in rats.
Animals↗
Brachioradial delay.
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Aortic Valve Stenosis↗
Nitroglycerin has more favourable effects on left ventricular afterload than apparent from measurement of pressure in a peripheral artery.
Nitroglycerin (0.3 mg) was administered sublingually to 14 patients undergoing cardiac catheterization, and pressure waves compared in the ascending aorta and brachial artery. After nitroglycerin, ascending aortic systolic pressure fell in all cases (by 6-44, average 22 mmHg) whereas brachial systolic pressure remained unchanged (in three) or fell to a lesser degree (4-33, average 12 mmHg). Diastolic pressure did not change significantly. Alterations in pressure and in wave contour were explained on the basis of arterial dilation, with reduction in wave reflection. Nitroglycerin reduces left ventricular afterload through arterial dilation as well as preload through venous dilation. This effect on afterload is not apparent from measurement of pressure in the brachial artery.
Administration, Sublingual↗
Echocardiographic and electrocardiographic study of the normal kangaroo heart.
Healthy kangaroos are prone to sudden death. To investigate possible causes of this phenomenon, echocardiographic and electrocardiographic studies were conducted in seven healthy sedated (intramuscular ketamine 20 mg/kg, xylazine 2 mg/kg) kangaroos aged 1.5-5 years weighing 5.5-48 kg. As in human hypertrophic cardiomyopathy, kangaroos showed relative left ventricular hypertrophy measured as a ratio of (internal left ventricular end-diastolic diameter)/(septal + posterior wall thickness): 1.7 (SD 0.2) in kangaroos and 1.3 (SD 0.4) in hypertrophic cardiomyopathy cf 2.6 (SD 0.6) in normal man (p less than 0.001 respectively). Peak left ventricular diastolic filling velocity was smaller in kangaroos (2.6 (SD 0.3)/sec) and hypertrophic cardiomyopathy (3.3 (SD 0.7)/sec) than in normal man (4.1 (SD 1.0)/sec) (p less than 0.01, p less than 0.05). The end of T wave occurred earlier than the closing of aortic valve. Corrected QT interval (0.20 (SD 0.02) sec) was shorter than the normal value for man (0.34-0.40 sec). In conclusion, kangaroos have cardiac hypertrophy of unknown aetiology, with impaired diastolic function, as in non-obstructive hypertrophic cardiomyopathy patients. Corrected QT interval was short. These echocardiographic and electrocardiographic findings may explain the mechanism of sudden death in kangaroos, a species which may be used as an experimental model of non-obstructive hypertrophic cardiomyopathy in man.
Animals↗
Effect of CCK antagonist L 364718 on meal-induced pancreatic secretion in rats.
The specific cholecystokinin (CCK)-receptor antagonist L 364718 was used to examine the role of CCK in meal-induced pancreatic secretion. Unanesthetized rats with gastric, jugular vein, bilepancreatic, and duodenal cannulas were used; bile-pancreatic juice was recirculated. Basal amylase secretion (30% of maximal) was not inhibited by L 364718 doses of 0.5 or 2 mg/kg intravenously. L 364718 (0.02 to 2 mg/kg) caused dose-related inhibition of the maximal amylase response to CCK-8 (200 pmol.kg-1.h-1), with greater than 80% inhibition at doses greater than or equal to 0.5 mg/kg. L 364718 (0.5 mg/kg) shifted the dose-response curve to CCK-8 (25-3,200 pmol.kg-1.h-1) to the right (ED50 increased 10-fold) but did not alter maximal amylase output consistent with competitive inhibition of CCK in vivo. Ingestion of liquid food significantly increased amylase output threefold above basal. L 364718 (0.5 mg/kg) completely blocked this response. These results suggest that although CCK does not regulate basal pancreatic enzyme secretion, it is the primary mediator of pancreatic enzyme secretion in response to a liquid meal.
Amylases↗