不同剂量胺碘酮联合氯沙坦治疗阵发性房颤患者复律后的窦性心律维持效果

目的:研究不同剂量胺碘酮联合氯沙坦治疗阵发性房颤患者复律后的窦性心律维持效果。方法:选取2013年1月到2014年1月我院收治的阵发性房颤患者130例,按照随机数字表法将患者分为A组和B组,每组65例,两组均给予氯沙坦治疗,A组给予胺碘酮600 mg/d,1-2周后改用200 mg/d维持1年;B组给予胺碘酮600 mg/d,1-2周后改用200 mg/d,1个月后改为100mg/d维持1年,比较两组治疗前后转复维持有效率、心率、血压、左房内径(LAD)、左房舒张末期容积(LAEDV)、左房收缩末期容积(LAESV)、左心房射血分数(LAEF)以及不良反应。结果:两组转复维持有效率比较差异无统计学意义(P0.05);治疗后收缩压、舒张压、LAEDV和LAESV均优于治疗前(P0.05),但治疗后两组组间心率、收缩压、舒张压、LAD、LAEDV、LAESV、LAEF比较差异无统计学意义(P0.05);B组不良反应发生率显著低于A组,两组比较差异具有统计学意义(P0.05)。结论:小剂量胺碘酮联合氯沙坦与大剂量胺碘酮联合氯沙坦治疗阵发性房颤转复效果相当,但是不良反应较少。     

Effect of long-term prazosin treatment on certain humoral and metabolic factors in patients with primary hypertension]

An effect of the long-term prazosin therapy on sympathetic activity, renin plasma activity and beta-endorphin and lipid blood levels was investigated in 23 patients with the primary arterial blood hypertension. Group A included 18 patients treated with prazosin, and group B - 5 patients treated with prazosin combined with propranolol. Mean daily dose of prazosin in group A was 3.0-10.0 +/- 1.3 mg in different phases of therapy whereas in group B mean daily dose of prazosin was 3.0-6.5 +/- 1.8 mg and propranolol 50-80 mg. Significant decrease in diastolic and systolic blood pressure (p < 0.01) was achieved in both groups. Additionally significant decrease in pulse rate (p < 0.01) was seen in group B. It was found that prazosin produced significant increase in plasma noradrenaline in group A and decrease in 4-hydroxy-3-methoxyglycol excretion with the urine (p < 0.05) in both groups. Moreover, negative correlation between a decrease in blood pressure (diastolic) and noradrenaline excretion with the urine (p < 0.05) was noted in group A. No effect of prazosin therapy on plasma renin activity, beta-endorphin and lipids blood levels was observed in both groups. These results suggest that prazosin therapy in patients with the primary blood hypertension exerts an effect on sympathetic activity and does not change plasma renin activity or blood beta-endorphin and lipids levels.     

松龄血脉康胶囊联合低剂量厄贝沙坦治疗65岁以上高血压患者疗效观察

目的观察松龄血脉康胶囊联合低剂量厄贝沙坦治疗65岁以上老年高血压病患者的临床疗效。方法将90例65岁以上高血压患者随机分为松龄血脉康胶囊联合低剂量厄贝沙坦治疗组和高剂量厄贝沙坦对照组。治疗组给予松龄血脉康胶囊1.5g,每天3次,同时加厄贝沙坦75mg/d;对照组单纯给予厄贝沙坦150mg/d治疗。两组治疗周期为1个月进行比较血压控制情况及不良反应等指标水平。结果治疗后,两组患者收缩压和舒张压均较治疗前下降,差异有统计学意义(P0.05);治疗后两组患者的收缩压、舒张压比较,差异无统计学意义(P0.05)。结论松龄血脉康联合低剂量厄贝沙坦治疗高血压疗效确切,无明显不良反应,值得临床应用。     

Hydralazine once daily in hypertension.

The effects of hydralazine formulation and dose interval were assessed in 20 patients with hypertension well controlled on conventional hydralazine tablets, 100 mg twice daily, in addition to atenolol and a diuretic. The double-blind study used four regimens crossed over in random order at five-week intervals; placebo; conventional hydralazine 100 mg twice daily; conventional hydralazine 200 mg once daily; and slow-release hydralazine 200 mg once daily. Blood pressure and pulse rate were assessed soon after (2.5 +/- 0.9 h) and immediately before taking hydralazine (previous dose: once daily, 26.5 +/- 0.9 h; twice daily, 13.6 +/- 2.0 h). Seventeen patients completed the study. All hydralazine regimens were associated with significant falls in blood pressure. Once-daily treatment with conventional hydralazine was unsatisfactory, as its hypotensive effect waned at 24 h; there was a significant difference between the peak and trough effects on blood pressure and pulse in rapid acetylators. Compared with placebo twice-daily conventional hydralazine and once-daily slow-release hydralazine gave satisfactory control for 24 hours in both rapid and slow acetylators, though the hypotensive effect was larger in the slow acetylators. It is concluded that there is no need to administer hydralazine more than twice daily.     

Why hypertensive patients vary in their response to oral debrisoquine.

The relation between dose, systemic availability, and response to oral debrisoquine was studied in 13 hypertensive patients receiving no other treatment. In 11 who received the same daily dose (40 mg) the fall in mean standing systolic blood pressure varied between 0-3 and 44-4 mm Hg. There was a ninefold difference in the daily urinary excretion and pre-dose plasma concentration of unchanged drug but an inverse correlation between daily urinary excretion of debrisoquine and its 4-hydroxy metabolite (r= -0-86), suggesting that a low recovery of debrisoquine occurs because of extensive metabolism. There was a significant correlation between the fall in standing systolic blood pressure and the mean daily urinary excretion (r= +0-82) and pre-dose plasma concentration (r= +0-82) of unchanged debrisoquine. In contrast, there was a significant inverse correlation between the urinary recovery of the metabolite and the fall in blood pressure (r= -0-82). The availability of debrisoquine is the major determinant of response to this drug. In the absence of side effects a poor response may be an indication to increase the daily dose rather than add another hypotensive agent.     

Effects of various doses of captopril on plasma aldosterone concentrations in patients with essential hypertension

Various doses (5 mg, 12.5 mg and 25 mg) of angiotensin I converting enzyme inhibitor (SQ 14,255, captopril) were administered to 8 patients with essential hypertension on a three-crossover study design, and the time course of mean blood pressure (MBP), plasma renin activity (PRA), plasma angiotensin converting enzyme activity (ACE-A), plasma cortisol (PC) and plasma aldosterone (PA) were determined following administration of the drug. MBP fell in a dose dependent manner, and PRA showed a minor but significant increases in cases receiving 5 and 12.5 mg of the drug. A large and significant increase in PRA was observed following 25 mg of captopril. ACE-A was also reduced in a dose dependent manner. There was no difference between changes in PC at any of the three dose levels. The serum potassium concentration was determined before and 3 hr after 25 mg of captopril treatment and no significant change was observed. In spite of the dose dependent and theoretical changes in the above parameters, lowered responses of PA to each dose of the drug were shown in reverse order against an increasing dose. That is to say, the grade of fall in PA following 25 of captopril was smaller than that following the other doses of the drug, and 5 mg induced a greater decrease in PA than 12.5 mg. Based on these findings, the relatively high dose of captopril in the present study was apparently more effective in increasing some factors which suppressed reduction of PA by a fall in angiotensin II than a low dose of the drug.     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

In vivo measurements of the cerebral perfusion and cardiovascular effects of the novel guanidine ME10092 in the non-human primate, Papio ursinus

The novel guanidines N-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine (ME 10092) and N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N1-hydroxyguanidine (PR5) were recently reported to exhibit promising cardioprotective activities in myocardial ischaemia and reperfusion in rats. The current study investigated for the first time pharmacological effects of ME10092 in the primate, viz. the Cape baboon Papio ursinus. The effects of ME10092 (1 and 2 mg/kg doses) on the cerebral blood flow, heart rates and the systolic and diastolic blood pressure were investigated after intravenous injection to the baboon under anaesthesia. The cerebral perfusion effects of ME10092 were assessed using Single Photon Emission Computed Tomography according to the split-dose approach and 99mTc-hexamethyl-propylene amine oxime as brain perfusion tracer. The observation that the recovery times from the anaesthesia were unacceptably prolonged excluded doses beyond 2 mg/kg. The data indicate that no cerebral perfusion changes were induced at both the 1 and 2 mg/kg doses of ME10092. Both these doses of ME10092 showed blood pressure and heart rate effects, with the latter being more significant. Decreases in heart rate were seen directly after ME10092 administration reaching levels of about 20% for the 2 mg/kg dose and about 15% for the 1 mg/kg dose at around 6 min post drug administration. A transient decrease in both systolic and diastolic blood pressure was observed for the higher dose. The blood pressure data further suggest an attenuation of the anaesthesia induced increase in pressure usually present in non-intervention studies. ME10092 clearly exhibits mycocardial effects in the non-human primate, similar to the effects previously observed in the ischaemia-reperfusion rat model, where ME10092 showed strong protection.     

Effects of pirbuterol and sodium nitroprusside on pulmonary haemodynamics in hypoxic cor pulmonale.

The acute haemodynamic effects of oral pirbuterol (a beta-agonist) were contrasted with those of sodium nitroprusside, a vasodilator, in six patients with hypoxic chronic bronchitis and emphysema. Sodium nitroprusside (1-5 mg/kg intravenously) reduced mean pulmonary arterial pressure and total pulmonary vascular resistance significantly (p less than 0.01) without change in cardiac output or right ventricular ejection fraction, measured by radionuclide ventriculography. Oral pirbuterol (22.5 mg) produced a greater reduction in total pulmonary vascular resistance than sodium nitroprusside, largely as a result of increasing cardiac output. Right ventricular ejection fraction also increased significantly after pirbuterol (p less than 0.01). Pirbuterol in a lower dosage (15 mg by mouth) in six further patients with hypoxic chronic bronchitis and emphysema produced similar changes in total pulmonary vascular resistance and right ventricular ejection fraction. Nine of the patients who were studied acutely thereafter received pirbuterol 15 mg thrice daily for six weeks, which produced a significant fall in systolic pulmonary arterial pressure and a rise in right ventricular ejection fraction (p less than 0.01), without a significant fall in arterial oxygen tension. Pirbuterol acts as a vasodilator on the pulmonary circulation in these patients and may in addition improve right ventricular performance by an inotropic action.     

Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials

Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination.Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, β blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose.Subjects 40 000 treated patients and 16 000 patients given placebo.Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs.Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, β blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose.Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.     

Double-blind Evaluation of Verapamil,Propranolol, and Isosorbide Dinitrate against a Placebo in the Treatment of Angina Pectoris

In the treatment of angina pectoris a double-blind evaluation of verapamil (Cordilox) at two dose levels—namely, 80 mg thrice daily and 120 mg thrice daily—propranolol (Inderal) 100 mg thrice daily, and isosorbide dinitrate (Vascardin) 20 mg thrice daily has been made against a placebo. The assessment was based on relief from daily attacks of angina on effort and the response to a whole-body exercise test. We can find no statistically significant difference between the effects of verapamil (120 mg three times a day) and propranolol (100 mg three times a day) in the treatment of angina of effort. Both of these preparations are more effective than a placebo both in the reduction of daily attacks (P < 0·01) and in the prolongation of exercise test (P < 0·05). Isosorbide dinitrate (20 mg three times a day) appears to be no more effective than a placebo in the treatment of angina on effort, but 14 out of 32 patients experienced headache of such severity that even when the dose was reduced to 10 mg thrice daily this drug therapy had to be withdrawn. Both propranolol (100 mg three times a day) and verapamil (120 mg three times a day) had a significant lowering effect on the diastolic blood pressure as measured with the patient standing (P < 0·01).     

The effects of posture changes on blood pressure and heart rate of anesthetized and reserpinized sloths

1. Tilting sloths anesthetized with chloralose from erect to supine or supine to erect produced little or no effect on heart rate. 2. Tilting anesthetized sloths from erect to supine increased both systolic and diastolic pressures significantly and by about the same amounts. The maximum effect was produced in 20 sec. 3. Pressures stabilized at a higher level than in the erect posture but below the maximum reached in tilting. 4. Tilting these sloths from the supine to the erect posture resulted in a rapid (20 sec) and dramatic fall in pressures to below the initial erect pressure levels. Return to initial erect levels took place slowly. 5. Tilting reserpinized sloths from erect to supine or supine to erect produced little or no effect on heart rate. 6. Tilting reserpinized sloths from erect to supine increased both systolic and diastolic pressures materially and by similar amounts. The maximum effect took 50 sec. 7. Pressures stabilized at higher levels than in the erect posture but less than maximum reached with tilting. 8. Tilting these sloths from supine to erect caused significant falls in pressure to slightly below the initial erect pressure, with maximum effect reached in 30 sec and eventual return to control level. 9. Pressure changes were almost entirely the result of altered venous return. 10. Neither chloralose nor reserpine completely blocked vascular control but reduced it materially.     

Relation between dose of bendrofluazide,antihypertensive effect,and adverse biochemical effects.

OBJECTIVE--To determine the relevant dose of bendrofluazide for treating mild to moderate hypertension. DESIGN--Double blind parallel group trial of patients who were given placebo for six weeks and then randomly allocated to various doses of bendrofluazide (1.25, 2.5, 5, or 10 mg daily) or placebo for 12 weeks. SETTING--General practices in Zealand, Denmark. PATIENTS--257 Patients with newly diagnosed or previously treated hypertension, aged 25-70, who had a mean diastolic blood pressure of 100-120 mm Hg after receiving placebo for six weeks. MAIN OUTCOME MEASURES--Reduction in diastolic blood pressure and changes in biochemical variables (potassium, urate, glucose, fructosamine, total cholesterol, apolipoprotein A I, apolipoprotein B, and triglyceride concentrations). RESULTS--All doses of bendrofluazide significantly reduced diastolic blood pressure to the same degree (10-11 mm Hg). Clear relations between dose and effect were shown for potassium, urate, glucose, total cholesterol, and apolipoprotein B concentrations. The 1.25 mg dose increased only urate concentrations, whereas the 10 mg dose affected all the above biochemical variables. CONCLUSION--The relevant range of doses of bendrofluazide to treat mild to moderate hypertension is 1.25-2.5 mg a day. Higher doses caused more pronounced adverse biochemical effects including adverse lipid effects. Previous trials with bendrofluazide have used too high doses.     

Cough and Cold Remedies: a Potential Danger to Patients on Monoamine Oxidase Inhibitors

Experiments have been carried out in healthy volunteers to study the effects of phenylpropanolamine on the blood pressure and possible interactions with monamine oxidase inhibitors.In three subjects 50 mg. of phenylpropanolamine taken orally produced a modest rise of systolic pressure. Two proprietary preparations containing this dose in a slow-release form had no significant effect on the blood pressure. In all three subjects 100 mg. of phenylpropanolamine taken orally caused a more pronounced rise of systolic pressure and a rise of diastolic pressure.In contrast, 50 mg. of phenylpropanolamine orally caused a rapid and potentially dangerous rise of blood pressure in a subject taking the monamine oxidase inhibitor tranylcypromine, and a similar acute rise of blood pressure occurred in this subject when given a proprietary cough linctus containing the same dose of phenylpropanolamine. These and other results suggest that severe hypertensive episodes are more likely to occur when preparations containing phenylpropanolamine in a free form, rather than in slow-release form, are taken by patients being treated with monoamine oxidase inhibitors.The acute rise of blood pressure due to the interaction of phenylpropanolamine and monoamine oxidase inhibitors was reversed by intramuscular injection of phentolamine.     

Nifedipine and atenolol singly and combined for treatment of essential hypertension: comparative multicentre study in general practice in the United Kingdom

A randomised double blind parallel group study was performed to compare the efficacy and acceptability of slow release nifedipine (maximum dose 40 mg twice a day) with those of atenolol (maximum dose 100 mg once a day) as single agents for the treatment of essential hypertension. Of 410 patients recruited almost exclusively from general practices in 22 centres in the United Kingdom 210 received nifedipine and 200 atenolol. Both drugs significantly reduced blood pressure, and control—a reduction of the diastolic pressure to less than 95 mm Hg—was obtained in about 65% of patients. Those who received nifedipine had more pronounced reductions in systolic pressure than those who received atenolol. One hundred and forty nine patients who failed to respond adequately to either atenolol or nifedipine in low doses were given both drugs once daily for eight weeks in a fixed combination capsule that contained atenolol 50 mg and nifedipine 20 mg. All patients showed further reductions in blood pressure, although those who were taking β atenolol before the combination capsule had more pronounced reductions in systolic pressures. Twenty six patients (12%) were withdrawn because of adverse effects while taking nifedipine compared with 19 (10%) taking atenolol. Flushing and oedema were more common after the calcium antagonist, whereas diarrhoea and dyspepsia were more common after atenolol. The frequencies of headaches, dizziness, fatigue, and dyspnoea were equally distributed between the two groups. When the fixed combination capsule was taken side effects such as flushing and oedema continued.Nifedipine was more effective than atenolol in lowering systolic blood pressure, although neither drug used alone controlled the pressure of more than two thirds of the patients studied. When used in a fixed combination slightly better control of blood pressure was achieved with a lower dose of each drug.     

Antihypertensive efficacy of propranolol given twice daily.

The therapeutic efficacy of propranolol in four and two daily doses was compared in 63 treated hypertensive patients in a multicentre trial. After 3 months of a stable diastolic blood pressure while receiving propranolol four times a day the patients were switched to a twice-a-day regimen, the drug being given at 8 am and 8 pm, with the same total daily dose, for 3 more months. Blood pressures and heart rates were measured at 8 am, 12 noon, 4 pm and 8 pm at 4-week intervals. There were no significant changes in mean blood pressure after the change to the twice-a-day regimen, although some patients reported new side effects. Compliance appeared to be unaffected.     

Methyldopa and propranolol or practolol in moderate hypertension.

The effect of a low dose of methyldopa combined with (a) a non-selective and (b) a selective beta-adrenoceptor antagonist was studied in a double-blind crossover trial in 24 carefully selected patients with moderate hypertension (mean initial lying blood pressure 189/117 mm Hg). Each patient received methyldopa 750 mg/day, propranolol 240 mg/day, practolol 600 mg/day, methyldopa 750 mg/day combined with propranolol 240 mg/day, methyldopa 750 mg/day combined with practolol 600 mg/day, and placebo for four weeks each according to a random sequence. After four weeks of therapy the most effective treatment, methyldopa combined with propranolol, reduced lying and standing blood pressures by 36-5/21-4 mm Hg and 44-7/25 mm Hg respectively. Thic combination had similar effects to those of the combination of methyldopa with the cardioselective agent practolol except that it reduced lying diastolic pressure further. The combination was more effective than either treatment alone. No significant differences were found between the effects of propranolol, practolol, or methyldopa at the doses used.     

Trial of atenolol and chlorthalidone for hypertension in black South Africans.

Twenty-four black patients (Zulus) with hypertension participated in a double-blind, placebo-controlled cross-over trial of the efficacy of a beta-blocking agent (atenolol) 100 mg once daily as compared with chlorthalidone 25 mg once daily. The two drugs were also given combined at these doses and the effects compared with those of the drugs given alone. Atenolol as sole treatment had no appreciable effect on blood pressure as compared with placebo. Chlorthalidone produced a small decrease, but this was not statistically significant. Combining the two drugs, however, produced a significant reduction in blood pressure (mean lying blood pressure p < 0.001; mean standing blood pressure p < 0.0002). These findings suggest that beta-blockers should not be regarded as baseline treatment of hypertension in blacks.     

Effect of Tetracycline on Leucocyte Ascorbic Acid Levels

Fourteen men aged 73-94 showed a fall in leucocyte ascorbic acid levels during five days'' treatment with 1 g of tetracycline daily. A control group of nine men aged 74-90 showed no fall in leucocyte ascorbic acid levels. Of the control group, three were treated with phenobarbitone 60 mg thrice daily, three with phenylbutazone 200 mg thrice daily, and three with aloxiprin 1,200 mg four times a day. A further two men aged 87 and 90 showed increased urinary excretion of ascorbic acid while receiving 1 g of tetracycline daily.     

Phase I evaluation of coumarin (1,2-benzopyrone) and cimetidine in patients with advanced malignancies.

Fifty-four patients with advanced malignancies were treated on this phase I trial of coumarin and cimetidine. The dose of coumarin was escalated, with three patients treated at each dose level, while the cimetidine dose was held constant at 300 mg four times daily. Patients received coumarin alone as a single daily oral dose for 14 days; on day 15, cimetidine was added and both drugs were continued until progression of disease. This trial was initiated with patients receiving coumarin at 400 mg daily and closed at 7 g daily with four of five patients on this dose experiencing nausea and vomiting. Treatment was generally well tolerated over a wide range of coumarin doses. Symptomatic side effects were few, mild, and usually self limited. Side effects included insomnia, nausea, vomiting, diarrhea, and dizziness. Two patients withdrew from therapy because of daily nausea and vomiting. Typically, nausea, vomiting, and dizziness occurred 2.5-3 hours after a dose of coumarin. In most patients, these side effects abated spontaneously with continuation of therapy. There was no significant hematologic or renal toxicity. Hepatotoxicity occurred in only one patient and was manifested by asymptomatic abnormal elevations of serum hepatic transaminases. This toxicity was reversible upon interruption of therapy. Objective tumor regressions were observed in six patients with renal cell carcinoma. Responses occurred at coumarin doses ranging from 600 mg to 5 g daily. Coumarin is a relatively nontoxic, oral, outpatient therapy that warrants further investigations for the treatment of human malignancies. Because of its low toxicity, there is potential for combining coumarin with chemotherapeutic and/or biological agents in an attempt to improve on efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)