Experimental Evaluation of Mouse Hind Paw Edema Induced by Iranian Naja oxiana Venom.

Iranian Naja oxiana (the Elapidae family) known as cobra snake inhabits in the northwestern part of Iran. This study aimed to evaluate the edematogenic potency of the crude venom with intraplantar injection into mice. Additionally, the inhibitory effects of three different drugs (i.e., promethazine, dexamethasone, and piroxicam) on paw edema were examined. Moreover, the gelatinase activity of this venom was assessed using the zymography method. Paw edema was induced by the intraplantar injection of different concentrations of the venom (0.5-5 μg dissolved in 50 μl of normal saline) into the mice (six in each group). It was estimated through the measurement of the increase in the paw thickness (%) with a digital caliper. The paws were pretreated and the rate of changes was measured after the venom injection. Pathological findings in the treated paws were evaluated with hematoxylin and eosin staining. Paw thickness reached its maximum amount within 5 min and resolved after 1 h. This venom had no gelatinase activity using the zymography method ruling out its role in edema. It caused non-hemorrhagic diffuse edema with the infiltration of inflammatory cells (i.e., leukocytes and lymphocytes) in the dermis. Intraperitoneal pretreatment with drugs significantly inhibited the venom-induced (1 μg/paw) edema; however, all the mice died unexpectedly a day after piroxicam injection. This in vitro and in vivo preliminary study demonstrated for the first time that N. oxiana venom-induced non-hemorrhagic edema in a short time. Dexamethasone (phospholipase A2 inhibitor; 1 mg/kg) and promethazine (H1 inhibitor; 5 mg/kg) decreased the venom-induced edema (p <0.001). It is suggested to carry out further studies to identify different mediators in venom-induced edema formation.

Resveratrol protects adult cardiomyocytes against oxidative stress mediated cell injury.

Recent studies from our laboratory have showed that resveratrol, a polyphenol found predominantly in grapes rendered strong cardioprotection in animal models of heart disease. The cardioprotection which was observed was primarily associated with the ability of resveratrol to reduce oxidative stress in these models. The aim of the current study was to corroborate the role of resveratrol as an inhibitor of oxidative stress and explore the underlying mechanisms of its action in heart disease. For this purpose, we used a cell model of oxidative stress, the hydrogen peroxide (H(2)O(2)) exposed adult rat cardiomyocytes, which was treated with and without resveratrol (30 µM); cardiomyocytes which were not exposed to resveratrol served as controls. Cell injury, cell death and oxidative stress measurements as well as the activities of the major endogenous antioxidants superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were carried out in control and H(2)O(2) exposed cardiomyocytes, treated with and without resveratrol. Pharmacological blockade using specific blockers of the antioxidant enzymes were used to confirm their role in mediating resveratrol action in H(2)O(2) exposed cardiomyocytes. The status of H(2)O(2) and antioxidant enzymes in serum samples from spontaneously hypertensive rats (SHR) treated with and without resveratrol (2.5 mg/kg body weight) was also examined. Our results showed significant cell injury and death in H(2)O(2) exposed cardiomyocytes which was prevented upon resveratrol treatment. SOD and CAT activities were decreased in H(2)O(2) exposed adult rat cardiomyocytes; treatment with resveratrol significantly prevented this reduction. However, GPx activity was not altered in the H(2)O(2) exposed cardiomyocytes in comparison to controls. Pharmacological blockade of SOD and/or CAT prevented the beneficial effect of resveratrol. In SHR, H(2)O(2) levels were increased, but CAT activity was decreased, while SOD remained unchanged, when compared to WKY rats; resveratrol treatment significantly prevented the increase in H(2)O(2) levels and the decrease in CAT activities in SHR. Based on our results, we conclude that treatment with resveratrol prevents oxidative stress induced cardiomyocyte injury mainly by preserving the activities of critical antioxidant enzymes. This may be a crucial mechanism by which resveratrol confers cardioprotection.

Occupational dose assessment and National Dose Registry System in Iran.

This report presents status of external and internal dose assessment of workers and introducing the structure of National Dose Registry System of Iran (NDRSI). As well as types of individual dosemeters in use, techniques for internal dose assessment are presented. Results obtained from the International Atomic Energy Agency intercomparison programme on measurement of personal dose equivalent H(p) (10) and consistency of the measured doses with the delivered doses are shown. Also, implementation of dosimetry standards, establishment of quality management system, authorisation and approval procedure of dosimetry service providers are discussed.

The metabolic syndrome is not associated with homocysteinemia: the Persian Gulf Healthy Heart Study.

BACKGROUND: It is uncertain whether homocysteine and the metabolic syndrome or its components are related in the general population, as studies investigating the association between homocysteine levels and insulin resistance have shown conflicting results. METHODS: In an ancillary study to the Persian Gulf Healthy Heart Study, a cohort study of Iranian men and women aged >or=25 yr, a random sample of 1754 subjects were evaluated for the association of plasma homocysteine levels and the metabolic syndrome using National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP)-III criteria. Total homocysteine levels and high sensitivity C-reactive protein (CRP) were determined by enzyme-linked immunosorbent assays. RESULTS: Subjects with lower HDL-cholesterol and higher blood pressure showed significantly higher homocysteine levels (p=0.001 and p<0.0001; respectively). There was no significant difference in serum levels of homocysteine between subjects with and without the metabolic syndrome. In multiple logistic regression analysis, the metabolic syndrome did not show a significant association with serum homocysteine levels after adjusting for sex, age, smoking, fruit and vegetable intake pattern, body mass index, and physical inactivity. Concurrent elevated CRP levels and the metabolic syndrome also did not show a significant association with serum homocysteine levels after adjusting for sex, age, and lifestyle cardiovascular risk factors. CONCLUSIONS: There was no association between the metabolic syndrome using NCEP-ATPIII criteria and homocysteinemia in this study. These data refute the hypothesis that homocysteine levels are influenced by the metabolic syndrome, at least in general healthy population.

Pharmacological stress agents for evaluation of ischemic heart disease.

Ischemic heart disease is the leading cause of death in the developed countries for those older than 65 years of age. In patients suspected to have coronary artery disease a stress test should be performed to identify the vulnerability of the myocardium to ischemia. As a rule of thumb, the evaluation of coronary artery disease is best done by exercise stress test. In patients who are not able to exercise adequately, pharmacological stress agents are used. The commonly used agents are the coronary vasodilators, adenosine and dipyridamole and the catecholamines, dobutamine and arbutamine. These agents are combined with imaging techniques to increase the sensitivity and specificity of the test. These agents have been widely used and have an excellent safety profile. Another advantage in using pharmacological stress agents is that they do not affect the image quality, especially with echocardiography and magnetic resonance imaging. Ongoing developments hold promise for safer and more reliable pharmacological stress agents in the future.

The frequency of atrioventricular block during adenosine stress testing in young, middle-aged, young-old, and old-old adults.

The frequency of atrioventricular (AV) block was evaluated in 600 consecutive patients of different age groups referred for pharmacologic stress testing. Adenosine was infused at 140 mg/kg/min for a total of 6 minutes in conjunction with radionuclide myocardial perfusion imaging. Seventy-five patients (12.5%) were young adults (< 49 years old), 214 (35.6%) were middle-aged (50-65 years), 195 (32.6%) were young-old (66-75 years), and 116 patients (19.3%) were old-old (over 75 years). The frequencies of first-degree AV block in young adults, middle-aged, young-old, old-old, and all ages were 14.6%, 9.3%, 14.3%, 17.24%, and 13.16%, respectively. The frequencies of second-degree AV block were 14.65%, 7.0%, 8.7%, 15.5%, and 10.1%, respectively. The frequencies of third-degree AV block were 2.66%, 2.33%, 1.0%, 2.58%, and 2.0%, respectively. Comparison of the incidence of the three types of AV block for each age group vs. all patients showed no statistically significant difference (p > 0.08). All types of AV block were of short duration, were well tolerated, and did not require discontinuation of the adenosine infusion or specific treatment. This study confirms the safety of adenosine stress testing in all age groups for evaluation of coronary artery disease and risk assessment.

Update on digoxin therapy in congestive heart failure.

Congestive heart failure is a progressive disease with significant morbidity and mortality. Despite advances in the prevention and treatment of cardiovascular diseases, the incidence and prevalence of congestive heart failure have increased in recent years. Contributing factors include increased survival in patients with coronary artery disease (especially myocardial infarction), an aging population and significant advances in the control of other potentially lethal diseases. New and existing agents, including angiotensin-converting enzyme inhibitors, beta blockers and, more recently, spironolactone, are being used increasingly to prolong life in patients with heart failure. Although digoxin has been used to treat heart failure for more than 200 years, its role in patients with congestive heart failure and sinus rhythm is still debatable. Over the past decade, digoxin has received renewed attention because of recognition of its neurohormonal effect and the successful use of lower dosages. In recent trials, digoxin has been shown to reduce morbidity associated with congestive heart failure but to have no demonstrable effect on survival. The goal of digoxin therapy in patients with congestive heart failure is to improve quality of life by reducing symptoms and preventing hospitalizations.

Right ventricular infarction--diagnosis and treatment.

Right ventricular infarction (RVI) as assessed by various diagnostic methods accompanies inferior-posterior wall myocardial infarction (MI) in 30 to 50% of patients. Recognition of the syndrome of RVI is important as it defines a significant clinical entity, which is associated with considerable immediate morbidity and mortality and has a well-delineated set of priorities for its management. Patients may clinically present with hypotension, elevated jugular venous pulse (JVP), and occasionally shock, all in the presence of clear lung fields. The ST-segment elevation of > or = 0.1 mV in the right precordial leads V4R is a readily available electrocardiographic sign used for diagnosis of RVI. Other diagnostic approaches for assessing RVI include echocardiography, radionuclide ventriculography, technetium pyrophosphate scanning, and hemodynamic measurements. The proper management of RVI includes volume loading to maintain adequate right ventricular preload, ionotropic support, and maintenance of atrioventricular synchrony. Reperfusion therapy should be initiated at the earliest signs of right ventricular dysfunction. Finally, complete recovery over a period of weeks to months is a rule in a majority of patients, suggesting right ventricular "stunning" rather than irreversible necrosis has occurred.

Role of beta blockers in congestive heart failure.

Prolonged activation of the adrenergic nervous system has adverse consequences on the cardiovascular system in patients with congestive heart failure. Beta adrenergic receptor-blocker therapy modifies these deleterious effects. Beta blockers have been shown to improve myocardial function and survival when used in conjunction with conventional treatment with diuretics, angiotensin-converting enzyme inhibitors, and digoxin. Beta blocker therapy in mild-to-moderate heart failure should not be delayed because it causes some reversal of both neurohormonal compensatory mechanisms and the deleterious myocardial remodeling process. This paper reviews the beneficial effects of beta adrenergic receptor-blocker therapy on the pathophysiology, symptoms, left ventricular function, morbidity, and mortality in patients with congestive heart failure. (c)2000 by CHF, Inc.

The safety of adenosine pharmacologic stress testing in patients with first-degree atrioventricular block in the presence and absence of atrioventricular blocking medications.

BACKGROUND: Pharmacologic stress testing in conjunction with radionuclide myocardial perfusion imaging may be used in the diagnosis of coronary artery disease and risk assessment. Adenosine can cause atrioventricular nodal (AV) block during infusion. In this study, we evaluated whether patients with baseline first-degree AV block could safely undergo adenosine stress testing. METHODS AND RESULTS: We evaluated the frequency of second- and third-degree AV block in patients with baseline first-degree AV block during adenosine stress testing, in the presence and absence of AV blocking medications (digitalis, beta-blockers, diltiazem, verapamil). Six hundred consecutive patients underwent pharmacologic stress myocardial perfusion imaging with adenosine infusion at 140 microg/kg/min for 6 minutes. A total of 43 patients (7.16%) had baseline first-degree AV block (PR interval > 200 msec), and 557 patients had a baseline PR interval < 200 msec. Twenty-one of the 43 patients (48.8 %) had further prolongation of PR interval > 240 msec, compared with 58 of 557 patients (10.4%) in the control group (P < .0001). In 16 of the 43 patients (37.3 %), second-degree AV block developed, compared with 45 of 557 patients (8.0 %) in the control group (P < .0001). In 6 of the 43 patients (13.9%), third-degree AV block developed, compared with 6 of 557 patients (1.0%) in the control group (P < .0001). All types of AV block were short duration and were not associated with any specific symptoms. None of these episodes required specific treatment. The presence of AV blocking medications (digitalis, beta-blockers, diltiazem, verapamil) did not increase the incidence of AV block during adenosine infusion. CONCLUSION: In patients with baseline PR interval of more than 200 msec, the frequency of second- and third-degree AV block during adenosine stress testing was significantly higher than in patients with a normal baseline PR interval. AV blocking medications did not increase the incidence of second- and third-degree AV block during adenosine stress testing. We conclude that it is safe to perform adenosine pharmacologic stress testing in patients with baseline PR prolongation.

Indications for anticoagulation in atrial fibrillation.

Factors associated with an increased risk of thromboembolic events in patients with atrial fibrillation (AF) include increasing age, rheumatic heart disease, poor left ventricular function, previous myocardial infarction, hypertension and a past history of a thromboembolic event. Patients with AF should be considered for anticoagulation or antiplatelet therapy based on the patient's age, the presence of other risk factors for stroke and the risk of complications from anticoagulation. In general, patients with risk factors for stroke should receive warfarin anticoagulation, regardless of their age. In patients who are under age 65 and have no other risk factors for stroke, either aspirin therapy or no therapy at all is recommended. Aspirin or warfarin is recommended for use in patients between 65 and 75 years of age with no other risk factors, and warfarin is recommended for use in patients without risk factors who are older than 75 years of age.

Free radical generation and the role of allopurinol as a cardioprotective agent during coronary artery bypass grafting surgery.

OBJECTIVES: To determine the time course of free radical generation and the role of allopurinol as a cardioprotective agent during coronary artery bypass surgery. DESIGN: Patients were chosen on a strict 'first come, first chosen' basis, irrespective of their age and sex. SETTING: Tertiary referral-based hospital and medical research centre. PATIENTS: A total of 36 patients underwent nonurgent coronary artery bypass grafting surgery. Eighteen patients were treated with allopurinol and 18 patients acted as control. INTERVENTIONS: Allopurinol 300 mg was administered orally, twice a day for one day preoperatively and a single dose (600 mg) was administered on the morning of the day of the operation. MEASUREMENTS AND MAIN RESULTS: Lipid peroxidation products were measured by assays for thiobarbituric acid reactive substances, mainly malondialdehyde (MDA). There were no considerable changes in either MDA levels or creatine kinase isoenzyme with muscle and brain subunits (CK-MB) activity during the ischemic period. One minute after release of the cross-clamp the level of MDA was raised significantly (P<0.001). This rise correlated with the severity of ischemia in the group treated with allopurinol as well as the control group (r=0.58, P<0.05 and r=0.49, P<0.05, respectively). The level of MDA and the activity of CK-MB were significantly lower in patients treated with allopurinol (P<0.05 and P<0.001, respectively). The increase in CK-MB activity during reperfusion correlated with aortic cross-clamp time in both the groups (r=0.62, P<0.05 and r=0.69, P<0.05, respectively). Preliminary studies using electron spin resonance spin trapping technique also demonstrated a rise in free radical adducts during reperfusion and this corroborated well with the spectrophotometric method. CONCLUSION: The results of this study show that, during bypass surgery, there is an increase in lipid peroxidation products and cardiac creatine kinase enzyme at the onset of reperfusion indicating increased free radical activity. It also suggests that pretreatment with allopurinol could effectively attenuate post-ischemic reperfusion injury.

Assessment of cardiac risk in noncardiac surgery.

Surgical techniques have been refined so that complications directly resulting from surgical procedures are relatively small. However, with the high prevalence of coronary artery disease in the United States, many surgical patients have concomitant coronary artery disease. Anesthesia as well as the surgical procedure induce stresses on the heart and circulatory system which could result in perioperative cardiac morbidity and mortality. Assessing patients prior to surgical procedures by history, physical examination, laboratory data, and newer cardiovascular diagnostic procedures can stratify the cardiac risk and help to predict the incidence of perioperative cardiac morbidity and mortality. If great risk exists, an alternative therapy or cancellation of the surgical procedure may be considered. In certain subgroups of patients, coronary artery revascularization, valvular heart surgery, or beginning medical therapy of the underlying cardiac pathology could be performed prior to the surgical procedure. If this cannot be arranged for high-risk patients, more intensive and invasive hemodynamic monitoring and optimal medical management perioperatively might reduce cardiac complications.

Effect of cocaine on left ventricular function. Relation to increased wall stress and persistence after treatment.

BACKGROUND: To determine whether alterations in left ventricular (LV) function after a cocaine infusion are due to reduced myocardial contractility or changes in loading conditions, we examined LV function in 30 morphine-sedated, closed-chest dogs. We also wanted to determine the time course of the effects of cocaine on LV function after the infusion was stopped. METHODS AND RESULTS: Two-dimensional echocardiography and hemodynamics provided LV fractional shortening and end-systolic wall stress data. Radionuclide ventriculography was also performed. Four groups of dogs received saline or cocaine infusions of 10, 30, or 100 micrograms.kg-1.min-1. Cocaine was infused for 90 minutes with ECG and arterial pressure monitoring. Animals were monitored for an additional 120 minutes after the infusion ended. Arterial pressure rose over the course of the experiment in all four groups, but saline and cocaine 10 micrograms.kg-1.min-1 did not significantly change ejection fraction. Cocaine 30 and 100 micrograms.kg-1.min-1 acutely increased arterial pressure and heart rate but decreased ejection fraction from 0.64 +/- 0.06 to 0.45 +/- 0.08 and from 0.65 +/- 0.10 to 0.46 +/- 0.11, respectively. Additionally, cocaine 100 micrograms.kg-1.min-1 decreased fractional shortening from 36 +/- 9% to 23 +/- 12%. However, cocaine 30 and 100 micrograms.kg-1.min-1 also increased wall stress from 42 +/- 15 to 65 +/- 11 g/cm2 and from 37 +/- 15 to 90 +/- 33 g/cm2, respectively. These results were analyzed by use of the relation between wall stress and fractional shortening as an index of contractility. Fractional shortening after cocaine infusion was displaced downward as a result of increased wall stress rather than changes in contractility. In addition, alteration of afterload with phenylephrine (6 micrograms/kg) and sodium nitroprusside (10 micrograms/kg) before and during infusion of cocaine 100 micrograms.kg-1.min-1 showed similar regression lines for wall stress to fractional shortening. CONCLUSIONS: Ejection-phase indexes of LV function were reduced by cocaine in this model of conscious, sedated dogs, but effects were attributable to increased wall stress rather than to reduced myocardial contractility. These effects persisted for at least 2 hours after the infusion was stopped.

Evidence for free-radical mediated injury during coronary artery bypass surgery.

Prolonged global ischemia followed by reperfusion during coronary artery bypass graft (CABG) surgery leads to a burst of oxygen free-radical generation and subsequent myocardial impairment. Blood samples were collected at different time periods from the right atrium of patients (n = 55) who underwent CABG surgery. Free-radical activity was measured by assays for thiobarbituric acid reactive species (TBARS), mainly malondialdehyde (MDA), at zero minute (before aortic cross-clamp), one minute and 10 minutes after declamping i.e. reperfusion. There was a significant increase (p < 0.001) in the level of MDA at one minute of reperfusion which continued to be elevated up to 10 minutes. This increase was significantly correlated with aortic cross-clamp time (r = 0.525, p < 0.05). The activity of CPK and CPK-MB was raised by two fold (p < 0.001) after release of the clamp. Plasma Troponin-T level was estimated in 10 patients during CABG surgery and a significant increase (p < 0.01) was observed at one minute as well as 10 minutes of reperfusion which correlated well (r = 0.81, p < 0.01) with the severity of ischemia. The concomitant rise in TBARS (marker of free-radical activity), CPK, CPK-MB and Troponin-T (indicators of myocardial damage) on reperfusion implies that there is free-radical mediated damage to the cardiac membrane during CABG surgery.

High-grade atrioventricular block during dipyridamole stress testing.

Dipyridamole stress testing may be used in the diagnosis of coronary artery disease and risk assessment of patients who are unable to exercise. Although dipyridamole perfusion imaging has a good safety record, serious side-effects may rarely occur. We present a case in which dipyridamole induced high-grade atrioventricular (AV) block that responded promptly to intravenous aminophylline but not to atropine.