Biomedical subjects

E W Lee

Publications and source records attributed to E W Lee.

At least 19 recordsLinked to original sources

PubMed1998

Influence of endothelin-1 on clonidine-induced cardiovascular effects in anesthetized rabbits.

This study was designed to investigate the effect of endothelin-1 (ET-1) on clonidine-induced cardiovascular effects in urethane-anesthetized rabbits and to clarify the mechanism of its action. Clonidine (5, 10, and 20 micrograms/kg) given into a femoral vein (i.v.) produced a marked dose-dependent fall in arterial blood pressure and heart rate, but intracerebroventricular (i.c.v.) clonidine (2, 4, and 8 micrograms/kg) induced a slight depressor effect and bradycardia. Intravenous clonidine-induced hypotension was significantly enhanced by pretreatment with ET-1 or sarafotoxin, but the bradycardia was not affected. Intracerebroventricular clonidine-induced depressor responses were greatly inhibited by sarafotoxin pretreatment but not by ET-1. Both i.v. and i.c.v. ET-1 and sarafotoxin elicited marked hypotensive responses, with a slight decrease in heart rate. The depressor action evoked by i.v. ET-1 and sarafotoxin was significantly inhibited by nitroprusside but not by phentolamine or sodium acetylsalicylate. Furthermore, the weak bradycardia induced by ET-1 or sarafotoxin was not influenced by pretreatment with phentolamine, nitroprusside, or sodium acetylsalicylate. Taken together, these experimental data suggest that ET-1 potentiates clonidine-induced hypotensive responses in the urethane-anesthetized rabbit through facilitation of nitric oxide release, which appears to be associated with endothelin receptors.

Adrenergic alpha-Agonists↗

PubMed1998

Does low dose dopamine attenuate the decrease of renal function in the treatment of patients under controlled mechanical ventilation with positive end expiratory pressure?

Controlled mechanical ventilation (CMV) with positive and expiratory pressure (PEEP) is often used to improve the pulmonary gas exchange in patients with acute respiratory distress syndrome. However, this ventilatory technique may induce hemodynamic and hormonal changes which may lead to vital organ dysfunction, such as oliguria. Low dose dopamine, acting as a dopaminergic receptor agonist, may improve vital organ perfusions, i.e. renal, mesenteric and coronary perfusions. The purpose of this current study was to evaluate the effects of low dose dopamine on renal function and hemodynamic change during controlled mechanical ventilation with PEEP. The study was performed on 10 patients treated with PEEP in the surgical intensive care unit. Starting with 0 cmH2O of PEEP and adding 4 cmH2O of PEEP at 4-hour intervals until it reached 12 cmH2O of PEEP, dopamine, 2 ug/kg/min, was selectively, administered, intravenously during the last two hours of each four hour intervals. Following each procedure, hemodynamic parameters, urine output, creatinine clearance and fractional excretion of sodium were measured. The cardiac index and mean arterial pressure had both decreased, but the mean pulmonary arterial pressure was increased at 12 cmH2O of PEEP compared with 0 cmH2O of PEEP in both groups with and without low dose dopamine. The main result of this study was that low dose dopamine attenuated the decrease of the cardiac index, urine output and creatinine clearance induced by mechanical ventilation with PEEP at 12 cmH2O.

Adult↗

PubMed1998

Ionic mechanism of ibutilide in human atrium: evidence for a drug-induced Na+ current through a nifedipine inhibited inward channel.

This study examined the ionic mechanism of ibutilide, a class III antiarrhythmic in clinical use, on freshly isolated human atrial cells. Cells had resting potentials of -71.4 +/- 2.4 mV, action potentials with overshoot of 36.8 +/- 1.8 mV, duration of 265 +/- 89 msec at 90% repolarization and slow repolarization (n = 16). Ibutilide, at 10(-7) M, markedly increased action potential duration. Four types of outward currents were detected: Ito, Iso, a delayed rectifier and IK1. Ibutilide had no inhibitory effect on these outward currents at 10(-7) M (n = 28). In K(+)-free solutions and -40 mV holding potential, mean peak inward current at 20 mV was -1478 +/- 103 pA (n = 12). Ibutilide increased this current to -2347 +/- 75 pA at 10(-7) M, with half maximal effect (Kd) of 0.1 to 0.9 nM between -10 and +40 mV (n = 21). At similar concentrations, the drug increased APD, with Kd of 0.7 and 0.23 nM at 70 and 90% repolarization, respectively (n = 8). Ibutilide shifted the mid-point of the steady-state inactivation curve from -21 to -12.2 mV (n = 6), and reduced current decline during repetitive depolarization (n = 5). The drug induced inward current was carried by Na+o through a nifedipine inhibited inward channel because Na+o removal eliminated the effect, and nifedipine abolished the inward current and the drug induced APD prolongation. We propose that a Na+ current through the L-type Ca++ channel mediates ibutilide's potent clinical class III antiarrhythmic action.

Action Potentials↗

PubMed1998

The analysis of correlated panel data using a continuous-time Markov model.

We consider the analysis of correlated panel data in which two or more correlated multistate processes are periodically observed on each individual and the exact transition times between states are unknown. We describe a procedure that models each process marginally under a time-homogeneous Markov model allowing for covariates. The resulting estimators are shown to be asymptotically jointly normal with a covariance matrix that can be consistently estimated. Simultaneous inference procedures are also proposed. Methods are illustrated using data from an AIDS clinical trial to compare the toxic effects of two treatments on two hematologic variables, hemoglobin and absolute neutrophil count.

AIDS-Related Opportunistic Infections↗

PubMed1997

Pulsed magnetic and electromagnetic fields in experimental achilles tendonitis in the rat: a prospective randomized study.

OBJECTIVE: To investigate the effects of pulsed magnetic fields (PMF) and pulsed electromagnetic fields (PEMF) on healing in experimental Achilles tendon inflammation in the rat. DESIGN: Prospective randomized trial. SETTING: University medical school. METHODS: Exposure of the Achilles tendon and injury by a weight of 98.24 g falling from a height of 35cm in 180 male Sprague-Dawley rats. INTERVENTION: A daily 15-minute session with PMF of 17Hz or 50Hz, or PEMF of 15Hz or 46Hz, or a sham session. OUTCOME MEASURES: Random sacrifice 2 hours after the operation, and at 1, 3, 7, 14, or 28 days. Assessment of water content, weight, and histological appearance of the tendons. RESULTS: The time from injury and the various treatment modalities exerted a significant influence on the water content of the tendon after the injury (two-way ANOVA, p = .02). At day 3, the water content of the PEMF 46Hz group was significantly higher than in the other groups, decreasing sharply by day 7, and being similar to the other groups thereafter. By the end of the experiment, the PEMF 15Hz group was not significantly different from the control group. At day 7, the PMF 50Hz group showed significantly lower water content than the control group (p = .03), but at 14 days the PMF 50Hz group was not significantly different from the control group. PMF 50Hz suppressed the extravascular edema during early inflammation. PMF 17Hz showed a similar initial trend, producing a consistent lower water content throughout the experiment, reaching statistical significance by the end of treatment. By the end of the experiment, the collagen fibers had nearly regained their normal alignment in all groups, with a more physiological alignment seen in the PEMF 17Hz group. CONCLUSIONS: The tendon returned to histological normality in all groups, but the PMF 17Hz group showed better collagen alignment by the end of the study. PMF 17Hz resulted in a greater reduction of inflammation, with a better return of the tendon to histological normality. Different PMF and PEMF could be applied according to when treatment is started after the injury. If there is no delay between injury and beginning of pulsed magnetic treatment, PMF 17 should be used.

Achilles Tendon↗

PubMed1996

Two sample comparison for large groups of correlated binary responses.

Although there is much literature on testing the treatment effect in experiments with correlated binary outcomes, the existing methodologies only work well when the cluster size is small. In this paper, I propose a simple method to test the treatment effect in experiments with large groups of correlated binary outcomes. I use the weighted estimating equations approach to estimate the treatment effect. The proposal is appropriate under any correlation structure. Power comparisons show the advantage of the new procedure.

Computer Simulation↗

PubMed1995

Müller cell involvement in methanol-induced retinal toxicity.

Methanol is an ocular toxicant which causes visual dysfunction often leading to blindness after acute exposure. The physiological and biochemical changes responsible for this toxicity are poorly understood. Previously, we reported that the folate-reduced (FR) rat is an animal model which mimics the characteristic human methanol toxicities. The present study examines the hypothesis that depletion of ATP after methanol administration is the initiating event in methanol-induced retinal toxicity. ATP is reduced in retinae of methanol-treated FR rats to the same extent as is seen in retinae of FR and folate-sufficient (FS) rats treated with the Müller cell (retinal glial cell) toxin alpha-aminoadipic acid. Changes in the electroretinogram and the response of Müller cells to a potassium stimulus are also similarly eliminated in methanol-treated FR rats and alpha-aminoadipic acid-treated FR and FS rats. These results suggest that the Müller cell may be the initial target in methanol-induced visual system toxicity.

2-Aminoadipic Acid↗

PubMed1995

Role of retinal metabolism in methanol-induced retinal toxicity.

Methanol is a toxicant that causes systemic and ocular toxicity after acute exposure. The folate-reduced (FR) rat is an excellent animal model that mimics characteristic human methanol toxic responses. The present study examines the role of the methanol metabolites formaldehyde and formate in the initiation of methanol-induced retinal toxicity. After a single oral dose of 3.0 g/kg methanol, blood methanol concentrations were not significantly different in FR rats compared with folate-sufficient (FS) (control) rats. However, FR rats treated with 3.0 g/kg methanol displayed elevated blood (14.6 mM) and vitreous humor (19.5 mM) formate levels and abnormal electroretinograms (loss of b-wave) 48 h postdose. FR rats pretreated with disulfiram (DSF) prior to 3.0 g/kg methanol treatment failed to display these symptoms. Formaldehyde was not detected in blood or vitreous humor with or without DSF treatment, suggesting that formate is the toxic metabolite in methanol-induced retinal toxicity. Additionally, creating a blood formate profile (14.2 mM at 48 h) similar to that observed in methanol-treated rats by iv infusion of pH-buffered formate does not alter the electroretinogram as is observed with methanol treatment. These data suggest that intraretinal metabolism of methanol is necessary for the formate-mediated initiation of methanol-induced retinal toxicity.

Animals↗

PubMed1994

Evaluation of methanol-induced retinotoxicity using oscillatory potential analysis.

Methanol is an ocular toxicant which causes visual dysfunction often leading to blindness after acute exposure. While the manifestation of the toxicity has been widely studied, the mechanism by which the injury is produced is still uncertain. A major unanswered question pertains to the site of action, i.e. direct retinotoxicity versus primary optic nerve toxicity with secondary retinotoxicity. In the present study, the effect of methanol on the oscillatory potentials (OPs) of the electroretinogram (ERG) were evaluated in acutely treated folate sufficient (FS) and folate reduced (FR) Long-Evans rats. The OP amplitudes of the acutely dosed FR rats displayed non-selective decreases in all OP amplitudes and non-selective increases in all OP latencies at methanol doses ranging from 1.5 to 3.0 g/kg. Comparing decreases of op2 and ERG b-wave amplitudes with blood formate concentration demonstrates that the b-wave is more sensitive than op2 in a blood formate concentration range of 6-14 mM, suggesting that retinal ischemia is not involved in methanol-induced visual system toxicity.

Animals↗

PubMed1994

Estimation and sample size considerations for clustered binary responses.

Although there is much literature on sample size determination for clinical trials or experiments with independent responses, there is a lack of methodology to obtain sample sizes for dependent outcomes. This paper presents a simple way to calculate sample size for estimating treatment effects and diagnostic accuracy in the case of correlated binary outcomes. The proposed weighted procedure also has use in estimation, whose advantages we demonstrate through simulation. Recommendations are made for practical application.

Clinical Trials as Topic↗

PubMed1994

A rat model manifesting methanol-induced visual dysfunction suitable for both acute and long-term exposure studies.

A toxic dose of methanol can induce visual dysfunction and metabolic acidosis in humans. However, the methanol dose range capable of inducing such toxicities and the mechanism(s) of visual dysfunction are not clearly understood. Nonprimate laboratory animals do not develop the characteristic human methanol toxicities even after a lethal dose. In the present study, we investigated whether visual dysfunction can be induced by methanol in a folate-reduced (FR) rat model which accumulates formate. Methanol was administered to rats by either the oral or inhalation route. The latencies of P1 and N1 peaks of flash-evoked potentials were significantly increased in methanol-challenged FR rats (3.5 g/kg, po), indicating that methanol administration caused an adverse effect in the retinogeniculocortical visual pathway. Effects on retinal function were then assessed by evaluating the electroretinogram (ERG). A dose-related reduction in b-wave amplitude of the ERG was manifested following oral methanol administration (1.5 to 2.5 g/kg). The b-wave amplitude reduction was also manifested in FR rats exposed to methanol vapors (2000 ppm, a concentration which was nontoxic in monkeys). These observations were consistent with reported human methanol toxicity cases. Thus, our data suggest that the FR rat model could serve as a valuable human surrogate for studying mechanisms of methanol-induced visual dysfunction and providing reliable toxicity data on the visual system under various exposure scenarios.

Administration, Inhalation↗

PubMed1994

Abdominal expansion as a bridging technique in stage IV-S neuroblastoma with massive hepatomegaly.

Stage IV-S neuroblastoma has a relatively favorable outcome. However, urgent surgical treatment may be necessary for management of life-threatening complications related to massive hepatomegaly caused by metastatic tumor infiltration. The enlarged liver often becomes of primary concern because diaphragmatic elevation results in life-threatening respiratory embarrassment. An external SILAS-TIC dome has been used as a temporizing procedure to decrease the intraabdominal pressure. The authors developed a modification of this approach using an internal polytetrafluoroethylene patch to create a ventral hernia. This technique decreases the potential complications of prosthetic material use, namely, risk of infection. The graft may be left in place for an extended period and removed in staged operations as the bulk of the metastatic tumor regresses.

Adrenal Gland Neoplasms↗

PubMed1994

Animal model for the study of methanol toxicity: comparison of folate-reduced rat responses with published monkey data.

We attempted to develop a rodent model that exhibits characteristics of human methanol toxicities such as acidosis and visual dysfunction, which are correlated with an accumulation of formate, a toxic metabolite of methanol. Initially three groups of Long-Evans rats with different levels of liver folate were prepared and examined for formate accumulation after methanol administration (3.5 g/kg). The folate-reduced (FR) rats prepared by feeding a folate-deficient diet with 1% succinylsulfathiazole yielded blood formate levels equivalent to those found in methanol-intoxicated humans and developed signs of the visual system toxicity (a manuscript on the latter aspect is in preparation). Responses of FR rats to a variety of methanol exposure scenarios were then investigated, and the results were compared with those reported in the literature for monkeys. Formate accumulation and/or lethality were used as toxic parameters for this comparative evaluation. In FR rats dosed orally with 3 g/kg, the blood formate concentration was 9.2 mmol/L at 24 h postadministration and increased to 15.6 mmol/L at 48 h. The same dose given to monkeys yielded a plateau of 7.4 mmol/L at 12 h after methanol administration, and stayed at this level for an additional 12 h. The area under the concentration vs. time curve for blood formate in FR rats was 2.5-fold greater than that in monkeys when 2.0 g/kg methanol was administered. After a 6-h exposure to 1200 ppm and 2000 ppm methanol, the blood formate concentrations in FR rats were increased by 370% and 636% above the endogenous level, respectively. However, blood formate did not accumulate above the endogenous level when monkeys were exposed to methanol up to 2000 ppm for 6 h. Under acute inhalation exposure conditions, FR rats exposed to 3000 ppm methanol, 20 h/d, could not survive more than 4 d. On the other hand, monkeys exposed to 3000 ppm, 21 h/d, out-lived 20 d. Moreover, monkeys survived for more than 4 d even after an exposure to 10,000 ppm. Thus, these results indicate that FR rats are more sensitive to methanol challenges than monkeys, and suggest that the FR rat could be a congruous animal model for evaluating the health effects of methanol in humans.

Administration, Inhalation↗

PubMed1994

Modulation of three types of K+ currents in canine coronary artery smooth muscle cells by NS-004, or 1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone.

The effects of the cardioprotective, vasorelaxant agent NS-004 [1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H) benzimidazolone] on K+ currents of freshly isolated canine coronary artery smooth muscle cells were examined using the suction pipette method. The Ca(++)-sensitive K+ current (IK, Ca) was isolated by using a holding potential of 0 mV and 5 mM ATP in the internal perfusate. The voltage-dependent delayed rectifier K+ current (IK, DR) was recorded at potentials below 20 mV in internal solution containing 5 mM ATP. The ATP-sensitive K+ current (IK, ATP) was induced by removing ATP in the pipette solution and was measured at potentials negative to -30 mV where IK, Ca and IK, DR were absent. External application of NS-004 activated IK, Ca, which, at 80 mV, was increased from 0.28 +/- 0.03 to 1.1 +/- 0.2, to 3.2 +/- 1.0, to 5.6 +/- 1.6 and to 8.5 +/- 1.6 nA, respectively, by 12.5, 25, 50 and 100 microM NS-004. Structurally related flufenamic, niflumic and mefenamic acids, at 100 microM, also enhanced IK, Ca. The order of potency for IK, Ca activation was NS-004 >> flufenamic = niflumic > mefenamic. In contrast, NS-004 blocked IK, DR, beginning at 2 microM with 50% inhibition at 22 microM. NS-004 also inhibited IK, ATP with a Ki value of 2.4 microM and a Hill coefficient of 1.3 in 0 mM intracellular ATP. These results demonstrate that NS-004 is a more potent activator of IK, Ca than the fenamates and that it is also a relatively potent blocker of IK, DR and IK, ATP in canine coronary artery smooth muscle cells.

Animals↗

PubMed1993

Blood levels of organochlorine residues and risk of breast cancer.

BACKGROUND: Organochlorines such as DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] and PCBs (polychlorinated biphenyls), which have been used extensively as insecticides and as fluid insulators of electrical components, respectively, are known to be persistent environmental contaminants and animal carcinogens. These agents have been found in human tissue due to their inefficient metabolism and their solubility in lipids, which lead to lifelong sequestration in adipose tissue. Their association with human cancer occurrence, however, has been explored only marginally, with most studies having 20 or fewer cases. PURPOSE: This blinded study was designed to determine whether exposure to PCBs and to DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene], the major metabolite of DDT, is associated with breast cancer risk in women. METHODS: We analyzed sera from the stored blood specimens of 14,290 participants enrolled between 1985 and 1991 in the New York University Women's Health Study, a prospective cohort study of hormones, diet, and cancer. Cohort members who developed breast cancer were included as case patients in our nested case-control study. DDE and PCBs were measured by gas chromatography in the sera of 58 women with a diagnosis of breast cancer 1-6 months after they entered the cohort and in 171 matched control subjects from the same study population who did not develop cancer. RESULTS: Mean levels of DDE and PCBs were higher for breast cancer case patients than for control subjects, but paired differences were statistically significant only for DDE (P = .031). After adjustment for first-degree family history of breast cancer, lifetime lactation, and age at first full-term pregnancy, conditional logistic regression analysis showed a fourfold increase in relative risk of breast cancer for an elevation of serum DDE concentrations from 2.0 ng/mL (10th percentile) to 19.1 ng/mL (90th percentile). For PCBs, the relative risk for a change in serum levels from 3.9 ng/mL (10th percentile) to 10.6 ng/mL (90th percentile) was less than twofold, a nonsignificant association that was further reduced after adjustment for DDE. CONCLUSION: In this population of New York City women, breast cancer was strongly associated with DDE in serum but not with PCBs. IMPLICATIONS: These findings suggest that environmental chemical contamination with organochlorine residues may be an important etiologic factor in breast cancer. Given the widespread dissemination of organochlorine insecticides in the environment and the food chain, the implications are far-reaching for public health intervention worldwide.

Adult↗

PubMed1993

Membrane activity of class III antiarrhythmic compounds; a comparison between ibutilide, d-sotalol, E-4031, sematilide and dofetilide.

This study compares the membrane activity of ibutilide, d-sotalol, sematilide, E-4031 and dofetilide on single ventricular cells under identical experimental conditions. We found that ibutilide and dofetilide produced a 'bell-shaped' concentration-dependent effect on action potential duration. Ionic current measurement showed that ibutilide, at 10(-8) M, increased a late inward current; the other compounds had either no effect or decreased it. Moreover, only ibutilide, at a high concentration of 10(-5) M, increased an outward current, as oppose to a uniform depression of IK by d-sotalol, sematilide, E-4031 and dofetilide, and the depression of IK by the latter compounds could be reversed by 10(-5) M ibutilide. Finally, low concentration of ibutilide could further prolong the action potential duration that had already been prolonged by a K+ channel blocker, but a high concentration of ibutilide did just the opposite by reversing the prolongation caused by K+ channel blockers. Therefore, action potentials agree well with the ionic current results. Possible mechanistic advantage of ibutilide over K+ channel blockers was discussed.

Action Potentials↗

PubMed1993

Cigarette smoking, nicotine addiction, and its pharmacologic treatment.

Cigarette smoking is the most prevalent modifiable risk factor for increased morbidity and mortality in the United States and perhaps the world. Not only does the smoker incur medical risks attributable to smoking, passive smokers and society also bear ill effects and increased economic costs attributable to the smoker's habit. These risks of morbidity and mortality have been shown to be related to the addictive component of tobacco smoke, so that pharmacologic therapies have been studied in an attempt to modify the addiction, aid in smoking cessation, and prevent relapse. Presently, nicotine polacrilex and transdermal nicotine show some efficacy. Clonidine's efficacy has been equivocal. In addition, the combination of nicotine substitution and clonidine may be useful but will need formal investigation. Nicotine agonists and antagonists have not proven helpful. Antidepressants are being studied at this time. Nonpharmacologic modalities are briefly mentioned but play a major role in helping the smoker quit.

Chewing Gum↗

PubMed1993

Use of a modified Quengel hinge to prevent posterior displacement of the tibia during treatment of PCL injury.

During treatment of posterior cruciate ligament (PCL) injuries, posterior displacement of the tibia may occur inside the cast due to the effect of gravity on the lower leg. To prevent this problem the authors attempted to apply the original Quengel cast, first described by Mommsen in 1922 and perfected by Jordan, to correct the flexion contracture of the knee in hemophiliacs. However, the authors found that the cast was not effective in preventing the posterior displacement of the tibia during management of PCL injuries. They modified the design of the original Quengel hinge to obtain a more effective anterior traction on the tibia parallel to the knee joint line. Of the 32 patients who used the modified Quengel brace, 15 who could be followed had less than a 3 mm difference between the injured and uninjured knee 3 months postoperatively.

Adolescent↗