The effects of cyclooxygenase and nitric oxide synthase inhibition on cardiodynamic parameters and coronary flow in isolated rat hearts

BACKGROUND:

Despite the widespread clinical use of cyclooxygenase (COX) inhibitors, dilemmas regarding the potential impact of these drugs on the cardiovascular system persist.

OBJECTIVE:

To estimate the effects of different COX inhibitors (meloxicam, acetylsalicylic acid [ASA] and SC-560) on cardiac function and coronary flow in isolated rat hearts, with special focus on the L-arginine/nitric oxide system.

METHODS:

The hearts of eight-week-old male Wistar albino rats (n=72; 12 rats per group; body mass 180 g to 200 g) were retrogradely perfused according to the Langendorff technique at gradually increased perfusion pressure (40 cmH₂O to 120 cmH₂O). After control experiments, the hearts were perfused with the following drugs: 100 μM ASA, alone or in combination with 30 μM N(ω)-nitro-L-arginine monomethyl ester (L-NAME), 0.3 μM meloxicam with or without 30 μM L-NAME, 3 μM meloxicam with or without 30 μM L-NAME, 30 μM L-NAME and 0.25 μM SC-560. In the control and experimental groups, the following parameters of heart function were continuously recorded: maximum rate of left ventricular pressure development, minimum rate of left ventricular pressure development, systolic left ventricular pressure, diastolic left ventricular pressure, heart rate and mean blood pressure. Coronary flow was measured flowmetrically. The amount of released NO₂⁻ was determined spectrophotometrically in coronary venous effluent.

RESULTS:

While meloxicam and SC-560 were found to have an adverse influence on cardiac function and coronary perfusion, ASA did not negatively affect the intact model of the heart.

CONCLUSION:

It appeared that interaction between COX and the L-arginine/nitric oxide system truly exists in coronary circulation and may explain the causes of the observed effects.     

Effects of cigarette smoke, nicotine and cotinine on red blood cell hemolysis and their -SH capacity

BACKGROUND:

Smoking is a leading cause of premature death. Red blood cell (RBC) membrane lipids are rich in polyunsaturated fatty acids; therefore, the effect of oxygen on RBC membranes is more prominent than on other body tissues. The attachment of peroxidants to RBC membranes can result in hemolysis.

OBJECTIVES:

The present study was conducted to assess the sensitivity of RBCs to 2,2′-azo-bis-(2-amidinopropane) dihydrochloride in smokers and nonsmokers. The effect of cigarette smoke, nicotine (1 μg/mL, 1.5 μg/mL and 2.5 μg/mL) and cotinine (1.25 μg/mL, 2.5 μg/mL and 5 μg/mL) on RBC hemolysis was also examined.

RESULTS:

RBC hemolysis in smokers was 21.6% higher than in non-smokers (P<0.05). Cigarette smoke increased 2,2′-azo-bis-(2-amidino-propane) dihydrochloride-induced RBC hemolysis by 281.7%. Nicotine inhibited RBC hemolysis by 36.7% at the highest concentration used, but increased RBC hemolysis at the lower concentrations. Cotinine caused a 13.8% increase in RBC membrane peroxidation at the highest concentration used and its effects were dose-dependent. At their highest concentrations, nicotine and cotinine decreased -SH groups by 50%.

CONCLUSIONS:

The present study confirms the results from previous studies of the oxidative and destructive effects of cigarette smoke, which are detrimental to the health of both active and passive smokers.     

Serum levels of homocysteine in mice with malignant tumours

BACKGROUND:

Oxygen radicals and malondialdehyde (MDA) are tumourigenic. Homocysteine generates oxygen radicals. The possibility exists that hyperhomocysteinemia is a risk factor for cancer.

OBJECTIVE:

To investigate if serum levels of homocysteine and MDA are elevated in mice with malignant tumours.

METHODS:

Levels of serum homocysteine and MDA were estimated in 22 control and 22 tumour-bearing Balb/c mice.

RESULTS:

Serum homocysteine levels in control and tumour-bearing mice were 3.01±0.26 μmol/L and 4.05±0.46 μmol/L, respectively. The serum levels of MDA were 6.23±0.72 nmol/mL and 11.60±1.72 nmol/mL, respectively, in control and tumour-bearing mice.

CONCLUSION:

These results suggest that cancer in mice is associated with an increase in serum levels of homocysteine and the lipid peroxidation product MDA. It is, however, not known if this rise in homocysteine and MDA is due to cancer or if this rise causes cancer.     

Effects of a short course of inhaled corticosteroids in noneosinophilic asthmatic subjects

BACKGROUND:

Noneosinophilic asthma has been regarded as a distinct phenotype characterized by a poor response to inhaled corticosteroids (ICS).

OBJECTIVE:

To determine whether noneosinophilic, steroid-naive asthmatic subjects show an improvement in asthma control, asthma symptoms and spirometry after four weeks of treatment with ICS, and whether they further benefit from the addition of a long-acting beta-2 agonists to ICS.

METHODS:

A randomized, double-blind, placebo-controlled, multicentre study comparing the efficacy of placebo versus inhaled fluticasone propionate 250 μg twice daily for four weeks in mildly uncontrolled, steroid-naive asthmatic subjects with a sputum eosinophil count ≤2%. This was followed by an open-label, four-week treatment period with fluticasone propionate 250 μg/salmeterol 50 μg, twice daily for all subjects.

RESULTS:

After four weeks of double-blind treatment, there was a statistically significant and clinically relevant improvement in the mean (± SD) Asthma Control Questionnaire score in the ICS-treated group (n=6) (decrease of 1.0±0.5) compared with the placebo group (n=6) (decrease of 0.09±0.4) (P=0.008). Forced expiratory volume in 1 s declined in the placebo group (−0.2±0.2 L) and did not change in the ICS group (0.04±0.1 L) after four weeks of treatment (P=0.02). The open-label treatment with fluticasone propionate 250 μg/salmeterol 50 μg did not produce additional improvements in those who were previously treated for four weeks with inhaled fluticasone alone.

CONCLUSION:

A clinically important and statistically significant response to ICS was observed in mildly uncontrolled noneosinophilic asthmatic subjects.     

Ventricular pacing thresholds following high-energy implantable cardioverter defibrillator shocks in integrated bipolar defibrillation systems

BACKGROUND:

Increased ventricular pacing thresholds have been observed following monophasic implantable cardioverter defibrillator (ICD) shocks.

AIM:

To examine changes following high-energy biphasic shocks delivered by integrated bipolar ICD systems.

METHOD:

Ten episodes of ventricular fibrillation (VF) were induced at 10 min intervals in nine pigs with integrated ICD systems. After 10 s of each episode of VF, a 40 J biphasic shock was delivered, which successfully terminated VF (a total of 10 shocks). The bipolar pacing threshold at the right ventricular apex was measured before each shock and at 1 min intervals after each shock.

RESULTS:

The mean pacing threshold was 0.029±0.059 μJ before the first shock and gradually increased to 0.14±0.10 μJ after the 10th shock.

CONCLUSION:

It may be necessary to pace at a high-voltage output following biphasic shocks delivered by integrated bipolar ICD systems.     

Low-molecular-weight proteins as prognostic markers in idiopathic membranous nephropathy

Summary

Background

Accurate prediction of prognosis in idiopathic membranous nephropathy (iMN) allows restriction of immunosuppressive therapy to patients at high risk for ESRD. Here we re-evaluate urinary low-molecular-weight proteins as prognostic markers and explore causes of misclassification.

Design, setting, participants, & measurements

In a cohort of 129 patients with serum creatinine concentration <135 μmol/L and proteinuria ≥3.0 g/10 mmol, urinary α1- (uα1m) and β2-microglobulin (uβ2m) excretion rate was determined. Urinary α1m and uβ2m-creatinine ratio was also obtained. We defined progression as a rise in serum creatinine ≥50% or ≥25% and an absolute level ≥135 μmol/L.

Results

Median survival time was 25 months, and 47% of patients showed progression. The area under the receiver operating characteristic curve for uβ2m was 0.81 (95% CI: 0.73 to 0.89). Using a threshold value of 1.0 μg/min, sensitivity and specificity were 73% and 75%, respectively. Similar accuracy was observed for the uβ2m-creatinine ratio with sensitivity and specificity of 75% and 73%, respectively, at a threshold of 1.0 μg/10 mmol creatinine. Similar accuracy was found for uα1m and uα1m-creatinine ratio. Blood Pressure and cholesterol contributed to misclassification. Repeated measurements improved accuracy in patients with persistent proteinuria: the positive predictive value of uβ2m increased from 72% to 89% and the negative predictive value from 76% to 100%.

Conclusions

Urinary excretion of uα2m and uβ2m predict prognosis in iMN. A spot urine sample can be used instead of a timed sample. A repeated measurement after 6 to 12 months increases prognostic accuracy.     

Protective effect of flavonoids against red blood cell hemolysis by free radicals

BACKGROUND:

Flavonoids are polyphenolic substances with antioxidant properties, and they are found in different vegetables and fruits. Epidemiological studies have shown that the consumption of flavonoids reduces the prevalence of cardiovascular diseases. The use of synthetic antioxidants, however, has been limited because of their toxicity. Therefore, medical researchers have intensified their quest to find natural antioxidants.

OBJECTIVES:

To investigate the effect of several pure flavonoids, such as kaempferol, quercetin, morin and rutin, on red blood cell hemolysis and evaluate their -SH capacity as an indicator of membrane protection.

METHODS:

The rate of hemolysis and cell membrane -SH capacity were determined by spectrophotometry. Red blood cell peroxidation was induced using 2,2′-azo-bis-(2-amidinopropane) dihydrochloride. The effect of each flavonoid on hemolysis was examined at three concentrations (0.5 μg/mL, 5 μg/mL and 10 μg/mL), however, only the greatest concentration (10 μg/mL) of each flavonoid was used to study the effect on -SH groups.

RESULTS:

In all cases, the antioxidant activity was dose-dependent. Rutin showed the highest inhibitory effect on hemolysis among flavonoids (42.5%). The protective effect of kaempferol, rutin and morin against -SH group oxidation measured 7.7%, 23.3% and 26.4%, respectively.

CONCLUSIONS:

Results showed that flavonoids and flavonoid-containing plants can be used as natural antioxidants for the treatment and prevention of disease conditions, the pathogenesis of which is mediated by lipid peroxidation.     

The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells

Background

The redox-active isoflavene anti-cancer drug, phenoxodiol, has previously been shown to inhibit plasma membrane electron transport and cell proliferation and promote apoptosis in a range of cancer cell lines and in anti-CD3/anti-CD28-activated murine splenocytes but not in non-transformed WI-38 cells and human umbilical vein endothelial cells.

Design and Methods

We determined the effects of phenoxodiol on plasma membrane electron transport, MTT responses and viability of activated and resting human T cells. In addition, we evaluated the effect of phenoxodiol on the viability of leukemic cell lines and primary myeloid and lymphoid leukemic blasts.

Results

We demonstrated that phenoxodiol inhibited plasma membrane electron transport and cell proliferation (IC₅₀ 46 μM and 5.4 μM, respectively) and promoted apoptosis of rapidly proliferating human T cells but did not affect resting T cells. Phenoxodiol also induced apoptosis in T cells stimulated in HLA-mismatched allogeneic mixed lymphocyte reactions. Conversely, non-proliferating T cells in the mixed lymphocyte reaction remained viable and could be restimulated in a third party mixed lymphocyte reaction, in the absence of phenoxodiol. In addition, we demonstrated that leukemic blasts from patients with primary acute myeloid leukemia (n=22) and acute lymphocytic leukemia (n=8) were sensitive to phenoxodiol. The lymphocytic leukemic blasts were more sensitive than the myeloid leukemic blasts to 10 μM phenoxodiol exposure for 24h (viability of 23±4% and 64±5%, respectively, p=0.0002).

Conclusions

The ability of phenoxodiol to kill rapidly proliferating lymphocytes makes this drug a promising candidate for the treatment of pathologically-activated lymphocytes such as those in acute lymphoid leukemia, or diseases driven by T-cell proliferation such as auto-immune diseases and graft-versus-host disease.     

Evaluating the Effects of Dithiothreitol and Fructose on Cell Viability and Function of Cryopreserved Primary Rat Hepatocytes and HepG2 Cell Line

Background

Hepatocytes are used as an in vitro model to evaluate drug metabolism. Human hepatocyte transplant has been considered as the temporary treatment of acute liver failure. Optimization freezing methods is very important to preserve both cell viability and function which are achieved by cryopreservation mostly always.

Objectives

The present study aimed to investigate the cryoprotective effect of DTT and fructose on primary rat hepatocytes and HepG2 cells.

Materials and Methods

Both fresh rat hepatocytes and HepG2 cell line were incubated with fructose (100 and 200 mM) and dithiothreitol (DTT) (25, 50, 100, 250, and 500 μM) at 37°C for 1 and 3 hours, respectively. The preincubated hepatocytes were cryopreserved for two weeks. Hepatocytes viability and function were determined post thawing and the results were compared with the control group.

Results

The viability of both rat hepatocytes and HepG2 cells were significantly increased after one hour preincubation with fructose 200 mM. Preincubation with DTT (50 μM, 100 μM. 250 μM and 500 μM) improved the viability and function upon thawing in both cell types (P < 0.001). In rat hepatocytes, no significant change was observed in albumin, urea production, and LDH leakage after preincubation with fructose or DTT. In HepG2 cells, albumin and urea production were significantly increased after preincubation with DTT (500 μM, 1 hour). The GSH content was significantly increased in DTT (250 and 500 μM, 1 hour) groups in both rat hepatocyte and HepG2 cells.

Conclusions

Incubation of hepatocytes with fructose and DTT prior to the cryopreservation can increase the cell viability and function after thawing.     

The Impact of Postgraduate Training on USMLE? Step 3? and its Computer-Based Case Simulation Component

BACKGROUND

The United States Medical Licensing Examination® (USMLE®) Step 3® examination is a computer-based examination composed of multiple choice questions (MCQ) and computer-based case simulations (CCS). The CCS portion of Step 3 is unique in that examinees are exposed to interactive patient-care simulations.

OBJECTIVE

The purpose of the following study is to investigate whether the type and length of examinees’ postgraduate training impacts performance on the CCS component of Step 3, consistent with previous research on overall Step 3 performance.

DESIGN

Retrospective cohort study

PARTICIPANTS

Medical school graduates from U.S. and Canadian institutions completing Step 3 for the first time between March 2007 and December 2009 (n = 40,588).

METHODS

Post-graduate training was classified as either broadly focused for general areas of medicine (e.g. pediatrics) or narrowly focused for specific areas of medicine (e.g. radiology). A three-way between-subjects MANOVA was utilized to test for main and interaction effects on Step 3 and CCS scores between the demographic characteristics of the sample and type of residency. Additionally, to examine the impact of postgraduate training, CCS scores were regressed on Step 1 and Step 2 Clinical Knowledge (CK) scores. Residuals from the resulting regressions were plotted.

RESULTS

There was a significant difference in CCS scores between broadly focused (μ = 216, σ = 17) and narrowly focused (μ=211, σ = 16) residencies (p < 0.001). Examinees in broadly focused residencies performed better overall and as length of training increased, compared to examinees in narrowly focused residencies. Predictors of Step 1 and Step 2 CK explained 55% of overall Step 3 variability and 9% of CCS score variability.

CONCLUSIONS

Factors influencing performance on the CCS component may be similar to those affecting Step 3 overall. Findings are supportive of the validity of the Step 3 program and may be useful to program directors and residents in considering readiness to take this examination.KEY WORDS: USMLE, Step 3, CCS, postgraduate training, graduate medical education     

Plasma nitric oxide metabolite levels increase during successive exercise stress testing – A link to delayed ischemic preconditioning?

BACKGROUND:

Animal studies have shown that nitric oxide is involved in delayed ischemic preconditioning.

OBJECTIVES:

To determine whether plasma nitrates and nitrites (NO_x⁻, as measure of nitric oxide) are modified by two consecutive effort tests and whether these changes translate into clinical improvement

METHODS:

Twenty-two patients with ischemic heart disease each performed two effort tests at 24-h intervals. Plasma NO_x⁻ level was determined and compared before and after both stress tests. Peak effort, double product at peak effort and maximal ST segment depression were considered clinical endpoints and were compared between the two tests.

RESULTS:

Plasma NO_x⁻increased slightly after the first exercise test compared with pretest value (17.05±1.6 μmol/mL versus 15.38±1.4 μmol/mL). In turn, after the second test there was a significant rise in NO_x⁻ level (23.65±2.2 μmol/mL versus 15.10±1.3 μmol/mL, P<0.03). The pretest values were almost identical between the two tests. Peak effort and double product at peak effort remained unchanged between the two tests. Although ischemic stress was the same, ST depression was significantly lower (P<0.01) for the second test (0.85±0.06 mm versus 1.73±0.16 mm).

CONCLUSION:

Our study shows an increased plasma NO_x⁻level after the second of two consecutive exercise stress tests at 24-h intervals, along with a decrease of electrocardiographic consequences of approximately the same ischemic stress. These findings are consistent with experimental data in animals, which point to nitric oxide as a trigger and effector of ischemic preconditioning.     

Structure-function relationships in the regulation of energy transfer between mitochondria and ATPases in cardiac cells

The present study discusses the role of structural organization of cardiac cells in determining the mechanisms of regulation of oxidative phosphorylation and interaction between mitochondria and ATPases. In permeabilized adult cardiomyocytes, the apparent K_m (Michaelis-Menten constant) for ADP in the regulation of respiration is far higher than in mitochondria isolated from the myocardium. Respiration of mitochondria in permeabilized cardiomyocytes is effectively activated by endogenous ADP produced by ATPases from exogenous ATP, and the activation of respiration is associated with a decrease in the apparent K_m for ATP in the regulation of ATPase activity compared with this parameter in the absence of oxidative phosphorylation. It has also been shown that a large fraction of the endogenous ADP stimulating respiration remains inaccessible for the exogenous ADP trapping system, consisting of pyruvate kinase and phosphoenolpyruvate, unless the mitochondrial structures are modified by controlled proteolysis. These data point to the endogenous cycling of adenine nucleotides between mitochondria and ATPases. Accordingly, the current hypothesis is that in cardiac cells, mitochondria and ATPases are compartmentalized into functional complexes (ie, intracellular energetic units [ICEUs]), which appear to represent a basic pattern of organization of energy metabolism in these cells. Within the ICEUs, the mitochondria and ATPases interact via different routes: creatine kinase-mediated phosphoryltransfer; adenylate kinase-mediated phosphoryltransfer; and direct ATP and ADP channelling. The function of ICEUs changes not only after selective proteolysis, but also during contraction of cardiomyocytes caused by an increase in cytosolic Ca²⁺ concentration up to micromolar levels. In these conditions, the apparent K_m for exogenous ADP and ATP in the regulation of respiration markedly decreases, and more ADP becomes available for the exogenous pyruvate kinase-phosphoenolpyruvate system, which indicates altered barrier functions of the ICEUs. Thus, structural changes transmitted from the contractile apparatus to mitochondria clearly participate in the regulation of mitochondrial function due to alterations in localized restriction of the diffusion of adenine nucleotides. The importance of strict structural organization in cardiac cells emerged drastically from experiments in which the regulation of mitochondrial respiration was assessed in a novel cardiac cell line, that is, beating and nonbeating HL-1 cells. In these cells, the mitochondrial arrangement is irregular and dynamic, whereas the sarcomeric structures are either absent (in nonbeating HL-1 cells) or only rarely present (in beating HL-1 cells). In parallel, the apparent K_m for exogenous ADP in the regulation of respiration was much lower than that in permeabilized primary cardiomyocytes, and trypsin treatment exerted no impact on the low K_m value for ADP, in contrast to adult cardiomyocytes where it caused a marked decrease in this parameter. The HL-1 cells were also characterized by the absence of direct exchange of adenine nucleotides. The results further support the concept that the ICEUs in adult cardiomyocytes are products of complex structural organization developed to create the most optimal conditions for effective energy transfer and feedback between mitochondria and ATPases.     

A randomized controlled trial of two schedules of hepatitis B vaccination in predialysed chronic renal failure patients

Background

Patients with chronic renal disease should be vaccinated as soon as dialysis is forestalled, and this could improve the seroconversion of hepatitis B vaccination.

Objectives

In this study, we aimed to compare seroconversion and immune response rates using 4 doses of 40 μg and 3 doses of 20 μg Euvax B recombinant Hepatitis B surface Antigen (HBs Ag) vaccine administered to predialysis patients with chronic kidney disease (CKD).

Patients and Methods

In an open, randomized clinical trial, we compared seroconversion rates in 51 predialysis patients with mild and moderate chronic renal failure who received either 4 doses of 40 μg or 3 doses of 20 μg of Euvax B recombinant hepatitis B vaccine administered at 0, 1, 2, 6 and 0, 1, 6 months, respectively.

Results

Differences in seroconversion rates after 4 doses of 40 μg (80.88%) compared to 3 doses of 20 μg (92%) were not significant (P = 0.4124). The mean HBs antibody level after 4 doses of 40 μg at 0, 1, 2, and 6 months (182.2 ± 286.7) was significantly higher than that after 3 doses of 40 μg at 0,1, and 6 months (96.9 ± 192.1) (P = 0.004). Seroconversion after 4 doses of 40 μg (80.8%) was also significantly higher than that after 3 doses of 40 μg (77%) (P = 0.004). Multivariable analysis showed that none of the variables contributed to seroconversion.

Conclusions

We found that 4 doses of 40 μg did not lead to significantly more seroconversion than 3 doses of 20 μg.     

Bioluminescence imaging of glucose in tissue surrounding polyurethane and glucose sensor implants

Background

The bioluminescence technique was used to quantify the local glucose concentration in the tissue surrounding subcutaneously implanted polyurethane material and surrounding glucose sensors. In addition, some implants were coated with a single layer of adipose-derived stromal cells (ASCs) because these cells improve the wound-healing response around biomaterials.

Methods

Control and ASC-coated implants were implanted subcutaneously in rats for 1 or 8 weeks (polyurethane) or for 1 week only (glucose sensors). Tissue biopsies adjacent to the implant were immediately frozen at the time of explant. Cryosections were assayed for glucose concentration profile using the bioluminescence technique.

Results

For the polyurethane samples, no significant differences in glucose concentration within 100 μm of the implant surface were found between bare and ASC-coated implants at 1 or 8 weeks. A glucose concentration gradient was demonstrated around the glucose sensors. For all sensors, the minimum glucose concentration of approximately 4 mM was found at the implant surface and increased with distance from the sensor surface until the glucose concentration peaked at approximately 7 mM at 100 μm. Then the glucose concentration decreased to 5.5–6.5 mM more than 100 μmm from the surface.

Conclusions

The ASC attachment to polyurethane and to glucose sensors did not change the glucose profiles in the tissue surrounding the implants. Although most glucose sensors incorporate a diffusion barrier to reduce the gradient of glucose and oxygen in the tissue, it is typically assumed that there is no steep glucose gradient around the sensors. However, a glucose gradient was observed around the sensors. A more complete understanding of glucose transport and concentration gradients around sensors is critical.     

Effect of fluticasone 250 ��g/salmeterol 50 ��g and montelukast on exhaled nitric oxide in asthmatic patients

BACKGROUND:

Monitoring noninvasive biomarkers of inflammation is an important adjunct in asthma therapy.

OBJECTIVE:

The goal of the present study was to identify airway and alveolar site(s) of inflammation using exhaled nitric oxide (NO) as a marker in asthmatic patients, and to evaluate the NO response to maintenance fluticasone 250 μg/salmeterol 50 μg (F/S) and add-on montelukast 10 mg (M).

METHODS:

Thirty (24 women) nonsmoking, mild to moderate asthmatic patients were studied, mean age (± SD) 43±9 years, treated with F/S for more than one year. All were clinically stable for longer than eight weeks and had not taken oral corticosteroids and/or leukotriene antagonists for eight weeks before the present study. Spirometry, Juniper asthma symptom score, fractional exhaled NO (FENO) 100 mL/s, bronchial NO and alveolar NO concentration (CANO) were measured in a single-blind, nonrandomized crossover study.

PROTOCOL:

Visit 1: baseline F/S; visit 2: after four weeks of F/S plus M; visit 3: after four weeks of S plus M; and visit 4: after four weeks of S only. Values in asthmatic patients were also compared with 34 nonsmoking age-matched healthy controls with normal lung function.

RESULTS:

After 180 μg aerosolized metered dose inhaler albuterol, the forced expiratory volume in 1 s at baseline was 2.6±0.8 L (86%±16% of the predicted value) and the forced expiratory volume in 1 s over the forced vital capacity was 77%±9% (mean ± SD), and was similar at visits 2 to 4. Juniper scores were mildly abnormal at visits 1 to 3, but significantly worse (P=0.03) at visit 4 versus visits 1 to 3. FENO values at visits 1 to 3 were similar but significantly increased (P=0.007) at visit 4. Bronchial NO was higher (P=0.03) at visit 4, versus visits 1 and 2, and was no different at visit 3. Compared with the healthy subjects, FENO and bronchial NO values were abnormal (greater than the normal mean plus 2 SD) in 33% of asthmatic patients at visits 1 to 3. CANO was similar for visits 1 to 4. CANO was abnormal (greater than the normal mean + 2 SD) in 20% of asthmatic patients.

CONCLUSION:

In clinically stable asthmatic patients, despite controller treatment including moderate-dose inhaled corticosteroids and add-on M, 33% of mild to moderate asthmatic patients have ongoing nonsuppressed bronchial sites of increased NO production, compared with healthy control subjects. These controllers have no effect on CANO, which was abnormal in 20% of the asthmatic patients studied. The addition of add-on M to baseline moderate-dose inhaled corticosteroid did not further reduce total exhaled, bronchial and/or alveolar NO production.     

Influence of preload on left ventricular relaxation in isolated ejecting hearts during myocardial depression

BACKGROUND:

The controversially discussed intrinsic effect of end-diastolic pressure (EDP) on ventricular relaxation (lusitropy) is a prerequisite for interpretation of lusitropic changes induced by physiological and pharmacological interventions because the latter usually alter the ventricular loading conditions.

OBJECTIVES:

Characterization of the lusitropic effect of preload changes at low and high absolute EDP and after spontaneous cardiodepression.

METHODS:

Repeated preload tests (increasing cardiac inflow at constant mean aortic pressure) were performed in isolated ejecting rat and guinea pig hearts. Preload was quantified by left ventricular EDP, lusitropy was quantified using peak negative left ventricular pressure change velocity (−dP/dt), and relaxation time constant τ was calculated from monoexponential and four-parametric logistic pressure fall models. Regression coefficients of relaxation indexes, −dP/dt and τ versus EDP, were calculated and compared at different degrees of cardiac depression.

RESULTS:

Increasing EDP in the ejecting hearts less than 2 h after isolation caused τ to decrease and −dP/dt to increase initially at low EDP levels. Both parameters remained constant or even reversed at higher EDP levels. In the spontaneously depressed hearts, over 3 h after isolation, basic τ values were higher and −dP/dt values were lower, but EDP changes no longer had significant lusitropic effects. The same behaviour was observed in pentobarbital depressed hearts.

CONCLUSIONS:

A positive lusitropic effect (falling τ, rising −dP/dt) was observed when preload was increased in the range of lower EDP values in undepressed hearts early after isolation. However, preload changes did not influence lusitropy in isolated hearts either early after isolation at high EDP levels or in the spontaneously depressed condition at any EDP level.     

Effects of chromium malate on glycometabolism,glycometabolism‐related enzyme levels and lipid metabolism in type 2 diabetic rats: A dose–response and curative effects study

Aims/Introduction

The present study was designed to evaluate the effect of chromium malate on glycometabolism, glycometabolism-related enzyme levels and lipid metabolism in type 2 diabetic rats, and dose–response and curative effects.

Materials and Methods

The model of type 2 diabetes rats was developed, and daily treatment with chromium malate was given for 4 weeks. A rat enzyme-linked immunosorbent assay kit was used to assay glycometabolism, glycometabolism-related enzyme levels and lipid metabolism changes.

Results

The results showed that the antihyperglycemic activity increased with administration of chromium malate in a dose–dependent manner. The serum insulin level, insulin resistance index and C-peptide level of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly lower than that of the model, chromium trichloride and chromium picolinate groups. The hepatic glycogen, glucose-6-phosphate dehydrogenase and glucokinase levels of the chromium malate groups at a dose of 17.5, 20.0 and 20.8 μg chromium/kg bodyweight were significantly higher than that of the model, chromium trichloride and chromium picolinate groups. Chromium malate at a dose of 20.0 and 20.8 μg chromium/kg bodyweight significantly changed the total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides levels compared with the chromium trichloride and chromium picolinate groups.

Conclusions

The results showed that chromium malate exhibits greater benefits in treating type 2 diabetes, and the curative effect of chromium malate is superior to chromium trichloride and chromium picolinate.     

Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study

Background

Poor anticoagulant stability in patients using vitamin K antagonists is a risk factor for both bleeding and thrombosis. In previous studies supplementation with low dose vitamin K₁ was shown to improve the stability of anticoagulant control. We set up a study to confirm earlier reports and to determine the optimal daily dose of vitamin K₁ in preparation of a large study with clinical endpoints.

Design and Methods

Four hundred patients from two anticoagulation clinics starting with vitamin K antagonists, independently of a possible history of instable anticoagulation, were randomized to receive either placebo or 100, 150 or 200 μg of vitamin K₁ together with their treatment with vitamin K antagonists. The treatment was administered for 6 to 12 months. Anticoagulation stability, expressed as the percentage of time that the International Normalized Ratio was within the therapeutic range, was compared between the groups.

Results

After adjustment for age, sex, vitamin K antagonist used, anticoagulation clinic and interacting drugs as confounding factors the difference in percentage of time with the International Normalized Ratio within the therapeutic range between the placebo group and the vitamin K₁ groups was 2.1% (95% CI: −3.2% – 7.4%) for the group taking 100 μg, 2.7% (95% CI: −2.3% –7.6%) for the group taking 150 μg and 0.9% (95% CI: −4.5% – 6.3%) for the group taking 200 μg vitamin K₁ group, in favor of the vitamin K₁ groups. The patients from both the 100 μg group and the 150 μg group had a 2-fold higher chance of reaching at least 85% of time with the International Normalized Ratio within the therapeutic range. There were no differences in thromboembolic or hemorrhagic complications between the groups.

Conclusions

In patients starting vitamin K antagonists, supplementation with low dose vitamin K₁ resulted in an improvement of time that anticoagulation was within the therapeutic range. Differences between doses were, however, small and the improvement is unlikely to be of clinical relevance. For future studies we recommend selecting only patients with instable anticoagulant control. (This study was registered at www.isrctn.org as ISRCTN37109430)     

Prevention of contrast-induced nephropathy: A randomized controlled trial of sodium bicarbonate and N-acetylcysteine

BACKGROUND:

Contrast-induced nephropathy (CIN) continues to be a common cause of acute renal failure in high-risk patients undergoing radiocontrast studies. However, there is still a lack of consensus regarding the most effective measures to prevent CIN.

METHODS:

One hundred eighteen patients with diabetes mellitus and/or renal insufficiency, scheduled for coronary angiography or intervention, were randomly assigned to one of four treatment groups: intravenous (IV) 0.9% NaCl alone, IV 0.9% NaCl plus N-acetylcysteine (NAC), IV 0.9% sodium bicarbonate (NaHCO₃) alone or IV 0.9% NaHCO₃ plus NAC. All patients received IV hydration as a preprocedure bolus and as maintenance. Iso-osmolar contrast was used in all patients. CIN was defined as an increase of greater than 25% in the serum creatinine concentration from baseline to 72 h.

RESULTS:

The overall incidence of CIN was 6%. There was no statistically significant difference in the incidence of CIN among the groups. There was a CIN incidence of 7% in the NaCl only group, 5% in the NaCl/NAC group, 11% in the NaHCO₃ only group and 4% in the NaHCO₃/NAC group (P=0.86). The maximum increase in serum creatinine was 14.14±12.38 μmol/L in the NaHCO₃ group, 10.60±29.14 μmol/L in the NaCl only group, 9.72±13.26 μmol/L in the NaCl/NAC group and 0.177±15.91 μmol/L for the NaHCO₃/NAC group (P=0.0792).

CONCLUSION:

CIN in high-risk patients may be effectively minimized solely through the use of an aggressive hydration protocol and an iso-osmolar contrast agent. The addition of NaHCO₃ and/or NAC did not have an effect on the incidence of CIN.     

Comparison of adverse effects related to pegylated interferon-based therapy for patients with chronic hepatitis B and chronic hepatitis C in Taiwan

Purpose

Pegylated interferon (Peg-IFN)-based therapy is effective in treating chronic hepatitis B (CHB) and C (CHC) but frequently induces adverse events (AEs). This study was conducted to compare the incidence of Peg-IFN-based therapy-associated AEs in Taiwanese patients with CHB and CHC.

Methods

Fifty-six patients with CHB and 103 age-, sex- and treatment duration-matched patients with CHC were enrolled. Patients with CHB were treated with Peg-IFN-α-2a 180 μg/week for 24 weeks (HBeAg⁺, n = 31) or 48 weeks (HBeAg⁻, n = 25); patients with CHC were treated with Peg-IFN-α-2a 180 μg/week plus ribavirin 1,000–1,200 mg/day for 24 weeks (genotype 2/3, n = 57) or 48 weeks (genotype 1, n = 46).

Results

Significantly higher incidences of Peg-IFN-related AEs, especially neuropsychiatric symptoms, and ribavirin-associated skin manifestations were observed in patients with CHC compared with those with CHB, with either the 24- or 48-week regimen. Frequencies of laboratory abnormalities, except for anemia, were comparable in both groups. Neither group showed overt hepatic decompensation. Frequency of dose reduction was similar between the groups. Substantially higher rates of early termination and severe AEs were observed in patients with CHC.

Conclusions

Patients with CHB treated with Peg-IFN had fewer AEs than patients with CHC treated with Peg-IFN/ribavirin. All patients were treated safely.