Glyburide prevents isoflurane’s reducing effects on hydroxyl radical formation in the postischemic reperfused rat heart

BACKGROUND:

The role of K_ATP channels in isoflurane’s reducing effects on oxygen free radical formation are not well known.

OBJECTIVES:

To investigate whether glyburide, an ATP-regulated potassium (K_ATP) channel blocker, abolishes isoflurane-induced cardioprotective effects and whether it affects hydroxyl radical formation in the postischemic reperfused heart.

ANIMALS AND METHODS:

Thirty-nine male Wistar rats were divided into four groups: group C (control, n=10), group I (isoflurane, n=9), group G (glyburide, n=10) and group GI (glyburide and isoflurane, n=10). The hearts were perfused as a Neely’s working heart model. Afterwards, global heart ischemia was induced for 15 min followed by reperfusion for 20 min. The formation of hydroxyl radicals in the coronary effluent and heart was measured with high performance liquid chromatography.

RESULTS:

Isoflurane alone and glyburide alone produced significant decreases in the duration of ventricular fibrillation during reperfusion (group C 452±345, group I 247±60, group G 261±135 s; P<0.05). In the presence of glyburide, isoflurane did not further decrease the duration of arrhythmia (group GI 230±48 s). Isoflurane reduced hydroxyl radical formation significantly in the coronary effluent during ischemia and reperfusion, but this was prevented by glyburide.

CONCLUSION:

The results suggest that isoflurane reduces hydroxyl radical formation, at least in part, through activation of K_ATP channels.     

Ischemic preconditioning and diazoxide limit mitochondrial Ca2+ overload during ischemia/reperfusion: Role of reactive oxygen species

BACKGROUND:

Generation of reactive oxygen species (ROS) is associated with cardioprotection imparted by ischemic preconditioning (IPC) and pharmacological PC (PPC). The authors have previously shown that IPC or PPC, using the mitochondrial ATP-sensitive K⁺ channel opener diazoxide (DZ), reduce mitochondrial Ca²⁺ ([Ca²⁺]_m) during ischemia and reperfusion.

OBJECTIVES:

To test the hypothesis that both IPC and PPC (using DZ) lead to reduced [Ca²⁺]_m and improved functional recovery via a ROS-dependent mechanism.

METHODS:

Intracellular Ca²⁺ ([Ca²⁺]_i) and [Ca²⁺]_m were measured in isolated perfused rat hearts loaded with the fluorescent indicator indo-1 acetoxymethyl ester. [Ca²⁺]_m was determined by quenching the cytosolic indo-1 signal using manganese before ischemia (25 min). IPC and DZ (100 μM) group hearts were studied with and without the ROS scavenger N-2-mercaptopropionyl glycine (400 μM) (2-MPG).

RESULTS:

Both IPC and DZ significantly reduced [Ca²⁺]_i and [Ca²⁺]_m on reperfusion compared with the control. Administration of 2-MPG with washout before ischemia significantly attenuated the reduction in [Ca²⁺]_m observed on reperfusion in both the IPC and DZ groups. Additionally, the myocardial functional protection imparted by IPC or DZ was lost with the administration of 2-MPG.

CONCLUSIONS:

The [Ca²⁺]_m-reducing effect of IPC and DZ was attenuated with the administration of 2-MPG, resulting in decreased myocardial functional performance and increased release of creatine kinase, a marker of cellular injury. It can be concluded that IPC and DZ impart their protective effect via a mechanism involving ROS generation before the ischemic episode.     

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.     

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.     

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.     

Intracellular energetic units in healthy and diseased hearts

BACKGROUND:

The present review examines the role of intra-cellular compartmentation of energy metabolism in vivo.

OBJECTIVE:

To compare the kinetics of the activation of mitochondrial respiration in skinned cardiac fibres by exogenous and endogenous adenine nucleotides in dependence of the modulation of cellular structure and contraction.

METHODS:

Saponin-permeabilized cardiac fibres or cells were analyzed using oxygraphy and confocal microscopy.

RESULTS:

Mitochondria respiration in fibres or cells was upregulated by cumulative additions of ADP to the medium with an apparent K_m of 200 μM to 300 μM. When respiration was stimulated by endogenous ADP produced by intracellular ATPases, a near maximum respiration rate was achieved at an ADP concentration of less than 20 μM in the medium. A powerful ADP-consuming system, consisting of pyruvate kinase and phosphoenolpyruvate, that totally suppressed the activation of respiration by exogenous ADP, failed to abolish the stimulation of respiration by endogenous ADP, but did inhibit respiration after the cells were treated with trypsin. The addition of up to 4 μM of free Ca²⁺ to the actively respiring fibres resulted in reversible hypercontraction associated with a decreased apparent K_m for exogenous ADP. These changes were fully abolished in fibres after the removal of myosin by KCl treatment.

CONCLUSIONS:

Mitochondria and ATPases, together with cytoskeletal proteins that establish the structural links between mitochondria and sarcomeres, form complexes – intracellular energetic units (ICEUs) – in cardiac cells. Within the ICEUs, the mitochondria and ATPases interact via specialized energy transfer systems, such as the creatine kinase- and adenylate kinase-phosphotransfer networks, and direct ATP channelling. Disintegration of the structure and function of ICEUs results in dyscompartmentation of adenine nucleotides and may represent a basis for cardiac diseases.     

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.     

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.     

Acetylcholine-regulated K+ current remodelling in the atrium after myocardial infarction and valsartan administration

BACKGROUND:

Atrial fibrillation (AF) is a common complication of myocardial infarction (MI). Angiotensin II receptor antagonists prevent the promotion and propagation of AF. However, the activation of the acetylcholine-regulated K⁺ current (I_K,ACh) in the atrium after MI and the effect of valsartan on I_K,ACh are less understood.

METHODS:

Twenty-four adult rabbits were randomly divided into three groups: sham-operated, MI and MI plus valsartan administration (MI+valsartan). The sham-operated group received a median sternotomy without left ventricular coronary artery ligation. Both the MI group and the MI+valsartan group received a median sternotomy followed by ligation of the midpoint of the left ventricular coronary artery. The MI+valsartan group was administered oral valsartan for 12 weeks. After 12 weeks, the initiation of AF was measured by vagal stimulation followed by quick excision of the heart. I_K,ACh in the left atrial myocardium was measured by the patch clamp technique.

RESULTS:

AF was induced in four animals in the MI group, two in the sham-operated and two in the MI+valsartan groups, with the total AF duration expectedly longer in the MI group than in the sham-operated and MI+valsartan groups (38 s versus 9 s and 9 s, respectively). Furthermore, the mean (± SEM) density of I_K,ACh increased significantly more in the left atrial myocardia of the MI group than in the sham-operated and the MI+valsartan groups (−13±0.42 pA/pF versus −9±0.38 pA/pF and −10±0.37 pA/pF, respectively at −100 mV; and 4.1±0.28 pA/pF versus 3.1±0.27 pA/pF and 3.3±0.27 pA/pF, respectively at 20 mV; P<0.05). However, there was no statistically significant difference in I_K,ACh between the sham-operated group and the MI+valsartan group.

CONCLUSIONS:

AF is associated with increased I_K,ACh after MI. Inhibition of increased I_K,ACh may be the mechanism by which valsartan prevents AF following MI.     

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.     

Comparison Pharmacokinetics of Two Concentrations (0.7% and 1.0%) of Nasulin?, an Ultra-Rapid-Acting Intranasal Insulin Formulation

Background

This pharmacokinetic (PK) study was designed to characterize the dose response of two concentrations (0.7% and 1%) of a nasal spray of recombinant regular human insulin in combination with cyclopentadecalactone (CPE-215), a compound that enhances absorption of molecules across mucous membranes (Nasulin™, CPEX Pharmaceuticals). Nasulin has been effective in lowering blood glucose in both normal subjects and diabetes patients, and additional dosing options would allow greater titration flexibility.

Method

A five-period crossover study of 24 healthy, nonsmoking subjects (ages 18-50, basal metabolic index <33 kg/m², weight >70 kg) were studied. Subjects were in a fasted state for 5 h before and 45 min after administration for PK assessment and were then given a meal. Each spray contained 100 μl. Doses tested were 25, 35, 50, 70, and 100 U. Maximum concentration (C_max) and area under the curve (AUC) were estimated for each dose group. Glucose measurements were also performed.

Results

A dose response (slope of the natural log response versus dose) was demonstrated by baseline-adjusted C_max of 22, 27, 56, 62, and 84 μU/ml for the 25, 35, 50, 70, and 100 U doses (p < .0001), respectively, and by baseline-adjusted AUC_{(0–45 min)} values of 491, 592, 1231, 1310, and 1894 μU/ml/min (p < .0001). Glucose AUC_{(0–45 min)} determinations also demonstrated a pharmacodynamic (PD) dose response.

Conclusions

Proportional and linear dose responses for both PK and PD parameters were demonstrated for the two concentrations, making multiple doses available for clinical development.     

Aggregation of mononuclear and red blood cells through an ��4��1-Lu/basal cell adhesion molecule interaction in sickle cell disease

Background

Abnormal interactions between red blood cells, leukocytes and endothelial cells play a critical role in the occurrence of the painful vaso-occlusive crises associated with sickle cell disease. We investigated the interaction between circulating leukocytes and red blood cells which could lead to aggregate formation, enhancing the incidence of vaso-occlusive crises.

Design and Methods

Blood samples from patients with sickle cell disease (n=25) and healthy subjects (n=5) were analyzed by imaging and classical flow cytometry after density gradient separation. The identity of the cells in the peripheral blood mononuclear cell layer was determined using antibodies directed specifically against white (anti-CD45) or red (anti-glycophorin A) blood cells.

Results

Aggregates between red blood cells and peripheral blood mononuclear cells were visualized in whole blood from patients with sickle cell disease. The aggregation rate was 10-fold higher in these patients than in control subjects. Both mature red blood cells and reticulocytes were involved in these aggregates through their interaction with mononuclear cells, mainly with monocytes. The size of the aggregates was variable, with one mononuclear cell binding to one, two or several red blood cells. Erythroid Lu/basal cell adhesion molecule and α₄β₁ integrin were involved in aggregate formation. The aggregation rate was lower in patients treated with hydroxycarbamide than in untreated patients.

Conclusions

Our study gives visual evidence of the existence of circulating red blood cell-peripheral blood mononuclear cell aggregates in patients with sickle cell disease and shows that these aggregates are decreased during hydroxycarbamide treatment. Our results strongly suggest that erythroid Lu/basal cell adhesion molecule proteins are implicated in these aggregates through their interaction with α₄β₁ integrin on peripheral blood mononuclear cells.     

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.     

Inflammation and platelet activation in peripheral arterial occlusive disease

OBJECTIVES

Epidemiological evidence indicates that inflammation accompanies the progression of atherosclerosis. The aim of the present cross-sectional study was to define relationships between platelet activation and inflammation in patients with mild to severe (stages II to IV) peripheral arterial occlusive disease (PAOD) and matched controls. The effect of chronic administration of low-dose acetylsalicylic acid was investigated.

METHODS

Subjects were studied on a single occasion. C-reactive protein (CRP) and two indexes of in vivo platelet activation were measured – the urinary excretion of 11-dehydrothromboxane (TX) B₂ by immunoassay and circulating platelet-monocyte aggregates (PMAs) by flow cytometry.

RESULTS

Plasma PMAs and urinary 11-dehydro-TXB₂ were significantly increased in PAOD patients compared with controls (P<0.01 for all). A positive correlation between 11-dehydro-TXB₂ and CRP was found in the study population (r_s=0.63, P<0.001). Using logistic regression analysis, CRP was the only independent correlate of 11-dehydro-TXB₂ (β_CRP=11.9, P<0.01), whereas only the presence of PAOD was an independent predictor of high PMA levels (β_PAOD=13.7, P=0.001). Chronic administration of acetylsalicylic acid reduced 11-dehydro-TXB₂, but not PMA and CRP.

CONCLUSIONS

There is evidence that platelet activation in patients with PAOD is related to the vascular disease and is dependent on the severity of inflammation.     

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.     

Prediction and prevention of upper gastrointestinal bleeding after cardiac surgery: a case control study

BACKGROUND:

Gastrointestinal (GI) complications of cardiovascular surgery, particularly bleeding, occur frequently.

OBJECTIVE:

To determine factors that predict upper GI bleeding (UGIB) after cardiac surgery to improve prognostication and, thus, outcomes.

METHODS:

The present case-control study reviewed institutional records spanning 2002 to 2005 for consecutive patients who developed in-hospital UGIB following cardiovascular surgery. Each case was matched to two to three controls for age, sex and date of hospital admission. Demographics, pharmacotherapy (including use of in-hospital acid suppression), endoscopic findings and outcomes were recorded. After adjustment for possible confounders, including Parsonnet score and demographic parameters, conditional logistic regression analysis identified independent significant predictors of the subsequent development of UGIB.

RESULTS:

The study population consisted of 131 cases (mean [± SD] age 68.8±10.2 years, 69.5% male, mean Parsonnet score 24.6±14.2) and 387 matched controls (mean age 68.8±10.8 years, 70.0% male, mean Parsonnet score 20.9±14.2). UGIB events occurred a mean of 10.3±7.7 days after cardiac surgery. Duration of mechanical ventilation (OR 3.01 [95% CI 1.44 to 6.28]), elevation of international normalized ratio (OR 1.91 [95% CI 1.31 to 2.78]) and occurrence of Clostridium difficile colitis before bleeding (OR 3.15 [95% CI 1.19 to 8.36]) were independent risk factors. Use of histamine type 2 receptor antagonists (H₂RAs) (OR 0.65 [95% CI 0.38 to 1.12]) or proton pump inhibitors (PPIs) (OR 0.60 [95% CI 0.27 to 1.32]) demonstrated trends toward protecting against UGIB after cardiac surgery.

CONCLUSIONS:

GI bleeding events occurred approximately 10 days after cardiac surgery in patients with a complicated postoperative course. Significant predictors of subsequent bleeding included increased duration of mechanical ventilation and elevation of international normalized ratio; routine acid suppression with PPIs should be considered in such patients. C difficile colitis also significantly predicted UGIB, and H₂RAs should be considered for acid suppression. Neither H₂RAs nor PPIs were effective in preventing UGIB, although the small number of patients limits definitive conclusions regarding the role of acid suppression.     

Study of damage to red blood cells exposed to different doses of γ-ray irradiation

Background.

The aims of this research were to study alterations in the ultrastructure of red blood cells, the changes in concentrations of plasma electrolytes and the killing effect of lymphocytes in samples of blood exposed to different doses of γ-ray irradiation.

Materials and methods.

Blood samples were treated with different doses of γ-ray irradiation and then preserved for different periods. Specimens were prepared for standard electron microscopy and transmission electron microscopy. At the same time, changes in the concentrations of Na⁺, K⁺ and Cl⁻ and pH values in the plasma as well as Fas and FasL expression of lymphocytes before and after irradiation were determined.

Results.

The proportions of reversibly and irreversibly transformed cells, for example, echinocytes, sphero-echinocytes, and degenerated forms, increased with increasing doses of irradiation and storage period, while the number of discocyte shaped red blood cells decreased. The change in K⁺ concentration was greater than that of Na+ or Cl⁻ after irradiation and was dosage-dependent. Plasma pH was influenced by different doses of radiation and storage time. After exposure to ¹³⁷Cs γ-irradiation, the expression of both Fas and FasL in lymphocytes differed significantly from that in the control group: the expression was positively correlated with irradiation dose (r=0.95, 0.96), but no significant difference in the Fas/FasL ratio was observed (P>0.05).

Discussion.

We conclude that the ultrastructure of red blood cells is not changed obviously by irradiation with some doses of γ-rays and various periods of storage. However, irradiation does have some dose-dependent and time-dependent adverse effects on the erythrocytes.     

PI3K expression and PIK3CA mutations are related to colorectal cancer metastases

AIM: To assess the significance of phosphatidylinositol 3-kinase (PI3K) in colorectal cancer (CRC) and toxicity of {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 in CRC cells with different metastatic abilities.METHODS: Sixty formalin-fixed and paraffin-embedded CRC tumor specimens were investigated. Adjacent normal colonic mucosa specimens from 10 of these cases were selected as controls. PI3K protein was detected by immunohistochemistry and PIK3CA mutations were investigated by gene sequencing analysis. A flow-cytometry-based apoptosis detection kit was used to determine PI3K inhibitor-induced apoptosis in CRC cell lines SW480 and SW620. Expression of phosphorylated protein kinase B in CRC cell lines was detected by Western blotting.RESULTS: There was a significant difference in the proportion of primary lesions (30%, 18/60) vs metastatic lesions (46.7%, 28/60) that were positive for PI3K (P < 0.05). Mutations were detected in exon 9 (13.3%) and exon 20 (8.3%). Out of 60 cases, seven mutations were identified: two hotspot mutations, C.1633G>A resulting in E545A, and C.3140A>G resulting in H1047R; two novel missense mutations C.1624G>A and C.3079G>A; and three synonymous mutations (C.1641G>A, C.1581C>T and C.3027T>A). Exposure of SW480 cells to PI3K inhibitor for 48 h resulted in a significant increase of apoptotic cells in a dose-dependent manner [3.2% apoptotic cells in 0 μmol/L, 4.3% in 5 μmol/L, 6.3% in 10 μmol/L (P < 0.05), and 6.7% in 20 μmol/L (P < 0.05)]. Moreover, PI3K inhibitor induced a similar significant increase of apoptotic cells in the SW620 cell line for 48 h [3.3% apoptotic cells in 0 μmol/L, 13.3% in 5 μmol/L (P < 0.01), 19.2% in 10 μmol/L (P < 0.01), and 21.3% in 20 μmol/L (P < 0.01)].CONCLUSION: High PI3K expression is associated with CRC metastasis. PI3K inhibitor induced apoptosis in CRC cells and displayed strong cytotoxicity for highly metastatic cells. PI3K inhibition may be an effective treatment for CRC.     

Improvement of cardiac function and reversal of gap junction remodeling by Neuregulin-1β in volume-overloaded rats with heart failure

Objective We performed experiments using Neuregulin-1β (NRG-1β) treatment to determine a mechanism for the protective role derived from its beneficial effects by remodeling gap junctions (GJs) during heart failure (HF). Methods Rat models of HF were established by aortocaval fistula. Forty-eight rats were divided randomly into the HF (HF, n = 16), NRG-1β treatment (NRG, n = 16), and sham operation (S, n = 16) group. The rats in the NRG group were administered NRG-1β (10 μg/kg per day) for 7 days via the tail vein, whereas the other groups were injected with the same doses of saline. Twelve weeks after operation, Connexin 43 (Cx43) expression in single myocytes obtained from the left ventricle was determined by immunocytochemistry. Total protein was extracted from frozen left ventricular tissues for immunoblotting assay, and the ultrastructure of myocytes was observed by transmission electron microscopy. Results Compared with the HF group, the cardiac function of rats in the NRG group was markedly improved, irregular distribution and deceased Cx43 expression were relieved. The ultrastructure of myocytes was seriously damaged in HF rats, and NRG-1β reduced these pathological damages. Conclusions Short-term NRG-1β treatment can rescue pump failure in experimental models of volume overload-induced HF, which is related to the recovery of GJs structure and the improvement of Cx43 expression.