Protective effects of melatonin,vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: a comparative study

Acetaminophen (AA) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis and nephrotoxic effects in both humans and experimental animals. It has been reported that the toxic effects of AA are the result of oxidative reactions that take place during its metabolism. In this study we investigated if melatonin, vitamin E or N-acetylcysteine (NAC) are protective against AA toxicity in mice. The doses of the antioxidants used were as follows: melatonin (10 mg/kg), vitamin E (30 mg/kg) and NAC (150 mg/kg). Blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels in blood, and glutathione (GSH), malondialdehyde (MDA), oxidized protein levels and myeloperoxidase (MPO) activity in liver and kidney tissues were measured. BUN and serum creatinine, ALT and AST levels which were increased significantly following AA treatment decreased significantly after pretreatment with either vitamin E, melatonin or NAC; however, they were not reduced to control levels. ALT and AST levels were significantly higher at 4 hr compared with the 24 hr levels after AA administration. However, BUN and creatinine levels were significantly elevated only at 24 hr. GSH levels were reduced while MDA, MPO and oxidized protein levels were increased significantly following AA administration. These changes were reversed by pretreatment with either melatonin, vitamin E or NAC. Liver toxicity was higher at 4 hr, whereas nephrotoxicity appeared to be more severe 24 hr after treatment with AA. Vitamin E was the least efficient agent in reversing AA toxicity while melatonin, considering it was given as at lower dose than either vitamin E or NAC, was the most effective. This may be the result of the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes.     

Estrogenicity of isoflavones on human endometrial stromal and glandular cells

Endometrium consists of different cell populations such as epithelial and stromal cells and is mainly regulated by sex steroids. Isoflavones are plant-derived estrogenic compounds that have estrogenic and antiestrogenic properties in a cell-specific manner. We hypothesized that one of the potential health benefits of isoflavones may be their ability to regulate endometrial cell function. The present study was conducted to assess estrogenic and/or antiestrogenic effects of isoflavones (genistein, genistin, daidzein, and daidzin) in cultured human endometrial stromal and glandular (Ishikawa) cells by MTT colorimetric cell proliferation assay, proliferating cell nuclear antigen expression, and alkaline phosphatase activity assays. Experiments were performed in a time- (24-96 h) and concentration-dependent (10(-12) to 10(-5) M) manner. All isoflavones used in the present study induced endometrial stromal and Ishikawa cell proliferation when compared with control (vehicle) group in a time- (at 48 h and afterward) and concentration-dependent manner (at 10(-8) M and above) (P < 0.05). However, isoflavones (at 10(-8) and above concentrations) were also antiestrogenic when combined with estradiol (E(2)) (P < 0.05). The isoflavones revealed a weak estrogenic activity (39-67% less than E(2)) as assessed by alkaline phosphatase activity (P < 0.05), but when administered together with E(2), they antagonized estrogen induced alkaline phosphatase activity by 36-89% (P < 0.05). We conclude that, although isoflavones alone have weak estrogenic effects on endometrial stromal and glandular cells, in the presence of E(2) they act as antiestrogens.     

Biliary stones and stenoses: diagnostic value of magnetic resonance cholangiography.

BACKGROUND/AIMS: To evaluate the accuracy of magnetic resonance cholangiography for detection of bile duct calculi and stenosis. METHODS: Half-Fourier single-shot rapid acquisition with relaxation enhancement sequence magnetic resonance cholangiography was performed prospectively in 68 patients who were suspected of having choledocholithiasis or biliary tree stenosis. On the basis of findings at ultrasound, computed tomography, endoscopic retrograde or percutaneous cholangiography, intraoperative cholangiography or choledocoscopy and exploration, final diagnoses were normal bile ducts (n=8), choledocholithiasis (n=28), benign or malignant stenosis (n=32). RESULTS: Choledocholithiasis was diagnosed with a sensitivity of 96% and a specificity of 98%. False negative readings occurred due to stones less than two mm at in size at the distal common bile duct. A false diagnosis of choledocholithiasis (single impacted stone) by magnetic resonance cholangiography occurred in only one case for whom the final diagnosis was main bile duct adenocarcinoma, suspected on endoscopic retrograde cholangiography and confirmed at surgery. Bile duct stenosis was diagnosed with a sensitivity of 97% and a specificity of 94%. CONCLUSIONS: With magnetic resonance cholangiography, bile duct calculi and stenosis can be diagnosed with high accuracy. It is a fast, accurate and noninvasive alternative to endoscopic retrograde cholangiography in the evaluation of biliary tract disease.     

Henoch Schonlein purpura in childhood: clinical analysis of 254 cases over a 3-year period

We aimed to evaluate the patients who were diagnosed as Henoch Schonlein purpura (HSP) for disease characteristics and prognosis of those with joint, gastrointestinal (GI), and renal involvement. Two hundred and fifty-four children who were followed up with the diagnosis of HSP in the Pediatric Nephrology Clinics of Meram Medical Faculty of Selcuk University and Medical Faculty of Gazi University between January 2003 and June 2006 were retrospectively evaluated. The clinical follow-up and treatment regimens of patients in whom renal biopsy was performed were evaluated in detail. The study group consisted of 254 children, 147 boys (57.8%) and 107 girls (42.2%), and the ratio of boys to girls was 1.37. The percentages of skin, joint, GI, and renal manifestations were 100%, 66%, 56%, and 30%, respectively. Eight patients had intussusception. Five of them recovered with steroid treatment only while three patients were operated on. Sixty-four patients (44%) with GI involvement had severe disease and were successfully treated with steroids. Renal biopsy was performed in 26 patients. Among those 26 patients, two of them recovered spontaneously within 3 and 4 weeks. Ten patients improved with only steroid treatment while 12 patients recovered with steroid and cyclophosphamide treatment. Two patients were resistant to steroid and cyclophosphamide treatment and were treated with cyclosporine A. We believe that steroid therapy given to the HSP patients with GI manifestations might be helpful to prevent probable complications such as GI bleeding and intussusception. In addition, combined therapy with steroid and cyclophosphamide can usually be an appropriate treatment for patients with nephrotic proteinuria.     

The predictors of post-transplant coronary events among liver transplant recipients

Background/purpose

Cardiac morbidities can occur during the peri- and post-liver transplant (LT) period, affecting the long-term survival. The purpose of this study was to identify the potential factors that predict a coronary event post-transplantation.

Methods

Medical records of patients who underwent liver transplantation at Johns Hopkins Hospital between 2009 and 2013 were retrospectively reviewed. We looked at pre-liver transplant cardiac risk factors and the diagnostic tests utilized for coronary artery disease screening. Patients with and without post-liver transplant coronary events were compared.

Results

There were a total of 146 patients with a mean age at LT of 55.3 years. The prevalence of hypertension, tobacco use and diabetes within the patient population was 61.6 % (n = 90), 39 % (n = 57) and 37.6 % (n = 55), respectively. There were 29 deaths and 30 coronary events over a median follow-up period of 1.75 years. Age at the time of liver transplant was predictive of coronary event (OR 1.11, CI 1.01–1.20). The 1-year survival in patients with a coronary event was 47 versus 94 % in patients without a coronary event. The combined use of a dobutamine stress echocardiogram and coronary artery calcium score predicted a coronary event with a sensitivity of 62.5 % and specificity of 66.7 %.

Conclusion

In conclusion, LT recipients with cardiac events had limited survival as compared to the cohort without coronary events. Identification of such patients with noninvasive screening may provide a practical alternative to an invasive cardiac workup. Further improvement in screening strategies may minimize the liver transplant cardiac morbidity.

     

FX minirail balloon angioplasty for the treatment of patients with in-stent restenosis: a matched comparison of 6 months’ outcome with conventional balloon angioplasty

The optimal treatment for in-stent restenosis (ISR) is a subject of controversy. Recently, FX minirail balloon angioplasty (BA) has emerged as a management tool for ISR. We assessed the hypothesis that the FX minirail BA has advantages over conventional percutaneous transluminal balloon angioplasty (PTCA) in the treatment of ISR. FX minirail BA or PTCA were applied to 116 patients with ISR (145 lesions) at our institution. Using a computer algorithm, an attempt was made to match each lesion in the FX minirail BA group with a corresponding lesion in the PTCA group. The lesion pairs should match with respect to the patients age and sex, type of target vessel and stent, reference vessel diameter, and baseline minimal lumen diameter (MLD). Following the matching process, 46 ISR lesion pairs were identified. Baseline patient characteristics were similar among the groups (P = not significant). There was no difference in the in-hospital major adverse cardiac events (MACE) between the groups, whereas MACE at follow-up were significantly lower in the FX minirail BA group than in the PTCA group (19.6% vs 41.3%, P < 0.05). The recurrent ISR rate was significantly lower in the FX minirail BA group than in the PTCA group (19.6% vs 39.1%, P < 0.05). Also, a diffuse pattern of recurrence was more common in lesions treated with PTCA, whereas the focal pattern of recurrence was more common in the FX minirail BA group (22.2% vs 50%, P < 0.05). The MLD at follow-up, the acute gain, and net gain were significantly higher in the group of lesions treated with the FX minirail BA than in the PTCA group. In addition, a significantly higher late loss and loss index at follow-up were observed in the PTCA group compared in the FX minirail BA group. The FX minirail BA has advantages over PTCA in the treatment of patients with ISR, with better immediate and follow-up angiographic outcomes, and a better clinical outcome on follow-up.     

Pharmacological Stimulation of β <Subscript>2</Subscript>-adrenergic Receptors (β <Subscript>2</Subscript>AR) Enhances Therapeutic Effectiveness of β <Subscript>1</Subscript>AR Blockade in Rodent Dilated Ischemic Cardiomyopathy

Background. We have reported that β ₂ adrenoreceptor (β ₂AR) stimulation is anti-apoptotic, and has strong beneficial effect on cardiac remodeling in an experimental model of post myocardial infarction chronic heart failure (CHF) in rats. Here we investigate whether the addition of chronic pharmacological β ₂AR stimulation enhances the therapeutic effects of β ₁AR blockade on cardiac remodeling in the same model. Methods and Results. Metoprolol, a β ₁AR blocker, given alone (β ₁) or in combination with β ₂AR agonist, fenoterol (β ₁β ₂) were administered to rats via drinking water for 6 weeks, beginning 2 weeks following permanent coronary ligation. Progressive left ventricular (LV) remodeling of untreated animals, assessed by repeated echocardiography, occurred during the observation time, i.e., 42% and 25% increases in end-systolic and end-diastolic LV volumes respectively, 27% fall in ejection fraction, and 35% infarct expansion. Pressure-volume loop analyses at 2d and 8th post infarction weeks showed continuous deterioration of systolic and diastolic functions and arterio-ventricular mismatch. Histological evaluation at the end of 8 weeks revealed the MI expansion and hypertrophy of cardiomyocytes. β ₁β ₂ prevented LV remodeling, MI expansion and cardiomyocytes hypertrophy to a greater degree than β ₁, due, in large part, to a vasodilatory effect of β ₂AR stimulation and thus improvement of arterio-ventricular mismatch. The abnormal diastolic performance improved only in β ₁β ₂. β ₁β ₂ treatment reduced myocardial apoptosis throughout myocardium, but β ₁ reduced apoptopsis only in the areas remote from MI. Conclusion. The therapeutic effects of chronic β ₁AR blockade on cardiac remodeling of heart failure are enhanced and extended when supplemented with β ₂AR stimulation. This research was supported by the Intramural Research Program of the National Institute on Aging, NIH.     

Carotid Endarterectomy versus Carotid Artery Stenting: Findings in Regard to Neuroclinical Outcomes and Diffusion-Weighted Imaging

The purpose of our study was to evaluate prospectively the frequency and significance of brain lesions after elective carotid endarterectomy (CAE) and carotid artery stenting (CAS) by using diffusion-weighted magnetic resonance imaging (DW MRI) and then to correlate imaging findings with neuroclinical outcomes.From February 2003 through March 2005, 95 consecutive patients underwent surgical endarterectomy or CAS (with a cerebral protection device) at our institution. A total of 59 CAE procedures were performed in 46 consecutive patients (mean age, 65.8 ± 9 yr), and 56 CAS procedures were performed in 49 consecutive patients (mean age, 66.3 ± 9 yr). Diffusion-weighted magnetic resonance imaging of the brain was performed in all patients within 24 hours of the procedure, both before and after.The post-procedural stroke rate was slightly higher in the CAS group, but this difference was not significant (5.4% vs 0). One early and 1 late death occurred in the stent group. Although the incidence of ischemic lesions was similar in both groups (surgery group, 12.5%; stent group, 13.5%), new DW MRI lesions were higher in the endarterectomy group (27.1% vs 12.5%, P=0.041). This difference was due chiefly to nonischemic lesions such as hemorrhage and watershed ischemia. In the analysis of patients with embolic ischemia, incidences of symptomatic stroke (P=0.046) and large infarct (P=0.013) were higher in the stent group.When we used protective devices during CAS, the incidence of embolic complications was similar to that of surgical enarterectomy. On the other hand, the clinical results of CAS need improvement.Key words: Arterial occlusive diseases, brain ischemia, carotid stenosis, cerebral infarction, cerebrovascular disorders, endarterectomy, carotid, intracranial embolism and thrombosis, ischemic attack, transient, prospective studies, stents, stroke/prevention & controlThe purpose of treating a stenosis of the carotid artery is to prevent stroke and to otherwise reduce the risk of cerebral ischemia. At present, carotid artery endarterectomy (CAE) and carotid artery stenting (CAS) are accepted as major therapeutic methods. The efficacy and safety of CAE in symptomatic and asymptomatic patients have been carefully evaluated in large randomized clinical trials.^1–4 Nevertheless, CAS has become an attractive treatment for patients because of shorter hospital stays and the avoidance of general anaesthesia, surgical incision, and risk of cranial nerve injury.^5,6 However, large-scale randomized clinical trials are needed to determine whether CAS should be the procedure of choice.Both CAE and CAS carry risk. These procedures, which are known to be associated with temporary or permanent neurologic defects, must be performed with low rates of morbidity and mortality in order to maintain short- and long-term benefits superior to those of medical treatment. Therefore, procedure-related embolic complications have become a critical issue for both CAE and CAS.Several separate studies^7–12 by means of diffusion-weighted magnetic resonance imaging (DW MRI) have documented the frequency of new lesions, which presumably are infarctions due to distal embolization from friable plaque after CAE and CAS. Although most of these lesions have been clinically silent, impairment of cognitive function may occur in CAE and CAS patients and warrants further investigation.¹³ Diffusion-weighted magnetic resonance imaging has been shown to be a highly sensitive tool for the detection of cerebral ischemia, because it enables the visualization of recently ischemic regions as hyperintense areas within minutes of onset.¹⁴ During the 24 hours after onset, conventional magnetic resonance imaging is less sensitive than computed tomography for the detection of hemorrhage.¹⁵ However, on diffusion-weighted images the core of the acute hemorrhagic lesion is hyperintense and is initially observed at 4 hours after onset, similar to findings in cases of nonhemorrhagic lesion.¹⁶ The value of transcranial Doppler detection of emboli has probably been overestimated in the comparison of interventional approaches.¹⁷ We therefore used DW MRI to investigate the relevance of intraoperative microemboli to cerebral ischemia and other cerebral lesions such as hemorrhage, in patients who were undergoing CAE and CAS.The purpose of our prospective study was to evaluate the frequency and significance of brain lesions after elective CAE and CAS by using DW MRI and to correlate imaging findings with neuroclinical outcomes.     

Evaluation of Effects of Intra aortic Balloon Counterpulsation on Autonomic Nervous System Functions by Heart Rate Variability Analysis

Background: In patients with acute myocardial infarction (AMI), intraaortic balloon counterpulsation (IABC) may improve cardiac performance, decrease the incidence of recurrent ischemia, and improve survival. Although there have been several reports concerning circulatory maintenance with the IABC, response of the autonomic nervous system to these hemodynamic changes is not clear. Heart rate variability (HRV) analysis has been extensively used to evaluate autonomic modulation of sinus node and to identify patients at risk for an increased cardiac mortality. In this study, we evaluated effects of the IABC on autonomic nervous system functions by HRV analysis. Methods: The study group was composed of 32 consecutive patients (13 female, 19 male aged 61.8 ± 8.8 years) undergoing IABC. Transthoracic echocardiography and 1‐hour Holter recordings for HRV analysis in each IAB pumping mode were obtained. Results: The IABC improved left ventricular diastolic and systolic functions as well as caused an increase in SDNN1, PNN50(1), RMSSD1, and HF1 and a decrease in LF1, LF/HF1, mean heart rate, and the number of ventricular extrasystoles. The improvements in HRV parameters were correlated with some hemodynamic changes such as the increase in MAP and CO during counterpulsation. The only independent factors affecting in‐hospital mortality were the change in LF/HF1 ratio (ΔLF/HF1) and the change in the number of ventricular extrasystole (ΔVES). The decrease in LF/HF1 ≥4.9 decreased the mortality by 1.7‐folds (RR = 0.6, P = 0.04, 95% CI: 0.1–2.3). The decrease in VES ≥27/15 minutes resulted in mortality reduction by 16‐folds (RR = 0.06, P = 0.02, 95% CI: 0.01–0.4). Conclusions: As a result, the IABC, especially in 1:1 support, causes an increase in HRV, decrease in sympathetic overactivity, and improvement in sympathovagal balance besides the favorable hemodynamic changes, and these electrophysiologic changes may explain the role of the IABC in the treatment of ventricular arrhythmias.