Apoptosis of colon cancer cells under the effect of geldanamycin derivate.

AIM: The apoptotic effect of geldanamycin derivative may be important for the colorectal cancer therapy. The mechanisms of apoptosis require understanding of the behavior of colon cancer cell line Colo-205 which mimics colon adenocarcinoma. Therefore, the effect of IC50 dose of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on the colon cancer cells in vitro was studied for its anti-apoptotic activity. METHOD: Apoptotic ratio of the Colo-205 cells was determined after 17-AAG application with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and apoptosis related genes. Apoptosis signal path related key mitochondrial proteins, cytochrome c, bcl-2, caspase 9 and Apaf-1 expression were examined with RT-PCR method. RESULTS: 17-AAG caused induction of cell death. Apoptotic related genes such as cytochrome-c, Apaf-1 and caspase-9 protein expressions were increased significantly (p < 0.05) and anti-apoptotic bcl-2 expression was decreased significantly (p < 0.05). Our results indicated that the application of 17-AAG on Colo-205 cells showed anticancer effect by the apoptosis due to alteration of apoptotic genes. CONCLUSION: The apoptotic effect of 17-AAG as an natural product for alternative medicine would be very important for the success and quality of life during the treatment of colon carcinoma with the combination of anticancer drugs (Tab. 1, Fig. 2, Ref. 32).

Vertebral osteomyelitis: clinical features and diagnosis.

We aimed to describe clinical and diagnostic features of vertebral osteomyelitis for differential diagnosis and treatment. This is a prospective observational study performed between 2002 and 2012 in Ankara Numune Education and Research Hospital in Ankara, Turkey. All the patients with vertebral osteomyelitis were followed for from 6 months to 3 years. In total, 214 patients were included in the study, 113 out of 214 (53%) were female. Out of 214 patients, 96 (45%) had brucellar vertebral osteomyelitis (BVO), 63 (29%) had tuberculous vertebral osteomyelitis (TVO), and 55 (26%) had pyogenic vertebral osteomyelitis (PVO). Mean number of days between onset of symptoms and establishment of diagnosis was greater with the patients with TVO (266 days) than BVO (115 days) or PVO (151 days, p <0.001). In blood cultures, Brucella spp. were isolated from 35 of 96 BVO patients (35%). Among 55 PVO patients, the aetiological agent was isolated in 11 (20%) patients. For tuberculin skin test >15 mm, sensitivity was 0.66, specificity was 0.97, positive predictive value was 0.89, negative predictive value was 0.88, and receiver operating characteristics area was 0.8. Tuberculous and brucellar vertebral osteomyelitis remained the leading causes of vertebral osteomyelitis with delayed diagnosis. In differential diagnosis of vertebral osteomyelitis, consumption of unpasteurized cheese, dealing with husbandry, sweating, arthralgia, hepatomegaly, elevated alanine transaminase, and lumbar involvement in magnetic resonance imaging were found to be predictors of BVO, thoracic involvement in magnetic resonance imaging and tuberculin skin test > 15 mm were found to be predictors of TVO, and history of spinal surgery and leucocytosis were found to be predictors of PVO.

Effects of the blockade of cardiac sarcolemmal ATP-sensitive potassium channels on arrhythmias and coronary flow in ischemia-reperfusion model in isolated rat hearts.

Activation of ATP-sensitive K+ channels (K ATP) during ischemia leads to arrhythmias and blockade of these channels exert antiarrhythmic action. In this study, we investigated the effects of HMR1098, a sarcolemmal K ATP channel blocker and 5-hydroxydeconoate (5-HD), a mitochondrial K ATP channel blocker on cardiac function and arrhythmias in isolated rat hearts. The hearts were subjected to 30 min coronary occlusion, followed by 30 min reperfusion. In the preischemic period, both HMR 1098 and 5-HD slightly increased coronary perfusion pressure. Coronary occlusion increased the perfusion pressure and decreased the left ventricular developed pressure (LVDP) in both control and drug-treated hearts. However, inhibition of LVDP was greater and recovery of the perfusion pressure was lower in 30 micromol/l HMR1098 and 100 micromol/l 5-HD-treated hearts compared to control (P < 0.05). HMR1098, at 3 micromol/l, but not at 30 micromol/l, significantly reduced the ratio of bigeminis, couplets and salvos (P < 0.05). Ventricular tachycardia and ventricular fibrillation were not prevented by HMR1098, at both concentrations, and with 5-HD (100 micromol/l). These results suggest that blockade of sarcK ATP and mitoK ATP channels exert weak antiarrhythmic action, but reduce the recovery of coronary perfusion and contractile force, implying that both types of K(ATP) channels have beneficial role in the recovery of ischemic rat myocardium.

Role of leukotrienes on coronary vasoconstriction in isolated hearts of arthritic rats: effect of in vivo treatment with CI-986, a dual inhibitor of cyclooxygenase and lipoxygenase.

In this study, coronary perfusion pressure and force of contraction were investigated in isolated hearts removed from arthritic rats by using the Langendorff method. A strong coronary vasoconstriction was determined in arthritic hearts which was associated with elevated levels of arachidonate 5-lipoxygenase (5-LOX) products, leukotriene B(4) (LTB(4)) and LTC(4) in coronary effluents. In vivo treatment with the dual inhibitor of cyclooxygenase (COX) and LOX, CI-986 (2 and 10 mg/kg/day) on days 14- 26 following adjuvant injection, prevented the coronary vasoconstriction and the increased production of LTB(4) and LTC(4). These results suggest that the coronary vasoconstriction in the isolated arthritic hearts is associated with an increased activity of the LOX system and CI-986 could have a preventive effect on constriction of coronary arteries.

The antinociceptive effect of leukotriene D(4) receptor antagonist, MK-571, in mice: possible involvement of opioidergic mechanism.

The effect of a leukotriene D(4) receptor antagonist, (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl(3-dimethyl amino-3-oxo propyl)thio)methyl)thio) propanoic acid (L-660,711; MK-571), was investigated on nociceptive responses in mice using three different assays: acetic-acid-induced abdominal constrictions, formalin response and tail-flick test. MK-571 (8-32 mg/kg, i.v.) produced dose-dependent protection against acetic-acid-induced abdominal constriction (ED(50)=30 mg/kg). The compound (10-80 mg/kg, i.p.) was also effective, in a dose-dependent manner, on the second phase of the formalin response (ED(50)=26 mg/kg). However, it had no effect on the first phase of the formalin response and in the tail-flick test. Naloxone (1 mg/kg, i.v.), an opioid antagonist, almost completely blocked the antinociceptive effect of MK-571 in both acetic-acid-induced abdominal constriction and the second phase of the formalin test. These results provide evidence for an antinociceptive action of MK-571 at peripheral sites and suggest that opioid mechanisms are involved.

Possible contribution of leukotrienes in the arrhythmogenic effects of digoxin on isolated guinea-pig hearts.

The effect of a leukotriene D4 (LTD4) receptor antagonist, L-648,051, was investigated in digoxin-induced cardiac toxicity in isolated guinea-pig hearts (Langendorff preparation). Digoxin infusion (25 microg.ml-1, 0.5 ml.min-1) increased perfusion pressure and contractile force initially, but decreased them later. The onset of first ventricular premature beats (VPBs) matched the increase phase, but the decrease phase was accompanied by ventricular tachycardia (VT) and fibrillation (VF). In the presence of L-648,051 (5 micromol. l-1), the initial phase was similar to that observed with digoxin alone, but the marked reduction was inhibited. This drug increased the concentration of digoxin required for VBSs and cardiac arrest, but it could not prevent the formation of VT and VF. The duration of VT was significantly decreased by L-648,051. It is concluded that the leukotriene receptor antagonist might have beneficial effects on digoxin-induced arrhythmias. Whether this effect depends on direct or indirect actions is uncertain.

Effect of vitamin E on vascular responses of thoracic aorta in rat experimental arthritis.

1. Vascular contractile and relaxant responses were evaluated in isolated aortic rings of adjuvant-induced arthritic rats in comparison with control rats, and the effect of an antioxidant treatment on the development of the arthritis was investigated by vitamin E administration (100 mg/kg/day, i.m., for 26 days). 2. Arthritis was induced by an intradermal injection of Freund's complete adjuvant into rat paw. Vascular responses, arthritic lesions and serum copper levels were evaluated after 26 days from adjuvant inoculation. 3. Serum copper levels were significantly lower in arthritic rats than in the control. 4. The contractile response of aortic rings to phenylephrine (PE), but not to KCl, was increased in preparations from arthritic rats, which could be explained by an enhancement of intracellular calcium contents. 5. Acetylcholine (Ach)-mediated endothelium-dependent and sodium nitroprusside (SNP)-mediated endothelium-independent relaxations were not changed significantly in vascular preparations from arthritic rats. 6. In arthritic rats, vitamin E treatment improved arthritic lesions with an increase in copper levels. Despite this ameliorating effect, vitamin E treatment caused an increase in contractile response to PE and a decrease in the relaxant response to Ach and SNP in arthritic rats. 7. These data show that vitamin E provides ameliorating effects in improving systemic signs of experimental arthritis, but it fails to restore abnormalities in vascular function, indicating that adjuvant-induced alterations in vascular function may include mechanisms other than oxygen-free radical formation.

Psychological preparedness for trauma as a protective factor in survivors of torture.

BACKGROUND: Although much research has focused on mechanisms of traumatization and factors related to post-trauma psychological functioning in survivors of trauma, there have been few studies of survivors of torture despite the widespread practice of torture in the world. The aim of this study was to examine the role of 'psychological preparedness' for trauma in post-traumatic stress responses in survivors of torture. METHOD: Thirty-four torture survivors who had no history of political activity, commitment to a political cause or group, or expectations of arrest and torture were compared with 55 tortured political activists, using structured interviews and measures of anxiety, depression, and post-traumatic stress disorder. RESULTS: Compared with tortured political activists, tortured non-activists were subject to relatively less severe torture but showed higher levels of psychopathology. Less psychological preparedness related to greater perceived distress during torture and more severe psychological problems, explaining 4% of the variance in general psychopathology and 9% of the variance in post-traumatic stress disorder symptoms. CONCLUSIONS: The study findings lend support to the role of prior immunization to traumatic stress and to unpredictability and uncontrollability of stressors in the effects of traumatization. Further research aimed at identifying the behavioural and cognitive components of psychological preparedness that play a role in traumatization may provide useful insights into effective treatment strategies for survivors of torture.

Effects of a lipoxygenase inhibitor on digoxin-induced cardiac arrhythmias in the isolated perfused guinea-pig heart.

1. The effects of a lipoxygenase inhibitor, BW A4C, on digoxin-induced arrhythmias and cardiac dynamics (contractile force, perfusion pressure, heart rate) were investigated in Langendorff-perfused isolated guinea-pig hearts. In the control group, arrhythmias were induced by 25 micrograms/ml digoxin at a perfusion rate of 0.5 ml/min. In the treated groups, BW A4C (1 and 0.3 microM) perfused continuously from 15 min prior to digoxin until cardiac arrest occurred. Digoxin exposure (microgram/g wet weight of heart) for the occurrence of arrhythmias and cardiac arrest were the parameters evaluated to assess cardiotoxicity. 2. Digoxin caused a marked increase in leukotriene B4 release in the coronary effluent, and was collected during tachyarrhythmias. BW A4C markedly inhibited the digoxin-induced elevation of LTB4. 3. BW A4C (1 and 0.3 microM) did not prevent the onset of ventricular fibrillation and ventricular tachycardia despite a slight delay in the occurrence of ventricular fibrillation and cardiac arrest at the 0.3 microM concentration. 4. Contractile force increased significantly after digoxin infusion which was concomitant with the time of onset of arrhythmias. In the presence of BW A4C, the contractile force increased, but not significantly. Perfusion pressure increased initially after digoxin infusion in the absence and the presence of BW A4C, but not significantly. 5. These findings show that the lipoxygenase inhibitor lacked any protective action on digoxin-induced arrhythmias despite its effective suppression of digoxin-induced elevation of LTB4 in coronary effluent.

The effect of edothelium on the response to propofol on bovine coronary artery rings.

In this study, the effect of propofol on isolated bovine coronary artery tone was studied in artery rings precontracted with PGF2a. Propofol, in concentrations of 10-6-10-5 M did not change vascular smooth muscle tone, but at high concentrations (10-4-10-1 M) produced relaxation in rings with intact endothelium. In rings denuded of endothelium or treated with methylene blue, propofol produced relaxation at 10-3-10-1 M concentrations, but there was a significant decrease in relaxation compared to endothelium intact rings. In the presence of a calcium agonist (Bay K 8644; 10-5 M), propofol produced constriction in rings denuded of endothelium. These results suggest that high concentrations of propofol may have vasorelaxant effect on bovine coronary artery and that these effects may be due to actions on the endothelium and mediated by calcium channels.

Effects of a leukotriene D4 receptor antagonist, L-648,051, and a dual inhibitor lypoxygenase and cyclooxygenase, BW-755C, on digoxin-induced arrhythmias in guinea-pigs.

In this study, we investigated the effects of leukotrienes on digitalis-induced arrhythmias in guinea-pigs, utilizing a dual inhibitor of lypoxygenase and cyclooxygenase, BW-755C, and a leukotriene D4 receptor antagonist, L-648,051. Guinea-pigs, anaesthetized with urethane (1.5 g/kg, intraperitoneally) and breathing spontaneously, received an intravenous injection of BW-755C (5, 10 and 20 mg/kg) or L-648,051 (5 and 10 mg/kg) 15 min prior to digoxin. Digitalis arrhythmias were induced by a 50 micrograms/kg intravenous bolus injection, followed, 15 min later, by a 400 micrograms/kg/hr intravenous infusion. Compared with the control group, L-648,051 (5 mg/kg) significantly increased the digoxin dose causing ventricular tachycardia and mortality. BW-755C (5 and 10 mg/kg, but not 20 mg/kg) significantly increased the digoxin dose causing mortality. Both L-648,051 (5 mg/kg) and BW-755C (10 mg/kg) significantly prevented the incidence of ventricular fibrillation. At a higher dose (20 mg/kg), BW-755C caused a more rapid development of ventricular fibrillation and mortality than in other doses. These data suggest that inhibitors of lypoxygenase and leukotriene receptor antagonists may have protective effects and that endogenously released leukotrienes may play an important role in digoxin-induced arrhythmias in guinea-pigs.

Sister chromatid exchanges in lymphocytes of nurses handling antineoplastic drugs.

The effects of handling antineoplastic drugs were examined in a group of 23 nurses working in the hematology and oncology departments of different university hospitals in Ankara and in a group of 50 unexposed controls. The cytogenetic repercussions of exposure were assessed by examining sister chromatid exchanges (SCEs) in circulating lymphocytes which result from the breakage and rejoining of DNA at apparently homologous sites on the 2 chromatids of a single chromosome. A significant increased frequency of SCE is observed in nurses in daily contact with antineoplastics (n = 23, mean SCEs/cell +/- SE 6.5 +/- 0.2) as compared to a group of controls (n = 50, mean SCEs/cell 5.2 +/- 0.2). The nurses who smoked also had a higher SCE frequency (n = 15, mean SCEs/cell 7.0 +/- 0.3) than non-smokers, (n = 8, mean SCEs/cell 5.5 +/- 0.3). A significant increase (P less than 0.001) in the mean number of SCE was found for non-smoking nurses as compared to non-smoking controls (n = 27, mean SCEs/cell 4.1 +/- 0.2).

Increased frequency of sister chromatid exchanges in the peripheral lymphocytes of cigarette smokers.

The incidence of sister chromatid exchanges (SCEs) in the peripheral lymphocytes of 23 smokers was significantly higher than that in 27 non-smokers (6.5 +/- 0.3 compared with 4.1 +/- 0.2 per cell, mean +/- SEM). Both the duration of smoking and the number of cigarettes smoked per day appeared to influence SCE frequency. Significantly higher frequencies of SCEs were observed in those who smoked more than 10 cigarettes per day than in those who smoked less than 10 cigarettes per day. The frequency of SCEs in those who had habitually smoked for over 10 years was significantly greater than that in those who had smoked for less than 10 years.

Sister chromatid exchanges in peripheral lymphocytes of urinary tract infection treated with nitrofurantoin.

Nitrofurantoin, a widely used antibacterial agent in the therapy of urinary tract infections of bacterial origin, has been widely discussed in recent years due to its genotoxicity. Sister chromatid exchanges (SCE) were studied in lymphocyte cultures of 15 urinary tract infection patients before and after medication with daily oral doses of 10 mg/kg or 400 mg nitrofurantoin for 10 days. Both stages exhibited similar average numbers of SCE in circulating lymphocytes. The number of SCE was larger in smokers. The results of this study suggest that the short-term exposure to nitrofurantoin does not cause detectable cytogenetic abnormalities.