Synergic actions of botulinum neurotoxin A and oxaliplatin on colorectal tumour cell death through the upregulation of TRPM2 channel-mediated oxidative stress.

Botulinum neurotoxin A (BoNT) is being shown to have anticancer action as a potential adjuvant treatment. The transient receptor potential (TRP) melastatin 2 (TRPM2) stimulator action of BoNT was reported in glioblastoma cells, but not in colorectal cancer (HT29) cells. By activating TRPM2, we evaluated the impacts of BoNT and oxaliplatin (OXA) incubations on oxidant and apoptotic values within the HT29 cells. Control, BoNT (5 IU for 24 h), OXA (50 µM for 24 h) and their combinations were induced. We found that TRPM2 protein is upregulated and mediates enhanced BoNT and OXA-induced Ca2+ entry in cells as compared to control cells. The increase of free reactive oxygen species (ROS), but the decrease of glutathione is the main ROS responsible for TRPM2 activation on H29 exposure to oxidative stress. BoNT and OXA-mediated Ca2+ entry through TRPM2 stimulation in response to H2 O2 results in mitochondrial Ca2+ overload, followed by mitochondrial membrane depolarization, apoptosis and caspase-3/-8/-9, although they were diminished in the TRPM2 antagonist groups (N-(p-amylcinnamoyl)anthranilic acid and carvacrol). In conclusion, by increasing the susceptibility of HT29 tumour cells to oxidative stress and apoptosis, the combined administration of BoNT and OXA via the targeting of TRPM2 may offer a different approach to kill the tumour cells.

The effects of botulinum toxin A and papaverine on human saphenous vein and internal mammary artery grafts: an in vitro study.

Introduction: Autologous saphenous vein (SV) and internal mammary artery (IMA) are used as bypass conduits during coronary artery bypass graft surgery. Vasospasm of the arterial and venous grafts may constitute a significant clinical problem. Pretreatment with a vasodilator drug of the graft ex vivo or intraluminal injection before implantation may be used for spasm prophylaxis. This in vitro study was designed to assess the vasoactive effects and time-dependent changes of botulinum toxin A (BTX-A) and papaverine pretreatment on vasospasm of human SV and IMA grafts. Also, histomorphology of the vessels was assessed. Material and methods: SV and IMA segments were suspended in organ baths, and isometric contraction responses to 2 different concentrations of 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) were recorded after incubation with 2 different concentrations of BTX-A and papaverine at 2 time points (0 h and 2 h). Results: The results revealed the following: 1) incubation with BTX-A and papaverine relaxes both SV and IMA rings contracted with 5-HT and ET-1; 2) the duration of the relaxant effect of BTX-A lasts longer than papaverine; and 3) no apparent histomorphological changes were observed in the grafts under light microscopy. Conclusions: This study demonstrates that in human SV and IMA grafts, pretreatment with both BTX-A and papaverine are safe and have a potent inhibitory effect depending on the vessel and vasoconstrictor agent. The long-lasting vasodilatory effect of BTX-A on vascular smooth muscle may provide promising results in the prevention of venous and arterial graft spasm.

Trends in traditional and complementary medicine practices in Turkey: Results of two consecutive surveys 2012-2018.

OBJECTIVE: To determine the knowledge, opinions, experiences and trends regarding herbal treatment, traditional medicine and other complementary and alternative medicine. METHODS: Two cross-sectional studies were conducted at Meram Faculty of Medicine Hospital, Konya, Turkey, in 2012 and 2018, comprising subjects of either gender aged >18 years. Data was collected using a survey form prepared in the light of relevant literature. Data was summarised and compared between the two studies. RESULTS: Of the 810 subjects in the two studies, there were 405(50%) in 2012 with a mean age of 32.5±14.0 years, while the remaining 405(50%) were part of the 2018 study with a mean age of 34.4±13.8. There were significant differences between the two group of subjects about the use and indications of traditional and complementary medicine as those who believed traditional and complementary medicine was proper to use increased and those who believed it should not be used decreased significantly (p<0.001). There was a twofold increase in the use of social media as the source of relevant information (p<0.001). CONCLUSIONS: Significant changes in trends related to the use of traditional and complementary medicine between 2012 and 2018 were observed.

Inhaled Dry Powder Mannitol Treatment in Pediatric Patients with Cystic Fibrosis: Evaluation of Clinical Data in a Real-World Setting.

Background: Cystic fibrosis (CF) is a genetic disorder, in which defective clearance of airway secretions leads to progressive lung function loss. Inhaled mannitol is used to increase sputum and mucociliary clearance. There are little data from real-world studies on the effectiveness of mannitol in children. Our objective was to evaluate the spirometry and clinical results of mannitol in pediatric patients. Methods: We retrospectively reviewed the records of 30 children and adolescents with CF receiving inhaled mannitol who were already on recombinant human deoxyribonuclease (rhDNase) treatment. The change in forced expiratory volume in 1 second (FEV1) from baseline at 2-4 months was the primary outcome. Secondary measures were other spirometry results, body mass index (BMI), hospital admissions, sputum characteristics, and positive bacterial colonization. Results: Compared to baseline, we found significant improvement in percent predicted FEV1 at 2-4 months of treatment; 84.50 (58.00-99.00) vs. 96.00 (66.00-106.00) (P = 0.0007). The absolute change in FEV1 was +11.5% at 2-4 months, +6.5% at 5-7 months, and +4% at 8-12 months. Also, significant improvements in other spirometry results were observed. Adolescents had significantly lower FEV1 results, but the improvement in their lung function was sustained for a more extended period than children. Mannitol provided easier sputum removal, increased sputum volume, significant decline in hospitalizations, and significantly fewer patients with positive sputum cultures. A significant increase in BMI at 8-12 months was observed. Cough was the most frequent adverse effect. Conclusion: In a real-world setting, our results demonstrated that adding mannitol to rhDNase therapy is tolerable in pediatric patients with CF and may provide improved spirometry and clinical outcomes. In addition, our results showed that mannitol provided recovery in overall lung function at 2-4 months, which was sustained up to 12 months together with improved BMI, easier sputum removal, and a decline in bacterial colonization and hospital admissions. However, cough was the most frequent side effect.

Effects of Sevoflurane and Propofol Anesthesia on Cerebral Oxygenation in Patients Undergoing Carotid Endarterectomy.

AIM: To compare the effects of sevoflurane and propofol anesthesia on perioperative cerebral oxygenation in patients undergoing carotid endarterectomy (CEA) under general anesthesia by using near-infrared spectroscopy (NIRS) monitoring. MATERIAL AND METHODS: Institutional approval was obtained, and the perioperative data of 33 patients undergoing CEA were retrospectively evaluated. The study groups were organized according to the anesthesia drugs used for maintenance: sevoflurane (n=17) and propofol (n=16). The regional cerebral oxygen saturation (rScO < sub > 2 < /sub > ) of the ipsilateral and contralateral hemispheres was monitored continuously using a NIRS instrument and analyzed at specific time points starting from induction to the 12th hour postoperation. The data were analyzed using the appropriate tests, and a p value of < 0.05 was considered significant. RESULTS: Compared with those of groups with non-clamped hemispheres, the rScO < sub > 2 < /sub > values of the sevoflurane and propofol groups decreased significantly during clamping (p < 0.05) and increased to above-preoperative values after declamping (p < 0.05). When the sevoflurane and propofol groups were compared, a significant decrease in rScO < sub > 2 < /sub > was noted during extubation in the sevoflurane group (p < 0.05). In the propofol group, female patients had significantly lower rScO < sub > 2 < /sub > values compared with male patients during clamping of the carotid artery (p < 0.05). None of the observed decreases was greater than 20%, which is considered an indication for shunting. CONCLUSION: Our NIRS monitoring results indicate that sevoflurane or propofol anesthesia does not generally cause significant differences in cerebral oxygenation during and after cross-clamping in patients undergoing CEA. The finding of sex-related differences in cerebral oxygenation in patients receiving propofol and decreased oxygenation during extubation in patients receiving sevoflurane warrants further studies.

Successful Use of Early Therapeutic Hypothermia in an MDMA and Amphetamine Intoxication-Induced Out-of-Hospital Cardiac Arrest: A Case Report.

BACKGROUND: Deaths caused by recreational drug abuse have increased considerably in recent years. Therapeutic hypothermia offers the potential to improve neurological outcomes in post-resuscitation patients. CASE REPORT: A 19-year-old man was brought to our emergency department after suffering out-of-hospital ventricular fibrillation (VF) cardiac arrest. He was resuscitated at our emergency department again due to VF. Urine analysis showed high levels of amphetamine and 3,4 methylenedioxymethamphetamine (MDMA) (ecstasy). The patient was intubated, sedated, and ventilated. Within 1 h after the return of spontaneous circulation and hemodynamic stabilization, therapeutic hypothermia was initiated for neurologic protection. An external-cooling device was used for cooling. He was maintained at 33oC for 72 h. The patient was weaned from the ventilator and extubated on day 5. He was discharged from the hospital on the day 10 with good cerebral performance. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Initiation of early therapeutic hypothermia within 1 h after return of spontaneous circulation might contribute to better neurologic outcome in patients who suffer VF cardiac arrest. We suggest that early therapeutic hypothermia may be considered in patients who suffer out-of-hospital cardiac arrest due to MDMA and amphetamine intoxications.

The effects of intra-articular injection of ibuprofen on knee joint cartilage and synovium in rats.

OBJECTIVE: The aim of this animal study was to investigate the short and long-term local histomorphologic effects and the utility of intra-articular application of ibuprofen. METHODS: Forty-six Wistar Albino rats were used in the study. The rats were randomized into 5 groups of 8 and a sham group of 6. The 40 rats in the study groups were anaesthetised with 60 mg/kg of ketamine, then 0.25 ml ibuprofen (25 mg) was injected to the right knee joint of each rat (ibuprofen group) and 0.25 ml 0.9% saline to the left knee joint as the control group. To the 6 rats in the sham group, only puncture was applied to both knee joints. The rats in each of the 5 study groups were sacrificed on days 1, 2, 7, 14 and 21 respectively. The histomorphologic changes were graded on a 6-point scale regarding inflammation of the synovia, cartilage tissue, and subchondral bone. Inflammation scores were compared using the Mann Whitney U-test and comparisons of the sacrifice day and drug used were evaluated with the Kruskal Wallis test. The p values below 0.05 were considered as significant. RESULTS: Statistically significant difference was found between the ibuprofen injected knees (10/40) and the saline injected (0/40) and sham knees (0/12) in respect of hematoma positivity (p = 0.002). Significantly higher inflammation scores were found in ibuprofen injected knees on the 1st, 2nd, 7th and 14th days compared to controls and sham (p < 0.05). Inflammation scores were similar in ibuprofen injected knees with and without hematoma (p > 0.05). Inflammation of the ibuprofen injected group was most severe on day one and the severity of inflammation reduced gradually throughout the 3 weeks. CONCLUSION: Our results show that intra-articular injection of ibuprofen can cause intra-articular hematoma. It also leads to transient inflammation of the synovia that is more severe in the early period, which gradually recovers.

Relaxation matters: comparison of in-vitro vasodilatory role of botulinum toxin-A and papaverine in human radial artery grafts.

BACKGROUND: Radial artery (RA) is widely used in coronary artery bypass (CABG) surgery and the prevention of spasm is crucial for graft patency. Botulinum toxin A (BTX-A) and B are commonly used for aesthetic reasons and neuromuscular disorders. They are proven to raise blood flow and increase survival of ischemic skin flaps. In this study we evaluated and compared the vasodilator effects of BTX-A and papaverine on human RA grafts. METHODS: After resting 60 min in isolated organ baths, human RA grafts were examined. Contraction responses for different doses of serotonin (5-HT) and endothelin-1 (ET-1) were evaluated as a percent of maximum contraction response elicited by 80 mM potassium chloride (KCl). The inhibitory effects of BTX-A and papaverine on contraction responses taken at the 0th hour were compared with the 1st and 2nd hour responses. Inhibitory effects of BTX-A and papaverine against the contractile agent were evaluated by comparing the results of the first and last (0th and 2nd hour) application. RESULTS: In low concentrations, when we compared the effects of BTX-A (10- 8 M) and papaverine (10- 6 M) on 5-HT, papaverine was found to be more effective at both the 0th and 2nd hour (p < 0.05). Both BTX-A and papaverine inhibited the maximum contractile effect of ET-1 to the same extent at the 0th hour; but, the inhibitory effect of BTX-A was significantly stronger at the 2nd hour (p < 0.05). In high concentrations, when we compared the effects of BTX-A (10- 6 M) and papaverine (10- 4 M) on 5-HT, papaverine showed stronger inhibition (p < 0.05), whereas both agents had similar action of inhibition on ET-1 mediated maximum contraction responses. CONCLUSION: BTX-A inhibits both ET-1 and 5-HT induced contractions and its effectiveness does not decrease over time as observed with papaverine. This study is the first in the literature using human RA for prevention of vasospasm by BTX-A.

The Relationship Between Vasoactive-Inotropic Score and Mortality in Adult Patients with Traumatic Brain Injury.

AIM: To assess the feasibility of the vasoactive-inotropic score (VIS) in determining the amount of vasoactive support and its relationship with the mortality rate and characteristics of the patients with traumatic brain injury (TBI). MATERIAL AND METHODS: This study was conducted with a retrospective design involving the years 2013-2018 in a university hospital which provides tertiary intensive care service. A total of 102 patients who were admitted in the ICU with the diagnosis of severe TBI, and also were followed by neurosurgery service and who received vasoactive and inotropic support were analyzed concerning VIS value. RESULTS: The median age of the patients was 34 years, and 69.6% of the patients were male. Mortality rate was 43.1%. In the group with mean VISâ‰A10, the admission duration in the ICU and hospital were shorter (p < 0.0001) whereas mortality rates were higher (81.1% vs 21.5% and p < 0.0001). Besides, the number of patients with a VIS score of â‰A10, â‰A15 and â‰A20 were higher in the group of patients who died (p < 0.0001). The results of the multivariate analysis such as VISâ‰A10 were significant. CONCLUSION: We can conclude that VIS, which is used to determine the amount of vasoactive and inotropic medicines during cardiac surgery and in sepsis patients, may be useful in predicting mortality in TBI patients.

Delayed recovery from rocuronium block in an infant.

Prolonged duration of action of rocuronium in an infant patient is rare. We report an unusual case of prolonged neuromuscular blockade with rocuronium in an infant undergoing cleft lip repair anesthetized with sevoflurane and management of the patient.

Vapocoolant spray vs lidocaine/prilocaine cream for reducing the pain of venipuncture in hemodialysis patients: a randomized, placebo-controlled, crossover study.

OBJECTIVE: Patients undergoing hemodialysis are repeatedly exposed to stress and pain from approximately 300 punctures per year to their arteriovenous fistula. This study was designed to measure pain associated with venepuncture during AVF cannulation and to compare the effectiveness of ethyl chloride vapocoolant spray, topical eutectic mixture of local anesthetics (EMLA) cream and placebo in controlling pain caused by venepuncture of arteriovenous fistula patients undergoing chronic hemodialysis. METHODS: This randomized, placebo-controlled, crossover study, included 41 patients undergoing conventional hemodialysis three times a week. First intervention was conducted as baseline pain assessment (control). In the three consecutive dialysis sessions, every patient randomly received 1) ethyl chloride vapocoolant spray, 2) EMLA, or 3) placebo cream before venepuncture. Pain perception was recorded by patients immediately after cannulation on a 0-100 mm visual analogue scale (VAS). p<0.05 was considered as significant. RESULTS: VAS scores presented a marked inter-individual variation during venepuncture. EMLA application resulted in significantly lower total pain scores compared to control and all other interventions (p<0.05). No patient experienced severe pain with EMLA or vapocoolant. The patients reported less moderate and severe pain with EMLA, and vapocoolant spray compared to control and placebo interventions. Moderate and severe pain scores were similar between EMLA and vapocoolant spray (p>0.05). CONCLUSION: Venipuncture for AVF cannulation causes mild to moderate pain in hemodialysis patients. Although local application of EMLA is more effective than in preventing venepuncture pain, ethyl chloride vapocoolant is as effective as EMLA for preventing mild to moderate puncture pain in patients undergoing hemodialysis.

Effects of intrathecal fentanyl on quality of spinal anesthesia in children undergoing inguinal hernia repair.

BACKGROUND: The effect of intrathecal fentanyl on the characteristics of spinal anesthesia has not been investigated in children undergoing inguinal hernia repair. The purpose of this study was to assess whether the incidence and severity of pain during peritoneal sac traction is decreased by addition of fentanyl to bupivacaine in children undergoing inguinal hernia repair with spinal anesthesia. METHODS: Children (6-14 years) were randomized into two groups. Group F (n = 25): hyperbaric bupivacaine plus 0.2 microg.kg(-1) of fentanyl. Group P (n = 25): hyperbaric bupivacaine plus 0.9% NaCl (placebo). The dose of bupivacaine was 0.4 mg.kg(-1). The primary variable was the incidence and severity of pain during peritoneal sac traction. Spinal block characteristics, duration of spinal anesthesia assessed by recovery of hip flexion and duration of analgesia were the secondary variables measured, and the side effects were noted. RESULTS: There were significant differences in incidence of pain and pain scores during sac traction with lower incidence and scores in the fentanyl group (P = 0.009). Two groups were similar regarding the level of sensory block during sac traction and duration of spinal anesthesia. Duration of spinal analgesia was prolonged significantly in the fentanyl group (P = 0.025). CONCLUSION: Intrathecal fentanyl at a dose of 0.2 microg.kg(-1) added to bupivacaine significantly improves the quality of intraoperative analgesia and prolongs postoperative analgesia in children undergoing inguinal hernia repair with spinal anesthesia.

Effect of cooling on the responses of human saphenous vein to fentanyl, remifentanil and sufentanil.

We studied the vasodilatory effects of fentanyl, remifentanil and sufentanil on the human saphenous vein strips at 37, 32 and 28 degrees C. Fentanyl produced concentration-dependent relaxation of human saphenous vein strips precontracted with 5-hydroxytryptamine (5-HT) at every temperature studied. Compared with vein strips at 37 degrees C, relaxant responses to each one concentration of fentanyl were significantly reduced at 32 and 28 degrees C. Remifentanil relaxed vein strips in a concentration-dependent way and the relaxation for all concentrations were significantly greater at 32 and 28 degrees C compared with 37 degrees C. Sufentanil produced concentration-dependent relaxation in saphenous vein strips precontracted with 5-HT. These relaxant responses were similar at 32 degrees C compared with 37 degrees C. When bath temperature was lowered from 37 to 28 degrees C, the relaxant responses to sufentanil were significantly reduced. In summary, the present study suggests that cooling reduces the relaxation caused by fentanyl and sufentanil on human saphenous veins but augments the relaxation with remifentanil. The augmented vasodilatory effect of remifentanil with cooling may be useful on systemic vascular resistance and organ preservation under hypothermic conditions like cardiopulmonary bypass surgery.