Alpha-synuclein interaction with mitochondria is the final mechanism of ferroptotic death induced by erastin in SH-SY5Y cells.

Ferroptosis has been characterized as a form of iron-dependent regulated cell death accompanied by an accumulation of reactive oxygen species and lipid oxidation products along with typical morphological alterations in mitochondria. Ferroptosis is activated by diverse triggers and inhibited by ferrostatin-1 and liproxstatin-1, apart from iron chelators and several antioxidants, and the process is implicated in multiple pathological conditions. There are, however, certain ambiguities about ferroptosis, especially regarding the final executioner of cell death subsequent to the accumulation of ROS. This study uses a typical inducer of ferroptosis such as erastin on SH-SY5Y cells, and shows clearly that ferroptotic death of cells is accompanied by the loss of mitochondrial membrane potential and intracellular ATP content along with an accumulation of oxidative stress markers. All these are prevented by ferrostatin-1 and liproxstatin-1. Additionally, cyclosporine A prevents mitochondrial alterations and cell death induced by erastin implying the crucial role of mitochondrial permeability transition pore (mPTP) activation in ferroptotic death. Furthermore, an accumulation of α-synuclein occurs during erastin induced ferroptosis which can be inhibited by ferrostatin-1 and liproxstatin-1. When the knock-down of α-synuclein expression is performed by specific siRNA treatment of SH-SY5Y cells, the mitochondrial impairment and ferroptotic death of the cells induced by erastin are markedly prevented. Thus, α-synuclein through the involvement of mPTP appears to be the key executioner protein of ferroptosis induced by erastin, but it needs to be verified if it is a generalized mechanism of ferroptosis by using other inducers and cell lines.

GLUT inhibitor WZB117 induces cytotoxicity with increased production of amyloid-beta peptide in SH-SY5Y cells preventable by beta-hydroxybutyrate: implications in Alzheimer's disease.

BACKGROUND: Inhibitors of glucose transporters are being explored as potential anti-cancer drugs. Decreased cerebral glucose utilization with reduced levels of several glucose transporters is also an important pathogenic signature of neurodegeneration of Alzheimer's disease, but its exact role in the pathogenesis of this disease is not established. We explored in an experimental model if inhibitors of glucose transporters could lead to altered amyloid-beta homeostasis, mitochondrial dysfunction, and neuronal death, which are relevant in the pathogenesis of Alzheimer's disease. METHODS: SH-SY5Y cells (human neuroblastoma cell line) were exposed to an inhibitor (WZB117) of several types of glucose transporters. We examined the effects of glucose hypometabolism on SH-SY5Y cells in terms of mitochondrial functions, production of reactive oxygen species, amyloid-beta homeostasis, and neural cell death. The effect of ß-hydroxybutyrate in ameliorating the effects of WZB117 on SH-SY5Y cells was also examined. RESULTS: We observed that exposure of SH-SY5Y cells to WZB117 caused mitochondrial dysfunction, increased production of reactive oxygen species, loss of cell viability, increased expression of BACE 1, and intracellular accumulation of amyloid ß peptide (Aß42). All the effects of WZB117 could be markedly prevented by co-treatment with ß-hydroxybutyrate. Cyclosporine A, a blocker of mitochondrial permeability transition pore (mPTP) activation, could not prevent cell death caused by WZB117. CONCLUSION: Results in this neuroblastoma model have implications for the pathogenesis of Alzheimer's disease and warrant further explorations of WZB117 in primary cultures of neurons and experimental animal models.

Protective effects of cyclosporine A on neurodegeneration and motor impairment in rotenone-induced experimental models of Parkinson's disease.

The development of neuroprotective drugs targeting mitochondria could be an important strategy in combating the progressive clinical course of Parkinson's disease. In the current study, we demonstrated that in SH-SY5Y cells (human dopaminergic neuroblastoma cell line), rotenone caused a dose-dependent (0.25-1 µM) and time-dependent (up to 48 h) loss of cell viability and a loss of cellular ATP content with mitochondrial membrane depolarization and an increased formation of reactive oxygen species; all these processes were markedly prevented by the mitochondrial permeability transition pore blocker cyclosporine A, which did not affect complex I inhibition by rotenone. The nuclear morphology of rotenone-treated cells for 48 h indicated the presence of both necrosis and apoptosis. We then examined the effects of cyclosporine A on the rotenone-induced model of Parkinson's disease in Wistar rats. Cyclosporine A significantly improved the motor deficits and prevented the loss of nigral dopaminergic neurons projecting into the striatum in rotenone-treated rats. Being a marketed immuno-suppressive drug, cyclosporine A should be further evaluated for its putative neuroprotective action in Parkinson's disease.

Eye-Tracking Technology in Surgical Training.

The aim of this review was to amalgamate literature on the use of eye tracking methodology as an adjunct to surgical training. The PRISMA Guidelines were used to undertake this systematic review. Our review studies has shown that recording a surgeon's eye movements; time to first fixation and gaze pattern through the use of eye tracking technology would be beneficial for surgical training.

A unique complication of self-expandable metal stent placement in malignant duodenal obstruction.

Intestinal obstruction is a common complication in patients with advanced gastrointestinal malignancies. In the last two decades, endoscopic placement of duodenal stents has become a mainstay of palliative treatment in patients with unresectable obstructive duodenal pathology. Self-expandable metal stents have been reported to have excellent success rates, besides dramatically improve the patient's quality of life by reinstating the oral feeding ability. Re-intervention rates remain high, commonly as a consequence of tumour ingrowth resulting stent occlusion. We describe a unique case of duodenal stent obstruction secondary to impacted gallstones. To the best of our knowledge, this is the first case described in the literature and should alert clinicians to this unusual complication.

Gamma radiation shielding and health physics characteristics of diaspore-flyash concretes.

Different gamma radiation interaction parameters has been measured experimentally for the prepared diaspore-flyash concretes at 59.54, 662, 1173 and 1332 keV using narrow-beam transmission geometry and results are found to be in good agreement with theoretical values computed with a computer programme, WinXCom. The radiation exposure rate and absorbed dose rate for the gamma radiation with and without shielding of diaspore-flyash concretes have been determined using linear attenuation results. The results show that on average, there is reduction of 95%, 53% and 40% in dose rate for gamma sources (241)Am, (137)Cs and (60)Co, respectively with diaspore-flyash concretes as shielding material. Other health physics parameters namely equivalent dose, effective dose, gamma flux and energy fluence rate have also been determined.

Primary Epiphyseal Aneurysmal Bone Cyst Of Distal Ulna.

INTRODUCTION: Aneurysmal Bone Cyst (ABC) is a benign expansile cystic blood filled reactive lesion of the bone, most common in the first 2 decades of life. Though it can involve any bone in the body but tibia, humerus, femur and posterior elements of spine are most commonly affected. They most commonly involve metaphysis or metaphysio-diaphyseal part of the bone. Primary involvement of epiphysis is rarely reported. Here we present a case of 6 year old male child with an epiphyseal ABC of distal ulna. Its diagnosis, surgical management, clinical outcome with review of literature is discussed.

Gamma radiation shielding analysis of lead-flyash concretes.

Six samples of lead-flyash concrete were prepared with lead as an admixture and by varying flyash content - 0%, 20%, 30%, 40%, 50% and 60% (by weight) by replacing cement and keeping constant w/c ratio. Different gamma radiation interaction parameters used for radiation shielding design were computed theoretically and measured experimentally at 662keV, 1173keV and 1332keV gamma radiation energy using narrow transmission geometry. The obtained results were compared with ordinary-flyash concretes. The radiation exposure rate of gamma radiation sources used was determined with and without lead-flyash concretes.

Post-endoscopic retrograde cholangiography laparoscopic cholecystectomy: challenging but safe.

BACKGROUND AND OBJECTIVES: Up to 19% of patients undergoing laparoscopic cholecystectomy (LC) have common bile duct stones and may require endoscopic retrograde cholangiography (ERCP) before LC. The risk of complications of LC after ERCP is higher, and the optimal interval between ERCP and LC is disputed. In our unit, LC is performed approximately 6 weeks after ERCP. This study aims to compare outcomes between subsets of patients undergoing LC with or without prior ERCP. METHODS: All patients undergoing ERCP and elective laparoscopic cholecystectomy (ELC) over a 1-year period were included. Outcome measures included ERCP outcomes, duration of surgery, intraoperative findings, and postoperative outcomes. Two groups of patients were compared: LC after ERCP and ELC. RESULTS: The study included 190 ELC patients and 43 patients with LC after ERCP (ERCP-LC) (December 2008 to December 2009). At ERCP, 25 patients (58%) had ductal stones. The post-ERCP complication rate was 5%. The median time to LC was 42 days, and 6 patients (14%) were readmitted before LC. There were more severe adhesions and longer median operating times in the ERCP-LC group (75 minutes for ELC vs 110 minutes for ERCP-LC, P = .013). We found no significant differences in rates of conversion to open surgery, postoperative complications, lengths of stay, and readmission rates. CONCLUSION: Interval LC after ERCP is a more technically challenging procedure but is associated with a low rate of complications. Although there is emerging evidence that early LC after ERCP is feasible, our study shows that our current practice of delaying LC by approximately 6 weeks is safe.

Two-phase laparoscopic-assisted oesophago-gastrectomy: a single-unit experience of 111 consecutive cases and outcomes.

BACKGROUND: Minimal access surgery for oesophago-gastric cancer is topical and demanding, and approaches vary significantly. There is little data on the hybrid technique of laparoscopic-assisted two-phase oesophago-gastrectomy (LA2OG). Here we aim to review our experience, which exceeds 10 years, of this technique for oesophageal malignancy. METHODS: From June 1998 to May 2009, 111 patients underwent LA2OG. Patients included 84 men and 27 women with mean age 65 years (range 35-85 years). Retrospective analysis of indications, outcome, staging, complications and survival was performed. RESULTS: The majority of resections (96%) were performed for gastro-oesophageal junction or distal oesophageal pathology. Indications included adenocarcinoma (84.7%), squamous cell carcinoma (7.2%) and high-grade dysplasia (5.4%). Of patients, 67.6% received neoadjuvant chemotherapy. The median time for the laparoscopic phase was 207 min (range 105-600 min), and 420 min (range 210-780 min) overall. Estimated blood loss was 330 ml (range 100-1,200 ml). Median critical care and post-operative stays were 3 and 14 days, respectively. Over time, the radicality of surgery increased. From 1998 to 2001 median lymph node yield was 5, from 2002 to 2005 it was 12 nodes, and from 2006 to 2009 it was 28 nodes (p < 0.001). The overall complication rate was 38.7%, minor in 24.3%, with anastomotic leak rate of 5.5%. Median survival was 38.5 ± 5.4 months. Thirty-day and in-hospital mortality were 1.8 and 2.7%, respectively. CONCLUSIONS: Two-stage laparoscopic-assisted oesophago-gastrectomy is a safe staged method of developing minimal access surgery for oesophago-gastric cancer. This study provides a useful reference for comparison with other minimally invasive methods.