A Dual Role of ATM in Ischemic Preconditioning and Ischemic Injury.

The ataxia-telangiectasia mutated (ATM) protein is regarded as the linchpin of cellular defenses to stress. Deletion of ATM results in strong oxidative stress and degenerative diseases in the nervous system. However, the role of ATM in neuronal ischemic preconditioning and lethal ischemic injury is still largely unknown. In this study, mice cortical neurons preconditioned with sublethal exposure to oxygen glucose deprivation (OGD) exhibited ATM/glucose-6-phosphate dehydrogenase pathway activation. Additionally, pharmacological inhibition of ATM prior to the preconditioning reversed neuroprotection provided by preconditioning in vitro and in vivo. Meanwhile, we found that ATM/P53 pro-apoptosis pathway was driven by lethal OGD injury, and pharmacological inhibition of ATM during fatal oxygen-glucose deprivation/reperfusion injury promoted neuronal survival. More importantly, inhibition of ATM activity after cerebral ischemia protected against cerebral ischemic-reperfusion damage in mice. In conclusion, our data show the dual role of ATM in neuronal ischemic preconditioning and lethal ischemic injury, involving in the protection of ischemic preconditioning, but promoting neuronal death in lethal ischemic injury. Thus, the present study provides new opportunity for the treatment of ischemic stroke.

Chloroquine pretreatment attenuates ischemia-reperfusion injury in the brain of ob/ob diabetic mice as well as wildtype mice.

Chloroquine, a prototype anti-malaria drug, has been reported to possess anti-inflammatory effects. Moreover, chloroquine pretreatment could improve DNA damage repair. It is therefore reasonable to hypothesize that chloroquine pretreatment could attenuate ischemia/reperfusion injury in the brain. Considering the fact that chloroquine could also improve glucose metabolism, we speculated that the potential effects of chloroquine on ischemia/reperfusion injury might be particularly pronounced in diabetic mice. In this study, chloroquine pretreatment protected neurons from Oxygen Glucose Deprivation (OGD) induced cytotoxicity and apoptosis. In vivo, Ob/ob mice and wildtype (WT) mice were pretreated with chloroquine for 3 weeks. Then, ischemic stroke was induced by 60 min Middle Cerebral Artery Occlusion (MCAO). We found that chloroquine pretreatment normalized blood glucose in diabetic ob/ob mice, and reduced cerebral damage after ischemic stroke especially for diabetic mice. In addition, chloroquine pretreatment reduced High-mobility group box 1 (HMGB1) content in the cerebrospinal fluid (CSF) and serum and lowered myeloperoxidase (MPO) activity and inflammatory cytokines gene expression both in the ob/ob diabetic mice and WT mice. Moreover, harmful DNA damage-signaling responses, including PARP activation and p53 activation, were also attenuated by chloroquine pretreatment in these two kinds of mice. In conclusion, chloroquine pretreatment could reduce cerebral damage after ischemic stroke especially in diabetic mice through multiple mechanisms, which include reducing neural cell DNA injury, restoring euglycemia and anti-inflammatory effects. The findings may provide potential for the development of chloroquine in the prevention and treatment of stroke in diabetic high-risk patients.

Clinical Significance of Prothrombin Time in Cholangiocarcinoma Patients with Surgeries.

Background: Prothrombin time (PT) can predict survival in several types of malignancies. This study aims to investigate the predictive values of PT levels in patients with cholangiocarcinoma (CCA). Methods: We retrospectively analyzed the PT from 86 CCA patients who underwent curative resection in our hospital from December 2008 to August 2017. The relationship between PT and survival times was analyzed through univariate and multivariate analyses (Cox proportional hazards model). Kaplan-Meier curves and log-rank test were used to assess the effects of PT on overall survival (OS) and tumor recurrence-free survival (RFS). Results: Increased PT level was an effective predictor for OS (P = 0.021; hazard ratio (HR), 1.799) and RFS (P = 0.016; HR, 1.871) in CCA patients, independent of age, tumor differentiation, and TNM stage. In the low PT level group (PT < 12.3 s), patients showed a higher mean OS (23.03 m vs. 14.38 m, P = 0.0250) and RFS (17.78 m vs. 8.30 m, P = 0.0511) than those with high PT levels (PT ≥ 12.3 s). A highly significant association was observed between high PT level and shortened OS (P = 0.0373) and worse RFS (P = 0.0151). Conclusion: Preoperative increase in PT can serve as a simple but effective predictor of poor survival in CCA patients who undergo curative surgeries.

Effect of Hemodialysis on the Red Blood Cell Life Span in Patients with End-Stage Kidney Disease.

The aim of this study was to use a CO breath test to investigate hemodialysis effects on red blood cell lifespan in patients with chronic kidney disease. A cohort of 17 non-smoking men with end-stage kidney disease undergoing hemodialysis via a polysulfone dialysis membrane (as opposed to a traditional cellulose acetate membrane) were subjected to a repeated Levitt's CO breath test to compare red blood cell lifespan before vs. after dialysis. None of the patients showed significant fluctuations in endogenous CO concentration during the dialysis procedure. The mean red blood cell lifespan was 66.0 ± 31.0 days before dialysis and 72.0 ± 26.0 days after dialysis, with no significant difference between the assessment time points (P > 0.05). In conclusion, dialysis using a polysulfone membrane did not appear to disrupt red blood cells or reduce their lifespan in patients with end-stage kidney disease.

Gastrotracheal fistula: treatment with a covered self-expanding Y-shaped metallic stent.

A 67-year-old man had a sev-ere cough and pulmonary infection for 1 wk before seeking evaluation at our hospital. He had undergone esophagectomy with gastric pull-up and radiotherapy for esophageal cancer 3 years previously. After admission to our hospital, gastroscopy and bronchoscopy revealed a fistulous communication between the posterior tracheal wall near the carina and the upper residual stomach. We measured the diameter of the trachea and bronchus and determined the site and size of the fistula using multislice computed tomography and gastroscopy. A covered self-expanding Y-shaped metallic stent was implanted into the trachea and bronchus. Subsequently, the fistula was closed completely. The patient tolerated the stent well and had good palliation of his symptoms.

Delineating the vascular territory (perforasome) of a perforator in the lower extremity of the rabbit with four-dimensional computed tomographic angiography.

BACKGROUND: The anatomy of any particular vascular perforator relative to its vascular territory (perforasome) and flow characteristics is unique and complex. This arterial perforasome study with laboratory rabbits was conducted to assess four-dimensional computed tomographic angiography as an imaging tool for the design of individualized tissue transfers. This study offers clinically relevant information that should improve flap survival. METHODS: Six New Zealand White rabbits weighing 3.0 to 3.25 kg underwent contrast-enhanced four-dimensional computed tomographic angiography in a 128-slice scanner after intraarterial injection of iopromide iodinated contrast material. Based on the image data, the perforasome of the posterior thigh perforator was marked onto the posterior thigh skin. The perforasome size was confirmed by microangiography. Data from four-dimensional computed tomographic angiography and microangiography were statistically compared. RESULTS: Four-dimensional computed tomographic angiography clearly and accurately delineated the perfusion and vascular territories of the perforators. The area of the perforator flap as measured with four-dimensional computed tomographic angiography compared favorably to that obtained by means of microangiography; there was no statistically significant difference in the results from the two methods. CONCLUSIONS: This study demonstrated that four-dimensional computed tomographic angiography was capable of accurately characterizing the vascular territory and flow characteristics of the arterial perforator in live rabbits. This technique for determining perforator location, axiality, and optimal perfusion territory will potentially benefit human patients.