RIP3/MLKL-mediated neuronal necroptosis induced by methamphetamine at 39℃

Methamphetamine is one of the most prevalent drugs abused in the world.Methamphetamine abusers usually present with hyperpyrexia (39℃),hallucination and other psychiatric symptoms.However,the detailed mechanism underlying its neurotoxic action remains elusive.This study investigated the effects of methamphetamine + 39℃ on primary cortical neurons from the cortex of embryonic Sprague-Dawley rats.Primary cortex neurons were exposed to 1 mM methamphetamine + 39℃.Propidium iodide staining and lactate dehydrogenase release detection showed that methamphetamine + 39℃ triggered obvious necrosis-like death in cultured primary cortical neurons,which could be partially inhibited by receptor-interacting protein-1 (RIP1) inhibitor Necrostatin-1 partially.Western blot assay results showed that there were increases in the expressions of receptor-interacting protein-3 (RIP3) and mixed lineage kinase domain-like protein (MLKL) in the primary cortical neurons treated with 1 mM methamphetamine + 39℃ for 3 hours.After pre-treatment with RIP3 inhibitor GSK’872,propidium iodide staining and lactate dehydrogenase release detection showed that neuronal necrosis rate was significantly decreased;RIP3 and MLKL protein expression significantly decreased.Immunohistochemistry staining results also showed that the expressions of RIP3 and MLKL were up-regulated in brain specimens from humans who had died of methamphetamine abuse.Taken together,the above results suggest that methamphetamine + 39℃ can induce RIP3/MLKL regulated necroptosis,thereby resulting in neurotoxicity.The study protocol was approved by the Medical Ethics Committee of the Third Xiangya Hospital of Central South University,China (approval numbers: 2017-S026 and 2017-S033) on March 7,2017.     

Therapeutic effect of regulating autophagy in spinal cord injury: a network meta-analysis of direct and indirect comparisons

Objective:An increasing number of studies indicate that autophagy plays an important role in the pathogenesis of spinal cord injury,and that regulating autophagy can enhance recovery from spinal cord injury.However,the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear.Therefore,in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison,in an effort to provide a basis for further research.Data source:Relevant literature published from inception to February 1,2018 were included by searching Wanfang,CNKI,Web of Science,MEDLINE(OvidSP),PubMed and Google Scholar in English and Chinese.The keywords included"autophagy","spinal cord injury",and"rat".Data selection:The literature included in vivo experimental studies on autophagy regulation in the treatment of spinal cord injury(including intervention pre-and post-spinal cord injury).Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy,and subgroup analyses were also conducted.Outcome measure:Basso,Beattie,and Bresnahan scores.Results:Of the 622 studies,33 studies of median quality were included in the analyses.Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=1.80,95%CI:0.81-2.79,P=0.0004),3 days(MD=0.92,95%CI:0.72-1.13,P<0.00001),1 week(MD=2.39,95%CI:1.85-2.92,P<0.00001),2 weeks(MD=3.26,95%CI:2.40-4.13,P<0.00001),3 weeks(MD=3.13,95%CI:2.51-3.75,P<0.00001)and 4 weeks(MD=3.18,95%CI:2.43-3.92,P<0.00001)after spinal cord injury with upregulation of autophagy compared with the control group(drug solvent control,such as saline group).Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=6.48,95%CI:5.83-7.13,P<0.00001),2 weeks(MD=2.43,95%CI:0.79-4.07,P=0.004),3 weeks(MD=2.96,95%CI:0.09-5.84,P=0.04)and 4 weeks(MD=4.41,95%CI:1.08-7.75,P=0.01)after spinal cord injury with downregulation of autophagy compared with the control group.Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso,Beattie,and Bresnahan scores at 1 day(MD=-4.68,95%CI:-5.840 to-3.496,P=0.94644),3 days(MD=-0.28,95%CI:-2.231-1.671,P=0.99448),1 week(MD=1.83,95%CI:0.0076-3.584,P=0.94588),2 weeks(MD=0.81,95%CI:-0.850-2.470,P=0.93055),3 weeks(MD=0.17,95%Cl:-2.771-3.111,P=0.99546)or 4 weeks(MD=-1.23,95%Cl:-4.647-2.187,P=0.98264)compared with the control group.Conclusion:Regulation of autophagy improves neurological function,whether it is upregulated or downregulated.There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury.The variability in results among the studies may be associated with differences in research methods,the lack of clearly defined autophagy characteristics after spinal cord injury,and the limited autophagy monitoring techniques.Thus,methods should be standardized,and the dynamic regulation of autophagy should be examined in future studies.     

Detecting Optic Atrophy in Multiple Sclerosis Patients Using New Colorimetric Analysis Software: From Idea to Application

Neuro-ophthalmologists typically observe a temporal pallor of the optic disc in patients with multiple sclerosis. Here, we describe the emergence of an idea to quantify these optic disc color changes in multiple sclerosis patients. We recruited 12 multiple sclerosis patients with previous optic neuritis attack and obtained photographs of their optic discs. The Laguna ONhE, a new colorimetric software using hemoglobin as the reference pigment in the papilla, was used for the analysis. The papilla of these multiple sclerosis patients showed greater pallor, especially in the temporal sector. The software detected the pallor and assigned hemoglobin percentages below normal reference values. Measurements of optic disc hemoglobin levels obtained with the Laguna ONhE software program had good ability to detect optic atrophy and, consequently, axonal loss in multiple sclerosis patients. This new technology is easy to implement in routine clinical practice.     

United States comparative costs and absenteeism of diabetic ophthalmic conditions

Objective: This retrospective cohort study examined the impact of diabetic macular edema (DME), diabetic retinopathy (DR), or diabetes on annual health benefit costs and absenteeism in US employees. Methods: Claims data from 2001 to 2012 was extracted from the Human Capital Management Services Group Research Reference Database on annual direct/indirect health benefit costs and absences for employees aged ≥ 18 years. Employees with DME, DR, or diabetes were identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Employees were divided into two groups, drivers or nondrivers, and examined in separate analyses. For drivers and nondrivers, the DME, DR, and diabetes cohorts were compared with their respective control groups (without diabetes). Two-part regression models controlled for demographics and job-related characteristics. Results: A total of 39,702 driver and 426,549 nondriver employees were identified as having ≥ 1 year’s continuous health plan enrollment. Direct medical costs for drivers with DME, DR, or diabetes were $6470, $8021, and $5102, respectively (>2.8 times higher and statistically significant compared with driver controls). Nondrivers with DME and DR incurred significantly higher sick leave and short-term disability costs compared with the nondrivers with diabetes and nondriver controls. In drivers with DME, the majority of days of absence were for short- and long-term disability (12.41 and 11.43 days, respectively). In drivers with DR, the majority of days of absence were for short-term disability (10.70 days). In nondrivers with DME and nondrivers with DR, the majority of days of absence were for sick leave (5.74 and 4.93 days, respectively) and short-term disability (5.08 and 4.93 days, respectively). Conclusion: DME and DR are associated with substantial direct medical cost and absenteeism in this real-world sample of medically insured employees. This research highlights the negative impact of DME and DR on annual costs and absenteeism and may assist employers in assessing the impact of these conditions on employees.     

Trap Exploration in Amorphous Boron-Doped ZnO Films

This paper addresses the trap exploration in amorphous boron-doped ZnO (ZnO:B) films using an asymmetric structure of metal-oxide-metal. In this work, the structure of Ni/ZnO:B/TaN is adopted and the ZnO:B film is deposited by RF magnetron sputtering. The as-deposited ZnO:B film is amorphous and becomes polycrystalline when annealing temperature is above 500 °C. According to the analysis of conduction mechanism in the as-deposited ZnO:B devices, Ohmic conduction is obtained at positive bias voltage because of the Ohmic contact at the TaN/ZnO:B interface. Meanwhile, hopping conduction is obtained at negative bias voltage due to the defective traps in ZnO:B in which the trap energy level is lower than the energy barrier at the Ni/ZnO:B interface. In the hopping conduction, the temperature dependence of I-V characteristics reveals that the higher the temperature, the lower the current. This suggests that no single-level traps, but only multiple-level traps, exist in the amorphous ZnO:B films. Accordingly, the trap energy levels (0.46–0.64 eV) and trap spacing (1.1 nm) in these multiple-level traps are extracted.