Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission.

Mitochondria play an essential role in pathophysiology of both inflammatory and neuropathic pain (NP), but the mechanisms are not yet clear. Dynamin-related protein 1 (Drp1) is broadly expressed in the central nervous system and plays a role in the induction of mitochondrial fission process. Spared nerve injury (SNI), due to the dysfunction of the neurons within the spinal dorsal horn (SDH), is the most common NP model. We explored the neuroprotective role of Drp1 within SDH in SNI. SNI mice showed pain behavior and anxiety-like behavior, which was associated with elevation of Drp1, as well as increased density of mitochondria in SDH. Ultrastructural analysis showed SNI induced damaged mitochondria into smaller perimeter and area, tending to be circular. Characteristics of vacuole in the mitochondria further showed SNI induced the increased number of vacuole, widened vac-perimeter and vac-area. Stable overexpression of Drp1 via AAV under the control of the Drp1 promoter by intraspinal injection (Drp1 OE) attenuated abnormal gait and alleviated pain hypersensitivity of SNI mice. Mitochondrial ultrastructure analysis showed that the increased density of mitochondria induced by SNI was recovered by Drp1 OE which, however, did not change mitochondrial morphology and vacuole parameters within SDH. Contrary to Drp1 OE, down-regulation of Drp1 in the SDH by AAV-Drp1 shRNA (Drp1 RNAi) did not alter painful behavior induced by SNI. Ultrastructural analysis showed the treatment by combination of SNI and Drp1 RNAi (SNI + Drp1 RNAi) amplified the damages of mitochondria with the decreased distribution density, increased perimeter and area, as well as larger circularity tending to be more circular. Vacuole data showed SNI + Drp1 RNAi increased vacuole density, perimeter and area within the SDH mitochondria. Our results illustrate that mitochondria within the SDH are sensitive to NP, and targeted mitochondrial Drp1 overexpression attenuates pain hypersensitivity. Drp1 offers a novel therapeutic target for pain treatment.

[Influencing Factors in the Chronicity of Immune Thrombocytopenia in Children].

OBJECTIVE: To explore the influencing factors in children with chronicity immune thrombocytopenia (ITP), and to provide basis for judging the prognosis and treatment in children with ITP. METHODS: The clinical data of children with ITP admitted to The Second Affiliated Hospital of Anhui Medical University in the past 5 years were retrospectively analyzed and followed up for more than 1 year. According to the inclusion criteria, the eligible cases (328 cases in total) were selected and collected through medical record system retrieval, outpatient clinic and telephone follow-up. Independent influencing factors affecting the prognosis of children with ITP were obtained through single-factor and multi-factor logistic analysis, and their predictive value for the prognosis of ITP in children were evaluated. RESULTS: Of 328 children with ITP, 208 were newly diagnosed with ITP (64%), 54 were persistent ITP (16%), 66 were chronic ITP (20%), and the remission rate within 1 year was 79.9%. The results of univariate analysis showed that, age, pre-morbidity history of infection and vaccination, antinuclear antibodies, initial absolute lymphocyte count（ALC） and treatment options were related to the prognosis of the children (P<0.05). Multivariate analysis showed that the history of infection and vaccination before onset, initial treatment options, and ALC at the time of initial diagnosis were independent factors affecting the prognosis of children with ITP (P<0.05). The time for platelet recovery to 100×109/L in the initial treatment group combined with intravenous immunoglobulin (IVIG) was shorter than that in the single corticosteroids group (P<0.01). The receivers operating characteristic (ROC) was drawn with the development of chronic disease (course >12 months) as state variable and ALC or ALC combined with preceding infection or vaccination history as test variable. The results showed that when the absolute value of lymphocytes was 3.80×109/L, the area under the curve was the largest (0.787), the sensitivity was 80.6%, and the specificity was 65.53% (P<0.01), the combined results showed that the maximum area under the curve was 0.859, the sensitivity was 77.61%, and the specificity was 78.41%. CONCLUSION: The initial treatment plan combined with IVIG can reduce the occurrence of chronicity in children with ITP, and its efficacy is better than that of the single corticosteroids group (the platelet recovery time is shorter); history of preceding infection or vaccination, ALC at the time of initial diagnosis are independent factors affecting the prognosis of children with ITP, and the combination of the two shows a better predictive value for the prognosis.

Analgesic Effect of Noninvasive Brain Stimulation for Neuropathic Pain Patients: A Systematic Review.

INTRODUCTION: The objective of this review is to systematically summarize the consensus on best practices for different NP conditions of the two most commonly utilized noninvasive brain stimulation (NIBS) technologies, repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). METHODS: PubMed was searched according to the predetermined keywords and criteria. Only English language studies and studies published up to January 31, 2020 were taken into consideration. Meta-analyses, reviews, and systematic reviews were excluded first, and those related to animal studies or involving healthy volunteers were also excluded. Finally, 29 studies covering 826 NP patients were reviewed. RESULTS: The results from the 24 enrolled studies and 736 NP patients indicate that rTMS successfully relieved the pain symptoms of 715 (97.1%) NP patients. Also, five studies involving 95 NP patients (81.4%) also showed that tDCS successfully relieved NP. In the included studied, the M1 region plays a key role in the analgesic treatment of NIBS. The motor evoked potentials (MEPs), the 10-20 electroencephalography system (EEG 10/20 system), and neuro-navigation methods are used in clinical practice to locate therapeutic targets. Based on the results of the review, the stimulation parameters of rTMS that best induce an analgesic effect are a stimulation frequency of 10-20 Hz, a stimulation intensity of 80-120% of RMT, 1000-2000 pulses, and 5-10 sessions, and the most effective parameters of tDCS are a current intensity of 2 mA, a session duration of 20-30 min, and 5-10 sessions. CONCLUSIONS: Our systematically reviewed the evidence for positive and negative responses to rTMS and tDCS for NP patient care and underscores the analgesic efficacy of NIBS in patients with NP. The treatment of NP should allow the design of optimal treatments for individual patients.

Benefit of a single simulated hypobaric hypoxia in healthy mice performance and analysis of mitochondria-related gene changes.

Simulated hypobaric hypoxia (SHH) training has been used to enhance running performance. However, no studies have evaluated the effects of a single SHH exposure on healthy mice performance and analyzed the changes of mitochondria-related genes in the central nervous system. The current study used a mouse decompression chamber to simulate mild hypobaric hypoxia at the high altitude of 5000 m or severe hypobaric hypoxia at 8000 m for 16 h (SHH5000 & SHH8000, respectively). Then, the mouse behavioral tests were recorded by a modified Noldus video tracking. Third, the effects of SHH on 8 mitochondria-related genes of Drp1, Mfn1, Mfn2, Opa1, TFAM, SGK1, UCP2 and UCP4, were assessed in cerebellum, hippocampus and gastrocnemius muscles. The results have shown that a single mild or severe HH improves healthy mice performance. In cerebellum, 6 of all 8 detected genes (except Mfn2 and UCP4) did not change after SHH. In hippocampus, all detected genes did not change after SHH. In muscles, 7 of all 8 detected genes (except Opa1) did not change after SHH. The present study has indicated the benefit of a single SHH in healthy mice performance, which would due to the stabilized mitochondria against a mild stress state.

Drp1 is widely, yet heterogeneously, distributed in the mouse central nervous system.

OBJECTIVES: Drp1 is widely expressed in the mouse central nervous system and plays a role in inducing the mitochondrial fission process. Many diseases are associated with Drp1 and mitochondria. However, since the exact distribution of Drp1 has not been specifically observed, it is difficult to determine the impact of anti-Drp1 molecules on the human body. Clarifying the specific Drp1 distribution could be a good approach to targeted treatment or prognosis. METHODS: We visualized the distribution of Drp1 in different brain regions and explicated the relationship between Drp1 and mitochondria. GAD67-GFP knock-in mice were utilized to detect the expression patterns of Drp1 in GABAergic neurons. We also further analyzed Drp1 expression in human malignant glioma tissue. RESULTS: Drp1 was widely but heterogeneously distributed in the central nervous system. Further observation indicated that Drp1 was highly and heterogeneously expressed in inhibitory neurons. Under transmission electron microscopy, the distribution of Drp1 was higher in dendrites than other areas in neurons, and only a small amount of Drp1 was localized in mitochondria. In human malignant glioma, the fluorescence intensity of Drp1 increased from grade I-III, while grade IV showed a declining trend. CONCLUSION: In this study, we observed a wide heterogeneous distribution of Drp1 in the central nervous system, which might be related to the occurrence and development of neurologic disease. We hope that the relationship between Drp1 and mitochondria may will to therapeutic guidance in the clinic.

[Clinical Analysis of Deep Venous Thromboembolism in Children with Acute Lymphocytic Leukemia].

OBJECTIVE: To explore clinical characteristics and outcome of deep vein thrombosis(DVT) in children with acute lymphoblastic leukemia (ALL). METHODS: A tatol of 266 patients were diagnosed as ALL from January 1, 2010 to May 31, 2016. The clinical data of 12 cases of patients with DVT were retrospectively analyzed, 183 cases diagnosed before January 1, 2015 were received chemotherapy with the scheme of SCMC-05. The other cases were treated by the scheme of CCCG. All the patients received central venous catheter. RESULTS: The DVT happened in 12 cases including 10 cases of limb DVT and 2 cases of intacranial venous sinus thrombosis. The DVT mostly occured in intermediate risk ALL patients, the infection and coagulopathy existed in most patients. They were treated with low molecular heparin(LWHP), among them 5 cases were given extubation; the thrombus disappeared in 6 cases after 1 week; the intracranial venous sinus thrombosis in 1 case did not obviously improved after 6 months of treatment. The ALL children with DVT were treated with LWHP when using L-ASP, as a result no thrombuses happened. CONCLUSION: Centralvenous catheter and chemotherapeutic drugs were the major cause of DVT. Abnormal coagulation, infection, and risk stratification are another risk factors for thrombosis. ALL children thrombosis are benefited from LWHP prevention when using L-ASP again.