IntroductionThe prognosis of relapsed/refractory acute myeloid leukemia (r/rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/rAML patients receiving the anti-PD-1+HMA+CAG regimen.MethodsFifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT.ResultsFour patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, non-relapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group.ConclusionThe anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HID-HSCT showed preliminary survival advantage.

BackgroundAlthough calcium channel blockers (CCBs) are useful in stroke prevention, their specific role in preventing stroke in hypertensive patients with intracranial aneurysms undergoing endovascular stent placement remains unclear.MethodsWe retrospectively examined 458 hypertensive patients with intracranial aneurysms who underwent stent treatment, drawn from a larger multicenter cohort comprising 1326 patients across eight centers. Patients were dichotomized into two groups according to use of a CCB. Propensity score matching (PSM) was performed to balance group differences in patient and aneurysm characteristics. We conducted a comparison of patient and aneurysm characteristics, ischemic complications, and clinical outcomes between the two groups.ResultsThe CCB and non-CCB groups comprised 279 and 179 patients, respectively. PSM resulted in 165 matched pairs. After PSM, the incidence of ischemic events within 1 month of the procedure (4.2% vs 10.9%; P=0.022) and proportion of patients with modified Rankin Scale score >2 at last follow-up (1.5% vs 7.8%; P=0.013) were significantly lower in the CCB group. Among patients treated with combination therapy, inclusion of a CCB was associated with a lower incidence of ischemic events (1.5% vs 13.3%; P=0.345), but the difference was not statistically significant after correction.ConclusionsCCB use in hypertensive patients undergoing endovascular stenting for treatment of intracranial aneurysms is associated with a lower incidence of ischemic events and a lower incidence of unfavorable neurological outcomes, especially when used in combination therapy.

IntroductionMesenchymal stromal cells (MSCs) have been extensively studied as a potential treatment for steroid refractory acute graft-versus-host disease (aGVHD). However, the majority of clinical trials have focused on bone marrow-derived MSCs.MethodsIn this study, we report the outcomes of 86 patients with grade III-IV (82.6% grade IV) steroid refractory aGVHD who were treated with human umbilical cord-derived mesenchymal stromal cells (UC-MSCs). The patient cohort included 17 children and 69 adults. All patients received intravenous infusions of UC-MSCs at a dose of 1 × 106 cells per kg body weight, with a median of 4 infusions (ranging from 1 to 16).ResultsThe median time between the onset of aGVHD and the first infusion of UC-MSCs was 7 days (ranging from 3 to 88 days). At day 28, the overall response (OR) rate was 52.3%. Specifically, 24 patients (27.9%) achieved complete remission, while 21 (24.4%) exhibited partial remission. The estimated survival probability at 100 days was 43.7%. Following a median follow-up of 108 months (ranging from 61 to 159 months), the survival rate was approximately 11.6% (10/86). Patients who developed acute lower GI tract and liver GVHD exhibited poorer OR rates at day 28 compared to those with only acute lower GI tract GVHD (22.2% vs. 58.8%; p= 0.049). No patient experienced serious adverse events.DiscussionThese finding suggest that UC-MSCs are safe and effective in both children and adults with steroid refractory aGVHD. UC-MSCs could be considered as a feasible treatment option for this challenging conditon. (NCT01754454).

Abstract Background: Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. First-line treatment of aGVHD is corticosteroid. Second-line therapy mainly comprises immunosuppressants. However, ∼ 25% of the patients have a steroid-resistant and therapy-refractory disease, which is associated with a very poor prognosis. An alternative therapy option for steroid-refractory and therapy-refractory aGVHD is the use of mesenchymal stromal cells (MSCs). Here, we report the results of 88 patients with grade III-IV aGVHD treated with human umbilical cord derived mesenchymal stromal cells (UC-MSC). Methods: There were 18 children and 70 adults with grade III/ IV aGVHD (82% grade IV). These patients were either resistant to steroids or refractory to 1–5 additional immunosuppressants. UC-MSCs were transfused at a median dose of 1 × 106 cells/kg with a median of 4 times (range, 1 to 16). Results: Median time between the onset of aGVHD and the first infusion of UC-MSC was 7 days (range, 3–88). The day 28 overall response rate was 51.14%, of these, 24 patients (27.27%) showed complete remission (CR), 21 (23.86%) showed partial remission (PR). The estimated survival probability at 100 days was 43.3%. And after a median follow-up of 66 months (26–122 months), the survival rate was approximately 33% (29/88). Patients developed acute gastrointestinal (GI) tract and liver GVHD showed worse overall response in day 28 than patients only with acute GI GVHD (21% vs. 58%; p= 0.037). No patient had severe side effects. Conclusions: These results suggest that UC-MSC treatment was safe and effective in children and adults, and should be considered for treating steroid-refractory aGVHD. Trial registration: ClinicalTrials: NCT01754454. Registered 21 December 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01754454?cond=msc+gvhd&draw=2&rank=8

The treatment of complex cerebrovascular diseases (CCVDs) at the skull base, such as complex intracranial aneurysms, carotid-cavernous sinus fistulas, and intracranial artery traumatic injuries, is a difficult clinical problem despite advances in endovascular and surgical therapies. Covered stents or stent graft insertion is a new concept for endovascular treatment that focuses on arterial wall defect reconstruction, differing from endovascular lesion embolization or flow diverter therapies. In recent years, covered stents specifically designed for cerebrovascular treatment have been applied in the clinical setting, allowing thousands of patients with CCVDs to undergo intraluminal reconstruction treatment and achieving positive results, even in the era of flow diverters. Since there is no unified reference standard for the application of covered stents for treating CCVDs, it is necessary to further standardize and guide the clinical application of this technique. Thus, we organized authoritative experts in the field of neurointervention in China to write an expert consensus, which aims to summarize the results of covered stent insertion in the treatment of CCVDs and propose suitable standards for its application in the clinical setting. Based on the contents of this consensus, clinicians can use individualized intraluminal reconstruction treatment techniques for patients with CCVDs.

Background Previous studies have shown the effect of MTHFR A1298C gene polymorphism on stroke risk. But the results of published studies remained inconclusive and controversial. So we conducted a meta-analysis to accurately estimate the potential association between MTHFR A1298C gene polymorphism and stroke susceptibility. Methods A systematic literature search on Embase, Pubmed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) and WanFang electronic database identified 40 articles including 5725 cases and 8655 controls. Strength of association was evaluated by pooled odds ratio (OR), 95% confidence interval (CI) and p value. Funnel plots and Begger’s regression test were applied for testing the publication bias. Statistical analysis of all data was performed by Stata 12.0. Results The meta-analysis results indicated a significant relationship between MTHFR gene A1298C polymorphisms and stoke risk under the C allelic genetic model (OR = 1.19, 95%CI = 1.07–1.32, p = 0.001), dominant genetic model (OR = 1.19, 95%CI = 1.06–1.33, p = 0.004) and recessive genetic model (OR = 1.43, 95%CI =1.15–1.77, p = 0.001). In subgroup analysis, we discovered obvious correlation in three genetic model of Asian, stroke type, adult by ethnicity, population, stroke type, source of control and case size. Additionally, in studies of control from hospital and case size equal 100, obvious correlation was also found in the three genetic model. Conclusions Our meta-analysis results indicated that there was evidence to support the correlation between M THFR A1298C polymorphism and stroke susceptibility, especially in adults and ischemic stroke.

Background: Health care-associated-infection (HAI) is an important issue in neurosurgery department. With the aging population, we are receiving an increasing number of elderly patients who have a higher risks of HAI. AIM: We want to better understand risk factors of HAI and prevent HAI in elderly patients who accept neurosurgeries. Methods: This was a case-control study. We took review of the medical records of patients aged 60 and older who underwent neurosurgical operations from 1 January to 31 December 2016 in a single centre. Patients with infection and intubation before admission were excluded. Risk factors and outcomes were analysed, including age, sex, activities of daily living (ADL) score, smoking history, emergency admission status, ICU stay, ventilator use, ventilation time, diabetes, coronary heart disease, immune system disease, consciousness at admission, albumin decrease, blood sugar, unplanned second operation, indwelling venous catheter, external ventricular drainage (EVD), discharge ADL, length of stay (LOS), and medical costs. Results: A total of 1757 geriatric patients over 60 years underwent neurosurgical procedure were enrolled. Their age ranged from 60 to 93 years, with an average of 67.56 ± 6.16 years, including 1083 males(61.6%)and 674 females(38.4%).Among 1757 patients in 14703 hospital days, 95 cases of infection were diagnosed with HAIs in 78 patients, The HAI rate was 4.4% (78/1757) and HAI case rate was 5.4%(95/1757),incidence of HAI in neurosurgical geriatric patients was 6.5‰. Of these 95 infections, the most common types were pneumonia (65.3%), followed by primary bloodstream infection (13.7%), central nervous system infection (8.4%), urinary tract infection (6.3%), and wound infection (6.3%). Multivariable logistic regression showed that the independent risk factors for HAI in elderly patients were ICU stay, mechanical ventilation, plasma albumin below 35g/L, unplanned reoperation, and venous catheterization. Conclusions: To prevent HAI, we should improve the ICU standards, decrease ventilation time, improve the nutrition supply, and dynamically evaluate the necessity of deep venous catheters and remove them as early as possible. Such measures could not only help reduce HAI and shorten hospital stays for elderly patients, but also decrease medical insurance cost for the government.

OBJECTIVE:To explore the role of bone marrow microenvironment(niche) in the development of acute myeloid leukemia (AML) and the effect of AML patients-derived MSC on the proliferation, cell cycle and immuno-phenotypes of HL-60 cells.METHODS:The MSC derived from bone marrow of patients with newly diagnosed AML were isolated and co-cultured with HL-60 cells. The effect of MSC on proliferation of HL-60 cells was detected by using 3H-TdR incorporation method, the cell cycle and immunophenotypes of HL-60 cells were detected by flow cytometry.RESULTS:The results of 3H-TdR incorporation assay showed that both AML-MSCs and normal MSCs remarkably suppressed the HL-60 cell proliferation in a time- and dose-dependent manner. The results of cell cycle analysis demonstrated that AML MSCs and normal MSCs induced arrest of the HL-60 cells in G0/G1 phase. The results of immunophenotyping revealed that MSCs suppressed the expression of CD11a and CD154 on the surface of HL-60 cells. Moreover, AML MSCs exhibited increased inhibitory effects than that of normal MSCs. However, no remarkable effect of MSCs on CD54 expressions of HL-60 cells was observed in the current study.CONCLUSION:AML-MSCs possess effects on HL-60 cell proliferation, cell cycle and immunophenotypes similiar to normal MSCs, but exhibited increased suppressive capacity on the expression of CD11a and CD154.

Although thymus-independent donor-derived T cell expansion may determine the occurrence of graft-versus-host disease (GVHD) and relapse after transplantation, the characteristics and dynamics of the expansion process remain unclear. To address this issue, we monitored T cell receptor beta repertoire at day 0, day 28, and day 61 after transplantation in 30 patients with hematologic malignancies by next-generation sequencing. The clonality index showed an increasing clonality over time (P=.001). The top 200 clonotypes accounted for more than half of the total clonotypes (median frequency, 63.55%) at day 61, and there was a remarkable overlapping between the top 200 clonotypes of each repertoire and its former repertoire (>50%). A normalized index, called the T Cell Response Index (TCRI), was designed on the basis of rank-shift analysis to quantify antigen-driven expansion. The TCRI during the first month was not related to relapse or GVHD (P>.05), whereas the TCRI during the second month was related to relapse (P=.006). Recipients with a TCRI below 1.0 during the second month had a higher cumulative relapse rate (31.25% versus 0%, P=.0323) and had a lower 1-year survival rate (56.25% versus 78.57%, P=.281). The clonotypes with strong competitiveness in the second month in the nonrelapse group preferentially used TRBV2, TRBV12-3, TRBJI-1 and TRBJ1-5 segments (P<.01). In conclusion, homeostatic expansion predominates in the first month due to nonspecific T cell proliferation, whereas antigen-driven expansion predominates in the second month and results in a graft-versus-tumor (GvT) effect. Moreover, TCRI could serve as a quantitative indicator of GvT against relapse within the first year. The difference in V and J segment usage reveals that T cells responsible for potent GvT effect are similar among patients. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Mutual trust is the most important basis in social networks. However, many malicious nodes often deceive, collaboratively cheat, and maliciously recommend other nodes for getting the more benefits. Meanwhile, because of lacking effective incentive strategy, many nodes are neither to evaluate nor to recommend. Thus, malicious actions have been aggravated in social networks. To solve these issues, we designed a bidding strategy to incentivise nodes to do their best to recommend or evaluate service node. At the same time, we also employed TOPSIS method of selecting a correct service node for system from networks. To guarantee reliability of service node selected, we brought recommendation time influential function, service content similarity function and recommendation acquaintance function into the model to compute general trust of node. Finally, we gave an update method for trust degree of node and experiments analysis.

OBJECTIVETo explore the role of bone marrow niche in the chemotherapy resistance of patient with acute myeloid leukemia (AML), and to investigate the effects of the MSCs on the apoptosis of HL-60 cell and its underlying mechanisms.METHODSMSCs were derived from the bone marrow of newly diagnosed AML patients (AML-MSCs) and health donors(MSCs) were co-cultured with HL-60 cells respectively. The apoptosis of HL-60 cells in the presence/absence of MSCs and/or Daunorubicin were determined by flow cytometry with Annexin V/PI double staining. In addition, the morphological features of HL-60 cells were observed by Wright-Giemsa staining, and the ratio of blasts and differentiated cells were counted. Furthermore, the expressions of apoptosis-related factors including Caspase-3, Caspase-8,Caspase-9 and Survivin were detected by Western blot.RESULTSThe flow cytometry showed that there was no significant change in apoptosis of HL-60 cells co-cultured with MSC derived from healthy donors or AML patients. After adding Daunorubicin into different cultural systems, the apoptotic rates of HL-60, HL-60 co-cultured with normal MSCs and HL-60 co-cultured with AML-MSCs were (49.57±7.44)%, (30.72±4.05)% and (22.99±4.08)%, respectively, which showed that normal MSCs and AML-MSCs could remarkably supress Daunorubicin-induced HL-60 apoptosis, however, there was no statistically significant difference of apoptosis between HL-60 co-cultured with normal MSCs and HL-60 co-cultured with AML-MSCs. Wright-Giemsa staining showed that most of the HL-60 cells co-cultured with AML-MSCs were primitive, and cell differentiation was unusual. In AML-MSCs co-cultured group, the cell apoptosis and differentiation caused by DNR was significant decreased, and most of HL-60 cells were initial. Western blot showed that the cleavage activity of Caspase-3 of HL-60 in AML-MSCs and normal MSCs co-cultured group was decreased, compared with HL-60 in single cultured group, moreover, the decrease was significantly in AML-MSC group. Additionally, the expression of survivin in AML-MSCs and normal MSCs co-cultured group was increased, compared with that in single cultured group, and increase was significant in AML-MSCs group.CONCLUSIONMSCs can suppress Daunorubicin-induced HL-60 apoptosis via inhibiting Caspase-3 and maintaining survivin level.

OBJECTIVE:To study the influence of acute myeloid leukemia (AML) microenvironment on mesenchymal stem cells (MSCs).METHODS:MSCs were isolated from the bone marrow of newly diagnosed AML patients (AML-MSCs) and were cultured. The morphology of MSC was observed by inverted microscopy, the immunophenotypes of MSC were detected by flow cytometry, the proliferation ability of MSC was detected by using MTT method, the multi-differentation ability of MSC was assayed by osteogenic, lipogenic and chrondrogenic induction. The morphologic features, immunophenotypic characteristics, cell proliferation, and multipotential differentiation capability were compared between the MSC derived from normal healthy donors and AML patients.RESULTS:AML-MSCs presented the morphological features similar to the normal MSCs. In addition, AML-MSCs highly expressed CD29, CD44, CD73, CD105 and HLA-ABC. Meanwhile, they were homogenously negative for CD14，CD31, CD34, CD45, CD80, CD86 and HLA-DR. Further-more, AML-MSCs showed cell proliferation ability similar to normal MSCs. Notably, AML-MSCs exerted increased osteogenic-differentiation capacity as compared with normal MSCs.CONCLUSION:AML-MSCs possess typical MSC phenotypes but displayed enhanced osteogenic-differentiation capacity.

Mesenchymal stem cells (MSCs) have been widely used in allogeneic stem cell transplantation. We compared immunologic and hematopoietic characteristics of MSCs derived from whole human umbilical cord (UC), as well as from different sections of UCs, including the amniotic membrane (AM), Wharton's jelly (WJ), and umbilical vessel (UV). Cell phenotypes were examined by flow cytometry. Lymphocyte transformation test and mixed lymphocyte reaction were performed to evaluate the immuno-modulatory activity of MSCs derived from UCs. The mRNA expression of cytokines was detected by real-time polymerase chain reaction. Hematopoietic function was studied by co-culturing MSCs with CD34(+) cells isolated from cord blood. Our results showed that MSCs separated from these four different sections including UC, WJ, UV, and AM had similar biological characteristics. All of the MSCs had multi-lineage differentiation ability and were able to differentiate into osteoblasts, adipocytes, and chondrocytes. The MSCs also inhibited the proliferation of allogeneic T cells in a dose-dependent manner. The relative mRNA expression of cytokines was examined, and the results showed that UCMSCs had higher interleukin-6 (IL6), IL11, stem cell factor, and FLT3 expression than MSCs derived from specific sections of UCs. CD34(+) cells had high propagation efficiencies when co-cultured with MSCs derived from different sections of UCs, among which UCMSCs are the most efficient feeding layer. Our study demonstrated that MSCs could be isolated from whole UC or specific sections of UC with similar immunomodulation and hematopoiesis supporting characteristics.

Objective:To observe curative effect of constraint-induced movement therapy(CIMT)on upper limb function in sub-acute stroke patients.Method :Thirty-six patients with sub-acute stroke were randomly divided into contrast group(n=18)and Treatment group(n=18).Techniques of Bobath,Rood and Brunnstrom were adopted by contrast group in upper—limb and hands functional exercises,2h/d,five times a week,continuous for two weeks.CIMT was adopted by interference group,involving restriction of movement of the intact upper extremity by placing it in a sling for 90% of waking in a whole day and simultaneously training(by shaping)the affected upper extremity for 6h/d,five times a week,continuous for two weeks.Results:After treatment,the scores on UEFT and STEF were increased in two groups and were all better than before,the difierences were very obvious(PO.05).Comparing the scores of the two groups between pre-treatment and post—treatment the differences were very significant(PO.01).Conclusion:CIMT might be an efficacious method of improving function and use of the more affected arnls of sub—acute stroke patients,and compared with routine therapy.it shows significan t clinical improvements in upper function.CIMT with short—term intervention appears to precede motor limb improvement in many ways and the motor recovery plateau wuld be delayed.

AIM: To explore the complementary action and mechanism of traction rotatory manipulation of lumbar spine and silver needle heat conductive treatment for lumbar disc herniation (LDH). METHODS: Totally 240 LDH patients diagnosed with CT scanning or MRI examination were selected from the Department of Rehabilitation Medicine, Chinese PLA General Hospital between February 2002 and August 2005. They were randomly divided into three groups with 80 patients in each group. Group A: Traction rotatory manipulation of lumbar spinetreatment was performed to the segment of the intervertebral disc herniation, once per week totally for 2 times. Group B: Silver needle heat conductive treatment was conducted to patient's waist and buttocks, once per week totally for tow weeks. Group C: Traction rotatory manipulation of lumbar spinetreatment and silver needle heat conductive treatment were successively done, each for 2 weeks. The numeric rating scale (NRS) score and improvements of clinical signs as well as curative effects were compared in three groups before treatment and 3-6 months after treatment. Evaluation standards of curative effect:①Disappeared symptom: The pain in waist and legs were extinctive, and the clinical signs all turned to be negative. The patients could recover to their works.②Effective: The pain in waist and legs fundamentally disappeared, and 2-3 items of clinical signs turned to be negative. The patients could make some mild works.③Improved: The pain in waist and legs relieved, and only one clinical sign turned to be negative. The patients still needed further treatment.④Ineffective: There was no change in the pain and sign before and after treatment. RESULTS: All the patients accomplished the treatment and index assessment, thus entered the result analysis.①The NRS scores decreased in three groups after 3-month treatment, especially in group C (t=8.52, P < 0.01), And most of the painful symptoms were controlled after 6-month treatment, obviously in group C (t=7.08,P < 0.01). There were significant differences between group A and group B, and between group B and group C (t=9.09,9.82,P < 0.05).②After three-month treatment, the clinical signs of three groups were all improved notably, especially the positive rate of straight-leg raising test. The difference was quite significant between group C and group B, and between group C and group A (χ2=9.27,9.04,P < 0.01), whereas insignificant between group A and group B (χ2=11.51,P > 0.05).③The percentage of validity (fully recovery or effective) was 72% in group A, 73% in group B and 88% in group C. Moreover, there were also quite significant differences between group A and group C, and between group C and group B (χ2=6.31,6.13, P < 0.01). CONCLUSION: Traction rotatory manipulation of lumbar spinetreatment is effective for relieving the muscle spasm and relaxing the nerve root adhesion, while silver needle heat conductive treatment has effects on eliminating the aseptic inflammation of the soft tissues in or out of vertebral canal, improving the blood supply and relaxing the muscles. So the two therapies are complementary for treating LDH patients.

目的:比较结构性速度依赖性平板训练和常规步行训练对脑卒中偏瘫患者下肢运动功能、平衡功能、ADL能力、步行能力和速度的影响.方法:解放军总医院康复医学科2002-09/2004-08收治脑卒中偏瘫患者50例,所有患者均可独立或在监视下步行16 m以上,且步行速度1 min超过10 m,排除存在限制活动的并发症者.将50例脑卒中偏瘫患者分层随机为速度依赖性组(25例)和常规步行训练组(25例).速度依赖性组进行结构速度依赖性平板步行训练治疗,常规步行训练治疗以神经易化技术为主.20 min/次,1次/d,5次/周,连续4周治疗.两组患者仍进行除步行训练以外的其他训练内容.在治疗前、后对两组患者进行下肢Fugl-Meyer运动功能评价、Berg平衡量表、步行功能性分级、功能独立性测量和步行速度的评定.结果:45例患者完成研究,5例脱落.速度依赖性组(23例)和常规步行训练组(22例)经过4周治疗后,两组患者的平衡功能、步行功能、功能独立性和步行速度变化较治疗前均明显改善(P＜0.001),但在平衡功能、步行功能、功能独立性和步行速度方面的改善效果上结构性速度依赖性平板训练比常规步行训练更为有效(ES=0.69～0.89),但在下肢运动功能改善效果方面两者比较差异无显著性意义(ES=0.35).所有参与研究的患者(包括脱落的5例)在训练期间没有出现心脏症状和其他副反应.结论:结构性速度依赖性平板训练比常规步行训练更为有效.在改善脑卒中偏瘫患者功能障碍的训练策略上,结构速度依赖性平板步行训练是一新的,安全可行的治疗方式.