AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

[Case-control studies on therapeutic effects of combined methods of minimally invasive percutaneous proximal humerus locked osteosynthesis plate with injectable bone for the treatment of proximal humerus fractures in elderly patients].

OBJECTIVE: To evaluate the clinical effects of combined methods of minimally invasive percutaneous proximal humeral internal locking system (PHILOS) and injectable bone for the treatment of proximal humerus fractures in elderly patients. METHODS: From January 2006 to January 2012, 80 patients with proximal humerus fractures were randomly divided into two groups (n = 40). The patients in the research group were treated with minimally invasive PHILOS fixation combined with injectable bone, including 20 males and 20 females, with an average age of (68.4 +/- 11.9) years; according to AO classification, 2 cases of type A1, 3 cases of type A2, 6 cases of type B1, 7 cases of type B2, 9 cases of type B3, 6 cases of type C1, 7 cases of type C2. The patients in the control group were treated with PHILOS fixation, including 18 males and 22 females, with an average age of (65.4 +/- 10.7) years; according to AO classification, 3 cases of type A1, 4 cases of type A2, 5 cases of type B1, 8 cases of type B2, 10 cases of type B3, 5 cases of type C, and 5 cases of type C2. The BMD, satisfactory rate, postoperative complications,bone healing time, Constant-Murley score in the two groups were reviewed and compared. RESULTS: In the research group, no patients had necrosis of femoral head, 1 patient had shoulder varus, 1 patient had internal fixation loosening, 36 patients were satisfactory with the treatment results, BMD was (1.013 +/- 0.109) g/cm2, bone healing time averaged (12.00 +/- 3.79) weeks, and the Constant-Murley score was 97.2 +/- 4.6. In the control group, 3 patients had necrosis of femoral head, 5 patients had shoulder varus, 6 patients had internal fixation loosening, 32 patients were satisfactory with the treatment results, BMD was (0.812 +/- 0.089) g/cm2, bone healing time averaged (20.00 +/- 8.67) weeks,and the Constant-Murley score was 78.5 +/- 3.2. The results of BMD, satisfactory rate, postoperative complications, bone healing time, and Constant-Murley score in the research group were better than those of control group (P < 0.05). CONCLUSION: PHILOS combined with injectable bone for the treatment of proximal humerus fractures in elderly patients has advantages of minimal wound, stable fixation, and earlier rehabilitation.

[Case-control study of influence factors analysis on short-term recovery after total knee arthroplasty in old patients with osteoarehritis].

OBJECTIVE: To investigate the relationship between variable influence factors and postoperative 2 week hospital special surgery (HSS) of knee joint, thus offer the treatment suggestion to patients with osteoarthritis, and judge the comprehensive effective prognosis to the clinical patient. METHODS: From March 2008 to August 2010, 72 patients with 72 knees were treated with TKA (treatment group), including 30 males and 42 females with a mean age of (71.9 +/- 6.2) years (ranged, 60 to 86 years). Twenty-two patients with HoldenIV OA treated by arthroscopy were in the control group, including 10 males and 12 females with a mean age of (70.5 +/- 5.9) years. The index including height, weight, BMI, muscle strength,knee joint HSS score and ROM were evaluated before operation and at 1st, 2nd weeks after operation. RESULTS: The HSS knee score and ROMs of patients in the treatment group improved. The pre-operative ROM, HSS score, knee pain, continous passive motion (CPM) at different level (i.e.CPM initial angle) had a prominent positive correlation with HSS score in postoperative 2 weeks. The factors such as patients' age, height, weight, BMI, muscular strength, etc. had no obvious relevant to HSS score in postoperative 2 weeks. CONCLUSION: The pre-operative HSS score, knee pain, knee ROM, perioperative severe complications, and postoperative CPM initial angle have a positive correlation with the postoperative effects.

HLA-DR expression on regulatory T cells is closely associated with the global immune activation in HIV-1 infected subjects naïve to antiretroviral therapy / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The frequencies of regulatory T cells (Tregs) increased over the HIV infection but its counts actually decreased. We proposed that the decrease of Treg counts may cause the reduction of inhibitory effect and thereby account for the over-activation of Tregs during HIV infection. However, it remains unknown whether Tregs are also over-activated and thereafter the activation induced death may lead to the decrease of Tregs.</p><p><b>METHODS</b>Tregs were defined as CD4(+)CD25(+)CD127(lo/-) T cells. Eighty-one HIV-1 infected patients were enrolled in our study, and twenty-two HIV-1 seronegative donors were recruited as the control. The levels of HLA-DR on Tregs were determined by FACSAria flow cytometer.</p><p><b>RESULTS</b>Compared to HIV-1 seronegative donors, the levels of HLA-DR on CD4(+)CD25(+)CD127(lo/-) Tregs were significantly increased in HIV-1 infected patients, and its increase was positively associated with viral loads (r = 0.3163, P = 0.004) and negatively with CD4 T-cell counts (r = -0.4153, P < 0.0001). In addition, significant associations between HLA-DR expression on CD4(+)CD25(+)CD127(lo/-) Tregs and the percentages of HLA-DR, CD38, Ki67 expressing CD4(+) and CD8(+) T cells were also identified.</p><p><b>CONCLUSION</b>HLA-DR on Tregs is a good marker for viral replication and disease progression. The over-activation of Tregs might result in the decrease of Tregs.</p>