BACKGROUND: Mainly pathological changes of Parkinson disease (PD)are related to irreversible degeneration and reduction of dopamine neurons of substantia nigra in midbrain; however, oxidative stress reaction plays an important role in onset of PD. 3-nitropropionie acid (3-NP) is an inhibitor of mitochondria compound I, and it can inhibit oxidative phosphorylation so as to restrain energy metabolism. However, professor Riepe from Germany found that small dose of 3-NP can increase the tolerance of neurons to ischemic hypoxia. It is unclear whether it can also strengthen the tolerance of dopamine neurons to neurotoxin.OBJECTIVE: To investigate the possible mechanism and prevention of repetitively preconditioning 3-NP for treating PD.DESIGN: Controlled observational animal study. SETTING: Department of Neurology, Union Hospital affiliated to TongjiMedical College, Huazhong University of Science and Technology. MATERIALS: The experiment was carried out at the Neurological Lab oratory, Union Hospital affiliated to Tongji Medical College, Huazhong U niversity of Science and Technology from March to July 2004. A total of48 C57BL mice, weighing 18-20 g, aged 2-3 months, of both genders, were randomly divided into 6 groups with 8 in each group. ① Blank con trol group: Mice were not medicated. ② 3-NP single administrationgroup: Mice were intraperitoneally injected with 3-NP once. ③ 3-NPrepetitively administrations group: Mice were intraperitoneally injectedwith 3-NP every 5 days for 5 times in total. ④ Neurotoxin group: Micewere intraperitoneally injected with neurotoxin once every day for 5 timesin total. ⑤ 3-NP single preconditioning group: Mice were intraperitoneal ly injected with 3-NP once, and 3 days later, they were intraperitoneallyinjected with neurotoxin once every day for 5 times in total. ⑥ 3-NPrepetitively preconditionings group: Mice were intraperitoneally injectedwith 3-NP and repetitively every 5 days for 5 times in total; 3 days later, mice were intraperitoneally injected with neurotoxin once every day for5 times in total. Dosages of 3-NP and neurotoxin were 20 mg/kg and30 mg/kg, respectively. METHODS: Motor coordination of mice was scored with pole test andtraction test before experiment and at 3 days after the last injection ofneurotoxin. Three days after complete injection, mice were sacrificed rapid ly to measure the contents of malondialdehyde (MDA) and reduced glu tathione (GSH) in the substantia nigra of midbrain. MAIN OUTCOME MEASURES: ① Motor and behavior scores; ② con tent of MDA; ③ content of GSH.~ULTS: All 48 mice were involved in the final analysis. ① Scores of pole test and traction test were decreased in neurotoxin group as compared with those in control group (P＜0.01); but the scores were increased after 3-NP single/repetitively preconditionings, and there were significant difference (P＜0.05, P＜0.01). Meanwhile, there was also significant differencebetween 3-NP repetitively preconditionings group and 3-NP single preconditioning group (P＜0.05). ② Content of MDA was increased in neurotoxin group as compared with that in control group, and there was significant difference (P＜0.01); content of MDA was decreased after 3-NP single preconditioning as compared with that in neurotoxin group, and there was significant difference (P＜0.05); content of MDA was remarkably decreased after 3-NP repetitively preconditionings as compared with that in neurotoxin group, and there was greatly significant difference (P＜0.01); meanwhile, there was also significant difference between 3-NP repetitively preconditionings group and 3-NP single preconditioning group (P＜0.05). ③As compared with that in blank control group, content GSH in 3-NP single administration group was not changed; content of GSH in 3-NP repetitively administrations group was increased (P＜0.05); content of GSH in neurotoxin group was decreased as compared with that in blank control group (P＜0.01); content of GSH in 3-NP single preconditioning group was not changed as compared with that in neurotoxin group (P＞0.05); content of GSH was increased after 3-NP repetitively preconditionings, and there was significant difference (P＜0.05); meanwhile, there was significant difference between 3-NP repetitively preconditionings group and 3-NP single preconditioning group (P＜0.05).CONCLUSION: 3-NP repetitively preconditionings can activate synthesis of GSH, protect dopamine neurons through decreasing production of MDA.

This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells. One week before treatment with the drug, nerve growth factor (NGF) was added to the cultures at a final concentration of 50 ng/mL to induce neuronal differentiation. After drug treatment, HO-1 gene transcription was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Expression of HO-1 and NF-E2-related factor2 (Nrf2) and activation of extracellular signal-regulated kinase (ERK) and Akt were detected by Western blotting. The viability of the PC12 cells treated with different medicines was examined by MTT assay. The oxidative stress in the PC12 cells was evaluated qualitatively and quantitatively by DCFH-DA. The results showed that β-PGG up-regulated HO-1 expression and this increased expression provided neuroprotection against MPP(+)-induced oxidative injury. Moreover, β-PGG induced Nrf2 nuclear translocation, which was found to be upstream of β-PGG-induced HO-1 expression, and the activation of ERK and Akt, a pathway that is involved in β-PGG-induced Nrf2 nuclear translocation, HO-1 expression and neuroprotection. In conclusion, β-PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK- and Akt-dependent manner, and HO-1 expression by β-PGG may provide the PC12 cells with an acquired antioxidant defense capacity to survive the oxidative stress.

This study examined the ability of 1,2,3,4,6-penta-O-galloyl-β-D-glucose (β-PGG) to induce the expression of heme oxygenase-1 (HO-1) in the PC12 cells and its regulation in the PC12 cells. One week before treatment with the drug, nerve growth factor (NGF) was added to the cultures at a final concentration of 50 ng/mL to induce neuronal differentiation. After drug treatment, HO-1 gene transcription was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Expression of HO-1 and NF-E2-related factor2 (Nrf2) and activation of extracellular signal-regulated kinase (ERK) and Akt were detected by Western blotting. The viability of the PC12 cells treated with different medicines was examined by MTT assay. The oxidative stress in the PC12 cells was evaluated qualitatively and quantitatively by DCFH-DA. The results showed that β-PGG up-regulated HO-1 expression and this increased expression provided neuroprotection against MPP(+)-induced oxidative injury. Moreover, β-PGG induced Nrf2 nuclear translocation, which was found to be upstream of β-PGG-induced HO-1 expression, and the activation of ERK and Akt, a pathway that is involved in β-PGG-induced Nrf2 nuclear translocation, HO-1 expression and neuroprotection. In conclusion, β-PGG up-regulates HO-1 expression by stimulating Nrf2 nuclear translocation in an ERK- and Akt-dependent manner, and HO-1 expression by β-PGG may provide the PC12 cells with an acquired antioxidant defense capacity to survive the oxidative stress.
Animals ; Cell Death ; drug effects ; genetics ; Cell Line, Tumor ; Heme Oxygenase-1 ; genetics ; Hydrolyzable Tannins ; pharmacology ; MAP Kinase Signaling System ; drug effects ; genetics ; PC12 Cells ; Piperidines ; adverse effects ; Proto-Oncogene Proteins c-akt ; genetics ; Pyrazoles ; adverse effects ; Rats

Objective To evaluate the clinical efficacy and safety of short-segment pedicle screw fixation combined with vertebroplasty for the treatment of thoracolumbar osteoporotic compression fractures.Methods A retrospective case control study was conducted on 63 patients with fresh thoracic or lumbar osteoporotie compression fractures who were surgically treated from January 2010 to December 2013.There were 26 males and 37 females,with age of 63-87 years [(76.3 ± 5.7) years].According to the surgical method,the patients were assigned to simple vertebroplasty group (Group A),short-segment pedicle screw fixation group (Group B),and short-segment pedicle screw fixation group combined with vertebroplasty group (Group C),with 21 cases in each group.Length of hospital stay,operation time,and blood loss were recorded.The visual analog scale (VAS),anterior vertebral body height,angle of the kyphotic deformity,and complications before operation,immediately after operation,3 months after operation,and at the last follow up were compared among three groups.Complications of each group were recorded.Results The hospital stay,operation time,and blood loss in Group C were significantly higher than those in Group A (P ＜ 0.05),but there were no significant differences between Group B and Group C (P ＞ 0.05),except for a longer operation time in Group C.The pre-operative VAS showed no significant difference among three groups (P ＞ 0.05).However,the mean VAS in Groups A,B and C at the last follow up were 1.0(0.0,2.0)points,1.0(0.0,2.0)points,0.0(0.0,1.0)points,respectively.The VAS in Group C was significantly lower than that in Group B or A (P ＜ 0.05).The mean anterior vertebral body height and angle of the kyphotic deformity in Group C had no significant difference from that in Group A or B before operation and immediately after operation (P ＞ 0.05).At the last follow up,the mean anterior vertebral body height and angle of the kyphotic deformity in Groups A,B and C were (68 ±14.7)％,(72.3 ±9.0)％,(81.5 ±5.6)％ and (10.6 ±3.9)°,(10.7 ±5.0)°,(7.4 ± 5.0) °,respectively.The loss of anterior vertebral body height and angle of the kyphotic deformity correction in Group C were significantly less than that in Group A or B (P ＜ 0.05).Superficial infection was found in Groups B (n =2) and C (n =1),and the infection was cured after antibiotic therapy and dress change.Bone cement leakage was found in Groups A (n =8) and C (n =5),with no nerve compression.Internal fixation failure was seen in Group B (n =3),and the implant was removed directly.Conclusion Short-segment pedicle screw fixation combined with vertebroplasty can effectively reduce the loss of anterior vertebral body height and angle of the kyphotic deformity and hence enhance the clinical efficacy.

Objective:To perform a prospective cohort study to identify individual susceptibility of glucocorticoid (GC) -associated osteonecrosis of the femoral head (GA-ONFH) and their clinical and genetic risk factors. Methods:The present prospective cohort study enrolled patients who received their first GC therapy between July 2015 and January 2018 at Zhongshan Hospital. All patients did not receive any GC treatment before enrollment. Further, they planned to start GC treatment with the dose (equivalent prednisone) of ≥30 mg/d, lasted ≥3 weeks, or pulse dose ≥200 mg/d, lasted ≥3 d. Blood samples were collected before GC treatment to evaluate bone metabolism and its released factors. Hip MRI was performed at the 1st, 3rd, 6th, 12th and 24th month to diagnose GA-ONFH. All patients were followed-up for ≥2 years. The endpoint was regarded as diagnosis of GA-ONFH or completion of 2 years follow-up. Lasso regression was performed to determine which clinical features were associated with GA-ONFH. A nested case-control sub-cohort (A, n=12) was established prospectively based on the main cohort by 1∶1 matching. Whole exome sequencing was performed to screen differential and functional candidate single nucleotide polymorphisms and insertion-deletions (SNP/InDels). Another sub-cohort (B, n=50) was constructed retrospectively in patients with GA-ONFH and non-ONFH patients received standard high dose GC treatment for more than two years. The candidate SNP/InDels were verified by Sanger sequencing based on the patients from sub-cohort B. Results:A total of 96 patients were enrolled of which 88 of them (32 males and 56 females, mean age 42.30 years) completed follow-up. Eight cases (9.1%) were diagnosed with GA-ONFH. The median time from the start of GC therapy to the diagnosis of ONFH was 53.00(34.00,13.50) days. The baseline characteristics, such as age, sex and body mass index, indicated no significant difference between the ONFH group and the non-ONFH group. The cumulative GC dose of the ONFH patients in the first month was higher than that of non-ONFH [32.74(29.55, 47.05) mg/kg vs. 24.00(21.10, 29.45) mg/kg, Z=-2.410, P=0.016]. However, there was no significant difference of patients who underwent pulse therapy (37.5% vs. 10.0%, adjusted χ 2=2.829, P=0.093). The ratio of serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) in patients with ONFH was higher than that in non-ONFH group before GC use [0.95(0.80, 1.50) vs. 0.70(0.60, 0.80), Z=-2.875, P=0.000]. Due to the multicollinearity, Lasso regression model was performed to reduce overfitting. All variables were included in the model. The results suggested that higher ApoB/ApoA1 ratio, lower serum β-c-terminal telopeptide (β-CTX) and higher cumulative GC dose in the first month were the top three risk factors of GA-ONFH. This model had an accuracy of 0.982 in internal validation. Seven differential candidate SNP/InDels were found by whole exome sequencing of sub-cohort A. We further verified these SNP/InDels in sub-cohort B. The patients with COLEC12 mutation (rs2305027, G1816A) were at risk of GA-ONFH ( OR=6.00, 95% CI: 1.17, 30.73). Conclusion:Higher first-month GC dose, lower serum β-CTX level before treatment, higher ApoB/ApoA1 ratio and COLEC12 mutation (rs2305027, G1816A) could increase the risk of GA-ONFH.

OBJECTIVETo understand HIV rival suppression and drug resistance (HIVDR) among AIDS patients who were receiving antiretroviral treatment (ART) in Dehong prefecture, Yunnan province.

METHODSAll AIDS patients who were aged over 15 years and with experience more than six months on ART by the end of 2012 in Dehong prefecture, were enrolled to receive testing for HIV viral load in plasma and genetic mutations associated with HIVDR.

RESULTSA total of 4 390 AIDS patients were qualified for the study according to the selection criteria, of whom 3 964 (90.3%) finally participated in the study. Among them, 2 307(58.2%) had CD₄(+) cell counts more than 350 cells/mm³. 3 169 (79.9%) patients showed undetectable plasma HIV viral load which was lower than the detection threshold. Those who had the following factors as:resided in Ruili city, being female, older than 45 years of age, married, heterosexually infected with HIV, having received ART more than 5 years, and CD₄(+) cell counts >500 cells/mm³, were more likely to have undetectable plasma virus load, with the differences statistically significant. 402 (10.1%) patients had plasma viral load ≥ 1 000 copies/ml, of whom 353 (87.8%) were successfully amplified and examined for HIVDR. Among them, 198 (56.1% ) were identified to bear genetic mutations associated with HIVDR. Most mutations were related to the resistance to nucleotide reverse transcriptase inhibitors (NNRTIs) or non-nucleotide reverse transcriptase inhibitors (NNRTIs), with M184V and K103N most frequently seen. 12 patients (3.4%) were found to have mutations resistant to protease inhibitors (PI). Data from multiple logistic regression analysis indicated that the period of receiving ART and the initial ART regimen could both significantly predict the occurrence of HIV resistance.

CONCLUSIONViral suppression was highly achieved among ART-prescribed AIDS patients in Dehong prefecture,Yunnan province. However, among those who did not show effective viral suppression, the proportion of HIVDR was high, underscoring the needs for health education so as to improve the adherence to drugs as well as for improving testing for viral load and HIVDR among AIDS patients.

Acquired Immunodeficiency Syndrome ; drug therapy ; Adolescent ; Adult ; Anti-HIV Agents ; therapeutic use ; Drug Resistance, Viral ; genetics ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Mutation ; Viral Load ; drug effects ; Young Adult

Objective: To study the prevalence and correlates of diabetes among HIV/AIDS who were on antiretroviral therapy (ART) in Dehong Dai and Jingpo autonomous prefectures (Dehong), Yunnan province. Methods: The database of HIV/AIDS receiving ART in Dehong was downloaded by using the basic information system of AIDS prevention and control in China. In this cross-sectional study, HIV/AIDS patients who were currently on ART and aged 18 years or above, were consecutively recruited, between July 2017 and June 2018, in Dehong. All the subjects underwent hemoglobin A1c (HbA1c) testing. Patient with diabetes was defined as meeting any of these indicators (HbA1c ≥6.5%, baseline FPG ≥7.0 mmol/L, FPG ≥7.0 mmol/L in the most recent visit). Both univariate and multivariate logistic regression analysis were carried on to evaluate the correlates of diabetes among the HIV/AIDS patients. Results: In total of 4 376 HIV/AIDS patients were included for analysis, with the average age as (43.7±10.1) years, proportion of males as 53.8% (2 356/4 376) and the HCV positive rate as 24.1% (1 055/4 376). The mean years was (8.9±3.8) years after the HIV diagnosis was made, and the mean duration on treatment was (6.8±2.9) years. The prevalence of diabetes was 11.4% (500/4 376). Through multivariate logistic regression analysis, data showed that the risk factors of diabetes of HIV/AIDS on ART were: aged 40 years or above, being male, HCV positive, baseline body mass index ≥24.0 kg/m², elevated TG ≥1.70 mmol/L in the most recent visit and baseline antiretroviral regimens under Efavirenz (EFV). Conclusions Prevalence rate of diabetes appeared higher in HIV/AIDS patients who were on ART in Dehong. Prevention and control measures should be targeted on HIV/AIDS patients who were with risk factors of diabetes as being elderly, male, HCV positive, overweight and higher TG. Further esearch is needed to evaluate the association between the use of EFV and diabetes.