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In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease (PD). However, difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1. Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains. CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology. Importantly, PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival. Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.
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Objective:To investigate the changes of brain energy metabolism and cognitive function in mice with specifically knocking out AMP-activated protein kinase α1 subunit ( AMPKα1) gene in the excitatory neurons by Cre-loxP recombination system. Methods:Sixteen 6-month-old mice with genotype AMPKα1 flox/flox/Camk2a-Cre/ERT2 obtained by hybrid breeding were randomly divided into AMPKα1 knockout group ( n=8) and AMPKα1 wild-type group ( n=8). Mice in the AMPKα1 knockout group were intraperitoneally injected 0.1 mL tamoxifen (20 mg/mL, dissolved in corn oil) daily for a consecutive 5 d to control AMPKα1 gene knockout in the excitatory neurons; and mice in the AMPKα1 wild-type group were intraperitoneally injected 0.1 mL corn oil daily for a consecutive 5 d. Seven d after that, Morris water maze and T maze experiments were employed to detect the spatial learning and memory abilities and spatial working memory of these mice; chemical exchange saturation transfer imaging (CEST) was used to observe the glucose metabolism in the hippocampus and cortex surrounding the hippocampus; Western blotting was used to detect the AMPKα1 and glutamate receptor 1 (GluR1) protein expressions in the hippocampus and cortex surrounding hippocampus of two groups. Results:(1) Morris water maze showed that, as compared with those in the AMPKα1 wild-type group, mice in the AMPKα1 knockout group had significantly prolonged escape latency ([13.90±3.72] s vs. [22.40±6.28] s; [11.95±3.86] s vs. [22.39±9.77] s]) on the 3 rd and 4 th d of experiment, statistically decreased times crossing the platform ([5.25±1.83] times vs. [1.75±1.28] times, P<0.05). (2) T-maze experiment showed that as compared with that of the AMPKα1 wild-type group, the free alternation rate in mice of the AMPKα1 knockout group was significantly decreased ([73.21±9.16]% vs. [48.21±11.29]%, P<0.05). (3) CEST showed that the glucose metabolism levels in the hippocampus and cortex surrounding the hippocampus of AMPKα1 knockout group were significantly lower than those in AMPKα1 wild-type group (1.51±0.81 vs. 2.77±0.67; 1.31±0.83 vs. 2.42±0.95, P<0.05). (4) Western blotting showed that the AMPKα1 and GluR1 protein expressions in the hippocampus and cortex surrounding the hippocampus of the AMPKα1 wild-type group were significantly higher than those of the AMPKα1 knockout group (AMPKα1: 0.70±0.05 vs. 0.49±0.03, 0.98±0.04 vs. 0.64±0.06; GluR1: 1.22±0.18 vs. 0.60±0.11, 0.96±0.08 vs. 0.79±0.04, P<0.05). Conclusion:Specifically knocking out AMPKα1 in excitatory neurons can result in abnormal glucose metabolism in the brain of mice, and thus cause cognitive dysfunction, whose mechanism may be related to excitatory synaptic disorder caused by energy metabolism disorder.
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There are two phenotypes of microglia, M1 and M2. Microglia in M2 polarization may associate with the phagorytosis of be-ta-amyloid and inhibition of Tau hyperphosphorylation, as well as in other pathology. Electroacupuncture can impact the phenotypes of mi-croglia, which may play a role in the treatment for Alzheimer's disease.
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advocates painless acupuncture,arrival to strength the body and eliminate pathogenic factors,as well as enhancing the immune function. Also,he stresses the application of both the Chinese and western medicine theories. The academic thought and clinical experience of professorregulating the immune function are explored through three aspects,namely the application of 12-source points and loweracupoints,implementing moxibustion at health care points,the usage of acupoints related to immune organs.
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Objective o evaluate the association between IL-28B ( rs12979860 ) polymorphism andantiviraltherapeutic effectbydetecting the genotype of interleukin-28B( IL-28 B) in patients with hepatitis C ( HCV ) .Methods Of total 1153 HCV patients, 303 diagnosed with CHC had been treated with pegylated interferon plus ribavirin for 24-48 weeks.IL-28B ( rs12979860 ) was genotyped by two-color fluorescent TaqMan assay.Results Among 1153 patients, CC, CT and TT genotype frequencies of IL-28B rs12979860 are 83.26%, 16.22%and 0.52%respectively.The results of HCV genotypingof 580 in 1153 cases, the frequencies of 1b, 2a and their non-1b/2a type are 63.45%, 35.00%and 1.55%respectively;In 303 CHC patients with clear medical history, the proportion of SVR was71.98% in patients with CC genotype and 16.90%in those with either the CT or TT genotypes.Logistic regression model was adopted to analyze the association of rs12979860 with SVR while adjusting for age, gender, viral load and HCV GT factors.Populations carrying combined genotype ( CT +TT) are making it harder to get SVR compared with those with CC genotype (OR, 95%CI:11.10,5.35-23.04;P<0.000 1).The percentages of SVR in HVC patients with 1b and 2a genotypeare 48.02% and 81.19% respectively.there is a statistically significant difference between these subgroups (χ2 =30.639,P<0.000 1).Conclusion IL-28B rs12979860 genotype is closely related to SVR in CHCpatients.Patients with CC genotype have a higher virus sustained response rate than those carrying CT or TT genotype.The SNP , rs12979860, might be applied as a predictor of clinical antiviral efficacy in the furture.
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Objective To explore the association between tumor necrosis factor receptor associated factor 6 (TRAF6) polymorphisms and the susceptibility to sepsis. Method Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected from the HapMap database. The htSNPs were genotyped in 255 patients with sepsis and 260 control subjects by the Beckman SNP stream genotyping platform. The association with susceptibility to and severity of sepsis were estimated by logistic regression with adjustment for age, sex, smoking, drinking,chronic diseases status, APACHE Ⅱ score and critical illness. Results Of 13 TRAF6 ANPs, 7 were tagged by htSNPs. Of them, 5 htSNPs (rs5030496, rs5030411, rs5030416, rs5030445 and rs3740961) were used for final genotyping analysis. Genotype frequencies of those htSNPs were conformed to the Hardy-Weinberg law in both patients and controls. There were no significant association found between the 5 htSNPs and susceptibility to sepsis.Also, there was no significant association between the TRAF6 polymorphisms and the septic shock, death from sepsis as well as organ dysfunction. Conclusions The TRAF6 gene polymorphisms might not play a major role in severity of sepsis.
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OBJECTI VE: To observe the long termtherapeutic effect of compound glycyrrhizinin treating active cirrhosisfollowing chronic hepatitis B.METHODS:58patients with active cirrhosis received compound glycyrrhizin60ml intra-venously once a day for18consecutive months.The changes in clinical symptoms,signs,biochemical indicators,virologyindices after treat ment were observed.RESULTS:35cases of active cirrhosis remained stable after treat ment,ascites disap-pearedin5cases,and17patients returnedto work.The quantitated decreasein HBV-DNA was greater than103copies/ml,HBeAg negative rates reached33.3%.CONCLUSION:Long-termtreat ment with compound glycyrrhizin for active cirrhosisfollowing hepatitis B cani mprove liver function,prevent the worsening of patients’condition,andi mprove life quality.
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The treatment of total avulsion of the hand is somewhat difficult and the result usually not satisfactory. Four cases of such patients were treated from 1983 to 1987. After routine debridement, digital nerves and its surrounding adipose tissue were preserved. An "S" shape skin flap was designed an raised in the contralateral upper abdominal quadrant to cover the injured hand like a bag, so that both sides of the hand were covered. The donor area (12cm2) was directly sutured. Nerve endings might grow into the flaps because of the preservation of digital nerves. Three patients were followed-up for 2 to 6 years, the injured hands regained good pain sensation as well as stereognostic and temperatuer sensations. The function of the hand is satisfactory, but the flap looked bulky and multiple plastic operations were necessary to seperate the fingers.