Hypoxic preconditioning (HPC) refers to exposure of organisms, systems, organs, tissues or cells to moderate hypoxia/ischemia that is able to result in a resistance to subsequent severe hypoxia/ischemia in tissues and cells. The effects exerted by HPC are well documented. The original local in situ (LiHPC) is now broadened to remote ectopic organs-tissues (ReHPC) and extended crossly to cross pluripotential HPC(CpHPC) induced by a variety of stresses other than hypoxia/ischemia, including cancer, for example. We developed a unique animal model of repetitive autohypoxia in adult mice, and studied systematically on the effects and mechanisms of HPC on the model in our laboratory since the early 1960s. The tolerances to hypoxia and protection from injury increased significantly in this model. The adult mice behave like hypoxia-intolerant mammalian newborns and hypoxia-tolerant adult animals during their exposure to repetitive autohypoxia. The overall energy supply and demand decreased, the microorganization of the brain maintained and the spacial learning and memory ability improved but not impaired, the detrimental neurochemicals such as free radicals down-regulated and the beneficial neurochemicals such as adenosine(ADO) and antihypoxic gene(s)/factor(s) (AHGs/AHFs) up-regulated. Accordingly, we hypothesize that mechanisms for the tolerance/protective effects of HPC are fundamentally depending on energy saving and brain plasticity in particular. It is thought that these two major mechanisms are triggered by exposure to hypoxia/ischemia via oxygen sensing-transduction pathways and HIF-1 initiation cascades. We suggest that HPC is an intrinsic mechanism developed in biological evolution and is a novel potential strategy for fighting against hypoxia-ischemia and other stresses. Motivation of endogenous antihypoxic potential, activation of oxygen sensing--signal transduction systems and supplement of exogenous antihypoxic substances as well as development of HPC appliances and HPC medicines such as AHFs are encouraged based on our basic research on HPC. HPC may result in therapeutic augmentation of the endogenous cytoprotection in hypoxic-ischemic or suffering from other diseases' patients. Evolutionary consideration of HPC and clinical implications of HPC are both discussed to guide future research. The product of AHF is expected to be one of the most effective first aid medicines to rescue patients in critical condition. HPC is beginning to be used in surgery and is expected to be developed into a feasible adaptive medicine in the near future.
Animals ; Brain ; physiology ; Disease Models, Animal ; Hypoxia, Brain ; physiopathology ; Hypoxia-Inducible Factor 1 ; Ischemic Preconditioning ; Mice ; Signal Transduction

Animals ; Bilirubin ; toxicity ; Brain ; drug effects ; metabolism ; Nitric Oxide ; metabolism ; Rabbits

BACKGROUND:Human memory is significantly correlated with recognition. When recognition begins to decrease, a decrease in memory appears first. How about the memory of rural population?OBJECTIVE:To investigate the picture memory related factors of the rural households who are over 50 years old.SETTING:Department of Geriatrics,Huaian First Hospital,Nanjing Medical University;Department of Neurology, Huashan Hospital,Fudan University.PARTICIPANTS:Totally 50 rural inpatients at the Department of Geriatrics,Huaian First Hospital Nanjing Medical University,who would be recovered and out of charge,were selected from March 2003 to February2004. Meanwhile, 11 relatives of the patients and 55 healthy elderly people from Dingji Town,Huaiyin District, were also included.All the participants were over 50 years old.METHODS:Employing questionnaire,mini-mental state examination,auditory-verbal learning test (AVLT), pictorial learning test and many nonmemory tests were performed. According to the levels of education,participants were divided into illiterate group,primary school group,junior middle school group and higher than junior middle school group.The correlation of picture memory ability with sex,age,educational level and simple intelligence test was compared. And the interactions among variables of picture memory were also investigated.MAIN OUTCOME MEASURES:The relationships between the variablesof picture memory and age, sex, educational level and simple intelligence of rural households in Huaian city were calculated. And the interactions among these variables were all investigated.RESULTS:Practically, 103 participants entered the statistical analysis proage,sex,educational level and simple intelligence:Except for recurring figures, all the other variables of picture memory had positive correlations with simple intelligence and educational level (r=0.197-0.533, P ＜ 0.05-0.01).Among them, immediate memory showed the closest correlation with simple intelligence (r=0.533).Delayed recall memory of pictures, recurring figures,and serial memory 4 (the number of recalled pictures in the last 4 pictures in delayed recall test) had negative correlation with age (r=-0.194 to -0.324,P ＜ 0.05-0.01),among them, serial memory of 4 pictures had the closest correlation with age (r=-0.324),while, all the other variables were not related to age. All the variables of picture memory were not linked to sex. Recurring pictures was not linked to educational level 1 (period of education:0-11 years),2 (education level: illiterate, primary school, junior middle interactions among these variables:Recurring figures was not linked to serial memory 2 (the number of recalled pictures in the last 4 pictures in immediate memory test),serial memory 1 (the number of recalled pictures in the first4 pictures in immediate memory test) was not related to serial memory 2 and serial memory 4.Except for these cases, variables of picture memory had significant correlations with each other (r =0.206-0.855 ,P ＜ 0.05-0.01),and delayed recall memory of pictures had the closest relationship with conceptual memory 2 (r=0.855).CONCLUSION:Picture memory capacity of middle aged and elderly rural households is not linked to sex, while it is correlated with age,educational level and intelligence.

Advances in the understanding of cancer at the molecular level have led to much progress in the development of anti-cancer agents. Among the newly invented medications for targeted cancer therapy, protein kinase inhibitors target intracellular molecules crucial in signaling pathways for cancer cell survival, proliferation, and disease progression. The Raf serine/threonine kinases are pivotal molecules within the Raf/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway. The exact function of Raf in normal human cells is not yet understood; however, preclinical and clinical researches have shown that over expression of Raf gene or overreaction of Raf kinase isoforms have critical roles in many types of solid tumors, including renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer (NSCLC). Sorafenib is the first oral, multi-kinase inhibitor that targets the Raf kinases. It also has a broad spectrum activity against other receptor tyrosine kinases associated with vascular endothelial growth factor receptors and platelet-derived growth factor receptors. Sorafenib was recently approved by FDA for use in advanced renal cell cancer, and is currently undergoing active investigation in the treatment of other types of malignancies, such as melanoma, liver cancer, prostate cancer, and NSCLC. In this review, we will illustrate the role of Raf in both normal and malignant cells, the mechanism of sorafenib in the treatment of renal cell carcinoma, as well as clinical data that support its use and further investigation in advanced renal cell carcinoma, melanoma, and other tumor types.

Objective To identify the significance of expression and phosphorylation of protein kinase R(PKR) and nuclear factor NF-κB p65 in cervical lesions, and the effect of high-risk human papilloma virus(hsHPV) on expression and phosphorylation of R(PKR) and NF-κB p65. Methods A total of 67 patients with cervical cancer, 149 patients with cervi-cal intraepithelial neoplasia (CINⅠ-Ⅲ) and 15 normal control were included in this study. The expression levels of PKR, phosphorylated PKR (p-PKR), NF-κB p65 and phosphorylated NF-κB p65 (p-NF-κB p65) were detected by immunohisto-chemical SP method in three groups. Results The positive expression rates of PKR and p-PKR in cytoplasm were signifi-cantly lower in hsHPV positive group than those in hsHPV negative group (27.2% and 11.0% vs 41.1% and 21.1%,χ2 =4.858 and 4.371,P＜0.05). The positive expression rates of NF-κB p65 and p-NF-κB p65 in cytoplasm and nucleus were significantly higher in hsHPV positive group than those in hsHPV negative group (46.3%, 25.7%, 22.8% and 12.5% vs 32.6%, 14.7%, 11.6%and 4.2%,χ2=4.345,4.048,4.729 and 4.650 respectively,P＜0.05). The positive expression rates of PKR in kytoplasm and karyon were significantly lower in NF-κB p65 (+) group than those in NF-κB p65 (-) group (25.5%vs 38.0%and 20.4%vs 36.3%,χ2=3.898 and 4.396 respectively, P＜0.05). The positive expression rate of PKR in kyto-plasm was significantly lower in p-NF-κB p65 (+) group than those in p-NF-κB p65 (-) group (19.0%vs 36.0%,χ2=4.462, P＜0.05). Conclusion hsHPV may inhibit the expression and phosphorylation of PKR but promote the expression and phosphorylation of NF-κB p65. The expression and phosphorylation of NF-κB p65 may inhibit the expression of PKR. Regu-lating effects of three may be associated with the generation and progression of cervical cancer.

Objective To investigate the effects of p53 on expression and activity of protein kinase R (PKR) as well as biological characters of HeLa cells from cervical carcinoma patients. Methods Recombinant plasmid vector pEGFP-C1/p53 was constructed to over-express p53 then it was transfected into HeLa cells. Transcription levels of p53 and PKR mRNA were detected by reverse transcriptase polymerase chain reaction (RT-PCR) among pEGFP-C1/p53 transfection group, pEGFP-C1 transfection group and blank control group(only transfection reagent was added);Protein expression lev?els of p53, PKR, phosphated PKR(p-PKR)and phosphatedαsubunit of eukaryotic initiation factor 2(p-eIF2α)which is the downstream substrate of PKR were detected by Western Blot among three groups;Proliferation of HeLa cell were deter?mined by methyl thiazolyl tetrazolium(MTT)assay;Invasion of HeLa cell were determined by Transwell cell assay. Re?sults Recombinant plasmid vector pEGFP-C1/p53 was successfully constructed to overexpress p53;Transcription level of p53 and PKR mRNA in pEGFP-C1/p53 transfection group were higher than those in pEGFP-C1 transfection group and in blank control group (P<0.05),and there were no significant difference between their levels in pEGFP-C1 transfection group and in blank control group;Protein expression levels of p53, PKR, p-PKR andp-eIF2α in pEGFP-C1/p53 transfection group were higher than those in pEGFP-C1 transfection group and in blank control group (P<0.05),and there were no sig?nificant difference between those expression levels in pEGFP-C1 transfection group and in blank control group;MTT and Transwell cell results showed that proliferation and invasion of HeLa cells in pEGFP-C1/p53 transfection group were weaker than those in pEGFP-C1 transfection group and in blank control group (P<0.05),and there were no significant difference between proliferation and invasion of HeLa cells in pEGFP-C1 transfection group and in blank control group. Conclu?sion p53 can up-regulate the expression and activity of PKR, promote activation of PKR/eIF2αsignal transduction pas?sage and restrain cell proliferation and invasion of HeLa cells.

Multi-drug resistance of breast cancer remains a major obstacle for effective treatment,which involves many complicated mechanisms,including drug transport in the body,metabolism and drug targets.Recent researches find that the tradition Chinese medicine not only has good effects in improving the body resistance and general situation of patients and enhancing the effects of chemoradiotherapy,but also plays a vital roles in the muti-drug resistance reversal of breast cancer.

Background Studies showed that vascular endothelial growth factor (VEGF) plays an important role in the development and progress of diabetic retinopathy (DR),and the association between VEGF-2578C/A polymorphism(SNPs) and risk for DR is a hotspot.Objective This Meta analysis aimed to investigate the comprehensive and reliable conclusion in the association of VEGF-2578C/A SNPs and risk for DR in different races.Methods A systematic search of electronic databases including PubMed,Cochrane Library,EMbase,VIP,Wanfang technological,CNKI and reference lists of relevant articles was carried out until April,2014.Case-control studies on the relationship between VEGF-2578C/A SNPs and DR were selected based on inclusion and exclusion criteria,and the relevance of VEGF-2578C allele to DR,the relevance of VEGF-2578C/A SNPs to DR and the relevance of VEGF-2578A allele to Caucasian DR were quantitatively analyzed.Begger funnel plot of publication biases on the relationships of VEGF SNPs with the risk of DR under the allele and dominant models was drown.RevMan 5.0 software was used for the statistical analysis.The pooled odds ratio (OR) and corresponding 95％ confidence interval (CI) were used to assess the strength of the association.Results A total of 1 228 DR cases and 1 224 diabetes controls without retinopathy(DWR) were included from 8 independent studies (9 groups of data).A significant relationships between VEGF-2578A allelic gene and VEGF-2578AA gene type with DR were found in all samples,and the A allelic gene and AA gene type were the risk genes of DR (A versus C:OR=1.39,95％ CI=1.08-1.80,Z=2.52,P=0.01;AA versus CC+C/A:OR=1.53,95％ CI=1.05-2.24,Z=2.20,P=0.03;CC versus AA+C/A:OR=0.70,95％ CI=0.50-0.98,Z =2.10,P =0.04).When the other two studies which did not meet the HardyWeinberg Equilibrium were incorporated in a sensitivity analysis,the results were not materially altered.VEGF-2578 A allelic gene was the risk gene to Europeans with DR (OR =1.50,95％ CI=1.02-2.21,Z =2.07,P =0.04),but not among Asians in subgroup analysis (P＞0.05).No significant publication bias was found.Conclusions The Meta analysis demonstrates that VEGF-2578C/A is associated with DR in Europeans but not in Asians.Further case-control studies based on larger sample size are still needed,especially in Asians.

The carcinogenesis and development is a progress of multi-gene alterations in the human gastric cancer (HGC)．In order to determine the relation between the aberration of these genes and gastric cancer，we chose c-met (7q31)、hMLH1 (3p21)、E-cadherin (16q22.1) and HLA loci DQA1、DR2、DR3、DR4、DR7、DR9 and detected their changes in 32 tumor specimens of intestinal type HGC and 4 cell lines of gastric cancer by performing analysis of SSP/PCR、PCR/SSCP and MSI technigues．Our data show that none point mutation was detected in c-met gene．We examined two microsatellites loci D3S1298 and D3S1561 in hMLH1 gene and detected that 6 cases retain MSI (Microsatellite Instability) and 2 cases of LOH (Loss of Heterozygosity) at D3S1298 and 2 cases of MSI at D3S1561．We also examined E-cadherin gene at two microsatellites loci D16S3083 and D16S3095 close to the gene and detected that 5 cases retain MSI and 1 case of LOH at D16S3083 and no change at D16S3095．The point mutation incidence of HLA-DR4 loci is 9/20 (45%)，higher than the other loci in HLA-Ⅱ．High frequent deletion，expression deregulation and methylation of mts1/p16 gene were detected in cell lines and solid tumors from human gastric cancer patients． 　　Our data showed that the point mutation of c-met gene is not the main pattern of alteration in intestinal type HGC that is consistent with the previous results．E-cadherin and hMLH1 are related to intestinal type HGC but whether they are susceptibility gene still need further study．The point mutation of the HLA-Ⅱ loci DR4 is closely related to intestinal type HGC．Methylation of mts1/p16 gene 5 CpG island might be plays an important role in the carcinogenesis in HGC．

The paper is to investigate eco-design flaws in equipments for medical simulation training and explore methods to improve. The eco-design flaws in equipments for medical simulation training were elaborated from the aspects of accessories, modules, model volumes, recycling of waste equipments, and production materials. The improved methods of the flaws were demonstrated. The designs of equipments for medical simulation training can be more environment friendly by means of getting rid of unnecessary accessories, developing replaceable modules for manikin models, curtailing volumes of equipments, recycling waste equipment and using degradable production materials. As the tendency of being environment friendly in medical equipments becomes increasingly obvious, the eco-friend merits must be considered by multi-objective optimizations in the processes of design, manufacture, and employment of equipments for medical simulation training.