Relationship between HLA-DP gene polymorphisms and the risk of hepatocellular carcinoma: a meta-analysis.

The association between the HLA-DP single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 and hepatocellular carcinoma (HCC) has been reported, but results have been inconclusive and controversial. Therefore, to investigate the relationship between these HLA-DP SNPs and HCC susceptibility, a meta-analysis of studies published before January 2014 was carried out using the PubMed and Google Scholar databases. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated for HLA-DP alleles, and for co-dominant, dominant, and recessive genotype models of each SNP, based on fixed- or random-effects models. A total of nine studies from six published articles were included. The association study between rs3077 and HCC susceptibility was performed in four independent comparisons that contained 1871 cases with hepatitis B virus (HBV)-related HCC and 3207 carriers with persistent HBV. Association between rs9277535 and HCC susceptibility was examined in five separate comparisons that contained 2017 cases and 3930 carriers. Our analysis indicated a significant association of rs3077 and rs9277535 with HCC susceptibility, suggesting that rs3077 might act beneficially against HCC susceptibility (A vs G: OR = 0.884, 95%CI = 0.803-0.973, P = 0.012; GA vs GG: OR = 0.842, 95%CI = 0.733-0.967, P = 0.015; AA+GA vs GG: OR = 0.848, 95%CI = 0.744-0.968, P = 0.014), and that rs9277535 might promote HCC susceptibility (AA vs GA: OR = 1.202, 95%CI = 1.011-1.428, P = 0.037). This study suggested that HLA-DP rs3077 and rs9277535 polymorphisms are associated with HCC susceptibility in the Asian population.

New prognostic model for adult-to-adult living donor liver transplant recipients.

Adult-to-adult living donor liver transplantation (A-A LDLT) is an effective therapeutic modality to treat patients with end-stage liver disease. The aims of this study were to identify recipient characteristics of A-A LDLT seeking to determine variables that affected patient survival. We retrospectively examined a cohort of 154 consecutive A-A LDLT recipients with end-stage liver disease in our center over 4 years. All donors volunteered to give their partial livers with written consent. There were no organs from prisoners and no prisoner subjects. The overall survivals at 1, 2, 3, 6, 12, 24, 36, and 48 months were 93.5%, 90.9%, 88.9%, 86.3%, 80%, 65.6%, 63.8%, and 63.8%, respectively. About 31 pre- and intraoperative factors were analyzed to identify correlations with posttransplant survival using the Cox proportional-hazards regression model. Recipient age, serum creatinine concentration, intraoperative blood loss, and graft-to-recipient weight ratio were significant predictors of survival after transplantation. The prognostic index model, which was calculated by combining these four prognostic values with their regression coefficients, showed a c-statistic of 0.706 (95% confidence interval [CI] = 0.621-0.792) compared with the Model for End-stage Liver Disease value of 0.546 (95% CI = 0.350-0.558). There was a significant difference between the predictions achieved with the two models (P = .012). In conclusion, selecting younger recipients, better pretransplant renal condition, reduced intraoperative blood loss, and graft-to-recipient size match appeared to be advantageous to achieve better survivals among patients undergoing A-A LDLT.

Comparative study of serology and histology based detection of Helicobacter pylori infections: a large population-based study of 7,241 subjects from China.

Two detection methods for H. pylori infections, i.e. serological antibody titer measurements by Hp-ELISA and histological scoring by HE staining, have been compared to investigate the relationship between the diagnosis methods, to clarify the application scope of each diagnosis method and to determine its influencing factors. In the 7,241 subjects who participated in gastric cancer screening, H. pylori infection rate was 70.14% by the Hp-HE method and 41.87% by the Hp-ELISA method when 34EIU was recognized as the cut-off value. The IgG titers increased with the elevation of HE scores; however, the two methods were not closely correlated among those in different gastric disease status. Age, gender and drinking status did not have significant impact on the relationship between the two methods; however, smoking status seemed to significantly influence the correlation of the two diagnosis methods. In conclusion, it was necessary to reevaluate the cut-off value when using ELISA test kits in different population groups. In most cases, the results of two H. pylori infection diagnosis methods show high correlation. However, this relationship can be affected by smoking and gastric diseases status. Additionally, the dynamic change of H. pylori antibody titers is an indicator of gastric disease development.

Excision repair of adozelesin-N3 adenine adduct by 3-methyladenine-DNA glycosylases and UvrABC nuclease.

Adozelesin is a synthetic analog of the antitumor antibiotic CC-1065, which alkylates the N3 of adenine in the minor groove in a sequence-selective manner. Since the cytotoxic potency of a DNA alkylating agent can be modulated by DNA excision repair system, we investigated whether nucleotide excision repair (NER) and base excision repair (BER) enzymes are able to excise the bulky DNA adduct induced by adozelesin. The UvrABC nuclease and 3-methyladenine-DNA glycosylase, that exhibit a broad spectrum of substrate specificity, were selected as typical NER and BER enzymes, respectively. The adozelesin-DNA adduct was first formed in the radiolabeled restriction DNA fragment and its excision by purified repair enzymes was monitored on a DNA sequencing gel. The treatment of the DNA adduct with a purified UvrABC nuclease and sequencing gel analysis of cleaved DNA showed that UvrABC nuclease was able to incise the adozelesin adduct. The incision site corresponded to the general nuclease incision site. Excision of this adduct by 3-methyladenine-DNA glycosylases was determined following the treatment of the DNA adduct with a homogeneous recombinant bacterial, rat and human 3-methyladenine-DNA glycosylases. Abasic sites generated by DNA glycosyalses were cleaved by the associated lyase activity of the E. coli formamidopyrimidine-DNA glycosylase (Fpg). Resolution of cleaved DNA on a sequencing gel showed that the DNA glycosylase from different sources could not release the N3-adenine adducts. A cytotoxicity assay using E. coli repair mutant strains showed that E. coli mutant strains defective in the uvrA gene were more sensitive to cell killing by adozelesin than E. coli mutant strain defective in the alkA gene or the wild type. These results suggest that the NER pathway seems to be the major excision repair system in protecting cells from the cytotoxicity of adozelesin.

Estimation of burden of disease for smear-positive pulmonary TB and its infectivity.

The study investigated the burden of smear-positive pulmonary TB and its infectivity, using DALY (Disability-Adjusted Life Year) as an indicator. An assumed cohort of 2000 cases was set up based on the age-specific incidence of 794 newly registered smear positive cases of TB in Beijing in 1994. Prognostic trees and model diagrams of infectivity under natural history and DOTS (Direct Observed Treatment, Short-course) strategy were established according to the epidemiological evidence. The results show that 29.6% of DALYs would be neglected if the burden caused by the infectivity was not considered. The results also show that DOTS strategy may reduce 97.3% of the number of potential cases infected, 92.9% of DALYs related to TB-patients themselves, and 99.9% of DALYs caused by TB's infectivity as well.

Study on measuring burden of disease.

DALY (Disability Adjusted Life Years) was recommended as a new indicator to measure burden of disease (BOD). Although BOD combines information from both morbidity and mortality, it only reflects the burden from the patients themselves because of their illness or death. As a common indicator, BOD should not only include the burden from the patients, but also the burden to the society around the patients, such as the input and support from the society to the ill person, and the losses from the related events. The aim of this study is to explore the scope and the magnitude of the burden to the society using stroke as an example. Results show that the burden due to time lost for caring for patients in hospitals accounts for 2.4% of total BOD (in a narrow sense), which indicates that BOD may be underestimated if the burden to the society is ignored.

Cost effectiveness of DOTS and non-DOTS strategies for smear-positive pulmonary tuberculosis in Beijing.

The cost-effectiveness of DOTS (Directly Observed Treatment, short course) and non-DOTS strategies for smear-positive pulmonary tuberculosis in Beijing was evaluated. Cost calculation was based on the expenses of drugs, chest X-ray films, sputum smears and cultures for the patients. Effectiveness of the intervention was assessed in two aspects: direct benefits to the patients treated and indirect benefits to the others through reduced transmission of tuberculosis; disability adjusted life of year (DALY) was used as an index. The results showed that one DALY could be saved with 45.7 Yuan by DOTS and 471.4 Yuan by non-DOTS. DOTS is a good control strategy for smear-positive tuberculosis.

Child mortality patterns in rural areas of Anhui and Henan provinces in China, 1990.

County-based IMR and U5MR in Anhui and Henan provinces in China were estimated and analyzed by using the 1990 Census Data. Census was conducted on July 1, 1990, the number of deaths only occurred in the first half year of 1990 was collected. In order to obtain the total population and total number of deaths in the same year, the total number of deaths in each age-sex group for the whole 1990 was then estimated by taking the death number in the first half of 1990 as the base and multiplying a coefficient, which varied in different age-sex-region groups. Two major adjustments for some possible under-reporting cases in female birth and infant death were made. If the sex ratio at age 0 in some counties was beyond 1.2, then it was taken as 1.15 for rural counties and 1.10 for urban cities, which were the estimates of sex ratios for the children at age 5 in the national 1% Population Sampling Survey in 1995. The adjustment for IMR were made by comparing the segment of the county lift table from age 15 through 59 with that from the same age groups in the international and Chinese Model Life Tables. The IMR in the county life table would be substituted by the one in the closest Model Life Talbe, if it was less than in the latter. The findings of the analysis may be summarized as follows: (i) Total county-based IMR and U5MR were 33.4 per 1,000 and 41.4 per 1,000 respectively, with great variations between urban cities (25.4 per 1,000 for IMR and 31.4 per 1,000 for U5MR) and rural counties (35.1 per 1,000 for IMR and 43.6 per 1,000 for U5MR). There were also significant differences in child mortality between nationally identified poor counties and other counties in rural areas. In the poor counties the total IMR was 40.7 per 1,000 living births in average while in non-poor counties it was only 33.2 per 1,000 in average (P < 0.05). The U5MR in poor counties was 25 percent higher than in non-poor counties (51.5 vs 40.9 per 1,000 living births). (ii) Statistically significant correlation between child mortality and socio-economic variables was revealed from the data set, among which gross social economic products per capita was found to have the strongest relationship with child mortality. The negative correlation was found between child mortality and a set of so-called 'rich' variables including the gross social products, gross agricultural products, gross industrial products and the proportions of high-educated population at county level, whereas the positive correlation was found between child mortality and a set of 'poor' variables, such as proportions of residents with lower level of education and illiteracy rate. (iii) Differences in child mortality between these two provinces were found, which were identical to the trends of differences in socio-economic indicators between them. Lower child mortality proved to be associated with better socio-economic conditions (higher per capita products, higher proportions of residents with higher level of education, lower proportion of less educated people and illiteracy) in province Henan. (iv) A simple linear regression model was developed separately for Henan and Anhui to predict the IMR and U5MRs in each stage of economic development, where the dependent variables were the logarithm of IMR and U5MR, and the independent variables were the quintiles of the output value of gross products (GOP). It was found that at the first quintile, which was equivalent to 800 yuan of GOP in average, the predicted IMR and U5MR would reach 40 per 1,000 and 51 per 1,000 respectively. It would decline to 38 per 1,000 for IMR and 47 per 1,000 for U5MR in the second lowest quintile. Dramatic drop of child mortality was found between the second quintile and the third quintile, where 6 per 1,000 decline would occur for both IMR and U5MR. The decline would continue subsequently, but slower. The prediction of child mortality in rural counties could be used as a reference to assess counties at different stages of socio-

Competing risk model and its application in assessing the progression of pneumoconiosis.

In this paper a more general competing risk model is developed for dealing with censored data with multiple outcomes, as the result of the competition with other risk factors. More reasonable results are obtained by applying the model in the probability and the average duration of pneumoconiosis progress from stage I to stage II in Shanxi Province.

Trends in health services utilization in eight provinces in China, 1989-1993.

Continued pursuit of market-oriented reforms in China seems to have resulted in increasing income disparities. This has raised concerns about possible declines in the use of health services by the poor. Using data from three waves of the China Health and Nutrition Survey (1989, 1991, 1993), we examine whether people age 20-45 in eight provinces became less likely to seek care when ill. We carried out three probit estimations of seeking care when ill; the predictor variables include individual and workplace characteristics, a measure of the severity of illness and community level factors. Health care is broadly defined to include basic level clinics as well as urban hospitals. We find no evidence that health care utilization is decreasing. Rather, for people in a community survey reporting mainly mild or moderate illness, health care continues to be accessible. We consider possible limits of our study and discuss extensively the implications of the use of illness reports from the three cross-sectional surveys as health status indicators.

An evaluation on smoking-induced health costs in China (1988-1989).

A study on smoking-attributable health economic costs in China was conducted from 1988-1992, in which three major categories of chronic diseases, diseases of cancer, diseases of circulatory system, and diseases of respiratory system were included. A prevalence-based method which estimated the cumulative effect of cigarette smoking during the past 20-30 years was used. The results show that in 1989, the total smoking-attributable economic costs to health sectors in China were about 27.1 billion of Chinese Yuan, including about 7 billion Yuan in direct medical costs and 20 billion Yuan in indirect costs, which include indirect morbidity costs and indirect mortality costs. The relatively low direct costs reflected the low medical costs at hospitals in China at that time. And the high proportion of indirect costs relative to the total costs shows the high potential years of life lost due to cigarette smoking. The results also show the heavier health burden in urban areas than in rural areas, reflecting the worse situation in urban China at nowadays. But if considering that almost 80% of the Chinese are rural farmers with the higher smoking prevalence and relatively shorter history of manufactured cigarette smoking than their urban counterparts, the very frightful situation due to cigarette smoking would be for China in the next century.

Mutational analysis of the VirG protein, a transcriptional activator of Agrobacterium tumefaciens virulence genes.

The VirG protein of Agrobacterium tumefaciens is required in conjunction with the VirA protein for transcriptional activation of the virulence (vir) genes in response to plant phenolic compounds. These proteins are members of a family of two component regulatory systems. vir genes are activated via a cascade of phosphorylation reactions involving a specific aspartic acid residue of the VirG protein. We have conducted a mutational analysis of the VirG protein. By mutating conserved and nonconserved aspartic acid residues in the N-terminal domain, we demonstrated that two of three conserved aspartic acid residues located in two different regions are important for the phosphorylation of VirG by VirA phosphate. A third conserved N-terminal region was also shown to be critical for the biological function of VirG as a transcriptional activator. The identification of phosphorylatable but biologically inactive mutated VirG proteins suggests that not only phosphorylation but also a conformational change is necessary for its activity. We further demonstrated that phosphorylation is not required for sequence-specific binding to a vir gene regulatory sequence (vir box) and that the C-terminal domain is sufficient for DNA binding. The data support the model of a two-domain structure for the VirG protein and demonstrate that the sequence homologies to other two-component regulatory systems reflect both functional and structural homologies.

Phosphorylation of the VirG protein of Agrobacterium tumefaciens by the autophosphorylated VirA protein: essential role in biological activity of VirG.

Agrobacterium tumefaciens virulence genes are induced by plant signals through the VirA-VirG two-component regulatory system. The VirA protein is a membrane-spanning sensor molecule that possesses an autophosphorylating activity, and the VirG protein is a sequence-specific DNA-binding protein. In this report, we demonstrate that the VirG protein is phosphorylated by the VirA protein and that the phosphate is directly transferred from the phosphorylated VirA molecule (phosphohistidine) to the VirG protein. The chemical stability of the phospho-VirG bond suggested that the VirG protein was phosphorylated at the aspartate and/or glutamate residue. The phosphorylated VirG protein was reduced with tritiated sodium borohydride and subjected to proteolytic digestion with the Achromobacter protease I enzyme. The resulting peptide fragments were separated by C8 reversed-phase high-pressure liquid chromatography, and the tritium-labeled peptide was sequenced. Amino acid sequence data showed that the aspartate residue at position 52 was the only site phosphorylated. Changing this aspartate into asparagine resulted in a nonphosphorylatable and biologically nonfunctional gene product. As a control, a randomly chosen aspartate was changed into an asparagine (position 72), and no effect on its phosphorylation or biological activity was observed. Unlike its homologs, including CheA-CheY, EnvZ-OmpR, and NtrB-NtrC, the phospho-VirG molecule was very stable in vitro. The possible implications of these observations and the function of VirG phosphorylation in vir gene activation are discussed.

The regulatory VirG protein specifically binds to a cis-acting regulatory sequence involved in transcriptional activation of Agrobacterium tumefaciens virulence genes.

Virulence genes of Agrobacterium tumefaciens are induced in parallel in the presence of plant phenolic compounds such as acetosyringone and the two regulatory vir genes virA and virG. In this study we identified a cis-acting regulatory sequence in the 5'-noncoding region of the virE operon that is essential for this activation. To do this, we constructed a series of deletion mutants by using exonuclease Bal 31. Western blot (immunoblot) analysis showed that the 70 base pairs upstream of the transcriptional start site were sufficient for full virE gene induction. A conserved dodecadeoxynucleotide sequence (vir box), which was previously identified in the nontranscribed sequences of all vir genes, was located at 5' end of the minimum required promoter sequence. Deletion of this vir box only completely abolished induction of the virE gene. This demonstrates that the vir box functions as an upstream regulatory sequence. To study the role of the VirG protein in the activation process, we overproduced the native-sized VirG protein in Escherichia coli by fusing the lacZ' start codon ATG with the second virG codon AAA using site-directed mutagenesis. The VirG protein was purified and renatured from E. coli and was shown to bind to a specific sequence in two vir gene promoters. Footprinting analysis of the virE and virB promoters identified the 12-base-pair vir box as the VirG-binding core sequence.

Genes responsible for the supervirulence phenotype of Agrobacterium tumefaciens A281.

Agrobacterium tumefaciens A281 induces large, rapidly appearing tumors on a variety of plants and has a wider host range than other strains of A. tumefaciens. By using Tn3HoHo1 transposon mutagenesis and complementation analysis, a 2.5-kilobase DNA fragment which is responsible for the supervirulence phenotype was identified in the virulence (vir) region of the Ti plasmid. This fragment contains the virG locus, as well as the 3' end of the virB operon. A clone of this fragment conferred the supervirulence phenotype on A348, a nonsupervirulent strain. The increased virulence was correlated with an increased expression of vir genes, which could be achieved by introducing an extra copy of the transcriptional activator virG or the supervirulence region for maximum virulence. The virulence of the supervirulent strain A281 could be increased even further if the entire virB operon was added in addition to the virG operon. A plasmid, pToK47, containing virB and virG increased the virulence of all A. tumefaciens strains into which the plasmid was introduced. These data suggest that a highly virulent binary vector system can be constructed which might prove especially useful in the transformation of certain higher plants.