Liver transplantation for acute-on-chronic liver failure

Purpose: To evaluate the outcome of liver transplantation for acute-on-chronic liver failure. Patients and methods: From November 1991 to December 2007, 517 patients underwent liver transplantation at Queen Mary Hospital, Hong Kong. Among them, 149 had acute-on-chronic liver failure as defined in the recent Asian Pacific Association for the Study of Liver Consensus Meeting. Their clinical data were reviewed and their survival outcomes were compared with those of patients who underwent liver transplantation for fulminant hepatic failure and for cirrhosis only in the same period. Results: The patients with acute-on-chronic liver failure included 50 patients having acute exacerbation of chronic hepatitis B and 99 cirrhotic patients with acute deterioration. Their median model for end-stage liver disease scores were 35 and 37, respectively. Preoperative infection (35%), hepatorenal syndrome (38%), and respiratory failure (28.8%) were common. One hundred and three patients received living donor liver grafts and 46 patients received deceased donor liver grafts. The hospital mortality rate was 4.7%. The 5-year survival rates were 93.2% for patients with acute exacerbation of chronic hepatitis B and 90.5% for cirrhotic patients with acute deterioration. The results were similar to those of the patients with fulminant hepatic failure (n = 37) and the patients having cirrhosis only (n = 301). Conclusions: Liver transplantation for acute-on-chronic liver failure is life-saving, and the survival rates it attains are similar to those attained by transplantation for other liver conditions.published_or_final_versionSpringer Open Choice, 21 Feb 201

Impacts of household sources on air pollution at village and regional scales in India

Approximately 3 billion people worldwide cook with solid fuels, such as wood, charcoal, and agricultural residues. These fuels, also used for residential heating, are often combusted in inefficient devices, producing carbonaceous emissions. Between 2.6 and 3.8 million premature deaths occur as a result of exposure to fine particulate matter from the resulting household air pollution (Health Effects Institute, 2018a; World Health Organization, 2018). Household air pollution also contributes to ambient air pollution; the magnitude of this contribution is uncertain. Here, we simulate the distribution of the two major health-damaging outdoor air pollutants (PM_(2.5) and O₃) using state-of-the-science emissions databases and atmospheric chemical transport models to estimate the impact of household combustion on ambient air quality in India. The present study focuses on New Delhi and the SOMAARTH Demographic, Development, and Environmental Surveillance Site (DDESS) in the Palwal District of Haryana, located about 80 km south of New Delhi. The DDESS covers an approximate population of 200 000 within 52 villages. The emissions inventory used in the present study was prepared based on a national inventory in India (Sharma et al., 2015, 2016), an updated residential sector inventory prepared at the University of Illinois, updated cookstove emissions factors from Fleming et al. (2018b), and PM_(2.5) speciation from cooking fires from Jayarathne et al. (2018). Simulation of regional air quality was carried out using the US Environmental Protection Agency Community Multiscale Air Quality modeling system (CMAQ) in conjunction with the Weather Research and Forecasting modeling system (WRF) to simulate the meteorological inputs for CMAQ, and the global chemical transport model GEOS-Chem to generate concentrations on the boundary of the computational domain. Comparisons between observed and simulated O₃ and PM_(2.5) levels are carried out to assess overall airborne levels and to estimate the contribution of household cooking emissions. Observed and predicted ozone levels over New Delhi during September 2015, December 2015, and September 2016 routinely exceeded the 8 h Indian standard of 100 µg m⁻³, and, on occasion, exceeded 180 µg m⁻³. PM_(2.5) levels are predicted over the SOMAARTH headquarters (September 2015 and September 2016), Bajada Pahari (a village in the surveillance site; September 2015, December 2015, and September 2016), and New Delhi (September 2015, December 2015, and September 2016). The predicted fractional impact of residential emissions on anthropogenic PM_(2.5) levels varies from about 0.27 in SOMAARTH HQ and Bajada Pahari to about 0.10 in New Delhi. The predicted secondary organic portion of PM_(2.5) produced by household emissions ranges from 16 % to 80 %. Predicted levels of secondary organic PM_(2.5) during the periods studied at the four locations averaged about 30 µg m⁻³, representing approximately 30 % and 20 % of total PM_(2.5) levels in the rural and urban stations, respectively

Multiple Gene Polymorphisms in the Complement Factor H Gene Are Associated with Exudative Age-Related Macular Degeneration in Chinese

PURPOSE. Variants in the complement factor H (CFH) gene have been shown to be strongly associated with age-related macular degeneration (AMD). In this study, sequence alterations in CFH were investigated in 163 Chinese patients with exudative AMD and 155 unrelated Chinese control subjects. METHODS. All the 22 CFH exons, intron-exon boundaries, and promoter sequences were screened by polymerase chain reaction and DNA sequencing. RESULTS. Fifty-eight sequence changes, 42 of them novel, were identified. Six SNPs with an allele frequency Ͼ30% were significantly associated with exudative AMD. SNP rs3753396 was novel; the rest had been reported: rs3753394, rs551397, rs800292, rs2274700, and rs1329428. Two haplotype blocks were constructed. The TG haplotype for rs551397 and rs800292 was the major haplotype that conferred a significantly increased susceptibility to exudative AMD (P corr ϭ 0.0001, OR ϭ 1.91, 95% CI ϭ 1.36 -2.68). CONCLUSIONS. The findings support prior evidence that the CFH gene is one of the AMD-associated genes. There is a different distribution pattern of CFH variants in the Chinese compared with other populations. Individual SNP and haplotype analyses revealed that the ancient alleles at the 5Ј end of CFH contribute to an increased susceptibility to exudative AMD. (Invest Ophthalmol Vis Sci. 2008;49:3312-3317) DOI:10.1167/iovs.07-1517 A ge-related macular degeneration (AMD; MIM 603075; Mendelian Inheritance in Man) is a major cause of irreversible visual impairment and blindness in people older than 65 years in developed countries. 1,2 The occurrence of AMD is pan ethnic, and a high prevalence AMD has been reported in the elderly Chinese population. 5 Therefore, a greater understanding of the primary pathophysiology is needed to advance treatment and preventive measures. The etiology of AMD is complex and multifactorial, probably resulting from interactions between environmental and multigenetic factors. 6 Genetic association studies have revealed that single nucleotide polymorphisms (SNPs) in the complement factor H gene (CFH; MIM 134370; e.g., Tyr402His) are significantly associated with susceptibility to AMD. 25 A fine-scale linkage disequilibrium mapping of AMD in the CFH region detected a point location of a causal variant between exons 1 and 2 of CFH other than exon 9 for Tyr402His. MATERIALS AND METHODS Patients and Control Subjects 21 Also recruited and given complete ophthalmic examinations were 155 unrelated control subjects, 72 men and 83 women ranging in age at recruitment from 60 to 99 years (mean Ϯ SD, 73.1 Ϯ 6.5 years). They matched the patients by age and gender and had no sign of AMD or other eye diseases, except mild myopia or senile cataract. The study protocol was approved by the Ethics Committee on Human Research, the Chinese University of Hong Kong. All the procedures used conformed to the tenets of the Declaration of Helsinki. Informed consent was obtained from all study subjects after explanation of the nature of the study. Sample Collection, PCR Amplification, DNA Sequencing, and SNP Genotyping Venous blood was obtained from each study subject, and genomic DNA was extracted with a DNA blood kit (QIAamp; Qiagen, Hilden, Germany). The promoter sequence up to Ϫ867 upstream and all coding sequences of the CFH gene, including intron-exon boundaries, were screened for sequence alterations. Primers were generated based on the GenBank sequence of CFH (NM_000186.2; http://www.ncbi. nlm.nih.gov/Genbank; provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD). PCR was performed on a thermal cycler (model 9700; Applied Biosystems, Inc. [ABI], Foster City, CA) with optimized protocols 27 Statistical Analysis Hardy-Weinberg equilibrium (HWE) for each polymorphism was tested by 2 test. Allele or genotype frequencies between cases and control subjects were compared by 2 analysis or the Fisher exact test. The odds ratios (ORs) of the alleles and haplotypes were estimated by 2 test (SPSS ver.15.0; SPSS Inc., Chicago, IL). Population attributable risk (PAR) of the risk genotype was calculated with the formula f(R Ϫ 1)/R, where f is the faction of cases with the risk genotype and R is the measure of OR 8 . A pair-wise linkage disequilibrium (LD, DЈ) estimation between polymorphisms with a minor allele frequency (MAF) Ͼ 1%, and EM-based haplotype association analysis were performed with Haploview (ver. 3.32, from http://www.broad.mit.edu/mpg/ haploview/ provided in the public domain by the Broad Institute, Massachusetts Institute of Technology, Cambridge, MA). For multiple comparison, probabilities were corrected by permutation test (iterations, 10,000). Statistical significance was defined as a corrected P (P corr ) Ͻ 0.05. RESULTS CFH Variants in the Study Subjects A total of 58 sequence variations were identified, all of which followed Hardy Weinberg Equilibrium Six of the seven common variants Six SNPs were identified in the promoter, all supported decreased susceptibility to AMD Haplotype Association Analysis LD analysis revealed extension of LD throughout the CFH gene. We included SNPs with MAF Ͼ 5% and two missense changes, rs1061170 (Tyr402His) and Val837Ile, in our haplotype association analysis. Two distinct haplotype blocks were detected The haplotypes H3 and H4, which were defined by all six AMD-associated SNPs, conferred significantly reduced or increased AMD susceptibility (H3: OR ϭ 0.56, 95% CI ϭ 0.39 -0.80; H4: OR ϭ 1.63, 95% CI ϭ 1.19 -2.23). When a G allele of rs1065489 (Asp936Glu) was included in these two haplotypes, the H5, which contained all the alleles in H3, remain significantly associated with the disease (P corr ϭ 0.0012). However, when a G allele or a T allele was added to the H4, the newly constructed H6 and H7 were no longer AMD associated (P corr ϭ 0.052 and 0.177, respectively). We constructed two-allele haplotypes by using rs800292 (Val62Ile) with the uncommon SNPs rs1061170 (Tyr402His) and Val837Ile, to investigate the effects of the minor variants. H10 and H11, containing a T allele of rs1061170 (Tyr402His), remained significantly associated with AMD. However, the haplotypes containing a C allele of rs1061170 DISCUSSION Although the pathogenesis of exudative AMD has not been definitively elucidated, studies in the past few years have revealed important information on its genetic basis. Polymorphisms in the CFH gene have been shown to be AMD associated in different ethnic groups, although there are obvious differences in the occurrence of disease-susceptible SNPs between Caucasian and Oriental populations. 26 mapped a point location for a causal variant between exons 1 and 2, which approximates block 1 in our present study, suggesting that the 5Ј region of the CFH (N-terminal of factor H) is commonly associated with AMD in both Chinese and Caucasians. We found haplotype block 2 spanning a region from exon 10 to intron 15 and containing SNP rs2274700 (Ala473Ala, exon 10), which have recently been shown to have a strong association with AMD in Caucasians and Japanese. Besides the haplotypes in the two haplotype blocks, the haplotypes defined by the six common SNPs (H3, H4) were also significantly associated with exudative AMD. However, when Asp936Glu (in exon 18) was included in the at-risk haplotype H4 for association analysis, the haplotypes H6 and H7, including a G or a T allele respectively, were no longer significantly associated with the disease (P corr Ͼ 0.05). Thus, Asp936Glu is less likely to be a risk factor for exudative AMD in Chinese individuals, indicating the C-terminal of the factor H contributes less than other parts of the polypeptide to the development of exudative AMD. This observation is consistent with the findings of Hageman et al

Disease Burden of Clostridium difficile Infections in Adults, Hong Kong, China, 2006-2014

Cross-sectional studies suggest an increasing trend in incidence and relatively low recurrence rates of Clostridium difficile infections in Asia than in Europe and North America. The temporal trend of C. difficile infection in Asia is not completely understood. We conducted a territory-wide population-based observational study to investigate the burden and clinical outcomes in Hong Kong, China, over a 9-year period. A total of 15,753 cases were identified, including 14,402 (91.4%) healthcare-associated cases and 817 (5.1%) community-associated cases. After adjustment for diagnostic test, we found that incidence increased from 15.41 cases/100,000 persons in 2006 to 36.31 cases/100,000 persons in 2014, an annual increase of 26%. This increase was associated with elderly patients, for whom incidence increased 3-fold over the period. Recurrence at 60 days increased from 5.7% in 2006 to 9.1% in 2014 (p<0.001). Our data suggest the need for further surveillance, especially in Asia, which contains ≈60% of the world’s population

Constitutively Nuclear FOXO3a Localization Predicts Poor Survival and Promotes Akt Phosphorylation in Breast Cancer

Background: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. Methodology/Principal Findings: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway. Conclusions/Significance: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models. © 2010 Chen et al.published_or_final_versio

Heart Rate Variability Dynamics for the Prognosis of Cardiovascular Risk

Statistical, spectral, multi-resolution and non-linear methods were applied to heart rate variability (HRV) series linked with classification schemes for the prognosis of cardiovascular risk. A total of 90 HRV records were analyzed: 45 from healthy subjects and 45 from cardiovascular risk patients. A total of 52 features from all the analysis methods were evaluated using standard two-sample Kolmogorov-Smirnov test (KS-test). The results of the statistical procedure provided input to multi-layer perceptron (MLP) neural networks, radial basis function (RBF) neural networks and support vector machines (SVM) for data classification. These schemes showed high performances with both training and test sets and many combinations of features (with a maximum accuracy of 96.67%). Additionally, there was a strong consideration for breathing frequency as a relevant feature in the HRV analysis

Impact of genetic loci identified in genome-wide association studies on diabetic retinopathy in Chinese patients with type 2 diabetes

© 2016, Association for Research in Vision and Ophthalmology Inc. All rights reserved.PURPOSE. Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2DM). Genome-wide association studies (GWAS) had identified novel DRsusceptibility genetic variants in various populations. We examined the associations of these DR-associated single nucleotide polymorphisms (SNPs) with severe DR in a Chinese T2DM cohort. METHODS. Cross-sectional case-control studies on sight-threatening DR (STDR) and proliferative DR (PDR) were performed. We genotyped 38 SNPs showing top association signals with DR in previous GWAS in 567 STDR cases, including 309 with PDR and 1490 non-DR controls. Multiple logistic regression models with adjustment for conventional risk factors, including age, sex, duration of diabetes, and presence of hypertension, were employed. RESULTS. The strongest association was found at INSR rs2115386, an intronic SNP of INSR: Padjusted = 9.13 × 10-4 (odds ratio [OR],1.28; 95% confidence interval [95%CI], 1.11-1.48) for STDR, and Padjusted = 1.12 × 10-4 (OR [95%CI],1.44 [1.20-1.74]) for PDR. rs599019 located downstream of COLEC12 (Padjusted = 0.019; OR [95%CI],1.19 [1.03-1.38]) and rs4462262 located at an intergenic region between ZWINT and MRPS35P3 (Padjusted = 0.041; OR [95%CI],1.38[1.01-1.89]) also were significantly associated with STDR, but not with PDR alone. On the other hand, MYT1L-LOC729897 rs10199521 (Padjusted = 0.022; OR [95%CI],1.25 [1.03-1.51]) and API5 rs899036 (Padjusted = 0.049; OR [95%CI],1.36 [1.00-1.85]) showed significant independent associations only with PDR. Similar results were obtained when hemoglobin A1c also was included in the adjustment models. CONCLUSIONS. We demonstrated the significant and independent associations of several GWAS-identified SNPs with DR in Chinese T2DM patients with severe DR. The findings on INSR rs2115386 are supportive of the role of insulin resistance, or the compensatory hyperinsulinemia, in the pathogenesis of DR.Link_to_subscribed_fulltex

Heart Rate Variability Dynamics for the Prognosis of Cardiovascular Risk

Statistical, spectral, multi-resolution and non-linear methods were applied to heart rate variability (HRV) series linked with classification schemes for the prognosis of cardiovascular risk. A total of 90 HRV records were analyzed: 45 from healthy subjects and 45 from cardiovascular risk patients. A total of 52 features from all the analysis methods were evaluated using standard two-sample Kolmogorov-Smirnov test (KS-test). The results of the statistical procedure provided input to multi-layer perceptron (MLP) neural networks, radial basis function (RBF) neural networks and support vector machines (SVM) for data classification. These schemes showed high performances with both training and test sets and many combinations of features (with a maximum accuracy of 96.67%). Additionally, there was a strong consideration for breathing frequency as a relevant feature in the HRV analysis