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1.  Truth-telling to the patient, family, and the sexual partner: a rights approach to the role of healthcare providers in adult HIV disclosure in China 
AIDS care  2015;27(0 1):83-89.
Patients’ rights are central in today’s legislation and social policies related to health care, including HIV care, in not only Western countries but around the world. However, given obvious socio-cultural differences it is often asked how or to what extent patients’ rights should be respected in non-Western societies such as China. In this paper, it is argued that the patients’ rights framework is compatible with Chinese culture, and that from the perspective of contemporary patient rights healthcare providers have a duty to disclose truthfully the diagnosis and prognosis to their patients, that the Chinese cultural practice of involving families in care should – with consent from the patient – be promoted out of respect for patients’ rights and well-being, and that healthcare providers should be prepared to address the issue of disclosing a patient’s HIV status to sexual partner(s). Legally, the provider should be permitted to disclose without consent from the patient but not obliged to in all cases. The decision to do this should be taken with trained sensitivity to a range of ethically relevant considerations. Post-disclosure counseling or psychological support should be in place to address the concerns of potentially adverse consequences of provider-initiated disclosure and to maximize the psychosocial and medical benefits of the disclosure. There is an urgent need for healthcare providers to receive training in ethics and disclosure skills. This paper concludes also with some suggestions for improving the centerpiece Chinese legislation, State Council’s “Regulations on AIDS Prevention and Control” (2006), to further safeguard the rights and well-being of HIV patients.
doi:10.1080/09540121.2015.1071772
PMCID: PMC4685610  PMID: 26616129
HIV disclosure; patients’ rights; privacy; cultural differences; family; China; partner notification
2.  Load balancing prediction method of cloud storage based on analytic hierarchy process and hybrid hierarchical genetic algorithm 
SpringerPlus  2016;5(1):1989.
With the continuous expansion of the cloud computing platform scale and rapid growth of users and applications, how to efficiently use system resources to improve the overall performance of cloud computing has become a crucial issue. To address this issue, this paper proposes a method that uses an analytic hierarchy process group decision (AHPGD) to evaluate the load state of server nodes. Training was carried out by using a hybrid hierarchical genetic algorithm (HHGA) for optimizing a radial basis function neural network (RBFNN). The AHPGD makes the aggregative indicator of virtual machines in cloud, and become input parameters of predicted RBFNN. Also, this paper proposes a new dynamic load balancing scheduling algorithm combined with a weighted round-robin algorithm, which uses the predictive periodical load value of nodes based on AHPPGD and RBFNN optimized by HHGA, then calculates the corresponding weight values of nodes and makes constant updates. Meanwhile, it keeps the advantages and avoids the shortcomings of static weighted round-robin algorithm.
doi:10.1186/s40064-016-3619-x
PMCID: PMC5114220  PMID: 27917360
Radial basis function neural network (RBFNN); Analytic hierarchy process (AHP); HHGA (hybrid hierarchical genetic algorithm); Load balancing; Cloud storage; Group decision
3.  Occult HBV Infection in Immunized Neonates Born to HBsAg-Positive Mothers: A Prospective and Follow-Up Study 
PLoS ONE  2016;11(11):e0166317.
Objective
Occult HBV infection (OBI) has been reported in infants born to HBsAg-positive mothers despite immunization. This study aims to determine the maintenance of this status in a prospective birth cohort.
Methods
A total of 158 neonates born to HBsAg-positive mothers were enrolled. All received passive-active immunization against HBV according to a 0-1-6 schedule. Sera were collected at 7 months of age. Those diagnosed with OBI were serially followed up at 12, 24 and 36 months of age. HBV serological markers were determined by Abbott i2000 system. HBV DNA was quantitated by Abbott m2000 system. Standard PCR followed by direct sequencing were applied for mother-child HBV pairs. Homology and phylogenetic comparisons were done by BLAST and Mega 5.
Results
All the 158 neonates were HBsAg-negative and anti-HBs-positive at 7 months of age, and 32 (20.3%) of them were diagnosed with OBI, with a median HBV DNA level of 1.97 (1.20–3.71) log IU/mL. Of them, HBV DNA was positive in 25.0%, 21.9% and 7.7% at 12, 24 and 36 months of age, respectively. HBV DNA disappeared at one of the follow-up points in 31 neonates, however, rebounded to low levels in 6 of them thereafter. HBV DNA persisted at low levels during follow-ups in the other one neonate apart from the above 31. All remained negative for HBsAg. Only two (6.3%) neonates were positive for anti-HBc after 24 months of age. HBV showed close homology and phylogenetic relationships for mother-child pairs. S-escape mutant, G145R, was not discovered. The first vaccine dose within 6 hours of birth significantly reduced the occurrence of OBI (59.4% vs. 83.3%, p = 0.003).
Conclusions
HBV may be controlled in immunized neonates of HBsAg-positive mothers, after being diagnosed with OBI. Timely vaccination against HBV may provide the utmost protection. Long-term and close monitorings are needed.
doi:10.1371/journal.pone.0166317
PMCID: PMC5106040  PMID: 27835694
4.  The Association between the Lipids Levels in Blood and Risk of Age-Related Macular Degeneration 
Nutrients  2016;8(10):663.
Lipid metabolism may be involved in the pathogenic mechanism of age-related macular degeneration (AMD). However, conflicting results have been reported in the associations of AMD with blood lipids. We performed a meta-analysis including a total of 19 studies to evaluate associations between blood lipids and this disease. The result reported that the high level of high-density lipoprotein cholesterol (HDL-C) obtained with an increment of 1 mmol/L could result in a significantly increase in the AMD risk of approximately 18% (relative risk (RR), 1.18; 95% confidence interval (CI), 1.01 to 1.35; I2 = 53.8%; p = 0.007). High levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were significantly associated with a decreased risk of AMD (RRs ranging from 0.92 to 0.95; all p < 0.05). The stratified analysis based on AMD subtypes showed that these blood lipids were only significantly associated with the risk of early AMD (all p < 0.05). The association between the blood lipids and AMD risk did not differ substantially based on the other characteristics of the participants. A high HDL-C level was associated with an increased AMD risk, whereas participants with high TC, LDL-C, and TG concentrations may show a decreased risk for this disease. Further well-designed large studies are warranted to confirm the conclusions.
doi:10.3390/nu8100663
PMCID: PMC5084049  PMID: 27782072
age-related macular degeneration; blood lipids levels; HDL; meta-analysis
5.  The Association between LIPC rs493258 Polymorphism and the Susceptibility to Age-Related Macular Degeneration 
The purpose of this study was to evaluate the association of the hepatic lipase (LIPC) rs493258 polymorphism and susceptibility to age-related macular degeneration (AMD). A systematic search in PubMed, EMBASE, and ISI web of science databases was performed to identify eligible published studies without language restrictions up to April 2016. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) in different stages of AMD were estimated under different genetic models using meta-analytic methods. Seven studies comprising 20,559 cases and 17,200 controls met the inclusion criteria and were included in the meta-analysis. The LIPC rs493258 polymorphism showed a significant association with a lower risk of AMD under the allelic model (OR = 0.87, 95% CI = 0.84–0.90). Significant relationships between the variant and AMD were also observed in other genetic models (OR ranging from 0.71 to 0.86, all p < 0.05). Stratified analysis based on ethnicity found that LIPC rs493258 polymorphism had a significant association with the decreased risk of the disease in the Caucasian population, but not in the Asian population. For late AMD, significant associations of the rs493258 polymorphism with a lower risk of this disease were also observed in the allelic genetic model (OR = 0.87, 95% CI = 0.83–0.90). This meta-analysis demonstrates that the T allele in the LIPC rs493258 polymorphism was significantly associated with the risk of any and late AMD. The associations of the locus with early and late AMD risk in various populations need further exploration.
doi:10.3390/ijerph13101022
PMCID: PMC5086761  PMID: 27763569
age-related macular degeneration; LIPC; polymorphism; meta-analysis
6.  QiShenYiQi Attenuates Renal Interstitial Fibrosis by Blocking the Activation of β-Catenin 
PLoS ONE  2016;11(9):e0162873.
Chronic kidney disease (CKD) is becoming a worldwide problem. However, current treatment options are limited. In the current study we showed that QiShenYiQi (QSYQ), a water-ethanol extract from several Chinese medicines, is a potent inhibitor of renal interstitial fibrosis. QSYQ inhibited transforming growth factor-β1 (TGF-β1)-responsive α-smooth muscle actin (α-SMA), collagen I, and fibronectin up-regulation in obstructive nephropathy and cultured cells. Administration of QSYQ also inhibited the established renal interstitial fibrosis in obstructive nephropathy. Interestingly, QSYQ selectively inhibited TGF-β1-induced β-catenin up-regulation and downstream gene transcription. Taken together, our study suggests that QSYQ selectively inhibits TGF-β1-induced β-catenin up-regulation and might have significant therapeutic potential for the treatment of renal fibrosis.
doi:10.1371/journal.pone.0162873
PMCID: PMC5026381  PMID: 27636716
7.  Adequate vitamin D status is associated with the reduced odds of prevalent diabetic retinopathy in African Americans and Caucasians 
Background
Vitamin D status has been hypothesized to protect against development of diabetic retinopathy via its anti-inflammatory and anti-angiogenic properties. Additionally, in vitro and in vivo studies suggest vitamin D favorably influences blood pressure and blood glucose control, strong risk factors for diabetic retinopathy. We examined the association between vitamin D status and prevalent diabetic retinopathy in participants with diabetes from a population-based cohort.
Methods
Among participants in the Atherosclerosis Risk in Communities (ARIC) study with diabetes at visit 3 (1993–1995), 1339 (906 Caucasians, 433 African Americans) had serum 25-hydroxyvitamin (25[OH]D) concentrations assessed at visit 2 (1989–1992) and nonmydriatic retinal photographs taken at visit 3. Dietary intake of vitamin D was assessed at visit 1 (1987–1989). Logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for diabetic retinopathy by categories of season-adjusted 25(OH)D (<30 [referent], 30–<50, 50–<75 and ≥75 nmol/L), by quartile of vitamin D intake (IU/day), and use of vitamin D or fish oil supplements (yes/no). P for trend was estimated using continuous 25(OH)D or vitamin D intake. ORs were adjusted for race, and duration of diabetes. We further adjusted for HBA1c and hypertension to examine if 25(OH)D influenced diabetic retinopathy via its effects on either glycemic control or blood pressure.
Results
ORs (95 % CIs) for retinopathy, adjusted for race and duration, were 0.77 (0.45–1.32), 0.64 (0.37–1.10), and 0.39 (0.20–0.75), p for trend = 0.001, for participants with 25(OH)D of 30–<50, 50–<75, and ≥75 nmol/L, respectively. Further adjustment for hypertension minimally influenced results (data not show), but adjustment for HBA1c attenuated the OR among those with 25(OH)D ≥75 (0.47 [0.23–0.96], p for trend = 0.030). No statistically significant association was observed between vitamin D intake from foods or supplements and retinopathy.
Conclusions
25(OH)D concentrations ≥75 nmol/L were associated with lower odds of any retinopathy assessed 3 years later. We speculate this may be due in part to vitamin D’s influence on blood glucose control.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0434-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-016-0434-1
PMCID: PMC5009647  PMID: 27586865
Vitamin D; 25-hydroxy vitamin D; Diabetic retinopathy; Retinal diseases; Epidemiology; Cohort studies
8.  MicroRNAs: Novel immunotherapeutic targets in colorectal carcinoma 
World Journal of Gastroenterology  2016;22(23):5317-5331.
Colorectal carcinoma (CRC) is one of the most common types of cancer worldwide and the prognosis for CRC patients with recurrence or metastasis is extremely poor. Although chemotherapy and radiation therapy can improve survival, there are still numerous efforts to be performed. Immunotherapy is frequently used, either alone or in combination with other therapies, for the treatment of CRC and is a safe and feasible way to improve CRC treatment. Furthermore, the significance of the immune system in the biology of CRC has been demonstrated by retrospective assessments of immune infiltrates in resected CRC tumors. MicroRNAs (miRNAs) are short, non-coding RNAs that can regulate multiple target genes at the post-transcriptional level and play critical roles in cell proliferation, differentiation and apoptosis. MiRNAs are required for normal immune system development and function. Nevertheless, aberrant expression of miRNAs is often observed in various tumor types and leads to immune disorders or immune evasion. The immunomodulatory function of miRNAs indicates that miRNAs may ultimately be part of the portfolio of anti-cancer targets. Herein, we will review the potential roles of miRNAs in the regulation of the immune response in CRC and then move on to discuss how to utilize different miRNA targets to treat CRC. We also provide an overview of the major limitations and challenges of using miRNAs as immunotherapeutic targets.
doi:10.3748/wjg.v22.i23.5317
PMCID: PMC4910653  PMID: 27340348
Colorectal carcinoma; microRNAs; Tumor microenvironment; Immunotherapy; Inflammation; Inflammatory bowel disease; Immune response
9.  DNA demethylating agent decitabine broadens the peripheral T cell receptor repertoire 
Oncotarget  2016;7(25):37882-37892.
Purpose
Decitabine, a promising epi-immunotherapeutic agent has shown clinical responses in solid tumor patients, while the anti-tumor mechanisms were unclear. We aimed to investigate the immunomodulatory effect of decitabine in peripheral T cells.
Experimental design
We applied next-generation sequencing to investigate the complementarity-determining region 3 (CDR3) of the TCRβ gene, the diversity of which acts as the prerequisite for the host immune system to recognize the universal foreign antigens. We collected the peripheral blood mononuclear cells (PBMCs) from 4 patients, at baseline and after 2 cycles of low-dose decitabine therapy.
Results
An increase of the unique productive sequences of the CDR3 of TCRβ was observed in all of the 4 patients after decitabine treatment, which was characterized by a lower abundance of expanded clones and increased TCR diversity compared with before decitabine treatment. Further analysis showed a tendency for CD4 T cells with an increased CD4/CD8 ratio in response to decitabine therapy. In addition, the genome-wide expression alterations confirmed the effects of decitabine on immune reconstitution, and the increase of TCR excision circles (TRECs) was validated.
Conclusions
The low-dose DNMT inhibitor decitabine broadens the peripheral T cell repertoire, providing a novel role for the epigenetic modifying agent in anti-tumor immune enhancement.
doi:10.18632/oncotarget.9352
PMCID: PMC5122357  PMID: 27191266
T cell receptor repertoire; pharmacometabonomics; decitabine; epigenetic therapy; solid tumor
10.  Numb contributes to renal fibrosis by promoting tubular epithelial cell cycle arrest at G2/M 
Oncotarget  2016;7(18):25604-25619.
Numb is a multifunctional protein involved in diverse cellular processes. However, the function of Numb in kidney remains unclear. Here, we reported that Numb is expressed in renal tubules and glomeruli in normal adult kidney. Numb expression was upregulated in fibrotic kidneys induced by unilateral ureteral obstruction (UUO) in mice as well as in human fibrotic kidney tissues. Numb overexpression in cultured proximal tubular cells increased the G2/M cell population and upregulated the expression of TGF-β1 and CTGF. Whereas, proximal tubule Numb knockout (PEPCK-Numb-KO) mice showed reduced G2/M arrest, decreased expression of TGF-β1 and CTGF, and attenuated fibrotic lesions due to either UUO or unilateral ischemia reperfusion nephropathy. Inhibiting p53 activity by pifithrin-β dramatically mitigated Numb-induced G2/M arrest, indicating that Numb potentiates G2/M arrest via stabilizing p53 protein. Together, these data suggest that Numb is a potential target for anti-fibrosis therapy.
doi:10.18632/oncotarget.8238
PMCID: PMC5041930  PMID: 27016419
Numb; G2/M arrest; p53; proximal tubular cells; interstitial fibrosis
11.  The role of social relationship in HIV healing and its implications in HIV cure in China 
HIV is both a biomedical disease and a social phenomenon that is constructed in particular cultural contexts. A successful and humane HIV cure requires not only the science of eradicating pathogens, but also the art of healing to restore harmony between mind and body. Healing in the context of HIV cure will be both personal and interpersonal, biological and social, and will involve rebuilding connections between HIV patients and their social environment. Social conceptions of healing have been highlighted in many regions with rich non-biomedical healing traditions, including China. Based on an adapted theoretical model on social relationships and health, we address the essential role of social relations for HIV healing in Chinese cultural context, and propose several recommendations for reforming practices and policies regarding HIV healing. In general, family is still a core social unit in HIV patients’ medical journey from diagnosis to treatment. A positive patient–physician relationship based on mutual respect and trust also has critical impact on patients’ physical and mental health. Physicians may become a key or the main source of social support in circumstances when families are not actively engaged in healing. Reconnecting HIV patients with their communities should be a necessary component of HIV cure, as this will help patients engage more fully in the HIV healing process. We call for a family-centered approach in HIV healing intervention to strengthen patient–family ties; a series of policies to build up and sustain positive patient–physician ties; and multi-level strategies to empower patients and rebuild their bonds to community and larger society. We also call for more empirical research on how non-biomedical healing approaches in various cultural settings could (directly or indirectly) inform HIV cure research.
doi:10.1080/21642850.2015.1040405
PMCID: PMC4816495  PMID: 27042386
HIV cure; healing; social relationship; China
12.  Thidiazuron Triggers Morphogenesis in Rosa canina L. Protocorm-Like Bodies by Changing Incipient Cell Fate 
Thidiazuron (N-phenyl-N′-1,2,3-thiadiazol-5-ylurea; TDZ) is an artificial plant growth regulator that is widely used in plant tissue culture. Protocorm-like bodies (PLBs) induced by TDZ serve as an efficient and rapid in vitro regeneration system in Rosa species. Despite this, the mechanism of PLB induction remains relatively unclear. TDZ, which can affect the level of endogenous auxins and cytokinins, converts the cell fate of rhizoid tips and triggers PLB formation and plantlet regeneration in Rosa canina L. In callus-rhizoids, which are rhizoids that co-develop from callus, auxin and a Z-type cytokinin accumulated after applying TDZ, and transcription of the auxin transporter gene RcPIN1 was repressed. The expression of RcARF4, RcRR1, RcCKX2, RcCKX3, and RcLOG1 increased in callus-rhizoids and rhizoid tips while the transcription of an auxin response factor (RcARF1) and auxin transport proteins (RcPIN2, RcPIN3) decreased in callus-rhizoids but increased in rhizoid tips. In situ hybridization of rhizoids showed that RcWUS and RcSERK1 were highly expressed in columella cells and root stem cells resulting in the conversion of cell fate into shoot apical meristems or embryogenic callus. In addition, transgenic XVE::RcWUS lines showed repressed RcWUS overexpression while RcWUS had no effect on PLB morphogenesis. Furthermore, higher expression of the root stem cell marker RcWOX5 and root stem cell maintenance regulator genes RcPLT1 and RcPLT2 indicated the presence of a dedifferentiation developmental pathway in the stem cell niche of rhizoids. Viewed together, our results indicate that different cells in rhizoid tips acquired regeneration competence after induction by TDZ. A novel developmental pathway containing different cell types during PLB formation was identified by analyzing the endogenous auxin and cytokinin content. This study also provides a deeper understanding of the mechanisms underlying in vitro regeneration in Rosa.
doi:10.3389/fpls.2016.00557
PMCID: PMC4855734  PMID: 27200031
auxin; cytokinin; PLB; rhizoids; Rosa canina; stem cell; TDZ
13.  Truth-telling to the patient, family, and the sexual partner: a rights approach to the role of healthcare providers in adult HIV disclosure in China 
AIDS Care  2015;27(sup1):83-89.
Patients’ rights are central in today's legislation and social policies related to health care, including HIV care, in not only Western countries but around the world. However, given obvious socio-cultural differences it is often asked how or to what extent patients’ rights should be respected in non-Western societies such as China. In this paper, it is argued that the patients’ rights framework is compatible with Chinese culture, and that from the perspective of contemporary patient rights healthcare providers have a duty to disclose truthfully the diagnosis and prognosis to their patients, that the Chinese cultural practice of involving families in care should – with consent from the patient – be promoted out of respect for patients’ rights and well-being, and that healthcare providers should be prepared to address the issue of disclosing a patient's HIV status to sexual partner(s). Legally, the provider should be permitted to disclose without consent from the patient but not obliged to in all cases. The decision to do this should be taken with trained sensitivity to a range of ethically relevant considerations. Post-disclosure counseling or psychological support should be in place to address the concerns of potentially adverse consequences of provider-initiated disclosure and to maximize the psychosocial and medical benefits of the disclosure. There is an urgent need for healthcare providers to receive training in ethics and disclosure skills. This paper concludes also with some suggestions for improving the centerpiece Chinese legislation, State Council's “Regulations on AIDS Prevention and Control” (2006), to further safeguard the rights and well-being of HIV patients.
doi:10.1080/09540121.2015.1071772
PMCID: PMC4685610  PMID: 26616129
HIV disclosure; patients’ rights; privacy; cultural differences; family; China; partner notification
14.  Associations of intakes of magnesium and calcium and survival among women with breast cancer: results from Western New York Exposures and Breast Cancer (WEB) Study 
Magnesium (Mg) and calcium (Ca) antagonizes each other in (re) absorption, cell cycle regulation, inflammation, and many other physiologic activities. However, few studies have investigated the association between magnesium and calcium intakes and breast cancer survival, and the interaction between calcium and magnesium intake. In a cohort of 1,170 women with primary, incident, and histologically confirmed breast cancer from Western New York State, we examined the relationship between intakes of these two minerals and survival. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Mean follow-up time was 87.4 months after breast cancer diagnosis; there were 170 deaths identified. After adjustment for known prognostic factors, and intakes of energy, total vitamin D and total calcium, higher dietary intake of magnesium was inversely associated with risk of all-cause mortality (HR = 0.50, 95% CI, 0.28-0.90 for highest vs. lowest tertile; p trend = 0.02). Likewise, a marginal association was found for total Magnesium intake from foods and supplements combined (HR = 0.58, 95% CI, 0.31-1.08; p trend = 0.09). The inverse association of higher total magnesium intake with all-cause mortality was primarily presented among postmenopausal women and was stronger among women who had a high Ca:Mg intake ratio (>2.59). There were no clear associations for prognosis with intake of calcium. We found that magnesium intake alone may improve overall survival following breast cancer, and the association may be stronger among those with high Ca:Mg intake ratio.
PMCID: PMC4759402  PMID: 27073728
Magnesium; calcium; breast cancer survival; epidemiology
15.  A Comparative Study on the Uptake and Toxicity of Nickel Added in the Form of Different Salts to Maize Seedlings 
In soil ecotoxicological studies, a toxic metal is usually added in the form of either an inorganic or organic salt with relatively high solubility. Nitrate, chloride, acetate, or sulfate are commonly considered as valid options for that aim. However, recent studies have shown that different salts of the same metal at the same cationic concentration may exhibit different toxicities to plants and soil organisms. This information should be considered when selecting data to use for developing toxicological criteria for soil environment. A comparative study was carried out to evaluate the toxicity of five nickel (Ni) salts: NiCl2, NiSO4, Ni(II)-citrate, Ni(CH3COO)2, and Ni(II)-EDTA (ethylenediaminetetraacetate), on maize seedlings. The plant metrics used were plant height, shoot and root biomass, leaf soluble sugars and starch, and the Ni contents of the shoots and roots. The results indicated that when Ni was added to the soil, toxicity varied with the selected anionic partner with the following toxicity ranking NiSO4 < Ni(CH3COO)2 < Ni(II)-citrate < NiCl2 < Ni(II)-EDTA. Taking the plant-height metric as an example, the effective concentrations for 50% inhibition (EC50) were 3148 mg·kg−1 for NiSO4, 1315 mg·kg−1 for NiCl2, and 89 mg·kg−1 for Ni(II)-EDTA. Compared with the Ni in the other salts, that in Ni(II)-EDTA was taken up the most efficiently by the maize roots and, thus, resulted in the greatest toxic effects on the plants. Nickel generally reduced leaf soluble sugars, which indicated an effect on plant carbohydrate metabolism. The outcome of the study demonstrates that different salts of the same metal have quite different ecotoxicities. Therefore, the anionic counterpart of a potentially toxic metal cation must be taken into account in the development of ecotoxicological criteria for evaluating the soil environment, and a preferred approach of leaching soil to reduce the anionic partner should also be considered.
doi:10.3390/ijerph121214972
PMCID: PMC4690908  PMID: 26633435
maize; nickel salts; nickel toxicity; nickel accumulation; soil contamination
16.  A novel quantification method for the total demethylation potential of aquatic sample extracts from Bohai Bay using the EGFP reporter gene 
BMC Biotechnology  2015;15:107.
Background
The demethylation potential of environmental pollutants is possibly an innate part of their comprehensive health risk. This paper develops a novel method called TDQ to quantify the demethylation epigenetic toxicity, termed the 5-AZA-CdR demethylation toxic equivalency, of aquatic samples from the heavily polluted Bohai Bay using Hep G2 cell lines transiently transfected with the pEGFP-C3 plasmid containing a methylated promoter of the EGFP reporter gene inserted artificially in vitro.
Results
If the aquatic sample extract has strong total demethylation potential to the promoter, its methylation level will decrease, and increased green fluorescence will be observed under microscopy after TDQ co-incubation. The 5-AZA-CdR was selected as a representative demethylation agent to validate the principle of the TDQ method on three levels: significant dose–response relationships between the concentration of 5-AZA-CdR and the methylation level of promoters, mRNA expression level of the EGFP gene, and the fluorescence intensity of EGFP proteins. Twenty extracts from aquatic samples are successfully quantified with the TDQ test. Eight of them return meaningful results ranging from 0.00004 to 0.20053 μM 5-AZA-CdR toxicity equivalents.
Conclusions
The TDQ method is a reliable and rapid assay for the quantification of the DNA demethylation potential of aquatic sample extracts, which may shed light on the safety evaluation of food material.
Electronic supplementary material
The online version of this article (doi:10.1186/s12896-015-0224-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12896-015-0224-y
PMCID: PMC4660669  PMID: 26610601
Demethylation; Aquatic sample; EGFP; Metals; Bohai bay
17.  Oseltamivir Population Pharmacokinetics in the Ferret: Model Application for Pharmacokinetic/Pharmacodynamic Study Design 
PLoS ONE  2015;10(10):e0138069.
The ferret is a suitable small animal model for preclinical evaluation of efficacy of antiviral drugs against various influenza strains, including highly pathogenic H5N1 viruses. Rigorous pharmacokinetics/pharmacodynamics (PK/PD) assessment of ferret data has not been conducted, perhaps due to insufficient information on oseltamivir PK. Here, based on PK data from several studies on both uninfected and influenza-infected groups (i.e., with influenza A viruses of H5N1 and H3N2 subtypes and an influenza B virus) and several types of anesthesia we developed a population PK model for the active compound oseltamivir carboxylate (OC) in the ferret. The ferret OC population PK model incorporated delayed first-order input, two-compartment distribution, and first-order elimination to successfully describe OC PK. Influenza infection did not affect model parameters, but anesthesia did. The conclusion that OC PK was not influenced by influenza infection must be viewed with caution because the influenza infections in the studies included here resulted in mild clinical symptoms in terms of temperature, body weight, and activity scores. Monte Carlo simulations were used to determine that administration of a 5.08 mg/kg dose of oseltamivir phosphate to ferret every 12 h for 5 days results in the same median OC area under the plasma concentration-time curve 0–12 h (i.e., 3220 mg h/mL) as that observed in humans during steady state at the approved dose of 75 mg twice daily for 5 days. Modeling indicated that PK variability for OC in the ferret model is high, and can be affected by anesthesia. Therefore, for proper interpretation of PK/PD data, sparse PK sampling to allow the OC PK determination in individual animals is important. Another consideration in appropriate design of PK/PD studies is achieving an influenza infection with pronounced clinical symptoms and efficient virus replication, which will allow adequate evaluation of drug effects.
doi:10.1371/journal.pone.0138069
PMCID: PMC4603953  PMID: 26460484
18.  Patient–physician mistrust and violence against physicians in Guangdong Province, China: a qualitative study 
BMJ Open  2015;5(10):e008221.
Objective
To better understand the origins, manifestations and current policy responses to patient–physician mistrust in China.
Design
Qualitative study using in-depth interviews focused on personal experiences of patient–physician mistrust and trust.
Setting
Guangdong Province, China.
Participants
One hundred and sixty patients, patient family members, physicians, nurses and hospital administrators at seven hospitals varying in type, geography and stages of achieving goals of health reform. These interviews included purposive selection of individuals who had experienced both trustful and mistrustful patient–physician relationships.
Results
One of the most prominent forces driving patient–physician mistrust was a patient perception of injustice within the medical sphere, related to profit mongering, knowledge imbalances and physician conflicts of interest. Individual physicians, departments and hospitals were explicitly incentivised to generate revenue without evaluation of caregiving. Physicians did not receive training in negotiating medical disputes or humanistic principles that underpin caregiving. Patient–physician mistrust precipitated medical disputes leading to the following outcomes: non-resolution with patient resentment towards physicians; violent resolution such as physical and verbal attacks against physicians; and non-violent resolution such as hospital-mediated dispute resolution. Policy responses to violence included increased hospital security forces, which inadvertently fuelled mistrust. Instead of encouraging communication that facilitated resolution, medical disputes sometimes ignited a vicious cycle leading to mob violence. However, patient–physician interactions at one hospital that has implemented a primary care model embodying health reform goals showed improved patient–physician trust.
Conclusions
The blind pursuit of financial profits at a systems level has eroded patient–physician trust in China. Restructuring incentives, reforming medical education and promoting caregiving are pathways towards restoring trust. Assessing and valuing the quality of caregiving is essential for transitioning away from entrenched profit-focused models. Moral, in addition to regulatory and legal, responses are urgently needed to restore trust.
doi:10.1136/bmjopen-2015-008221
PMCID: PMC4606416  PMID: 26443652
QUALITATIVE RESEARCH; PUBLIC HEALTH
19.  Exposures in early life: associations with DNA promoter methylation in breast tumors 
There is evidence that epigenetic changes occur early in breast carcinogenesis; we hypothesized that early life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particularly, we examined DNA methylation patterns in breast tumors in association with several early life exposures in a population-based case-control study. Promoter methylation of E-cadherin, p16 and RAR-β2 genes was assessed in archived tumor blocks from 803 cases with real time methylation-specific PCR. Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth, and weight at age 20. In case-case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E - cadherin promoter methylation (OR = 2.79, 95% CI, 1.15–6.82, for ≤ 2.5 vs 2.6–2.9 kg); higher adult height with RAR-β2 methylation (OR =3.34, 95% CI, 1.19–9.39, for ≥ 1.65 vs <1.60 m); and not having been breast fed with p16 methylation (OR = 2.75, 95% CI, 1.14–6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ≥1 of the 3 genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early life exposures that persist into adulthood and affect breast cancer risk.
doi:10.1017/S2040174412000694
PMCID: PMC4539251  PMID: 25054684
early life exposure; breast cancer; epidemiology; epigenetics; promoter methylation
20.  AOPPs and the progression of kidney disease 
Kidney International Supplements  2014;4(1):102-106.
Advanced oxidation protein products (AOPPs) are the dityrosine-containing and crosslinking protein products formed during oxidative stress by reaction of plasma protein with chlorinated oxidants, and often carried by albumin in vivo. Accumulation of plasma and renal AOPPs is a common pathologic finding in chronic kidney disease (CKD) patients. Moreover, AOPP accumulation is an independent risk factor for cardiovascular events (CVDs) in CKD. Clinical and experimental studies indicate that AOPPs are involved in the structural changes of progressive nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy via the redox-dependent pathway. Mounting evidence supports the role of AOPPs as a new class of renal pathogenic mediators in the progression of CKD. This mini review describes the formation of AOPPs, the involvement of AOPPs in CKD pathogenesis, and the underlying mechanisms.
doi:10.1038/kisup.2014.19
PMCID: PMC4536974  PMID: 26312159
AOPPs; CD36; NAD(P)H oxidase; oxidative stress; RAGE
21.  Effects of High Fat Feeding on Adipose Tissue Gene Expression in Diabetic Goto-Kakizaki Rats 
Development and progression of type 2 diabetes is a complex interaction between genetics and environmental influences. High dietary fat is one environmental factor that is conducive to the development of insulin-resistant diabetes. In the present report, we compare the responses of lean poly-genic, diabetic Goto-Kakizaki (GK) rats to those of control Wistar-Kyoto (WKY) rats fed a high fat diet from weaning to 20 weeks of age. This comparison included a wide array of physiological measurements along with gene expression profiling of abdominal adipose tissue using Affymetrix gene array chips. Animals of both strains fed a high fat diet or a normal diet were sacrificed at 4, 8, 12, 16, and 20 weeks for this comparison. The microarray analysis revealed that the two strains developed different adaptations to increased dietary fat. WKY rats decrease fatty acid synthesis and lipogenic processes whereas GK rats increase lipid elimination. However, on both diets the major differences between the two strains remained essentially the same. Specifically relative to the WKY strain, the GK strain showed lipoatrophy, chronic inflammation, and insulin resistance.
doi:10.4137/GRSB.S25172
PMCID: PMC4533846  PMID: 26309393
diabetes; high fat diet; gene expression; microarray
22.  Suboptimal antiretroviral therapy adherence among HIV-infected adults in Guangzhou, China 
AIDS care  2014;26(8):988-995.
Despite China“s free antiretroviral treatment (ART) program, there are high rates of treatment failure, large sociodemographic disparities in care outcomes and emerging medication resistance. Understanding patient medication adherence behaviors and challenges could inform adherence interventions to maximize the individual and prevention benefits of ART. This study assessed recent non-adherence and treatment interruption among 813 HIV-infected adult outpatients in Guangzhou, China. Participants completed a behavioral survey, underwent chart review, and were tested for syphilis, gonorrhea, and chlamydia. Factors associated with suboptimal adherence were identified using univariate and multivariate logistic regression. Among 721 HIV-infected adults receiving ART, 18.9% reported recent non-adherence (any missed ART in the past 4 weeks) and 6.8% reported treatment interruption (four or more weeks of missed ART in the past year). Lower education, living alone, alcohol use and being on ART one to three years were associated with recent non-adherence. Male gender, lower education and being on ART one to three years were associated with treatment interruption. ART medication adherence interventions are needed in China that include individualized, long-term adherence plans sensitive to patients“ educational and economic situations. These interventions should also consider possible gender disparities in treatment outcomes and address the use of alcohol during ART. Successful ART medication adherence interventions in China can inform other international settings that face similar adherence challenges and disparities.
doi:10.1080/09540121.2014.897912
PMCID: PMC4024070  PMID: 24666239
antiretroviral therapy; ART; ARV; adherence; alcohol; China
23.  Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a 
PLoS ONE  2015;10(7):e0130421.
Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production.
doi:10.1371/journal.pone.0130421
PMCID: PMC4508059  PMID: 26192994
24.  United States Responses to Japanese Wartime Inhuman Experimentation after World War II: National Security and Wartime Exigency 
In 1945-46, representatives of the United States government made similar discoveries in both Germany and Japan, unearthing evidence of unethical experiments on human beings that could be viewed as war crimes. The outcomes in the two defeated nations, however, were strikingly different. In Germany, the U.S., influenced by the Canadian physician John Thompson, played a key role in bringing Nazi physicians to trial and publicizing their misdeeds. In Japan, the U.S. played an equally key role in concealing information about the biological warfare experiments and securing immunity from prosecution for the perpetrators. The greater force of appeals to national security and wartime exigency help to explain these different outcomes.
doi:10.1017/S0963180113000753
PMCID: PMC4487829  PMID: 24534743
25.  Actin Disorganization Plays a Vital Role in Impaired Embryonic Development of In Vitro-Produced Mouse Preimplantation Embryos 
PLoS ONE  2015;10(6):e0130382.
Assisted reproductive technology (ART) is being increasingly applied to overcome infertility. However, the in vitro production process, the main procedure of ART, can lead to aberrant embryonic development and health-related problems in offspring. Understanding the mechanisms underlying the ART-induced side effects is important to improve the ART process. In this study, we carried out comparative transcriptome profiling between in vivo- (IVO) and in vitro- produced (IVP) mouse blastocysts. Our results suggested that aberrant actin organization might be a major factor contributing to the impaired development of IVP embryos. To test this, we examined the effect of actin disorganization on the development of IVP preimplantation embryos. Specific disruption of actin organization by cytochalasin B (CB) indicated that well-organized actin is essential for in vitro embryonic development. Supplementing the culture medium with 10–9 M melatonin, a cytoskeletal modulator in adult somatic cells, significantly reversed the disrupted expression patterns of genes related to actin organization, including Arhgef2, Bcl2, Coro2b, Flnc, and Palld. Immunofluorescence analysis showed that melatonin treatment of IVP embryos significantly improved the distribution and organization of actin filaments (F-actin) from the 8-cell stage onwards. More importantly, we found that melatonin alleviated the CB-mediated aberrant F-actin distribution and organization and rescued CB-induced impaired embryonic development. This is the first study to indicate that actin disorganization is implicated in impaired development of IVP embryos during the preimplantation stage. We also demonstrated that improving actin organization is a promising strategy to optimize existing IVP systems.
doi:10.1371/journal.pone.0130382
PMCID: PMC4468147  PMID: 26076347

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