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1.  Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index 
AIM: To investigate whether central obesity is associated with nonalcoholic fatty liver disease (NAFLD) formation after adjusting for general obesity.
METHODS: The online databases PubMed, EMBASE, and ISI Web of Science were searched for studies estimating the influence of central obesity on NAFLD occurrence published through April 2014. Studies that did not adjust for body mass index (BMI) were excluded. In addition, the independent effect of BMI was also assessed with the included studies. The pooled effect sizes and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models based on the degree of heterogeneity. Furthermore, subgroup analyses, meta-regression, sensitivity analyses, and publication bias were performed.
RESULTS: Twenty eligible studies were identified. The summary odds ratio (OR) values per-unit increase in waist circumference (WC) and BMI for NAFLD formation were 1.07 (95%CI: 1.03-1.10, I2 = 73.9%, n = 11 studies) and 1.25 (95%CI: 1.13-1.38, I2 = 88.7%, n = 11 studies), respectively. When the indices were expressed as binary variables (with the non-obesity group as reference), the pooled OR in WC, waist-to-hip ratio, and BMI were 2.34 (95%CI: 1.83-3.00, I2 = 41.8%, n = 7 studies), 4.06 (95%CI: 1.53-10.79, I2 = 65.7%, n = 3 studies), and 2.85 (95%CI: 1.60-5.08, I2 = 57.8%, n = 5 studies), respectively. Using the same studies as the latter (n = 5), pooled OR in WC was 3.14 (95%CI: 2.07-4.77), which is greater than that in BMI.
CONCLUSION: Central obesity may pose a greater threat to national health than general obesity, although both are independently associated with increased risk of NAFLD.
PMCID: PMC4316109  PMID: 25663786
Central obesity; General obesity; Nonalcoholic fatty liver disease; Body mass index; Waist circumference
2.  Characterizing the Temporal Dynamics of Human Papillomavirus DNA Detectability Using Short-Interval Sampling 
Variable detection of human papillomavirus (HPV) DNA can result in misclassification of infection status, but the extent of misclassification has not been quantitatively evaluated.
In 2005–2007, 33 women aged 22–53 self-collected vaginal swabs twice per week for 16 consecutive weeks. Each of the 955 swabs collected was tested for 37 HPV types/subtypes. Assuming that a woman’s underlying infection status did not change over the short study period, biases in prevalence estimates obtained from single versus multiple swabs were calculated. Using event history analysis methods, time to recurrent gain and loss of at least one HPV type was determined, separately. Baseline any- and high risk-HPV prevalence was 60.6% and 24.2%, respectively. Cumulative any- and high risk-HPV prevalence over the 16-week period was 84.8% and 60.6%, separately.
Overall, there were 319 events of detection and 313 events of loss of detection. Median times to a recurrent detection and loss of detection was 11 and 7 days, respectively. Neither vaginal sex nor condom use during follow-up was associated with recurrent viral detection or loss of detection. Assuming the cumulative 16-week prevalence reflects the true prevalence of infection, the baseline any-HPV prevalence under-estimated infection status by 24.2%, with a bootstrapped mean of 20.2% (95% confidence interval [CI]: 8.9%, 29.6%).
These findings suggest that a substantial proportion of HPV-infected women are misclassified as being un-infected when using a single-time DNA measurement.
Short-term variation in detectable HPV DNA needs to be considered while interpreting the natural history of infections using single samples collected at long intervals.
PMCID: PMC3947138  PMID: 24130223
Epidemiology; Human papillomavirus; Interval sampling; Misclassification bias; Prevalence
3.  Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice 
Scientific Reports  2014;4:6894.
Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic β-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic β-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes.
PMCID: PMC4219158  PMID: 25367288
4.  Menstrual Cycle and Detectable Human Papillomavirus in Reproductive-age Women: A Time Series Study 
The Journal of Infectious Diseases  2013;208(9):1404-1415.
Background. Current evidence on the relationship between human papillomavirus (HPV) DNA detection and menstrual cycle has been inconsistent.
Methods. We included 21 nonoral contraceptive pill (non-OCP) users who self-collected vaginal samples twice per week for 16 weeks. We explored whether variable detection of HPV DNA exhibited cyclic or other structured temporal patterns. We also evaluated relationships between serial HPV prevalence, sexual behavior, and suspected bacterial vaginosis (BV) as defined by Nugent Gram stain score ≥7.
Results. During follow-up, any-type HPV prevalence varied between 61.1% and 85.0%. Although not statistically significant, we observed a maximum autocorrelation in serial HPV prevalence lagging 14 days (correlation coefficient [ρ], −0.24). Any-type HPV detection had a periodic behavior, generally repeating every 28.0 days (bootstrapped interquartile range, 22.4–28.0) and peaking around the ovulation time (adjusted odds ratio, 1.96; 95% confidence interval [CI], 1.06–3.62) as compared to menstruation. We also showed that an increase in any-type HPV prevalence preceded the beginning of a menstrual cycle by 9–12 days. There was no evidence of relationships between HPV prevalence and sexual activity or Nugent score.
Conclusions. Serially detected any-type HPV DNA showed a periodic behavior and was likely to peak in the periovulatory phase among non-OCP users.
PMCID: PMC3789568  PMID: 23885113
Auto-correlation; Bacterial Vaginosis; Human Papillomavirus; Menstrual Cycle; Nugent Score; Periodicity; Spectral Analysis; Time Series Analysis
5.  WISH/DIP/SPIN90 proteins form a class of Arp2/3 complex activators that function without preformed actin filaments 
Current biology : CB  2013;23(20):1990-1998.
Arp2/3 complex is a key actin cytoskeletal regulator that creates branched actin filament networks in response to cellular signals. WASP-activated Arp2/3 complex assembles branched actin networks by nucleating new filaments from the sides of pre-existing ones. WASP-mediated activation requires seed filaments, to which the WASP-bound Arp2/3 complex can bind to form branches, but the source of the first substrate filaments for branching is unknown.
Here we show that Dip1, a member of the WISH/DIP/SPIN90 family of actin regulators, potently activates Arp2/3 complex without preformed filaments. Unlike other Arp2/3 complex activators, Dip1 does not bind actin monomers or filaments, and interacts with the complex using a non-WASP-like binding mode. In addition, Dip1-activated Arp2/3 complex creates linear instead of branched actin filament networks.
Our data show the mechanism by which Dip1 and other WISH/DIP/SPIN90 proteins can provide seed filaments to Arp2/3 complex to serve as master switches in initiating branched actin assembly. This mechanism is distinct from other known activators of Arp2/3 complex.
PMCID: PMC3930447  PMID: 24120641
6.  Compound Danshen Dripping Pill Pretreatment to Prevent Contrast-Induced Nephropathy in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention 
Background. Contrast-induced nephropathy (CIN) limits the outcome of percutaneous coronary intervention (PCI). Objective. To investigate whether pretreatment with Compound Danshen Dripping Pills (CDDP) will decrease the incidence of CIN after PCI. Methods. A total of 229 patients with acute coronary syndrome (ACS) undergoing PCI were divided into the control group (n = 114) and the CDDP (containing salvia miltiorrhiza and sanqi) group (n = 115; given 20 CDDP pills, three times daily before PCI). Serum creatinine, creatinine clearance (CrCl), high-sensitivity C-reactive protein (hsCRP), P-selectin, and intercellular adhesion molecule-1 (ICAM-1) were measured at admission and 24 and 48 h after PCI. Results. CrCl decreased after PCI but recovered after 48 h. In the CDDP group, CrCl recovered more rapidly (P < 0.05). The procedure increased the hsCRP, P-selectin, and ICAM-1 levels, but these levels were less in the CDDP group (P < 0.05). Conclusions. Pretreatment with CDDP can decrease the occurrence of CIN in patients undergoing PCI, suggesting that the early use of CDDP is an appropriate adjuvant pharmacological therapy before PCI.
PMCID: PMC4216665  PMID: 25386219
7.  Obesity and Human Papillomavirus Infection in Perimenopausal Women 
The Journal of Infectious Diseases  2013;208(7):1071-1080.
Introduction. Obesity is known to increase susceptibility to certain infections in men. It is unclear whether obesity increases women's risk for human papillomavirus (HPV) infection.
Methods. In a prospective cohort of 696 perimenopausal women enrolled in 2008–2012, we sought to determine whether obesity predicted incident HPV detection or nondetection. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2.
Results. Baseline any type HPV prevalence was comparable between obese and nonobese women (18.7% vs 19.1%; P > .05). Over a median follow-up period of 17.9 months (interquartile range: 12.1–24.5), 187 new HPV detections occurred among 123 women, 60 of whom subsequently lost 76 detectable infections. When compared with nonobese participants, obese women had a similar rate of new HPV detection (7.1 vs 7.8 infections per 1000 infection-years; P > .05) or loss of detection (100.3 vs 85.8 infections per 100 infection-years; P > .05). Similar results were found after adjusting for age, menopausal status, smoking habit, and sexual exposure history.
Conclusions. Results from the current analysis suggest little effect of obesity on HPV detection and loss of detection in mid-adult women. More research is needed to determine whether adipokines or cytokines better capture the potential immune modulating effects of obesity on HPV infection.
PMCID: PMC3762384  PMID: 23840046
adipokine; body mass index; discrete-time survival analysis; frailty model; human papillomavirus; obesity; waist circumference
8.  Oral contraceptive pill use is associated with reduced odds of nonalcoholic fatty liver disease in menstruating women: results from NHANES III 
Journal of gastroenterology  2012;48(10):1151-1159.
Higher prevalence of nonalcoholic fatty liver disease (NAFLD) in men and postmenopausal women than in premenopausal women has suggested a potential role of sex hormones in the pathogenesis of the disease. We sought to evaluate the association between oral contraceptive pills (OCP) and NAFLD and to determine whether adiposity mediates any effect.
We included 4338 women aged 20–60 years who were enrolled in the Third National Health and Nutrition Examination Survey from 1988 to 1994 in a population-based cross-sectional study. We defined NA-FLD as moderate–severe steatosis on ultrasonography in women without excessive alcohol use or other identifiable causes. OCP use was based on self-report and was categorized as never, former or current use.
The overall weighted prevalence of NAFLD was 11.6 % but lower in current (6.7 %) than in former (12.0 %) or never users (15.6 %, P = 0.016). In the multivariable model, current OCP users experienced a 50 % lower odds of NAFLD than never users (adjusted odds ratio 0.50; 95 % confidence interval 0.26, 0.98) after adjusting for age, race/ethnicity, smoking status, history of diabetes or hypertension and education. Further adjustment for body mass index or waist circumference significantly attenuated the OCP–NAFLD relationship.
In this large US-representative population, OCP use was associated with reduced odds of NAFLD. However, this association could be mediated or confounded by adiposity. Prospective studies are needed to further clarify the causal role of sex hormone.
PMCID: PMC4170913  PMID: 23188092
Adiposity; Nonalcoholic fatty liver disease; Obesity; Oral contraceptive pill; Sex hormone
9.  Clinical Features and Molecular Analysis of Hb H Disease in Taiwan 
BioMed Research International  2014;2014:271070.
Thalassemia is highly prevalent in Taiwan, but limited data are available about the association between genotypes and clinical manifestations in Taiwanese patients with Hb H disease. Here, we studied α-globin gene abnormalities and clinical features in Taiwanese patients with Hb H disease. Of the 90 patients, sixty-four (71.1%) were deletional and twenty-six (28.9%) were nondeletional Hb H disease. The (- -SEA) type of α0-thalassemia mutation was detected in the majority of patients (>95%). The most common genotype was (- -SEA/-α3.7), followed by (- -SEA/αcsα). After further investigation of the genotype-phenotype correlation in 68 patients, we found that patients with nondeletional Hb H disease had more severe clinical features than those with deletional Hb H disease, including younger age at diagnosis, more requirement of blood transfusions, and larger proportion of patients with splenomegaly, hepatomegaly or jaundice. This is probably a consequence of the lower hemoglobin levels and the higher Hb H levels. The clinical severity was highly variable even among patients with an identical genotype, and the diversity was much more profound among patients with (- -/αcsα) genotype. Therefore, predicting the phenotype directly from the genotype in Hb H disease remains relatively difficult in Taiwan.
PMCID: PMC4163353  PMID: 25309906
10.  Berberine suppresses in vitro migration of human aortic smooth muscle cells through the inhibitions of MMP-2/9, u-PA, AP-1, and NF-κB 
BMB Reports  2014;47(7):388-392.
Berberine, a type of isoquinoline alkaloid isolated from Chinese medicinal herbs, has been reported to have various pharmacological activities. Studies have demonstrated that berberine has beneficial effects on vascular remodeling and alleviates restenosis after vascular injury. However, its mechanism of action on vascular smooth muscle cell migration is not fully understood. We therefore investigated the effect of berberine on human aortic smooth muscle cell (HASMC) migration. Boyden chamber assay was performed to show that berberine inhibited HASMC migration dosedependently. Real-time PCR and Western blotting analyses showed that levels of matrix metalloproteinase (MMP)-2, MMP-9, and urokinase-type plasminogen activator (u-PA) were reduced by berberine at both the mRNA and protein levels. Western blotting assay further confirmed that activities of c-Fos, c-Jun, and NF-κB were significantly attenuated. These results suggest that berberine effectively inhibited HASMC migration, possibly by down-regulating MMP-2, MMP-9, and u-PA; and interrupting AP-1 and NF-κB mediated signaling pathways. [BMB Reports 2014; 47(7): 388-392]
PMCID: PMC4163851  PMID: 24286329
Berberine; Human aortic smooth muscle cells; Matrix metalloproteinase; Migration; Restenosis
11.  Clinical characteristics of 26 patients with primary extranodal Hodgkin lymphoma 
Background: Most Hodgkin lymphoma (HL) patients present with disease in nodal regions. However, in a small subset, disease develops extranodal sites primarily, such as lung and liver. This study aims to identify the characteristics and outcomes of patients with primary extranodal HL. Methods: A retrospective analysis of patients with HL from 1998 to 2012 was enrolled. We selected 26 HL patients with primary extranodal involvement from 251 previously untreated HL patients. All data analyses were performed with SPSS software version 17.0 and GraphPad Prism 5. Results: We identified 26 patients with primary extranodal HL. Results in the series of young patients, male predominated. Pathologically, the major pathologic types were nodular sclerosis classical HL (NSCHL, 46.2%) and mixed cellularity classical HL (MCCHL, 38.5%). Thirteen patients had early stage (I or II stage). The most commonly primarily extranodal sites were the lung and the stomach and intestine, followed by the liver and bones. Fifteen of 26 received chemotherapy alone and 11 received combination therapy. Finally, primary extranodal HLs in our study have a favorable survival. Furthermore, there was no significant association between the international prognostic score (IPS) and survival in patients with extranodal HL. Conclusion: Our retrospective data in part reflect clinical characteristics of primary extranodal HL in China, and form the basis for further concerning researches.
PMCID: PMC4152067  PMID: 25197377
Hodgkin’s lymphoma; extranodal; prognosis; international prognostic score; survival; 18F-FDGPET-CT
12.  Effects of Dimethylaminoethanol and Compound Amino Acid on D-Galactose Induced Skin Aging Model of Rat 
The Scientific World Journal  2014;2014:507351.
A lasting dream of human beings is to reverse or postpone aging. In this study, dimethylaminoethanol (DMAE) and compound amino acid (AA) in Mesotherapy were investigated for their potential antiaging effects on D-galactose induced aging skin. At 18 days after D-gal induction, each rat was treated with intradermal microinjection of saline, AA, 0.1% DMAE, 0.2% DMAE, 0.1% DMAE + AA, or 0.2% DMAE + AA, respectively. At 42 days after treatment, the skin wound was harvested and assayed. Measurement of epidermal and dermal thickness in 0.1% DMAE + AA and 0.2% DMAE + AA groups appeared significantly thicker than aging control rats. No differences were found in tissue water content among groups. Hydroxyproline in 0.1% DMAE + AA, 0.2% DMAE + AA, and sham control groups was much higher than all other groups. Collagen type I, type III, and MMP-1 expression was highly upregulated in both 0.1% DMAE + AA and 0.2% DMAE + AA groups compared with aging control. In contrast, TIMP-1 expression levels of various aging groups were significantly reduced when compared to sham control. Coinjection of DMAE and AA into target tissue has marked antiaging effects on D-galactose induced skin aging model of rat.
PMCID: PMC4123624  PMID: 25133239
13.  Happy@Work: protocol for a web-based randomized controlled trial to improve mental well-being among an Asian working population 
BMC Public Health  2014;14:685.
Mental health issues pose a serious concern in the workplace for the huge productivity loss and financial burden associated with it. Unlike the traditional ‘fixing-what-is-wrong’ approach, positive psychology offers a less-stigmatized way to promote mental health. Psychological capital, a concept originated from positive psychology, has been proven effective in improving mental well-being and work performance. However, little evidence exists for its implementation among Asian working population or its cost-benefit for organizations adopting such promotion strategy. The current study is designed to assess the protective effects of a web-based psychology capital intervention among Hong Kong working population on individuals’ mental health and work performance, as well as organizations’ return-on-investment.
A two-arm randomized controlled trial design will be adopted. Eligible working adults will be randomly allocated to either the intervention group or the waiting-list control group, with 177 participants in each arm. The intervention, which consists of four web-based training sessions, each targeting one of the psychological capital components (hope, efficacy, optimism and resilience), will be implemented over a 4-week period. On-line surveys will assess the participants in each group at baseline, intervention completion, 1 and 3 months after the completion. The primary outcome is individuals’ psychological capital level; secondary outcomes include individuals’ well-being, depressive symptoms, work engagement and productivity. Return-on-investment will be calculated from the employers’ perspective based on productivity gain, savings in medical expenditure, as well as operation and time costs. Analysis will follow the intention-to-treat principle.
This is the first experimental study that explores the applicability of psychological capital development among Asian population. Through investigating changes in individuals’ work productivity from absenteeism and presenteeism, this will be one of the few studies that quantify productivity gains from any type of mental health promotion. By demonstrating effectiveness in improving mental well-being and a positive return-on-investment rate, the study may help convince more uptake of similar positive psychology interventions at workplace in Asia and elsewhere.
Trail Registration
Number (assigned by Centre for Clinical Trials, Clinical Trials Registry, The Chinese University of Hong Kong): CUHK_CCT00396. Registration Date: 2014/02/13
PMCID: PMC4096423  PMID: 24997007
Mental health; Promotion; Positive psychology; Psychological capital; Return-on-investment; Working population; Hong Kong
14.  Using Benthic Macroinvertebrate and Fish Communities as Bioindicators of the Tanshui River Basin Around the Greater Taipei Area — Multivariate Analysis of Spatial Variation Related to Levels of Water Pollution 
After decades of strict pollution control and municipal sewage treatment, the water quality of the Tanshui River increased significantly after pollution mitigation as indicated by the River Pollution Index (RPI). The pollution level of the estuarine region decreased from severe pollution to mostly moderately impaired. The most polluted waters are presently restricted to a flow track length between 15–35 km relative to the river mouth. From July 2011 to September 2012, four surveys of fish and benthic macroinvertebrates were conducted at 45 sampling sites around the Tanshui River basin. The pollution level of all the study area indicated by the RPI could also be explained by the Family Biotic Index (FBI) and Biotic Index (BI) from the benthic macroinvertebrate community, and the Index of Biotic Integrity (IBI) of the fish community. The result of canonical correlation analysis between aquatic environmental factors and community structure indicated that the community structure was closely related to the level of water pollution. Fish species richness in the estuarine area has increased significantly in recent years. Some catadromous fish and crustaceans could cross the moderate polluted water into the upstream freshwater, and have re-colonized their populations. The benthic macroinvertebrate community relying on the benthic substrate of the estuarine region is still very poor, and the water layer was still moderately polluted.
PMCID: PMC4113864  PMID: 25026081
bioindicator; benthic invertebrate; fish community; water quality
15.  A primary assessment of the endophytic bacterial community in a xerophilous moss (Grimmia montana) using molecular method and cultivated isolates 
Brazilian Journal of Microbiology  2014;45(1):163-173.
Investigating the endophytic bacterial community in special moss species is fundamental to understanding the microbial-plant interactions and discovering the bacteria with stresses tolerance. Thus, the community structure of endophytic bacteria in the xerophilous moss Grimmia montana were estimated using a 16S rDNA library and traditional cultivation methods. In total, 212 sequences derived from the 16S rDNA library were used to assess the bacterial diversity. Sequence alignment showed that the endophytes were assigned to 54 genera in 4 phyla (Proteobacteria, Firmicutes, Actinobacteria and Cytophaga/Flexibacter/Bacteroids). Of them, the dominant phyla were Proteobacteria (45.9%) and Firmicutes (27.6%), the most abundant genera included Acinetobacter, Aeromonas, Enterobacter, Leclercia, Microvirga, Pseudomonas, Rhizobium, Planococcus, Paenisporosarcina and Planomicrobium. In addition, a total of 14 species belonging to 8 genera in 3 phyla (Proteobacteria, Firmicutes, Actinobacteria) were isolated, Curtobacterium, Massilia, Pseudomonas and Sphingomonas were the dominant genera. Although some of the genera isolated were inconsistent with those detected by molecular method, both of two methods proved that many different endophytic bacteria coexist in G. montana. According to the potential functional analyses of these bacteria, some species are known to have possible beneficial effects on hosts, but whether this is the case in G. montana needs to be confirmed.
PMCID: PMC4059291  PMID: 24948927
bacterial diversity; endophytes; moss; molecular method; cultivated isolates
16.  Cytotoxic Effect of Icaritin and Its Mechanisms in Inducing Apoptosis in Human Burkitt Lymphoma Cell Line 
BioMed Research International  2014;2014:391512.
Icaritin (ICT), a hydrolytic product of icariin from Epimedium genus, exhibits antitumor activities in several human solid-tumor and myeloid leukemia cells with extensive influence on various cell signal molecules, such as MAPKs being involved in cell proliferation and Bcl-2 participating in cell apoptosis. However, the effect of icaritin on Burkitt Lymphoma has not been elucidated. In the present study, we first screened the potential effect of icaritin on Burkitt lymphoma Raji and P3HR-1 cell lines and found that icaritin showed cytotoxicity in both cell lines. We further found that icaritin could significantly inhibit Raji cells proliferation with S-phase arrest of cell cycle and induced cell apoptosis accompanied by activation of caspase-8 and caspase-9 and cleavage of PARP. We also observed that icaritin was able to decrease Bcl-2 levels, thus shifting the Bcl-2/Bax ratio, and it could obviously reduce c-Myc, a specific molecular target in Burkitt lymphoma. Our findings demonstrated that icaritin showed cytotoxicity, inhibited cell growth, caused S arrest, and induced apoptosis in Burkitt lymphoma cells and provided a rationale for the further evaluation of icaritin for Burkitt lymphoma therapy.
PMCID: PMC4033340  PMID: 24895574
17.  Co-grafting of neural stem cells with olfactory en sheathing cells promotes neuronal restoration in traumatic brain injury with an anti-inflammatory mechanism 
We sought to investigate the effects of co-grafting neural stem cells (NSCs) with olfactory ensheathing cells (OECs) on neurological behavior in rats subjected to traumatic brain injury (TBI) and explore underlying molecular mechanisms.
TBI was established by percussion device made through a weight drop (50 g) from a 30 cm height. Cultured NSCs and OECs isolated from rats were labeled by Hoechst 33342 (blue) and chloromethyl-benzamidodialkyl carbocyanine (CM-Dil) (red), respectively. Then, NSCs and/or OECs, separately or combined, were transplanted into the area surrounding the injury site. Fourteen days after transplantation, neurological severity score (NSS) were recorded. The brain tissue was harvested and processed for immunocytochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reverse transcription-polymerase chain reaction (RT-PCR).
Significant neurological function improvement was observed in the three transplant groups, compared to the TBI group, and co-transplantation gave rise to the best improvement. Morphological evaluation showed that the number of neurons in cortex from combination implantation was more than for other groups (P <0.05); conversely, the number of apoptotic cells showed a significant decrease by TUNEL staining. Transplanted NSCs and OECs could survive and migrate in the brain, and the number of neurons differentiating from NSCs in the co-transplantation group was significantly greater than in the NSCs group. At the molecular level, the expressions of IL-6 and BAD in the co-graft group were found to be down regulated significantly, when compared to either the NSC or OEC alone groups.
The present study demonstrates for the first time the optimal effects of co-grafting NSCs and OECs as a new strategy for the treatment of TBI via an anti-inflammation mechanism.
PMCID: PMC3977666  PMID: 24690089
Neural stem cells (NSCs); Olfactory en sheathing cells (OECs); Traumatic brain injury (TBI); Anti-inflammation
18.  Role of Neuregulin-1/ErbB Signaling in Stem Cell Therapy for Spinal Cord Injury-Induced Chronic Neuropathic Pain 
Stem cells (Dayton, Ohio)  2013;31(1):83-91.
Chronic neuropathic pain is a common and debilitating consequence of spinal cord injury (SCI). In a rat contusion injury model, we observed that chronic neuropathic pain is present on day 7 after SCI and persists for the entire 56-day observation period. However, currently available pain therapies are inadequate for SCI-induced neuropathic pain. In this study, we show that spinal transplantation of mouse embryonic stem cell-derived oligodendrocyte progenitor cells (OPCs) enhances remyelination in the injured spinal cord and reduces SCI-induced chronic neuropathic pain. Moreover, we found that SCI reduces the protein level of neuregulin-1 and ErbB4 in the injured spinal cord and that OPC transplantation enhances the spinal expression of both proteins after SCI. Finally, intrathecal injection of neuregulin-1 small interfering RNA, but not the control nontarget RNA, diminishes OPC transplantation-produced remyelination and reverses the antinociceptive effect of OPC transplantation. Our findings suggest that the transplantation of embryonic stem cell-derived OPCs is an appropriate therapeutic intervention for treatment of SCI-induced chronic neuropathic pain, and that neuregulin-1/ErbB signaling plays an important role in central remyelination under pathological conditions and contributes to the alleviation of such pain.
PMCID: PMC3682663  PMID: 23097328
Spinal cord injury; Chronic neuropathic pain; Stem cell transplantation; Neuregulin-1/ErbB signaling
19.  Hyperbaric oxygen therapy improves cognitive functioning after brain injury 
Neural Regeneration Research  2013;8(35):3334-3343.
Hyperbaric oxygen therapy has been widely applied and recognized in the treatment of brain injury; however, the correlation between the protective effect of hyperbaric oxygen therapy and changes of metabolites in the brain remains unclear. To investigate the effect and potential mechanism of hyperbaric oxygen therapy on cognitive functioning in rats, we established traumatic brain injury models using Feeney's free falling method. We treated rat models with hyperbaric oxygen therapy at 0.2 MPa for 60 minutes per day. The Morris water maze test for spatial navigation showed that the average escape latency was significantly prolonged and cognitive function decreased in rats with brain injury. After treatment with hyperbaric oxygen therapy for 1 and 2 weeks, the rats’ spatial learning and memory abilities were improved. Hydrogen proton magnetic resonance spectroscopy analysis showed that the N-acetylaspartate/creatine ratio in the hippocampal CA3 region was significantly increased at 1 week, and the N-acetylaspartate/choline ratio was significantly increased at 2 weeks after hyperbaric oxygen therapy. Nissl staining and immunohistochemical staining showed that the number of nerve cells and Nissl bodies in the hippocampal CA3 region was significantly increased, and glial fibrillary acidic protein positive cells were decreased after a 2-week hyperbaric oxygen therapy treatment. Our findings indicate that hyperbaric oxygen therapy significantly improves cognitive functioning in rats with traumatic brain injury, and the potential mechanism is mediated by metabolic changes and nerve cell restoration in the hippocampal CA3 region.
PMCID: PMC4145948  PMID: 25206655
neural regeneration; brain injury; hyperbaric oxygen; magnetic resonance spectroscopy; astrocytes; immunohistochemistry; choline; creatine; N-acetylaspartate; CA3 region; Morris water maze; hippocampus; neuroregeneration
20.  Characterization, pharmacokinetics, and hypoglycemic effect of berberine loaded solid lipid nanoparticles 
The high aqueous solubility, poor permeability, and absorption of berberine (BBR) result in its low plasma level after oral administration, which greatly limits its clinical application. BBR solid lipid nanoparticles (SLNs) were prepared to achieve improved bioavailability and prolonged effect. Developed SLNs showed homogeneous spherical shapes, small size (76.8 nm), zeta potential (7.87 mV), encapsulation efficiency (58%), and drug loading (4.2%). The power of X-ray diffraction combined with 1H nuclear magnetic resonance spectroscopy was employed to analyze chemical functional groups and the microstructure of BBR-SLNs, and indicated that the drug was wrapped in a lipid carrier. Single dose (50 mg/kg) oral pharmacokinetic studies in rats showed significant improvement (P<0.05) in the peak plasma concentration, area under the curve, and variance of mean residence time of BBR-SLNs when compared to BBR alone (P<0.05), suggesting improved bioavailability. Furthermore, oral administration of both BBR and BBR-SLNs significantly suppressed body weight gain, fasting blood glucose levels, and homeostasis assessment of insulin resistance, and ameliorated impaired glucose tolerance and insulin tolerance in db/db diabetic mice. BBR-SLNs at high dose (100 mg/kg) showed more potent effects when compared to an equivalent dose of BBR. Morphologic analysis demonstrated that BBR-SLNs potentially promoted islet function and protected the islet from regeneration. In conclusion, our study demonstrates that by entrapping BBR into SLNs the absorption of BBR and its anti-diabetic action were effectively enhanced.
PMCID: PMC3862509  PMID: 24353417
berberine; solid lipid nanoparticles; pharmacokinetic; hypoglycemic effect
21.  Changes in weight and health behaviors after pregnancies complicated by gestational diabetes mellitus: The CARDIA Study 
Obesity (Silver Spring, Md.)  2013;21(6):1269-1275.
We compared pre- to post-pregnancy change in weight, body mass index (BMI), waist circumference, diet and physical activity in women with and without gestational diabetes mellitus (GDM).
Using the Coronary Artery Risk Development in Young Adults (CARDIA) study we identified women with at least one pregnancy during 20 years of follow-up (n=1,488 with 3,125 pregnancies). We used linear regression with generalized estimating equations to compare pre- to post-pregnancy changes in health behaviors and anthropometric measurements between 137 GDM pregnancies and 1,637 non GDM pregnancies, adjusted for parity, age at delivery, outcome measure at the pre-pregnancy exam, race, education, mode of delivery, and interval between delivery and post-pregnancy examination.
Compared with women without GDM in pregnancy, women with GDM had higher pre-pregnancy mean weight (158.3 vs. 149.6 lb, p=0.011) and BMI (26.7 vs. 25.1 kg/m2, p=0.002), but non-significantly lower total daily caloric intake and similar levels of physical activity. Both GDM and non GDM groups had higher average postpartum weight of 7–8 lbs and decreased physical activity on average 1.4 years after pregnancy. Both groups similarly increased total caloric intake but reduced fast food frequency. Pre- to post- pregnancy changes in body weight, BMI, waist circumference, physical activity and diet did not differ between women with and without GDM in pregnancy.
Following pregnancy women with and without GDM increased caloric intake, BMI and weight, decreased physical activity, but reduced their frequency of eating fast food. Given these trends, postpartum lifestyle interventions, particularly for women with GDM, are needed to reduce obesity and diabetes risk.
PMCID: PMC3735637  PMID: 23666593
22.  New developments in the Induction and Antiviral Effectors of Type I Interferon 
Current opinion in immunology  2010;23(1):10.1016/j.coi.2010.11.003.
Type I Interferons are cytokines of the innate immune system that induce antiviral protein expression in response to viral infection. Various proteins and pathways have been shown to recognize nucleic acids ligands especially from RNA viruses. Here, we will review recent developments including transcription of DNA virus genomes into RNA ligands, and the recognition of viruses by TLR2 for interferon induction. The induced IFNs activate many interferon stimulated genes (ISGs) that have direct anti-viral effects. Recent studies have identified IFITM proteins as the first ISG to inhibit viral entry processes and revealed mechanistic understanding of known anti-viral ISGs such as ISG15 and Viperin.
PMCID: PMC3822007  PMID: 21123041
23.  Cardiovascular disease risk reduction in rural China: a clustered randomized controlled trial in Zhejiang 
Trials  2013;14:354.
Cardiovascular disease (CVD) is a major cause of death in China. Despite government efforts, the majority of hypertensive and diabetic patients in China do not receive proper treatment. Reducing CVD events requires long-term care that is proactive, patient-centred, community-based, and sustainable. We have designed a package of interventions for patients at high risk of CVD to be implemented by family doctors based in township hospitals (providers of primary care) in rural Zhejiang, China. This trial aims to determine whether the systematic CVD risk reduction package results in reduced CVD events among patients at risk of CVD compared with usual care, and whether the package is cost-effective and suitable for routine implementation and scale-up.
This is a prospective, open-label, cluster randomized controlled trial (RCT) with blinded data analysis. The trial will randomize 67 township hospitals with 31,708 participants in three counties in Zhejiang Province. Participants will be identified from existing health records and will comprise adults aged 50 to 74 years, with a calculated 10-year CVD risk of 20% or higher, or diabetes. In the intervention arm, participants will receive a package of interventions including: 1) healthy lifestyle counseling (smoking cessation, and salt, oil, and alcohol reduction); 2) prescription of a combination of drugs (antihypertensives, aspirin, and statin); and 3) adherence support for drug compliance and healthy lifestyle change. In the control arm, participants will receive usual care for hypertension and diabetes management at individual clinicians’ discretion. The primary outcome is the incidence of severe CVD events over 24 months of follow-up. All CVD events will be defined according to the World Health Organization (WHO) monitoring of trends and determinants in cardiovascular disease (MONICA) definitions, diagnosed at the county hospital or higher level, and reported by the Zhejiang surveillance system. Secondary outcomes include: mean systolic and diastolic blood pressure, blood glucose, serum total cholesterol (TC), and adherence to appointments, and drugs and lifestyle changes.
This trial focuses on risk reduction of CVD rather than specific diseases. It is not designed to compare therapeutic and healthy lifestyle interventions, but rather their combined effects in primary care settings. Through the trial, we intend to understand the effectiveness of the comprehensive CVD reduction package in routine practice. We also intend to understand the barriers and facilitators to implementing the package, and thus to advise on policy and practice change.
Trial registration
Current Controlled Trials: ISRCTN58988083
PMCID: PMC4015636  PMID: 24160442
Cardiovascular disease; Risk; Events; Randomized controlled trial; Primary care
24.  Targeted Delivery of an Antigenic Peptide to the Endoplasmic Reticulum: Application for Development of a Peptide Therapy for Ankylosing Spondylitis 
PLoS ONE  2013;8(10):e77451.
The development of suitable methods to deliver peptides specifically to the endoplasmic reticulum (ER) can provide some potential therapeutic applications of such peptides. Ankylosing spondylitis (AS) is strongly associated with the expression of human leukocytic antigen-B27 (HLA-B27). HLA-B27 heavy chain (HC) has a propensity to fold slowly resulting in the accumulation of misfolded HLA-B27 HC in the ER, triggering the unfolded protein response, and forming a homodimer, (B27-HC)2. Natural killer cells and T-helper 17 cells are then activated, contributing to the major pathogenic potentials of AS. The HLA-B27 HC is thus an important target, and delivery of an HLA-B27-binding peptide to the ER capable of promoting HLA-B27 HC folding is a potential mechanism for AS therapy. Here, we demonstrate that a His6-ubiquitin-tagged Tat-derived peptide (THU) can deliver an HLA-B27-binding peptide to the ER promoting HLA-B27 HC folding. The THU-HLA-B27-binding peptide fusion protein crossed the cell membrane to the cytosol through the Tat-derived peptide. The HLA-B27-binding peptide was specifically cleaved from THU by cytosolic ubiquitin C-terminal hydrolases and subsequently transported into the ER by the transporter associated with antigen processing. This approach has potential application in the development of peptide therapy for AS.
PMCID: PMC3796468  PMID: 24155957
25.  Microfluidic system for measuring neutrophil migratory responses to fast switches of chemical gradients† 
Lab on a chip  2005;6(2):191-198.
Experimental systems that provide temporal and spatial control of chemical gradients are required for probing into the complex mechanisms of eukaryotic cell chemotaxis. However, no current technique can simultaneously generate stable chemical gradients and allow fast gradient changes. We developed a microfluidic system with microstructured membranes for exposing neutrophils to fast and precise changes between stable, linear gradients of the known chemoattractant Interleukin-8 (IL-8). We observed that rapidly lowering the average concentration of IL-8 within a gradient, while preserving the direction of the gradient, resulted in temporary neutrophil depolarization. Fast reversal of the gradient direction while increasing or decreasing the average concentration also resulted in temporary depolarization. Neutrophils adapted and maintained their directional motility, only when the average gradient concentration was increased and the direction of the gradient preserved. Based on these observations we propose a two-component temporal sensing mechanism that uses variations of chemokine concentration averaged over the entire cell surface and localized at the leading edge, respectively, and directs neutrophil responses to changes in their chemical microenvironment.
PMCID: PMC3763904  PMID: 16450027

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