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author:("Zhao, lipins")
1.  Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice 
The ISME Journal  2014;9(1):1-15.
Structural disruption of gut microbiota and associated inflammation are considered important etiological factors in high fat diet (HFD)-induced metabolic syndrome (MS). Three candidate probiotic strains, Lactobacillus paracasei CNCM I-4270 (LC), L. rhamnosus I-3690 (LR) and Bifidobacterium animalis subsp. lactis I-2494 (BA), were individually administered to HFD-fed mice (108 cells day−1) for 12 weeks. Each strain attenuated weight gain and macrophage infiltration into epididymal adipose tissue and markedly improved glucose–insulin homeostasis and hepatic steatosis. Weighted UniFrac principal coordinate analysis based on 454 pyrosequencing of fecal bacterial 16S rRNA genes showed that the probiotic strains shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean mice fed a normal (chow) diet. Redundancy analysis revealed that abundances of 83 operational taxonomic units (OTUs) were altered by probiotics. Forty-nine altered OTUs were significantly correlated with one or more host MS parameters and were designated ‘functionally relevant phylotypes'. Thirteen of the 15 functionally relevant OTUs that were negatively correlated with MS phenotypes were promoted, and 26 of the 34 functionally relevant OTUs that were positively correlated with MS were reduced by at least one of the probiotics, but each strain changed a distinct set of functionally relevant OTUs. LC and LR increased cecal acetate but did not affect circulating lipopolysaccharide-binding protein; in contrast, BA did not increase acetate but significantly decreased adipose and hepatic tumor necrosis factor-α gene expression. These results suggest that Lactobacillus and Bifidobacterium differentially attenuate obesity comorbidities in part through strain-specific impacts on MS-associated phylotypes of gut microbiota in mice.
PMCID: PMC4274436  PMID: 24936764
2.  Statins and Cognitive Decline in Older Adults With Normal Cognition or Mild Cognitive Impairment 
Controversy exists regarding statins’ effects on cognitive decline in the healthy elderly. Prior longitudinal studies show mixed results; most have not evaluated normal and MCI subjects separately.
Design, Setting, and Participants
Participants were enrolled in the National Institute of Aging network of Alzheimer’s Disease Centers. We conducted a longitudinal study, comparing baseline cognition and rate of decline in statin users (n=1244) and non-users (n=2363) among research volunteers with normal cognition at baseline, evaluated an average 4.1 times over 3.4 years. Comparable analyses were conducted for 763 users and 917 non-users with mild cognitive impairment (MCI) at baseline (3.9 visits during 2.8 years). We conducted repeated measures analyses adjusted for age, gender, education, comorbidities, and family history of dementia.
Cognitive performance was assessed via ten neuropsychological indices and the Clinical Dementia Rating Sum of Boxes (CDR-SOB).
Among those with normal cognition at baseline, statin users performed significantly better across all visits in attention (Trails A). They also showed significantly slower annual worsening in CDR-SOB scores (p=0.006), and borderline significantly slower worsening in MMSE scores, compared with non-users (adjusting for multiple comparisons). For MCI subjects, statin users performed significantly better across all visits on attention measures (Trails A), verbal skills (Category Fluency) and executive functioning (Trails B, Digit Symbol, and Digits Backward). However, there were no differences in cognitive decline between users and non-users.
This study indicates elderly subjects with normal cognition at baseline who use statins have a slower rate of annual worsening in CDR-SOB than non-users.
PMCID: PMC3773248  PMID: 24000778
cognitive decline; statins
3.  Prevalence and Drug Resistance of Nontuberculous Mycobacteria, Northern China, 2008–2011 
Emerging Infectious Diseases  2014;20(7):1252-1253.
PMCID: PMC4073877  PMID: 24959839
Mycobacteria tuberculosis; nontuberculous; bacteria; mycobacteria; China; Mycobacteriaceae; antibiotic; antimicrobial; resistance
4.  Assessing the Effectiveness of Problem-Based Learning of Preventive Medicine Education in China 
Scientific Reports  2014;4:5126.
Problem-based learning (PBL) is defined as a student-centered pedagogy which can provide learners more opportunities for application of knowledge acquired from basic science to the working situations than traditional lecture-based learning (LBL) method. In China, PBL is increasingly popular among preventive medicine educators, and multiple studies have investigated the effectiveness of PBL pedagogy in preventive medicine education. A pooled analysis based on 15 studies was performed to obtain an overall estimate of the effectiveness of PBL on learning outcomes of preventive medicine. Overall, PBL was associated with a significant increase in students' theoretical examination scores (SMD = 0.62, 95% CI = 0.41–0.83) than LBL. For the attitude- and skill-based outcomes, the pooled PBL effects were also significant among learning attitude (OR = 3.62, 95% CI = 2.40–5.16), problem solved skill (OR = 4.80, 95% CI = 2.01–11.46), self-directed learning skill (OR = 5.81, 95% CI = 3.11–10.85), and collaborative skill (OR = 4.21, 95% CI = 0.96–18.45). Sensitivity analysis showed that the exclusion of a single study did not influence the estimation. Our results suggest that PBL of preventive medicine education in China appears to be more effective than LBL in improving knowledge, attitude and skills.
PMCID: PMC4038805  PMID: 24874915
5.  Effect of Saccharomyces cerevisiae on alfalfa nutrient degradation characteristics and rumen microbial populations of steers fed diets with different concentrate-to-forage ratios 
Live yeast (Saccharomyces cerevisiae) constitutes an effective additive for animal production; its probiotic effect may be related to the concentrate-to-forage ratio (CTFR). The objective of this study was to assess the effects of S. cerevisiae (SC) on fiber degradation and rumen microbial populations in steers fed diets with different levels of dietary concentrate. Ten Simmental × Local crossbred steers (450 ± 50 kg BW) were assigned to a control group or an SC group. Both groups were fed the same basal diet but the SC group received SC supplementation (8 × 109 cfu/h/d through the ruminal fistula) following a two-period crossover design. Each period consisted of four phases, each of which lasted 17 d: 10 d for dietary adaptation, 6 d for degradation study, and 1 d for rumen sample collection. From the 1st to the 4th phase, steers were fed in a stepwise fashion with increasing CTFRs, i.e., 30:70, 50:50, 70:30, and 90:10. The kinetics of dry matter and fiber degradation of alfalfa pellets were evaluated; the rumen microbial populations were detected using real-time PCR. The results revealed no significant (P > 0.05) interactions between dietary CTFR and SC for most parameters. Dietary CTFR had a significant effect (P < 0.01) on degradation characteristics of alfalfa pellets and the copies of rumen microorganism; the increasing concentrate level resulted in linear, quadratic or cubic variation trend for these parameters. SC supplementation significantly (P < 0.05) affected dry matter (DM) and neutral detergent fiber (NDF) degradation rates (cDM, cNDF) and NDF effective degradability (EDNDF). Compared with the control group, there was an increasing trend of rumen fungi and protozoa in SC group (P < 0.1); copies of total bacteria in SC group were significantly higher (P < 0.05). Additionally, percentage of Ruminobacter amylophilus was significantly lower (P < 0.05) but percentage of Selenomonas ruminantium was significantly higher (P < 0.05) in the SC group. In a word, dietary CTFR had a significant effect on degradation characteristics of forage and rumen microbial population. S. cerevisiae had positive effects on DM and NDF degradation rate or effective degradability of forage; S. cerevisiae increased rumen total bacteria, fungi, protozoa, and lactate-utilizing bacteria but reduced starch-degrading and lactate-producing bacteria.
PMCID: PMC4025562  PMID: 24883184
Concentrate-to-forage ratios; In situ; Real-time PCR; Rumen microorganism; Steers
6.  Association between Depression and Inflammation – Differences by Race and Sex: The META-Health Study 
Psychosomatic medicine  2011;73(6):462-468.
To test whether the association between depression and inflammation differs by race and sex. Depressive symptoms have been associated with higher levels of CRP. However few studies have examined this association in samples including a significant number of African Americans, or whether the association differs by race and gender.
Depressive symptoms and CRP were assessed in 512 African American and White participants, age 30–65 years, as part of the community-based META-Health Study. Depression was determined by responses to the Beck’s Depression Inventory-II (BDI-II). Multivariable linear regression models were used to adjust for demographic and metabolic risk factors.
African American men had higher total BDI-II scores than White men (p=0.03), while there was no difference in women. There was a significant race X gender X depression interaction in predicting CRP levels (p=0.02). White women with mild to severe depressive symptoms had higher levels of CRP compared to those with minimal to no depressive symptoms (p<0.05). There were no differences in levels of CRP by severity of depressive symptoms in White men or African Americans of either sex. Higher BDI-II scores were related to higher CRP levels in White women after adjusting for age and level of education (β=0.227, p=0.006). However the association was eliminated after further adjustment for metabolic risk factors (β=0.077, p=0.35).
Although depressive symptoms are associated with inflammation, the association varies by race and gender.
PMCID: PMC3951048  PMID: 21715300
depression; inflammation; race/ethnicity; gender
7.  A Pilot Study Comparing the Development of EIAV Env-Specific Antibodies Induced by DNA/Recombinant Vaccinia-Vectored Vaccines and an Attenuated Chinese EIAV Vaccine 
Viral Immunology  2012;25(6):477-484.
Data from successful attenuated lentiviral vaccine studies indicate that fully mature Env-specific antibodies characterized by high titer, high avidity, and the predominant recognition of conformational epitopes are associated with protective efficacy. Although vaccination with a DNA prime/recombinant vaccinia-vectored vaccine boost strategy has been found to be effective in some trials with non-human primate/simian/human immunodeficiency virus (SHIV) models, it remains unclear whether this vaccination strategy could elicit mature equine infectious anemia virus (EIAV) Env-specific antibodies, thus protecting vaccinated horses against EIAV infection. Therefore, in this pilot study we vaccinated horses using a strategy based on DNA prime/recombinant Tiantan vaccinia (rTTV)-vectored vaccines encoding EIAV env and gag genes, and observed the development of Env-specific antibodies, neutralizing antibodies, and p26-specific antibodies. Vaccination with DNA induced low titer, low avidity, and the predominant recognition of linear epitopes by Env-specific antibodies, which was enhanced by boosting vaccinations with rTTV vaccines. However, the maturation levels of Env-specific antibodies induced by the DNA/rTTV vaccines were significantly lower than those induced by the attenuated vaccine EIAVFDDV. Additionally, DNA/rTTV vaccines did not elicit broadly neutralizing antibodies. After challenge with a virulent EIAV strain, all of the vaccinees and control horses died from EIAV disease. These data indicate that the regimen of DNA prime/rTTV vaccine boost did not induce mature Env-specific antibodies, which might have contributed to immune protection failure.
PMCID: PMC3518545  PMID: 23171359
8.  Interleukin-22 deficiency alters colonic microbiota to be transmissible and colitogenic 
Interleukin-22 (IL-22) is a good candidate to play a critical role in regulating gut microbiota because it is an important inducer of antimicrobial peptides and mucins in the gut. However, whether IL-22 participates into immune homeostasis by way of modulating gut microbiota remains to be elucidated. In this study, we find through 16S rRNA gene pyrosequencing analysis that healthy IL-22 deficient mice had altered colonic microbiota, notably with decreased abundance of some genera including Lactobacillus and increased levels of others. Mice harboring this altered microbiota exhibited more severe disease during experimentally-induced colitis. Interestingly, this altered gut microbiota can be transmitted to co-housed wild-type animals along with the increased susceptibility to this colitis, indicating an important role of IL-22 in shaping the homeostatic balance between immunity and colonic microbiota for host health.
PMCID: PMC3646987  PMID: 23585682
9.  Structural resilience of the gut microbiota in adult mice under high-fat dietary perturbations 
The ISME Journal  2012;6(10):1848-1857.
Disruption of the gut microbiota by high-fat diet (HFD) has been implicated in the development of obesity. It remains to be elucidated whether the HFD-induced shifts occur at the phylum level or whether they can be attributed to specific phylotypes; additionally, it is unclear to what extent the changes are reversible under normal chow (NC) feeding. One group (diet-induced obesity, DIO) of adult C57BL/6J mice was fed a HFD for 12 weeks until significant obesity and insulin resistance were observed, and then these mice were switched to NC feeding for 10 weeks. Upon switching to NC feeding, the metabolic deteriorations observed during HFD consumption were significantly alleviated. The second group (control, CHO) remained healthy under continuous NC feeding. UniFrac analysis of bar-coded pyrosequencing data showed continued structural segregation of DIO from CHO on HFD. At 4 weeks after switching back to NC, the gut microbiota in the DIO group had already moved back to the CHO space, and continued to progress along the same age trajectory and completely converged with CHO after 10 weeks. Redundancy analysis identified 77 key phylotypes responding to the dietary perturbations. HFD-induced shifts of these phylotypes all reverted to CHO levels over time. Some of these phylotypes exhibited robust age-related changes despite the dramatic abundance variations in response to dietary alternations. These findings suggest that HFD-induced structural changes of the gut microbiota can be attributed to reversible elevation or diminution of specific phylotypes, indicating the significant structural resilience of the gut microbiota of adult mice to dietary perturbations.
PMCID: PMC3446802  PMID: 22495068
dietary perturbations; gut microbiota; obesity; resilience
10.  Budget impact and sustainability of medical care management for persons with serious mental illnesses 
The American journal of psychiatry  2011;168(11):1171-1178.
This study assesses the two-year outcomes, costs, and financial sustainability of a medical care management intervention for community mental health settings.
A total of 407 psychiatric outpatients with serious mental illnesses were randomized to usual care or to a medical care manager, who provided care coordination and education. Two-year follow-up chart reviews and interviews assessed quality and outcomes of care, and costs from both the health system and managerial perspective.
Subjects in the intervention group had sustained improvements in quality of primary care preventive services (p<0.001), quality of cardiometabolic care (p<0.001), and mental health-related quality of life (p<0.001). From a health system perspective, by year 2, the program showed a $932 reduction in total costs (95% CI (−1973, 102) with a 92.3% probability that the program was associated with lower costs than usual care. From the community mental health center perspective, the program would break even (i.e., revenues would cover setup costs) if 58% or more of clients had Medicaid or another form of insurance. Given that only 40.5% of clients in the study had Medicaid, the program was not sustainable after grant funding ended.
The positive long-term outcomes and favorable cost profile provided evidence of the potential value of this model. However, the discrepancy between health system and managerial cost perspectives limited the program’s financial sustainability. With anticipated insurance expansions under health reform, there is likely to be a stronger business case for safety net organizations considering implementing these and other evidence-based interventions.
PMCID: PMC3775649  PMID: 21676993
11.  The Primary Care Access Referral, and Evaluation (PCARE) Study: A Randomized Trial of Medical Care Management for Community Mental Health Settings 
The American journal of psychiatry  2009;167(2):151-159.
Poor quality of health care contributes to impaired health and excess mortality in individuals with severe mental disorders. This study tests a population-based medical care management intervention to improve primary medical care in community mental health settings.
A total of 407 subjects with severe mental illnesses at an urban community mental health center were randomized to either care management or usual care. For individuals in the intervention group, care managers provided communication and advocacy with medical providers, health education for patients, and support in overcoming system-level fragmentation and barriers to primary medical care.
At 12-month follow-up, the intervention group received an average of 58.7% of recommended preventive services, compared to 21.8% in the usual care group (p<0.001). They received a significantly higher proportion of evidence-based services for cardiometabolic conditions (34.9% vs. 27.7%, p=0.03), and were more likely to have a primary care provider (71.2% vs. 51.9%, p=0.003). On the SF-36, the intervention group showed significant improvement on the Mental Component Summary score (8.0% improvement in intervention versus 1.1% decline in the control group, p=0.008) with a nonsigificant improvement on the Physical Component Summary score. Among subjects with available laboratory data, Framingham Cardiovascular Risk Scores were significantly lower (better) for intervention (6.9%) than control (9.8%) subjects (p=0.02).
Medical care management was associated with significant improvements in quality and outcomes of primary care. The findings suggest that care management is a promising approach for improving medical care for patients treated in community mental health settings. identifier NCT00183313
PMCID: PMC3775666  PMID: 20008945
12.  Differences in Systemic Oxidative Stress Based on Race and the Metabolic Syndrome: The Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) Study 
Classification schema such as metabolic syndrome may underestimate cardiovascular disease (CVD) risk in African Americans, despite a higher burden of CVD in African Americans. Oxidative stress results from an imbalance of prooxidants and antioxidants and leads to endothelial dysfunction that promotes vascular inflammation and atherosclerosis. Aminothiol markers of oxidative stress are associated with CVD risk factors and metabolic syndrome; however, little is known about racial differences in levels of oxidative stress. We sought to investigate whether oxidative stress would be higher in African Americans compared to whites independently of traditional risk factor burden.
We assessed oxidative stress in a biracial, community-based cohort. In 620 subjects (59% female, 52% African American) in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study, we measured plasma levels of glutathione, an intracellular antioxidant, and its redox potential as a ratio of reduced and oxidized glutathione (Eh glutathione).
African Americans had lower glutathione levels (P<0.001) compared to whites. There was a trend toward more oxidized Eh glutathione (P=0.07) in African Americans; however, this did not reach statistical significance. After adjustment for demographics and CVD risk factors, African-American race remained a significant correlate of lower glutathione levels (P<0.001) and a more oxidized Eh glutathione (P=0.04). After further adjustment for high-sensitivity C-reactive protein (hsCRP), glutathione remained significantly lower in African Americans (P=0.001). African Americans with or without metabolic syndrome had lower glutathione levels compared to whites with or without metabolic syndrome, respectively (both P≤0.001), and African Americans without metabolic syndrome had a more oxidized Eh glutathione compared to whites without metabolic syndrome (P=0.003).
African Americans have higher levels of oxidative stress than whites, even after adjustment for differences in CVD risk factors and inflammation. Racial differences in oxidative stress may play a key role in understanding observed racial disparities in CVD.
PMCID: PMC3449394  PMID: 22385338
13.  Ulcerative Colitis and Perfluorooctanoic Acid (PFOA) in a Highly Exposed Population of Community Residents and Workers in the Mid-Ohio Valley 
Environmental Health Perspectives  2013;121(8):900-905.
Background: Little is known about environmental determinants of autoimmune diseases.
Objectives: We studied autoimmune diseases in relation to level of exposure to perfluorooctanoic acid (PFOA), which was introduced in the late 1940s and is now ubiquitous in the serum of residents of industrialized countries.
Methods: In 2008–2011 we interviewed 32,254 U.S. adults with high serum PFOA serum levels (median, 28 ng/mL) associated with drinking contaminated water near a chemical plant. Disease history was assessed retrospectively from 1952 or birth (if later than 1952) until interview. Self-reported history of autoimmune disease was validated via medical records. Cumulative exposure to PFOA was derived from estimates of annual mean serum PFOA levels during follow-up, which were based on plant emissions, residential and work history, and a fate-transport model. Cox regression models were used to estimate associations between quartiles of cumulative PFOA serum levels and the incidence of autoimmune diseases with ≥ 50 validated cases, including ulcerative colitis (n = 151), Crohn’s disease (n = 96), rheumatoid arthritis (n = 346), insulin-dependent diabetes (presumed to be type 1) (n = 160), lupus (n = 75), and multiple sclerosis (n = 98).
Results: The incidence of ulcerative colitis was significantly increased in association with PFOA exposure, with adjusted rate ratios by quartile of exposure of 1.00 (referent), 1.76 (95% CI: 1.04, 2.99), 2.63 (95% CI: 1.56, 4.43), and 2.86 (95% CI: 1.65, 4.96) (ptrend < 0.0001). A prospective analysis of ulcerative colitis diagnosed after the baseline 2005–2006 survey (n = 29 cases) suggested a positive but non-monotonic trend (ptrend = 0.21).
Discussion: To our knowledge, this is the first study of associations between this common environmental exposure and autoimmune diseases in humans. We found evidence that PFOA is associated with ulcerative colitis.
PMCID: PMC3734500  PMID: 23735465
autoimmune; inflammatory bowel disease; PFOA; ulcerative colitis
14.  Clinical significance of the thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase mRNA expressions in hepatocellular carcinoma patients receiving 5-fluorouracil-based transarterial chemoembolization treatment 
OncoTargets and therapy  2013;6:811-818.
To determine whether 5-fluorouracil (5-FU) sensitivity is associated with the mRNA expressions of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in patients with hepatocellular carcinoma (HCC) treated with 5-FU-based transarterial chemoembolization (TACE).
Formalin-fixed, paraffin-embedded tumor specimens from 40 patients treated with 5-FU-based TACE were selected for the examination of TS, DPD, and TP expression level by a quantitative real-time reverse transcription- polymerase chain reaction (PCR) technique. Patients were categorized into high and low expression groups according to the median expression level of each enzyme. Associations between the mRNA expression levels of TS, DPD, and TP and clinical parameters including treatment efficacies, clinicopathological factors, and prognosis were assessed.
High DPD expression was associated with worse treatment outcome, including intrahepatic disease progression rate (hazard ratio [HR] for high DPD versus low DPD, 2.212; 95% confidence interval [CI], 1.030–4.753; P = 0.042), extrahepatic disease progression rate (HR for high versus low DPD, 3.171; 95% CI, 1.003–10.023; P = 0.049), and progression-free survival (HR for high versus low DPD, 2.308; 95% CI, 1.102–4.836; P = 0.027). No correlation was found between the mRNA expression of TS/TP and treatment outcome.
DPD mRNA expression level was negatively correlated with the clinical outcomes of HCC patients treated with 5-FU-based TACE. These results provide indirect evidence that high DPD mRNA expression is a predictive marker of treatment resistance for 5-FU.
PMCID: PMC3704606  PMID: 23861589
dihydropyrimidine dehydrogenase; 5-fluorouracil; hepatocellular carcinoma; thymidylate synthase; thymidine phosphorylase; transarterial chemoembolization
15.  Mental Comorbidity and Quality of Diabetes Care Under Medicaid: A 50-State Analysis 
Medical Care  2012;50(5):428-433.
Patients with comorbid medical and mental conditions are at risk for poor quality of care. With the anticipated expansion of Medicaid under health reform, it is particularly important to develop national estimates of the magnitude and correlates of quality deficits related to mental comorbidity among Medicaid enrollees.
For all 657,628 fee-for-service Medicaid enrollees with Diabetes during 2003-4, the study compared HEDIS diabetes performance measures (Hemoglobin A1C, eye exams, LDL screening, and treatment for nephropathy), and admissions for ambulatory care-sensitive admissions (ACSCs) between persons with and without mental comorbidity. Nested hierarchical models included individual, county and state-level measures.
A total of 17.8% of the diabetic sample had a comorbid mental condition. In adjusted models, presence of a mental condition was associated with a 0.83 (0.82 - 0.85) odds of obtaining 2 or more HEDIS indicators, and a 1.32 (1.29-1.34) increase in odds of one or more ACSC hospitalization Among those with diabetes and mental comorbidities, living in a county with a shortage of primary care physicians was associated with reduced performance on HEDIS measures; living in a state with higher Medicaid reimbursement fees and department of mental health expenses per client were associated both with higher quality on HEDIS measures and lower (better) rates of ACSC hospitalizations.
Among persons with diabetes treated in the Medicaid system, mental comorbidity is an important risk factor for both underuse and overuse of medical care. Modifiable county and state-level factors may mitigate these quality deficits.
PMCID: PMC3360811  PMID: 22228248
16.  An opportunistic pathogen isolated from the gut of an obese human causes obesity in germfree mice 
The ISME Journal  2012;7(4):880-884.
Lipopolysaccharide endotoxin is the only known bacterial product which, when subcutaneously infused into mice in its purified form, can induce obesity and insulin resistance via an inflammation-mediated pathway. Here we show that one endotoxin-producing bacterium isolated from a morbidly obese human's gut induced obesity and insulin resistance in germfree mice. The endotoxin-producing Enterobacter decreased in relative abundance from 35% of the volunteer's gut bacteria to non-detectable, during which time the volunteer lost 51.4 kg of 174.8 kg initial weight and recovered from hyperglycemia and hypertension after 23 weeks on a diet of whole grains, traditional Chinese medicinal foods and prebiotics. A decreased abundance of endotoxin biosynthetic genes in the gut of the volunteer was correlated with a decreased circulating endotoxin load and alleviated inflammation. Mono-association of germfree C57BL/6J mice with strain Enterobacter cloacae B29 isolated from the volunteer's gut induced fully developed obesity and insulin resistance on a high-fat diet but not on normal chow diet, whereas the germfree control mice on a high-fat diet did not exhibit the same disease phenotypes. The Enterobacter-induced obese mice showed increased serum endotoxin load and aggravated inflammatory conditions. The obesity-inducing capacity of this human-derived endotoxin producer in gnotobiotic mice suggests that it may causatively contribute to the development of obesity in its human host.
PMCID: PMC3603399  PMID: 23235292
gut microbiota; germfree mice; endotoxin-producing bacterium; obesity; insulin resistance; high-fat diet
17.  Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers 
The ISME Journal  2011;6(2):320-329.
Despite a long-suspected role in the development of human colorectal cancer (CRC), the composition of gut microbiota in CRC patients has not been adequately described. In this study, fecal bacterial diversity in CRC patients (n=46) and healthy volunteers (n=56) were profiled by 454 pyrosequencing of the V3 region of the 16S ribosomal RNA gene. Both principal component analysis and UniFrac analysis showed structural segregation between the two populations. Forty-eight operational taxonomic units (OTUs) were identified by redundancy analysis as key variables significantly associated with the structural difference. One OTU closely related to Bacteroides fragilis was enriched in the gut microbiota of CRC patients, whereas three OTUs related to Bacteroides vulgatus and Bacteroides uniformis were enriched in that of healthy volunteers. A total of 11 OTUs belonging to the genera Enterococcus, Escherichia/Shigella, Klebsiella, Streptococcus and Peptostreptococcus were significantly more abundant in the gut microbiota of CRC patients, and 5 OTUs belonging to the genus Roseburia and other butyrate-producing bacteria of the family Lachnospiraceae were less abundant. Real-time quantitative PCR further validated the significant reduction of butyrate-producing bacteria in the gut microbiota of CRC patients by measuring the copy numbers of butyryl-coenzyme A CoA transferase genes (Mann–Whitney test, P<0.01). Reduction of butyrate producers and increase of opportunistic pathogens may constitute a major structural imbalance of gut microbiota in CRC patients.
PMCID: PMC3260502  PMID: 21850056
colorectal cancer; gut microbiota; pyrosequencing
18.  Prognostic Significance of the Combined Score of Endothelial Expression of Nucleolin and CD31 in Surgically Resected Non-Small Cell Lung Cancer 
PLoS ONE  2013;8(1):e54674.
Nucleolin is implicated to play a role in angiogenesis, a vital process in tumor growth and metastasis. However, the presence and clinical relevance of nucleolin in human non small cell lung cancer (NSCLC) remains largely unknown. In this study, we explored the expression and prognostic implication of nucleolin in surgically resected NSCLC patients. A cohort of 146 NSCLC patients who underwent surgical resection was selected for tissue microarray. In this tissue microarray, nucleolin expression was measured by immunofluorescence. Staining for CD31, a marker of endothelial cells, was performed to mark blood vessels. A Cox proportional hazards model was used to assess the prognostic significance of nucleolin. Nucleolin expression was observed in 34.2% of all patients, and 64.1% in high CD31 expression patients. The disease-free survival (DFS) was significantly shorter in patients with high nucleolin (CD31hiNCLhi) compared to patients with low tumor blood vessels (CD31loNCLlo) (5 ys of DFS 24% vs 64%, p = 0.002). Such a difference was demonstrated in the following stratified analyses: stage I (p<0.001), squamous cell carcinoma and adenosquamous cell carcinoma (p = 0.028), small tumor (<5 cm, p = 0.008), and surgery alone (p = 0.015). Multivariate analysis further revealed that nucleolin expression independently predicted for worse survival (p = 0.003). This study demonstrates that nucleolin is associated with the clinical outcomes in postoperative NSCLC patients. Thus, the expression levels of nucleolin may provide a new prognostic marker to identify patients at higher risk for treatment failure, especially in some subgroups.
PMCID: PMC3561357  PMID: 23382938
19.  Staphylococcus aureus autoinducer-2 quorum sensing decreases biofilm formation in an icaR-dependent manner 
BMC Microbiology  2012;12:288.
Staphylococcus aureus is an important pathogen that causes biofilm-associated infection in humans. Autoinducer 2 (AI-2), a quorum-sensing (QS) signal for interspecies communication, has a wide range of regulatory functions in both Gram-positive and Gram-negative bacteria, but its exact role in biofilm formation in S. aureus remains unclear.
Here we demonstrate that mutation of the AI-2 synthase gene luxS in S. aureus RN6390B results in increased biofilm formation compared with the wild-type (WT) strain under static, flowing and anaerobic conditions and in a mouse model. Addition of the chemically synthesized AI-2 precursor in the luxS mutation strain (ΔluxS) restored the WT phenotype. Real-time RT-PCR analysis showed that AI-2 activated the transcription of icaR, a repressor of the ica operon, and subsequently a decreased level of icaA transcription, which was presumably the main reason why luxS mutation influences biofilm formation. Furthermore, we compared the roles of the agr-mediated QS system and the LuxS/AI-2 QS system in the regulation of biofilm formation using the ΔluxS strain, RN6911 and the Δagr ΔluxS strain. Our data indicate a cumulative effect of the two QS systems on the regulation of biofilm formation in S. aureus.
These findings demonstrate that AI-2 can decrease biofilm formation in S. aureus via an icaR-activation pathway. This study may provide clues for therapy in S. aureus biofilm-associated infection.
PMCID: PMC3539994  PMID: 23216979
20.  Differences in Weight Perception Among Blacks and Whites 
Journal of Women's Health  2011;20(12):1805-1811.
The prevalence of obesity is higher in blacks than whites, especially in black women, and is known to be associated with major cardiovascular disease risk factors, which are also more prevalent in blacks than whites. Weight perception may contribute to these differences if blacks are more likely to underestimate their weight. We explored race and gender differences in underestimation of weight using body mass index (BMI) and waist circumference (WC), after adjusting for other cardiovascular risk factors.
Methods and Results
We studied 219 white and 240 black women and men as part of the META-Health Study. Perceived weight was assessed over the phone and categorized into three categories: underweight or normal weight, overweight, or obesity. Height, weight, and WC were measured at a subsequent visit, and BMI was calculated. Logistic regression was used to compare the likelihood of underestimating actual weight category by race, before and after adjusting for sociodemographic, lifestyle factors, and medical history. In multivariate analysis, the odds of underestimating BMI category was greater than threefold in blacks compared with whites (OR 3.1, 95% CI 1.9–4.8) and was larger for black women than for black men (p<0.01 for interaction). When abdominal adiposity was taken into account by utilizing WC as a measure of weight, the observed difference in weight underestimation remained.
Our data reveal a significant misperception of weight among blacks, particularly black women, who have the highest burden of obesity. A multifaceted approach with efficient identification of social, cultural, and environmental factors that give rise to obesity tolerance in blacks will provide potential targets for intervention, which may ameliorate weight misperception and the prevalence of excess weight in the black population.
PMCID: PMC3236990  PMID: 21988528
21.  Structural Changes of Gut Microbiota during Berberine-Mediated Prevention of Obesity and Insulin Resistance in High-Fat Diet-Fed Rats 
PLoS ONE  2012;7(8):e42529.
Berberine, a major pharmacological component of the Chinese herb Coptis chinensis, which was originally used to treat bacterial diarrhea, has recently been demonstrated to be clinically effective in alleviating type 2 diabetes. In this study, we revealed that berberine effectively prevented the development of obesity and insulin resistance in high-fat diet (HFD)-fed rats, which showed decreased food intake. Increases in the levels of serum lipopolysaccharide-binding protein, monocyte chemoattractant protein-1, and leptin and decrease in the serum level of adiponectin corrected for body fat in HFD-fed rats were also significantly retarded by the co-administration of berberine at 100 mg/kg body weight. Bar-coded pyrosequencing of the V3 region of 16S rRNA genes revealed a significant reduction in the gut microbiota diversity of berberine-treated rats. UniFrac principal coordinates analysis revealed a marked shift of the gut microbiota structure in berberine-treated rats away from that of the controls. Redundancy analysis identified 268 berberine-responding operational taxonomic units (OTUs), most of which were essentially eliminated, whereas a few putative short-chain fatty acid (SCFA)-producing bacteria, including Blautia and Allobaculum, were selectively enriched, along with elevations of fecal SCFA concentrations. Partial least square regression models based on these 268 OTUs were established (Q2>0.6) for predicting the adiposity index, body weight, leptin and adiponectin corrected for body fat, indicating that these discrete phylotypes might have a close association with the host metabolic phenotypes. Taken together, our findings suggest that the prevention of obesity and insulin resistance by berberine in HFD-fed rats is at least partially mediated by structural modulation of the gut microbiota, which may help to alleviate inflammation by reducing the exogenous antigen load in the host and elevating SCFA levels in the intestine.
PMCID: PMC3411811  PMID: 22880019
22.  Polymorphisms in RYBP and AOAH Genes Are Associated with Chronic Rhinosinusitis in a Chinese Population: A Replication Study 
PLoS ONE  2012;7(6):e39247.
The development of CRS is believed to be the result of combined interactions between the genetic background of the affected subject and environmental factors.
To replicate and extend our recent findings from genetic association studies in chronic rhinosinusitis (CRS) performed in a Canadian Caucasian population in a Chinese population.
In a case-control replication study, DNA samples were obtained from CRS with (n = 306; CRSwNP) and without (n = 332; CRSsNP) nasal polyps, and controls (n = 315) in a Chinese population. A total of forty-nine single nucleotide polymorphisms (SNPs) selected from previous identified SNPs associated with CRS in Canadian population, and SNPs from the CHB HapMap dataset were individually genotyped.
We identified two SNPs respectively in RYBP (rs4532099, p = 2.15E–06, OR = 2.59) and AOAH (rs4504543, p = 0.0001152, OR = 0.58) significantly associated with whole CRS cohort. Subgroup analysis for the presence of nasal polyps (CRSwNP and CRSsNP) displayed significant association in CRSwNP cohorts regarding to one SNP in RYBP (P = 3.24E–006, OR = 2.76). Evidence of association in the CRSsNP groups in terms of 2 SNPs (AOAH_rs4504543 and RYBP_rs4532099) was detected as well. Stratifying analysis by gender demonstrated that none of the selected SNPs were associated with CRSwNP as well as CRSsNP. Meanwhile 3 SNPs (IL1A_rs17561, P = 0.005778; IL1A_rs1800587, P = 0.009561; IRAK4_rs4251513, P = 0.03837) were associated with serum total IgE level.
These genes are biologically plausible, with roles in regulation of transcription (RYBP) and inflammatory response (AOAH). The present data suggests the potential common genetic basis in the development of CRS in Chinese and Caucasian population.
PMCID: PMC3378692  PMID: 22723975
23.  Development of Novel Biodegradable Polymer Scaffolds for Vascular Tissue Engineering 
Tissue Engineering. Part A  2011;17(9-10):1191-1200.
Functional connective tissues have been developed using tissue engineering approach by seeding cells on biodegradable scaffolds such as polyglycolic acid (PGA). However, a major drawback of tissue engineering approaches that utilize synthetic polymers is the persistence of polymer remnants in engineered tissues at the end of culture. Such polymer fragments may significantly degrade tissue mechanics and stimulate local inflammatory responses in vivo. In this study, several polymeric materials with a range of degradation profiles were developed and evaluated for their potential applications in construction of collagen matrix-rich tissues, particularly tissue-engineered blood vessels. The degradation characteristics of these polymers were compared as were their characteristics vis-à-vis cell adhesion and proliferation, collagen synthesis, and ability to support growth of engineered vessels. Under aqueous conditions at 37°C, Polymer I (comprising 84% glycolide and 16% trimethylene carbonate [TMC]) had a similar degradation profile to PGA, Polymer II (comprising 84% glycolide, 14% TMC, and 2% polyethylene succinate) degradedly more slowly, but Polymer III (comprising 87% glycolide, 7% TMC, and 6% polyethylene glycol) had a more extensive degradation as compared to PGA. All polymers supported cell proliferation, but Polymer III improved collagen production and engineered vessel mechanics as compared with PGA. In addition, more slowly degrading polymers were associated with poorer final vessel mechanics. These results suggest that polymers that degrade more quickly during tissue culture actually result in improved engineered tissue mechanics, by virtue of decreased disruption of collagenous extracellular matrix.
PMCID: PMC3079248  PMID: 21143045
24.  Adapting functional genomic tools to metagenomic analyses: investigating the role of gut bacteria in relation to obesity 
Briefings in Functional Genomics  2010;9(5-6):355-361.
With the expanding availability of sequencing technologies, research previously centered on the human genome can now afford to include the study of humans’ internal ecosystem (human microbiome). Given the scale of the data involved in this metagenomic research (two orders of magnitude larger than the human genome) and their importance in relation to human health, it is crucial to guarantee (along with the appropriate data collection and taxonomy) proper tools for data analysis. We propose to adapt the approaches defined for the analysis of gene-expression microarray in order to infer information in metagenomics. In particular, we applied SAM, a broadly used tool for the identification of differentially expressed genes among different samples classes, to a reported dataset on a research model with mice of two genotypes (a high density lipoprotein knockout mouse and its wild-type counterpart). The data contain two different diets (high-fat or normal-chow) to ensure the onset of obesity, prodrome of metabolic syndromes (MS). By using 16S rRNA gene as a genomic diversity marker, we illustrate how this approach can identify bacterial populations differentially enriched among different genetic and dietary conditions of the host. This approach faithfully reproduces highly-relevant results from phylogenetic and standard statistical analyses, used to explain the role of the gut microbiome in relation to obesity. This represents a promising proof-of-principle for using functional genomic approaches in the fast growing area of metagenomics, and warrants the availability of a large body of thoroughly tested and theoretically sound methodologies to this exciting new field.
PMCID: PMC3080776  PMID: 21266343
human microbiome; functional genomic; metagenomics
25.  Predictors of Incident Heart Failure in a Large Insured Population A One Million Person-Year Follow-Up Study 
Circulation. Heart failure  2010;3(6):698-705.
Studies on the incidence and predictors of heart failure (HF) are often restricted to elderly persons or identify only inpatient cases.
Methods and Results
We determined the incidence and predictors of new HF diagnosed in either outpatient or inpatient settings, among 359 947 women and men (age ≥18 years) insured by Kaiser Permanente Georgia at any time during calendar years 2000 to 2005. Subjects were free of HF at baseline, and incident HF was identified with ICD-9 codes (1 inpatient or 2 outpatient HF visits). We developed multivariable Cox models to assess the association of antecedent factors (coronary heart disease, hypertension, diabetes mellitus, atrial fibrillation, and valvular heart disease) with incident HF. Separate models were created for each sex and for newly diagnosed HF in outpatient or inpatient settings. There were 4001 incident HF cases (50% women and 48% in subjects <65 years old), during 1 015 794 person-years of follow-up. The incidence rate of HF was greater in men than in women (4.24 versus 3.68 per 1000 person-years) but was stable across the study interval in both sexes. Two thirds of incident HF cases from this population occurred in outpatients. These 5 antecedent factors and age yielded excellent discrimination for incident HF in both outpatients and inpatients and in both sexes (C >0.85 in all models).
Common modifiable risk factors accurately discriminate women and men at risk for HF diagnosed in either outpatient or inpatient settings. Approximately two thirds of new HF cases in our insured population were diagnosed in outpatients; more research is needed to characterize these subjects and their prognosis.
PMCID: PMC3113516  PMID: 20798277
heart failure; epidemiology; risk factors

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