Associations between HIV infection and frailty status and its individual components: Are frailty components disproportionally affected?

OBJECTIVE: We aimed to examine whether HIV infection was independently associated with frailty status and its individual components. METHODS: This cross-sectional investigation included people living with HIV (PLWH) and HIV-negative individuals from the baseline survey of the Comparative HIV and Aging Research in Taizhou (CHART) cohort, China. Frailty phenotype was based on five components: weight loss, low physical activity, exhaustion, weak grip strength and slow gait speed. Frailty was defined as the presence of at least three components, and prefrailty was defined as one or two components. Logistic regression models were used to analyse the factors associated with frailty and its components. RESULTS: In all, 2475 people living with HIV (age 45.5 ± 14.9 years; 76.2% male) and 4948 HIV-negative individuals (age 45.5 ± 14.8 years; 76.3% male) were included. Among PLWH, median CD4 count was 395 cells/µL and 78% were currently on antiretroviral therapy (ART). Frailty and prefrailty were significantly more prevalent in PLWH (3.2% vs 1.9% and 32.9% vs 27.9%) overall and at ages 18-39 (1.4% vs 0.2% and 22.7% vs 19.0%), 40-59 (2.5% vs 0.9% and 30.9% vs 27.9%) and 60-90 years (8.4% vs 7.4% and 57.1% vs 45.8%). HIV infection was associated with frailty and prefrailty [adjusted odds ratio (aOR) = 1.48, 95% confidence interval (CI): 1.06-2.08; and aOR = 1.18, 95% CI: 1.05-1.33, respectively] after adjusting for confounding variables, but were strengthened with further adjustment for multimorbidity (aOR = 1.62, 95% CI: 1.14-2.28; and aOR = 1.22, 95% CI: 1.09-1.37), and were no longer significant with further adjustment for depressive symptoms and sleep disorders (aOR = 1.02, 95% CI: 0.71-1.46; and aOR = 1.06, 95% CI: 0.94-1.20). Among individual components, HIV infection was positively associated with weak grip strength and slow gait speed, but negatively associated with low physical activity and exhaustion in all the adjusted models described. CONCLUSIONS: Frailty and prefrailty occur more often and earlier in PLWH. However, grip strength and gait speed are affected to a greater extent, highlighting their potential as screening and intervention targets to prevent or slow frailty among PLWH.

Genome-wide associated variants of subclinical atherosclerosis among young people with HIV and gene-environment interactions.

BACKGROUND: Genome-wide association studies (GWAS) have identified some variants associated with subclinical atherosclerosis (SCA) in general population but lacking sufficient validation. Besides traditional risk factors, whether and how would genetic variants associate with SCA among people with HIV (PWH) remains to be elucidated. METHOD: A large original GWAS and gene-environment interaction analysis of SCA were conducted among Chinese PWH (n = 2850) and age/sex-matched HIV-negative controls (n = 5410). Subgroup analyses by age and functional annotations of variants were also performed. RESULTS: Different from HIV-negative counterparts, host genome had a greater impact on young PWH rather than the elders: one genome-wide significant variant (rs77741796, P = 2.20 × 10-9) and eight suggestively significant variants (P < 1 × 10-6) were identified to be specifically associated with SCA among PWH younger than 45 years. Seven genomic loci and 15 genes were mapped to play a potential role on SCA among young PWH, which were enriched in the biological processes of atrial cardiac muscle cell membrane repolarization and molecular function of protein kinase A subunit binding. Furthermore, genome-wide interaction analyses revealed significant HIV-gene interactions overall as well as gene-environment interactions with alcohol consumption, tobacco use and obesity among PWH. The identified gene-environment interaction on SCA among PWH might be useful for discovering high-risk individuals for the prevention of SCA, particularly among those with tobacco use and alcohol consumption. CONCLUSION: The present study provides new clues for the genetic contribution of SCA among young PWH and is the starting point of precision intervention targeting HIV-related atherosclerosis.

Interaction of declined handgrip strength and HIV infection on neurocognitive impairment.

Neurocognitive impairment (NCI) persists among people living with HIV (PLWH) despite the success of combination antiretroviral therapy (cART). Although muscular waning or decreased handgrip strength has been widely reported to be associated with cognitive erosion in general elders, such association has not been examined in PLWH who commonly experience decreased handgrip strength and NCI. Furthermore, whether HIV infection modifies such association remains to be addressed. A cross-sectional analysis was conducted with 2808 HIV-positive and 5402 HIV-negative adults participating in the baseline survey of the CHART (Comparative HIV and Aging Research in Taizhou) cohort, China, 2017 - 2019. HIV-positive individuals showed weaker handgrip strength than HIV-negative controls (34.0 kg vs 37.7 kg). Multivariate logistic regression analysis indicated that both HIV infection (aOR = 4.35, p < 0.001) and every 5-kg decrease in "Handgrip strength" (aOR = 1.27, p < 0.001) were significantly associated with NCI, and there was a significant interaction between reduced handgrip strength and HIV infection on NCI (aOR = 1.14, p = 0.015). In stratified analyses adjusting for potential confounders, the association between reduced handgrip strength and NCI was significant among PLWH at all age groups but only significant among HIV-negative controls at 30 - 44 and 60 - 89 ages. Handgrip strength decline is significantly associated with the risk of NCI among PLWH. HIV infection may exacerbate the adverse effect of poor handgrip strength on NCI, especially at younger ages. Early detection of handgrip strength decline could facilitate delivery of compensatory strategies or assistive services to PLWH with or at high risk of NCI.

A ten-year assessment of the epidemiological features and fatal risk factors of hospitalised severe fever with thrombocytopenia syndrome in Eastern China.

Severe fever with thrombocytopenia syndrome (SFTS) virus has caused a large number of human infections since discovered in 2009. This study elucidated epidemiological features and fatal risk factors of SFTS cases accumulated up to ten years in Taizhou, a coastal prefecture of Zhejiang Province in Eastern China. A total of 188 hospitalised SFTS cases (including 40 deaths) reported to Taizhou Center for Disease Control and Prevention (CDC) during 2011-2020 were enrolled in the study. In the past decade, the annual incidence of SFTS increased over the years (P < 0.001) along with an expanding epidemic area, and the case fatality of hospitalised cases has remained high (21.3%). Although most cases occurred in hilly areas, a coastal island had the highest incidence and case fatality. The majority of cases were over the age of 60 years (72.3%), and both incidence and case fatality of SFTS increased with age. Multivariate logistic regression analysis showed that age (OR 7.47, 95% CI 1.32-42.33; P = 0.023), and haemorrhagic manifestations including petechiae (OR 7.76, 95% CI 1.17-51.50; P = 0.034), gingival haemorrhage (OR 5.38, 95% CI 1.25-23.15; P = 0.024) and melena (OR 5.75, 95% CI 1.18-28.07; P = 0.031) were significantly associated with the death of SFTS cases. Five family clusters identified were farmers, among four of which the index patients were female with a history of hypertension. Based on the study, age is a critical risk factor for incidence and case fatality of SFTS. With an increased annual incidence over the last ten years, SFTS remains a public health threat that should not be ignored. Further study is needed to look at the natural foci in the coastal islands.

Increased CD4+ T cell count is associated with lower anal human papillomavirus prevalence among HIV-positive male cohort in Taizhou, China: a cross-sectional study.

OBJECTIVES: This study aims to investigate the association between CD4+ T cell count and combined antiretroviral therapy (cART) with the prevalence of anal human papillomavirus (HPV) infection among HIV-positive male cohort in China. METHODS: A survey was conducted in men from a HIV cohort in Taizhou, China between 2016 and 2019. A face-to-face questionnaire interview was administered, and an anal-canal swab was collected for HPV genotyping. RESULTS: A total of 766 HIV-positive men were recruited. The HPV prevalence was lower among those with increased CD4+ T cell count than those with decreased or unchanged (46.5 vs. 56.6%, p = 0.033) from baseline. In multivariable models, having the current CD4+ T cell count of 350-499 cells/µL (aOR 0.28, 95% CI 0.13-0.64), and of ≥ 500 cells/µL (aOR 0.26, 95% CI 0.11-0.60) were associated with lower prevalence of any type HPV infection compared with those with < 200 cells/µL. Having taken NVP + 3TC + AZT was inversely associated with any high-risk (HR)-HPV (aOR 0.47, 95% CI 0.25-0.90) and any low-risk (LR)-HPV infection (aOR 0.40, 95% CI 0.18-0.88), compared with those taking EFV + 3TC + TDF. CONCLUSIONS: Increased CD4+ T cell count at follow-up was significantly associated with lower prevalence of anal HPV infection. Inverse associations between NVP + 3TC + AZT and HR-HPV or LR-HPV infecton were observed.

Incidence of impaired kidney function among people with HIV: a systematic review and meta-analysis.

BACKGROUND: In the era of combination antiretroviral therapy (ART), the incidence, manifestations and severity of kidney diseases have dramatically changed in people living with HIV (PLWH). Little is known about the incidence of impaired kidney function (IKF) measured by serum creatine-based estimated glomerular filtration rate (eGFR) in PLWH. METHODS: In this systematic review and meta-analysis, we searched PubMed, Ovid, Medline, Embase and Web of Science for studies published before May 7th, 2021, with estimates of incidence of IKF among PLWH. We independently reviewed each study for quality by using the Newcastle-Ottawa scale. The incidence and 95% confidence intervals (CIs) were calculated using random-effects model. RESULTS: Sixty out of 3797 identifiable studies were eligible for the meta-analysis. A total of 19 definitions of IKF were described and categorized into three types: the threshold of eGFR, an absolute or percent decrease in eGFR, and certain eGFR threshold combined with decrement in eGFR. The eGFR< 60 ml/min/1.73m2 was the most widely used definition or criterion for IKF, by which the pooled incidence rate of IKF was 12.50 (95%CI: 9.00-17.36) per 1000 person years (PYs). The second most-studied outcome was a > 25% decrease in eGFR, followed by eGFR< 90 ml/min/1.73m2, eGFR< 30 ml/min/1.73m2 and a combination of eGFR threshold plus decreased eGFR. The reported incidence rates of IKF differ widely by different definitions of IKF. The highest pooled incidence was observed for those with > 25% decrease in eGFR, while the lowest was observed in those with eGFR < 30 ml/min/1.73m2. Substantial heterogeneity was identified across most estimates. CONCLUSION: Our study provides a comprehensive summary of eGFR-based definitions and incidence rates of IKF in PLWH, not only promoting our understanding of IKF, but also underscoring needs for a concerted action to unify definitions and outcomes of IKF and their applications in AIDS care.

Analysis of the effect of meteorological factors on hemorrhagic fever with renal syndrome in Taizhou City, China, 2008-2020.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is endemic in Zhejiang Province, China, while few studies have concentrated on the influence of meteorological factors on HFRS incidence in the area. METHODS: Data on HFRS and meteorological factors from January 1, 2008 to December 31, 2020 in Taizhou City, Zhejiang Province were collected. Multivariate analysis was conducted to the relationship between meteorological factors including minimum temperatures, relative humidity, and cumulative rainfall with HFRS. RESULTS: The HFRS incidence peaked in November and December and it was negatively correlated with average and highest average temperatures. Compared with median of meteorological factors, the relative risks (RR) of weekly average temperature at 12 ℃, weekly highest temperature at 18 ℃relative humidity at 40%, and cumulative rainfall at 240 mm were most significant and RRs were 1.41 (95% CI: 1.09-1.82), 1.32 (95% CI: 1.05-1.66), 2.18 (95% CI: 1.16-4.07), and 1.91 (95% CI: 1.16-2.73), respectively. Average temperature, precipitation, relative humidity had interactions on HFRS and the risk of HFRS occurrence increased with the decrease of average temperature and the increase of precipitation. CONCLUSION: Our study results are indicative of the association of environmental factors with the HFRS incidence, probable recommendation could be use of environmental factors as early warning signals for initiating the control measure and response.

General and abdominal obesity and incident hypertension among people living with HIV on antiretroviral therapy.

Hypertension is highly prevalent among people living with HIV (PLWH). We sought to characterize the hypertension incidence among PLWH on antiretroviral therapy, focusing on the effect of change in general and abdominal obesity on hypertension during follow-up. This was a prospective analysis of 229 treated PLWH aged over 40 years without hypertension at baseline. Overall a median follow-up of 2.9 years, 26.2% PLWH developed hypertension. In multivariable models, compared to those without obesity measures at both baseline and follow-up visit, PLWH with general obesity at both occasions (adjusted odds ratio [aOR] = 3.83, P = 0.006) or at baseline only (aOR = 5.45, P = 0.003), abdominal obesity (measured as waist circumference) at both occasions (aOR = 3.87, P = 0.001) or at follow-up only (aOR = 2.27; 9P = 0.060), abdominal obesity (measured as waist-to-hip ratio) at both occasions (aOR = 2.27, P = 0.077) were at increased risk of incident hypertension. Our data show that both general and abdominal obesity especially in the persistent status increase the hypertension risk in treated PLWH.

Study problems and depressive symptoms in adolescents during the COVID-19 outbreak: poor parent-child relationship as a vulnerability.

BACKGROUND: Little is known about the prevalence of and risk factors for adolescent mental health problems during the COVID-19 outbreak. We aimed to investigate the prevalence of depressive symptoms, their association with study-relevant problems, and the moderating effect of parent-child relationship among Chinese adolescents during the school closures. METHODS: We performed a cross-sectional analysis with data collected in middle and high schools in Taizhou, China. Students completed an online survey between April 16 and May 14, 2020. Depressive symptoms were assessed using the Children's Depression Inventory. Three types of study problems were recorded, including having difficulty in studying at home, dislike of remote learning, and excessive screen entertainment time. Parental relationships were categorized into good or normal relationship and poor relationship. Linear regression and logistic regression analyses were conducted to investigate the associations between study-relevant problems and depressive symptoms. RESULTS: Using data from 6435 adolescents, we found that the prevalence of depressive symptoms was 17.7%. All the study problem measures were associated with more severe depressive symptoms. There was a moderating effect of the parental relationship on the associations between study problems and depressive symptoms. The association between number of study problems and depressive symptoms was stronger in adolescents with a poor parent-child relationship (regression coefficient 4.34 [95% CI 2.97, 5.72]) than those with a good or normal relationship (2.55 [2.35, 2.75]), p for interaction 0.002, on multivariable adjustment. CONCLUSIONS: Study problems due to school closures were particularly problematic for adolescents who had poor parent-child relationships. Public health initiatives could help students to adjust study habits and improve parent-child relationships, thereby protecting against the development of depression.

Quality of life during the epidemic of COVID-19 and its associated factors among enterprise workers in East China.

BACKGROUND: The COVID-19 related lockdown and home confinement might have an important impact on the quality of life in enterprise workers. We investigated the quality of life during the epidemic in enterprise workers who just returned to work, and assessed its potential influencing factors to have a better understanding of the impact of COVID-19 epidemic lockdown and home confinement. METHODS: This was a cross-sectional study of enterprise workers conducted in Deqing and Taizhou, Zhejiang Province, China. The Chinese version of EQ5D was used to assess life quality, and information about general characteristics and COVID-19 related factors was collected by a structured questionnaire, which was distributed through the social application "WeChat". Multiple liner regression was used to investigate potential influencing factors. RESULTS: A total of 2420 participants were enrolled, 59.5% of which worked in Deqing. About 50% of the participants reported worries about the COVID-2019 epidemic and 40.2% had a centralized or home quarantine during the epidemic. The mean EQ-5D score and VAS were 0.990 and 93.5. Multiple liner regression showed that the quality of life measures was related to physical activities (ß = 0.006) and keeping home ventilation (ß = 0.063) in Deqing, and were related to wearing a mask when going out (ß = 0.014), keeping home ventilation (ß = 0.061), other marital status (ß = - 0.011), worry about the epidemic (ß = - 0.005) and having a centralized or home quarantine (ß = - 0.005) in Taizhou. CONCLUSIONS: The quality of life for returning enterprise workers in areas with different risks of COVID-19 was affected by different factors. Associated factors identified from this study would help develop proper intervention measures for enterprise workers to reduce the impact of large-scale public health events like the COVID-19 on their quality of life.

Depression and anxiety symptoms among returning workers during the COVID-19 period in East China.

PURPOSE: To determine the prevalence of depression and anxiety and associated factors among returning workers with different epidemic experience in East China. METHODS: A cross-sectional study was conducted among 2435 employees from the enterprises located in Deqing (low-risk epidemic area) and Taizhou (high-risk epidemic area) of East China in March 2020. An online questionnaire covered information on sociodemographic and lifestyle factors as well as knowledge, attitude, behavior and experience about COVID-19. The Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7) were applied to assess depression and anxiety symptoms, respectively. Logistic regression model was used to estimate adjusted odds ratios (aORs) and their 95% confidence intervals (CIs) for depression and anxiety symptoms associated with risk factors. RESULTS: The participants were aged 36.3 ± 9.2 years on average, and nearly half of them were female. Overall, the prevalence of depression, anxiety and both were 19.4%, 12.3% and 9.8%, and decreased with age. After adjustment for covariates, 16 or more years of education, being a white-collar worker or working in the high-risk epidemic area were significantly associated with increased risks of both depression and anxiety, in contract regular physical exercise was associated with decreased risks of both mental disorders. CONCLUSION: The depression and anxiety problems were prevalent among returning workers during the COVID-19 period. Targeted psychological interventions should be developed and implemented to improve their mental health.

COVID-19 control strategies in Taizhou city, China.

PROBLEM: On 21 January 2020, the city of Taizhou, China, reported its first imported coronavirus disease 2019 (COVID-19) case and subsequently the number of cases rapidly increased. APPROACH: To organize the emergency responses, the government of Taizhou established on 23 January 2020 novel headquarters for prevention and control of the COVID-19 outbreak, by coordinating different governmental agencies. People at high risk of acquiring COVID-19, as well as probable and confirmed cases, were identified and quarantined. The government closed public venues and limited gatherings. The Taizhou Health Commission shared information about identified COVID-19 patients and probable cases with affected agencies. To timely track and manage close contacts of confirmed cases, Taizhou Center for Disease Control and Prevention did epidemiological investigations. Medical institutions or local centers for disease control and prevention reported confirmed cases to the national Center for Disease Control and Prevention. LOCAL SETTING: Taizhou, a city in Zhejiang province with about 6 million residents, reported 18 confirmed COVID-2019 cases by 23 January 2020, which ranked it third globally in number of cases after Wuhan and Xiaogan cities in the Hubei province. RELEVANT CHANGES: In total, 146 confirmed cases (85 cases imported and 61 cases through community transmission) and no deaths due to COVID-19 had been reported in Taizhou by 1 June 2020. Between 16 February and 1 June 2020, no confirmed case had been reported. LESSON LEARNT: Identifying and managing imported cases and people at risk for infection, timely information sharing, limiting gatherings and ensuring collaborations between different agencies were important in controlling COVID-19.

Sex differences in neurocognitive screening among adults living with HIV in China.

HIV-infected (HIV+) women may be more vulnerable to neurocognitive impairment (NCI) due to psychological and physiological factors but previous studies show mixed findings. We investigated the neurocognitive performances in HIV+ versus HIV- women and men. This cross-sectional analysis included 669 HIV+ patients (223 women) and 1338 HIV-uninfected (HIV-) controls (446 women) which were frequency matched on sex, education, and 5-year age categories. NCI was screened using the Mini-mental State Examination. Psychomotor speed was assessed using timed alternating hand sequence test. Prevalence of NCI was higher among women versus men in the HIV+ group (16.1% vs 10.5%) but not the HIV- group (4.3% vs 3.5%). HIV+ women performed worse compared to men on psychomotor speed, orientation, attention, and calculation, whereas HIV- women performed worse compared to men on attention and calculation. Adjusted interaction effects of HIV status × sex (women vs men) were significant on orientation, attention, and calculation, and marginally significant on psychomotor speed (p = 0.053). In multivariable models, among both HIV+ women and men, less years of education and depressive symptoms were associated with NCI. Waist-to-hip ratio above the cut-off was strongly associated with NCI among HIV+ women. HIV+ women perform worse on cognitive measures compared to HIV+ men. The association of central obesity with NCI in HIV+ women should be noted.

Low body mass index and efavirenz use are independently associated with self-reported fatigue in HIV-infected patients.

This retrospective cohort study was conducted from January 2009 to July 2016 to explore the occurrence and risk factors of self-reported fatigue within the first 6 months after receiving antiretroviral treatment (ART) among patients living with HIV in Taizhou City of Zhejiang province, Eastern China. In total, 1163 HIV-infected patients with a median follow-up duration of 27.8 months were included in the analysis. Among them, 261 (22.4%) reported fatigue within the first 6 months after ART. In the multivariable logistic regression analysis, self-reported fatigue within the first 6 months after ART was negatively associated with junior middle-school education or above, baseline CD4 cell count of 200-349 and >350 cells/µL (vs < 200 cells/µL), overweight at baseline (vs normal weight) but positively associated with ≥50 years old at initiation of ART (vs <30 years old), underweight at baseline, use of efavirenz (EFV) in the first-line regimen. Our data suggest that earlier initiation of ART and higher body mass index are preferred to restore the energy of HIV-infected patients with the EFV use in the era of ART in China.

Higher Prevalence of Frailty Among a Sample of HIV-Infected Middle-aged and Older Chinese Adults Is Associated With Neurocognitive Impairment and Depressive Symptoms.

We investigated the prevalence and correlates of prefrailty/frailty, determined on the basis of the Fried criteria, in Chinese patients with and those without human immunodeficiency virus (HIV) infection. HIV-infected patients were more likely to be frail or prefrail than controls, and this association remained significant after adjustment for potential confounders (odds ratio, 3.79). After additional adjustment for neurocognitive impairment and depressive and insomnia symptoms, this association remained significant but attenuated (odds ratio, 2.16). In the HIV-infected group, these 3 variables were independently associated with prefrailty/frailty. These findings suggest that neurocognitive impairment and depressive and/or insomnia symptoms may account for a higher prevalence of prefrailty/frailty in HIV-infected patients but require further longitudinal investigation.

Urinary Antibiotics of Pregnant Women in Eastern China and Cumulative Health Risk Assessment.

Exposure to antibiotics during pregnancy can pose a systematic effect on human health. A few biomonitoring studies have demonstrated an extensive exposure of children to antibiotics, but there is still a lack of data for pregnant women. To assess the exposure of pregnant women to antibiotics and potential health risk, we investigated 536 pregnant women aged 16-42 years from two geographically different study sites in Eastern China in 2015. We measured 21 antibiotics of five categories (seven fluoroquinolones, three phenicols, four tetracyclines, three macrolides, and four sulfonamides) in urine using the isotope dilution ultraperformance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The hazard index (HI) was calculated on the basis of estimated daily exposure dose and acceptable daily intakes. A total of 16 antibiotics were found in urine, with detection frequencies between 0.2 and 16.0%. Antibiotics were overall detected in 41.6% of urine, and two or more antibiotics were detected in 13.1% of urine. Ciprofloxacin, ofloxacin, and trimethoprim were most frequently detected in urine, with detection frequencies between 10 and 20%. The majority of the antibiotics tested had an estimated daily exposure dose less than 1 µg/kg/day, and 4.3% of pregnant women had a HI value of more than 1. These findings indicated that pregnant women were frequently exposed to antibiotics and some individuals were in the potential risk of adverse microbiological effects induced by antibiotics.

Mitochondrial DNA has a pro-inflammatory role in AMD.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly of industrialized nations, and there is increasing evidence to support a role for chronic inflammation in its pathogenesis. Mitochondrial DNA (mtDNA) has been recently reported to be pro-inflammatory in various diseases such as Alzheimer's and heart failure. Here, we report that intracellular mtDNA induces ARPE-19 cells to secrete inflammatory cytokines IL-6 and IL-8, which have been consistently associated with AMD onset and progression. The induction was dependent on the size of mtDNA, but not on specific sequence. Oxidative stress plays a major role in the development of AMD, and our findings indicate that mtDNA induces IL-6 and IL-8 more potently when oxidized. Cytokine induction was mediated by STING (Stimulator of Interferon Genes) and NF-κB as evidenced by abrogation of the cytokine response with the use of specific inhibitors (siRNA and BAY 11-7082, respectively). Finally, mtDNA primed the NLRP3 inflammasome. This study contributes to our understanding of the potential pro-inflammatory role of mtDNA in the pathogenesis of AMD.

The inhibitory effect of IFN-γ on protease HTRA1 expression in rheumatoid arthritis.

The high temperature requirement A1 (HTRA1) is a potent protease involved in many diseases, including rheumatoid arthritis (RA). However, the regulatory mechanisms that control HTRA1 expression need to be determined. In this study, we demonstrated that IFN-γ significantly inhibited the basal and LPS-induced HTRA1 expression in fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the inhibitory effect of IFN-γ on HTRA1 expression was evidenced in collagen-induced arthritis (CIA) mouse models and in human RA synovial cells. In parallel with the enhanced CIA incidence and pathological changes in IFN-γ-deficient mice, HTRA1 expression in the joint tissues was also increased as determined by real-time PCR and Western blots. IFN-γ deficiency increased the incidence of CIA and the pathological severity in mice. Neutralization of HTRA1 by Ab significantly reversed the enhanced CIA frequency and severity in IFN-γ-deficient mice. Mechanistically, IFN-γ negatively controls HTRA1 expression through activation of p38 MAPK/STAT1 pathway. Dual luciferase reporter assay and chromatin immunoprecipitation analysis showed that STAT1 could directly bind to HTRA1 promoter after IFN-γ stimulation. This study offers new insights into the molecular regulation of HTRA1 expression and its role in RA pathogenesis, which may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer.

Effects of a fruit-vegetable dietary pattern on oxidative stress and genetic damage in coke oven workers: a cross-sectional study.

BACKGROUND: Coke oven workers (COWs) are exposed to high level of genotoxic chemicals that induce oxidative stress and genetic damage. The dietary intake of certain types of foods may reverse these effects. METHODS: We conducted a cross-sectional study with 51 topside COWs, 79 other COWs, and 67 controls, to assess the effects of dietary patterns on oxidative stress and genetic damage. RESULTS: Compared to the controls, both topside and other COWs had significantly higher urinary 1-hydroxypyrene levels, serum oxidant levels [malondialdehyde, (MDA)], and genetic damage [micronucleus (MN) frequency & 8-oxo-2'-deoxyguanosine (8-OH-dG)], but lower antioxidant levels [superoxide dismutase (SOD) and glutathione peroxidase, (GPx)]. The fruit-vegetable (FV) dietary pattern was positively correlated with serum SOD levels and negative correlated with serum MDA, MN frequency, and urinary 8-OH-dG. COWs with an FV patter in the highest quartile (Q4) had significantly increased antioxidant levels (SOD and GPx) and decreased oxidant levels (MDA) and genetic damage (MN frequency and 8-OH-dG) than those with an FV pattern in the lowest quartile (Q1). CONCLUSION: Compared to control subjects, COWs had increased oxidative stress and genetic damage. A FV dietary pattern may reverse oxidative stress and genetic damage in COWs.