Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver.

RATIONALE: Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development. OBJECTIVE: We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level. METHODS AND RESULTS: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on Apoa1 promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient (Apoe-/-) mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin. CONCLUSIONS: Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.

Joint trajectories of disease activity, and physical and mental health-related quality of life in an inception lupus cohort.

OBJECTIVES: To examine for latent patterns of SLE disease activity trajectories that associate with specific latent patterns of health-related quality of life (HRQoL; Medical Outcomes Study Short Form-36), and to determine baseline predictors of class membership. METHODS: In this retrospective longitudinal inception cohort of 222 SLE adults over 10 years, trajectories of three outcomes were studied jointly: Short Form-36 physical (PCS) and mental (MCS) component summaries and adjusted mean SLEDAI-2000 (AMS). Group-based joint trajectory modelling was used to model latent classes; univariable and multivariable analyses were used to identify predictors of class membership. RESULTS: Four latent classes were identified: Class 1 (C1) (24%) had moderate AMS, and persistently low PCS and MCS; C2 (26%) had low AMS, moderate PCS and improved then worsened MCS; C3 (38%) had moderate AMS, and persistently high PCS and MCS; and C4 (11%) had high AMS, moderate-low PCS and improving MCS. Baseline older age was associated with lower HRQoL trajectories. Higher AMS trajectories did not associate with a particular pattern of HRQoL trajectory. A higher prevalence of fibromyalgia (44% in C1) was associated with worse HRQoL trajectories. Disease manifestations, organ damage and cumulative glucocorticoid were not differentially distributed across the latent classes. CONCLUSION: High disease activity did not necessarily associate with low HRQoL. More patients with worse HRQoL trajectories had fibromyalgia. Older age at diagnosis increased the probability of belonging to a class with low HRQoL trajectories. The care of SLE patients may be improved through addressing fibromyalgia in addition to disease activity.

Copy number and expression alterations of miRNAs in the ovarian cancer cell line OVCAR-3: impact on kallikrein 6 protein expression.

BACKGROUND: Kallikrein-related peptidase 6 (KLK6), a member of the serine protease family of kallikrein (KLK) genes, is dysregulated in ovarian carcinomas (OCa) and its overexpression is associated with poor prognosis. Regulation of its expression is poorly understood and is likely to be influenced by multiple mechanisms. The KLK locus is subject to copy number changes and heterogeneity in serous OCas. These copy number imbalances generally correlate with KLK6 protein expression; however, this is not always the case. In this study we explored the role of miRNAs in the posttranscriptional control of KLK6 expression and the contributions of copy numbers, not only of the KLK locus, but also of the miRNAs predicted to regulate it. METHODS AND RESULTS: By miRNA profiling of the KLK6-overexpressing OCa cell line, OVCAR-3, we identified overexpressed and underexpressed miRNAs. Publically available miRNA databases identified the human miRNA lethal 7 (hsa-let-7) family members as putative regulating miRNAs, from which hsa-let-7a was chosen for functional analysis. The transient transfection of hsa-let-7a to OVCAR-3 resulted in a decrease of KLK6 secreted protein. Moreover, such transfection was also able to weakly affect the expression of another member of the KLK gene family, KLK10 (kallikrein-related peptidase 10). Cytogenomic analysis, including array comparative genomic hybridization, fluorescence in situ hybridization, and spectral karyotyping revealed the overall net copy number losses of hsa-let-7a and other miRNAs predicted to target KLK6. CONCLUSIONS: The hsa-let-7 family member hsa-let-7a is a modulator of KLK6 protein expression that is independent of the KLK6 copy number status.

Prevalence and metric of depression and anxiety in systemic lupus erythematosus: A systematic review and meta-analysis.

OBJECTIVES: To systematically review and synthesize literature on 1) the overall prevalence of depression and anxiety in SLE patients in identified studies, and 2) the pooled prevalence per metrics of depression and anxiety in adult SLE patients. METHODS: This review used (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) PRISMA guidelines and in-depth searches in four databases (1954-2016; Ovid-based Medline, Embase, PsycINFO and CINAHL) to identify articles on the prevalence of depression and/or anxiety in adult SLE patients. Included studies were critically appraised and analyzed. The prevalence of depression and anxiety was studied for all included studies, and whenever possible, pooled prevalence (PP) was determined for more commonly used metrics. Statistical and publication bias was assessed using funnel plots. RESULT: A total of 3103 references were identified, 226 were selected for detailed review and 72 were included in the final analysis. OVERALL PREVALENCE: The depression PP, obtained from 69 studies representing 23,386 SLE patients, was 35.0% (95% CI: 29.9%-40.3%). The anxiety PP, obtained from 38 studies representing 4439 SLE patients, was 25.8% (95% CI: 19.2%-32.9%). PREVALENCE PER METRICS USED: The more commonly used instruments included the Centre for Epidemiological Studies - Depression (CES-D), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scales (HADS-A/D), and Hamilton Rating Scales for Depression/Anxiety (HAM-D/A)]. The CES-D was utilized in 13 studies including 1856 SLE patients; depression PP was 41.5% (95% CI: 35.1%-48.1%). The BDI was utilized in 14 studies including 1355 SLE patients and the BAI in 3 studies including 489 patients; depression PP was 39.9% (95% CI: 31.1%-49.1) and anxiety PP was 38.4% (95% CI: 34.2%-42.8%). The HADS-D was utilized in 14 studies including 1238 SLE patients and the HADS-A in 12 studies including 1099 patients respectively; its depression PP was 24.4% (95% CI: 19.1%-30.1%) and anxiety PP was 38.3% (95% CI: 29.1%-47.9%). The HAM-D was utilized in 4 studies including 267 SLE patients and the HAM-A in 4 studies including 213 patients respectively; its depression PP was 40.0% (95% CI: 23.0%-59.0%) and anxiety PP was 39.0% (95% CI: 32.0%-45.0%). CONCLUSION: There was high variability in the prevalence of depression and anxiety, ranging from 8.7%-78.6% and 1.1%-71.4%, respectively. This could be attributed to the lack of consistency in the metrics used and its definition for depression and anxiety in SLE. Studies that used a specific metric, such as the CES-D, BDI or HAM-D, yielded similar depression prevalence. The HADS-D had the lowest prevalence. All metrics of anxiety yielded similar anxiety prevalence.

Effect of complete or partial proteinuria recovery on long-term outcomes of lupus nephritis.

BACKGROUND/PURPOSE: We aimed to evaluate the effect of complete recovery (CR), partial recovery (PR), and no recovery (NR) of proteinuria at 2 years from the diagnosis of LN on long-term renal and extra-renal outcomes. METHODS: Patients with LN and proteinuria attending the Lupus Center from 1970 to 2015 were analyzed. At 2 years from diagnosis of LN, patients were divided into three groups (CR, PR, and NR), and long-term outcomes were studied up to 15 years or last visit available. CR was defined as resolution of proteinuria, PR as a reduction ≥50% in baseline proteinuria, and NR as a reduction <50% compared to baseline. Long-term outcomes examined included renal outcomes [low eGFR, ESRD, and composite renal (low eGFR, ESRD, and dialysis/transplant)], cardiovascular outcomes, damage, and death. Kaplan-Meier plots, time-independent and time-dependent Cox proportional hazards models were applied to examine the effect of CR, PR, or NR on long-term outcomes. RESULTS: Of 277 patients, 71.8% achieved CR, 18.4% PR, and 9.8% NR at 2 years. CR compared to NR and CR compared to PR were protective against low eGFR and composite renal outcome in time-independent and time-dependent analyses. CR compared to PR protected against damage in the time-independent analysis. Overall, the comparison of CR and PR favored CR for long-term renal outcomes. CONCLUSION: CR at 2 years from diagnosis of LN protected against renal outcomes (low eGFR, ESRD/dialysis, and transplant). CR is more favorable compared to PR and clinicians should aim for CR to improve long-term outcomes in LN.

Predictors of Good Long-Term Renal Outcomes in Lupus Nephritis: Results from a Single Lupus Cohort.

This study aims to elucidate the predictive capabilities of proteinuria, serum creatinine (Cr), and urine RBCs (uRBCs) with respect to long-term renal outcomes in lupus nephritis (LN) in patients followed in clinic. Methods. A retrospective analysis was performed on patients with LN. We evaluated the ability of proteinuria, serum Cr, and uRBCs at 12 months to predict good long-term renal outcomes defined as serum Cr ≤ 100 mmol/L and kidney transplant/dialysis-free at the 7th year. Receiver operator characteristic curves were generated for proteinuria, serum Cr, and uRBCs to study their ability to predict good long-term outcomes and to identify their best cut-off. Descriptive statistics studied the pattern of change of proteinuria and serum Cr. Results. Proteinuria of 0.6 g/d and Cr of 83 mmol/L performed independently moderately well in predicting good long-term renal outcomes while uRBC was less accurate. Combining serum Cr to proteinuria gave a small increase in positive predictive value with a trade-off in sensitivity. Proteinuria changed within the first year whereas serum Cr changed until the 7th year. Conclusions. Both proteinuria and Cr predict good long-term renal outcomes in LN. Proteinuria's ability to change faster at 12 months makes it a favorable endpoint for clinical trials and research studies.

Effect of governmental intervention on appropriateness of lumbar MRI referrals: a Canadian experience.

PURPOSE: In 2012, the Ontario government attempted to reduce inappropriate lumbar MRI referrals through guideline and decision-aid distributions to physicians as well as threats of financial penalties. The goals of this study were to determine if any change in lumbar MRI referral appropriateness occurred after this policy change at a tertiary care hospital in Ontario and to determine if any change in the number of new lumbar MRI referrals occurred after the policy change. METHODS: Six hundred lumbar MRI referral forms were randomly selected; 300 before and 300 after the policy change. The ACR Appropriateness Criteria for low back pain imaging were used to evaluate the appropriateness of each referral and assign it a score from 1 to 9. The numbers of new referrals during 3-month periods both before and after the policy change were recorded. Student's t test was performed to test for significant differences after the policy change. RESULTS: Before the policy change, 50.4% of lumbar MRI referrals were appropriate, and 47.9% were not appropriate. After the policy change, appropriateness increased, with 62.6% of referrals being appropriate and 37.1% not appropriate. The mean appropriateness score before the policy change was 5.08 (95% confidence interval, 4.74-5.42) and increased significantly after the policy change to 5.79 (95% confidence interval, 5.46-6.12) (P = .004). No significant difference in the number of new lumbar MRI referrals before (246 ± 20.1 per month) and after (232.7 ± 38.3 per month) the policy change was noted (P > .05). CONCLUSIONS: The Ontario government's interventions have significantly increased the appropriateness of lumbar MRI referrals. However, many referrals remain inappropriate, and no change in the number of new referrals has occurred.