What Makes Deviant Places?

Urban safety plays an essential role in the quality of citizens' lives and in the sustainable development of cities. In recent years, researchers have attempted to apply machine learning techniques to identify the role of location-specific attributes in the development of urban safety. However, existing studies have mainly relied on limited images (e.g., map images, single- or four-directional images) of areas based on a relatively large geographical unit and have narrowly focused on severe crime rates, which limits their predictive performance and implications for urban safety. In this work, we propose a novel method that predicts "deviance," which includes formal deviant crimes (e.g., murders) and informal deviant behaviors (e.g., loud parties at night). To do this, we first collect a large-scale geo-tagged dataset consisting of incident report data for seven metropolitan cities, along with corresponding sequential images around incident sites obtained from Google Street View. We then design a convolutional neural network that learns spatio-temporal visual attributes of deviant streets. Experimental results show that our framework is able to reliably recognize real-world deviance in various cities. Furthermore, we analyze which visual attribute is important for deviance identification and severity estimation with respect to social science as well as activated feature maps in the neural network. We have released our dataset and source codes on https://github.com/JinhwiPark/DevianceNet/.

Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5.

Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern-triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6- and chemokine ligand 2-dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation.

Development of the Short-Form Yin Deficiency Scale Using Three Item Reduction Approaches.

Background: Yin deficiency (YD) is a pathological condition characterized by emaciation, afternoon fever, dry mouth, and night sweats. The incidence of YD is 23.3%. A 27-item Yin Deficiency Scale (YDS) was developed to estimate the clinical severity of YD. This study aimed to develop three short-form YDS versions to reduce the burden of response time, using three item-reduction approaches: Rasch, equidiscriminatory item-total correlation (EITC), and factor-based analyses. Methods: Two datasets were analyzed from previous studies (169 outpatients from May to June 2009 and 237 healthy college students from January to April 2016). The optimal response category was examined using Rasch analysis. Items with higher item-total correlations were determined using the EITC. Using a factor-based approach, the items were reduced, while maintaining the original YDS construct. Reliability was estimated using the person separation index (PSI) and Cronbach's α values. The predictive accuracy was examined using the area under the curve (AUC). Finally, the relationship between YD and dysfunctional breathing (DB) was examined using factor scores from the YDS and the Korean version of the Nijmegen Questionnaire (KNQ). Results: We developed two 14-item YDS versions using the Rasch and EITC approaches, and a 16-item YDS version using a factor-based approach. Rasch analysis suggested an optimal response category of five points. The PSI of Rasch and Cronbach's α of the EITC and factor-based versions were 2.19, 0.855, and 0.827. The AUCs of the three short-form YDS were 0.812, 0.811, and 0.818. The sensitivity of the EITC-YDS was 0.632, which was lower than its specificity of 0.875. The fatigue-related scores of the factor-based YDS were fairly correlated with the factor scores of the KNQ estimating the DB (r = 0.349-0.499). Conclusion: The 14-item Rasch- and 16-item factor-based YDS may replace the original YDS during YD's primary screening, epidemiological surveys, and health checkups.

Association between the plasma concentration of melatonin and behavioral temperament in horses.

Aggression in horses may cause serious accidents during riding and non-riding activities. Hence, predicting the temperament of horses is essential for selecting suitable horses and ensuring safety during the activity. In certain animals, such as hamsters, plasma melatonin concentrations have been correlated with aggressive behavior. However, whether this relationship applies to horses remains unclear. To address this research gap, this study aimed to evaluate differences in the plasma melatonin concentrations among horses of different breeds, ages, and sexes and examine the correlation between plasma melatonin concentrations and the temperament of the horses, including docility, affinity, dominance, and trainability. Blood samples from 32 horses were collected from the Horse Industry Complex Center of Jeonju Kijeon College. The docility, affinity, dominance, and trainability of the horses were assessed by three professional trainers who were well-acquainted with the horses. Plasma melatonin concentrations were measured using an enzyme-linked immunosorbent assay. The consequent values were compared between the horses of different breeds, ages, and sexes using a three-way analysis of variance and least significant difference post hoc test. Linear regression analysis was employed to identify the relationship between plasma melatonin concentrations and docility, affinity, dominance, and trainability. The results showed that the plasma melatonin concentrations significantly differed with breeds in Thoroughbred and cold-blooded horses. However, there were no differences in the plasma melatonin concentrations between the horse ages and sexes. Furthermore, plasma melatonin concentrations did not exhibit a significant correlation with the ranking of docility, affinity, dominance, and trainability.

Association between blood glucose levels and arterial stiffness marker: comparing the second derivative of photoplethysmogram and cardio-ankle vascular index scores.

Objective: This study aimed to compare the association between fasting plasma glucose (FPG) and glycosylated hemoglobin A1c (HbA1c) levels using the second derivative of photoplethysmogram (SDPTG) index and the cardio-ankle vascular index (CAVI). Methods: Electronic medical records of 276 participants (160 men, 116 women) who visited the health promotion center of a university hospital were examined. Age, sex, body mass index (BMI), blood pressure, and lipid profile were considered as risk factors for arterial stiffness, together with the FPG, HbA1c, CAVI, and SDPTG indices. Hierarchical regression models were constructed, and all participants were divided into low-normal, high-normal, prediabetic, and diabetic groups to examine the group-based differences in CAVI and SDPTG indices. Results: FPG and HbA1c were independently predictive of increased CAVI, and their predictive powers for CAVI were equivalent (ß = 0.214 and 0.200, respectively). Risk factors, including age, BMI, and male sex, were also predictive of CAVI (ß= 0.593-0.630, -0.256 - -0.280, and 0.142-0.178, respectively). None of the FPG and HbA1c values were predictive of the SDPTG indices. The CAVI was higher in the diabetes group than in the other three groups according to HbA1c level, while the d/a index of the SDPTG decreased in the prediabetes group and increased in the diabetes group. Conclusions: CAVI may not be substituted for SDPTG indices when evaluating arterial stiffness based on the glucose level. Moreover, the progression rate of arterial stiffness may differ between the diabetic and nondiabetic stages.

Predictors for future development of systemic lupus erythematosus in Korean Sjögren's syndrome patients.

OBJECTIVE: This study determined the impact of demographic factors, clinical manifestations, disease activity, and serological tests at baseline on future SLE development in Sjögren's syndrome (SS) patients. METHODS: This retrospective study assessed 1,082 SS patients without other autoimmune diseases at baseline who visited our hospital between January 2012 and March 2021. We analyzed demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values at baseline between the two groups divided per future SLE development (SS/SLE group vs SS group). The probability and predictors of SLE development in SS patients were estimated using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: The median follow-up duration was 1083.5 days. Forty-nine patients (4.5%) developed SLE that met the 2012 Systemic Lupus International Collaborating Clinics or 2019 EULAR/ACR classification criteria. The baseline EULAR SS disease activity index (ESSDAI) score was significantly higher in the SS/SLE group (p < .001). The SS/SLE group had more lymphadenopathy and renal involvement (p = .015 and p = .017, respectively). Shorter SS disease duration (<3 years) (hazard ratio [HR] = 2.12, p = .0328), high ESSDAI (HR = 8.24, p < .0001), leukopenia (HR = 4.17, p = .0005), thrombocytopenia (HR = 3.38, p = .0059), hypocomplementemia (HR = 29.06, p<.0001), and positive for anti-dsDNA (HR = 13.70, p < .0001), anti-ribonucleoprotein (RNP) (HR = 3.82, p = .0027), and anti-ribosomal P (HR = 6.70, p = .0002) at baseline were SLE development predictors in SS patients. CONCLUSION: Shorter disease duration and higher disease activity of SS at baseline may be risk factors for future SLE development. Serologic predictors of SLE development are hypocomplementemia, leukopenia, thrombocytopenia, and positivity for anti-dsDNA, anti-RNP, and anti-ribosomal P antibodies. If the above factors are observed, close monitoring will be necessary during the follow-up period, considering the possibility of future SLE development.

Harmonic components of photoplethysmography and pathological patterns: A cross-sectional study.

This study aimed to examine whether the 3 harmonic components (HCs) of photoplethysmography (PTG) - total harmonic distortion (THD), harmonic power (HP), and normalized harmonic amplitude (HA) - have aging effects and may serve as an arterial stiffness marker and examine the relationship between HCs and clinical severity of pathological patterns. This study had a retrospective chart review design, and electronic medical records of 173 female patients (age: 38.57 ± 11.64 years) were reviewed. Patients were asked to complete the phlegm, blood stasis (BS), and food retention (FR) pattern questionnaires and underwent PTG and the second derivative of PTG measurements. THD, HP, and HA data were extracted till the 12th HCs from the raw PTG data. THD and HA had an aging effect (ß: -0.179 to -0.278) and were related to b/a (r: -02.76 to -0.455) and d/a (r: 0.265-0.360) of the second derivative of PTG. In the younger group (≤33 years), HP and HA were positively correlated with phlegm, BS, and FR patterns (r: 0.257-0.370), while HP was positively correlated with the FR pattern (r: 0.278-0.315) in the middle age group (34-45 years). In the older group (≥46 years), HP and HA were positively or negatively correlated with the phlegm pattern (r: ±0.263 to ±0.440). HCs may serve as an arterial stiffness marker, and may be partially related to phlegm, BS, and FR patterns. Aging effect needs to be considered when utilizing HCs as an indicator of phlegm, BS, and FR patterns.

Salivary ultrasonography and histopathologic evaluation of secondary Sjögren's syndrome in rheumatoid arthritis patients.

Novel modalities, such as salivary ultrasonography (SGUS) and shear wave elastography (SWE), have previously been introduced to evaluate Sjögren's syndrome (SS). However, in secondary SS (sSS), the diagnostic performance of SGUS and its relationship with clinicopathological characteristics have not yet been clearly defined. In this study, we aimed to investigate sSS in RA patients using SGUS and SWE and sought to determine its pathological correlations. Thirty-one RA patients who presented with sicca symptoms were included to be evaluated on SS, and were compared with 18 primary SS (pSS) patients. All subjects were assessed through SGUS, SWE, and conventional diagnostic approaches for SS, including minor salivary gland biopsy (MSGB). In SGUS evaluation, two separate scoring systems, suggested by Hocevar and OMERACT, were used. Among 31 RA patients with sicca symptoms, 19 (61.2%) were diagnosed as sSS. Similar to pSS, SGUS showed good diagnostic performance (sensitivity 68.4% and 78.9%, and specificity 91.7% and 75.0% for Hocever and OMERACT, respectively) in differentiating sSS from RA patients with simple sicca symptoms. The sSS and pSS patients exhibited significantly higher lymphoid infiltration areas in MSGB than RA patients without SS. Focus score and lymphoid infiltration areas correlated well with sonographic severity. Severity of fibrosis in MSGB showed better positive correlation with SWE than with SGUS. Similar to pSS, SGUS shows good diagnostic performance for sSS in RA patients. SWE reflects histopathologic chronicity of MSGB well in both pSS and sSS.

Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation.

BACKGROUND: High-temperature requirement serine protease A 2 (HtrA2) is known to be involved in growth, unfolded protein response to stress, apoptosis, and autophagy. However, whether HtrA2 controls inflammation and immune response remains elusive. METHODS: Expression of HtrA2 in the synovial tissue of patients was examined using immunohistochemistry and immunofluorescence staining. Enzyme-linked immunosorbent assay was used to determine the concentrations of HtrA2, interleukin-6 (IL-6), interleukin-8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor α (TNFα). Synoviocyte survival was assessed by MTT assay. For the downregulation of HtrA2 transcripts, cells were transfected with HtrA2 siRNA. RESULTS: We found that the concentration of HtrA2 was elevated in rheumatoid arthritis (RA) synovial fluid (SF) than in osteoarthritis (OA) SF, and its concentrations were correlated with the number of immune cells in the RA SF. Interestingly, HtrA2 levels in the SF of RA patients were elevated in proportion to synovitis severity and correlated with the expression of proinflammation cytokines and chemokines, such as IL-6, IL-8, and CCL2. In addition, HtrA2 was highly expressed in RA synovium and primary synoviocytes. RA synoviocytes released HtrA2 when stimulated with ER stress inducers. Knockdown of HtrA2 inhibited the IL1ß-, TNFα-, and LPS-induced release of proinflammatory cytokines and chemokines by RA synoviocytes. CONCLUSION: HtrA2 is a novel inflammatory mediator and a potential target for the development of an anti-inflammation therapy for RA.

Kynurenine pathway can be a potential biomarker of fatigue in primary Sjögren's syndrome.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease with low quality of life caused by various constitutional symptoms and glandular dysfunction. Although fatigue is one of the most frequent symptoms in pSS, its aetiology or biomarkers are poorly elucidated. We investigated potential relationship between severity of fatigue and the kynurenine pathway in pSS. METHODS: Clinical data and blood samples of 81 patients were obtained from a prospective cohort for pSS and compared with age- and sex-matched healthy controls (HC). Severity of fatigue was defined according to the fatigue domain scores in the ESSPRI. Potential biomarkers related to the kynurenine pathway were determined using ELISA. RESULTS: Of the total, 44 patients were defined as the "severe fatigue (ESSPRI fatigue ≥ 5)" group, whereas 37 as the "less fatigue (ESSPRI fatigue < 5)". Serum tryptophan levels in the severe fatigue group were significantly lower while those of kynurenine were higher. Serum interferon gamma, IDO1, and quinolinic acid levels were mostly higher in the less fatigue group. Kynurenine/tryptophan ratios were distinctly higher in the severe fatigue group than both HC and the less fatigue group (p < 0.001). This ratio showed a strong degree of positive correlation (r = 0.624, p < 0.001) with severity of fatigue in pSS while the other markers showed fair degrees of correlation. CONCLUSIONS: Serum markers related to the kynurenine pathway, especially the kynurenine/tryptophan ratio, may be associated with severity of fatigue in pSS. These results can provide guidance for further investigations on fatigue in pSS.

Roles of ZnT86D in Neurodevelopment and Pathogenesis of Alzheimer Disease in a Drosophila melanogaster Model.

Zinc is a fundamental trace element essential for numerous biological processes, and zinc homeostasis is regulated by the Zrt-/Irt-like protein (ZIP) and zinc transporter (ZnT) families. ZnT7 is mainly localized in the Golgi apparatus and endoplasmic reticulum (ER) and transports zinc into these organelles. Although previous studies have reported the role of zinc in animal physiology, little is known about the importance of zinc in the Golgi apparatus and ER in animal development and neurodegenerative diseases. In this study, we demonstrated that ZnT86D, a Drosophila ortholog of ZnT7, plays a pivotal role in the neurodevelopment and pathogenesis of Alzheimer disease (AD). When ZnT86D was silenced in neurons, the embryo-to-adult survival rate, locomotor activity, and lifespan were dramatically reduced. The toxic phenotypes were accompanied by abnormal neurogenesis and neuronal cell death. Furthermore, knockdown of ZnT86D in the neurons of a Drosophila AD model increased apoptosis and exacerbated neurodegeneration without significant changes in the deposition of amyloid beta plaques and susceptibility to oxidative stress. Taken together, our results suggest that an appropriate distribution of zinc in the Golgi apparatus and ER is important for neuronal development and neuroprotection and that ZnT7 is a potential protective factor against AD.

Comparative effectiveness of a low-calorie diet combined with acupuncture, cognitive behavioral therapy, meal replacements, or exercise for obesity over different intervention periods: A systematic review and network meta-analysis.

Objective: The aim of this study was to evaluate the comparative effectiveness of a low-calorie diet (LCD) combined with acupuncture, cognitive behavioral therapy (CBT), meal replacements (MR), and exercise on weight loss. Methods: The electronic databases MEDLINE, EMBASE, CENTRAL, CNKI, RISS, and KISS were searched systematically. Randomized controlled trials (RCTs) that directly compared the effect of a low-calorie diet (LCD)-combined acupuncture, CBT, and exercise and an MR-based diet on weight loss with LCD-alone for adults with simple obesity (body mass index [BMI] > 25) published before August 2021 were included in the study. Two investigators extracted and coded the data using a template. Any disagreements between investigators were resolved through discussion. Changes in BMI or weight were transformed to Hedges' g values with a 95% CI, and network meta-analyses using a Bayesian random-effects model were conducted. Results: A total of thirty-two trials involving 3,364 patients were finally included in the study. The effect sizes of four interventions were medium, in the order of acupuncture (Hedges' g = 0.48, 95% CI = 0.25 - 0.71), CBT (Hedges' g = 0.42, 95% CI = 0.20 - 0.63), MR (Hedges' g = 0.32, 95% CI = 0.19 - 0.45), and exercise (Hedges' g = 0.27, 95% CI = 0.06 - 0.46).In terms of intervention period, acupuncture was effective in the short period (≤ 12 weeks, Hedges' g = 0.39, 95% CI = 0.12 - 0.67) and the long period (>12 weeks, Hedges' g = 0.89, 95% CI = 0.37 - 1.40), whereas CBT (Hedges' g = 0.51, 95% CI = 0.26 - 0.76) and exercise (Hedges' g = 0.37, 95% CI = 0.12 - 0.59) were effective only in the long period. MR was effective only in the short period (Hedges' g = 0.35, 95% CI = 0.18 - 0.53). Conclusions: This study suggests that acupuncture, CBT, MR, and exercise for simple obesity show a medium effect size, and their effectiveness differs according to the intervention period.

Establishment of a humanized animal model of systemic sclerosis in which T helper-17 cells from patients with systemic sclerosis infiltrate and cause fibrosis in the lungs and skin.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by inflammation, microangiopathy, and progressive fibrosis in the skin and internal organs. To evaluate the pathophysiologic mechanisms and efficacies of potential therapeutics for SSc, a preclinical model recapitulating the disease phenotypes is needed. Here, we introduce a novel animal model for SSc using immunodeficient mice injected with peripheral blood mononuclear cells (PBMCs) from SSc patients. Human PBMCs acquired from SSc patients and healthy controls were transferred into NOD.Cg-PrkdcscidIl2rgtm1Wjl (NSG) mice with concurrent bleomycin injection. Blood, skin, and lung tissues were acquired and analyzed after PBMC engraftment. In addition, we investigated whether the humanized murine model could be used to assess the efficacy of potential therapeutics for SSc. Human PBMCs from SSc patients and healthy controls were engrafted into the blood, skin, and lung tissues of NSG mice. Histological analysis of affected tissues from mice treated with SSc PBMCs (SSc hu-mice) demonstrated substantial inflammation, fibrosis and vasculopathy with human immune cell infiltration and increased expression of IL-17, TGF-ß, CCL2, CCL3, and CXCL9. The proportions of circulating and tissue-infiltrating T helper 17 (Th17) cells were elevated in SSc hu-mice. These cells showed increased expression of CXCR3 and phosphorylated STAT3. SSc hu-mice treated with rebamipide and other potential Th17-cell-modulating drugs presented significantly reduced tissue fibrosis. Mice injected with patient-derived PBMCs show promise as an animal model of SSc.

Recent Advances in Cell Therapeutics for Systemic Autoimmune Diseases.

Systemic autoimmune diseases arise from loss of self-tolerance and immune homeostasis between effector and regulator functions. There are many therapeutic modalities for autoimmune diseases ranging from conventional disease-modifying anti-rheumatic drugs and immunosuppressants exerting nonspecific immune suppression to targeted agents including biologic agents and small molecule inhibitors aiming at specific cytokines and intracellular signal pathways. However, such current therapeutic strategies can rarely induce recovery of immune tolerance in autoimmune disease patients. To overcome limitations of conventional treatment modalities, novel approaches using specific cell populations with immune-regulatory properties have been attempted to attenuate autoimmunity. Recently progressed biotechnologies enable sufficient in vitro expansion and proper manipulation of such 'tolerogenic' cell populations to be considered for clinical application. We introduce 3 representative cell types with immunosuppressive features, including mesenchymal stromal cells, Tregs, and myeloid-derived suppressor cells. Their cellular definitions, characteristics, mechanisms of immune regulation, and recent data about preclinical and clinical studies in systemic autoimmune diseases are reviewed here. Challenges and limitations of each cell therapy are also addressed.

Lipidome profile predictive of disease evolution and activity in rheumatoid arthritis.

Lipid mediators are crucial for the pathogenesis of rheumatoid arthritis (RA); however, global analyses have not been undertaken to systematically define the lipidome underlying the dynamics of disease evolution, activation, and resolution. Here, we performed untargeted lipidomics analysis of synovial fluid and serum from RA patients at different disease activities and clinical phases (preclinical phase to active phase to sustained remission). We found that the lipidome profile in RA joint fluid was severely perturbed and that this correlated with the extent of inflammation and severity of synovitis on ultrasonography. The serum lipidome profile of active RA, albeit less prominent than the synovial lipidome, was also distinguishable from that of RA in the sustained remission phase and from that of noninflammatory osteoarthritis. Of note, the serum lipidome profile at the preclinical phase of RA closely mimicked that of active RA. Specifically, alterations in a set of lysophosphatidylcholine, phosphatidylcholine, ether-linked phosphatidylethanolamine, and sphingomyelin subclasses correlated with RA activity, reflecting treatment responses to anti-rheumatic drugs when monitored serially. Collectively, these results suggest that analysis of lipidome profiles is useful for identifying biomarker candidates that predict the evolution of preclinical to definitive RA and could facilitate the assessment of disease activity and treatment outcomes.

Time-integrated Cumulative Parameters Predictive of Radiographic Progression of Rheumatoid Arthritis: Real-world Data From a Prospective Single-center Cohort.

Objective: With many chronic inflammatory diseases, outcomes are determined by assessing both disease activity at presentation and cumulative activity over time. Here, we investigated whether cumulative activity better reflects the radiographic progression (RP) of rheumatoid arthritis (RA) than measurement of activity at a single time point. Methods: From a prospective cohort of RA patients, most of whom were treated with anti-rheumatic drugs, we selected 117 subjects for whom laboratory, clinical, and radiographic parameters potentially influencing RP were monitored serially for more than 1 year. X-ray images of both hands and both feet were scored using the van der Heijde modified total Sharp score (mTSS). In addition to cross-sectional values at baseline, longitudinal and cumulative values for each parameter were calculated in a time-integrated and averaged manner. Results: Among the values measured at baseline, mTSS, but not the baseline erythrocyte sedimentation rate (ESR) or C-reactive protein level, was associated with RP. By contrast, multivariate analyses identified cumulative values such as the cumulative ESR, cumulative tender joint count, cumulative swollen joint count (SJC), and cumulative Disease Activity Score 28-ESR as major determinants of RP. In particular, the cumulative SJC showed the best predictive performance for RP. Conclusion: This study highlights the importance of cumulative indices for predicting progression of RA. Specifically, dynamic and cumulative values of RA activity-related factors, particularly the cumulative SJC, may be the major determinants of RP in the current practice.

Lactobacillus acidophilus Supplementation Exerts a Synergistic Effect on Tacrolimus Efficacy by Modulating Th17/Treg Balance in Lupus-Prone Mice via the SIGNR3 Pathway.

Objective: Tacrolimus (Tac) is an immunosuppressant used in the treatment of systemic lupus erythematosus (SLE); however, it induces T cell subset imbalances by reducing regulatory T (Treg) cells. Lactobacillus acidophilus (LA) is reported to have therapeutic efficacy in immune-mediated diseases via T cell regulation. Methods: This study investigated whether a combination therapy of LA and Tac improves the therapeutic efficacy of Tac by modulating T cell subset populations in an animal model of SLE. Eight-week-old MRL/lpr mice were orally administered with 5 mg/kg of Tac and/or 50 mg/kg of LA daily for 8 weeks. Cecal microbiota compositions, serum autoantibodies levels, the degree of proteinuria, histological changes in the kidney, and populations of various T cell subsets in the spleen were analyzed. Results: Mice presented with significant gut dysbiosis, which were subsequently recovered by the combination treatment of Tac and LA. Double negative T cells in the peripheral blood and spleens of MRL/lpr mice were significantly decreased by the combination therapy. The combination treatment reduced serum levels of anti-dsDNA antibodies and Immunoglobulin G2a, and renal pathology scores were also markedly alleviated. The combination therapy induced Treg cells and decreased T helper 17 (Th17) cells both in vitro and in vivo. In vitro treatment with LA induced the production of indoleamine-2,3-dioxygenase, programmed death-ligand 1, and interleukin-10 via the specific intracellular adhesion molecule-3 grabbing non-integrin homolog-related 3 receptor signals. Conclusion: The present findings indicate that LA augments the therapeutic effect of Tac and modulates Th17/Treg balance in a murine model of SLE.

Hypergammaglobulinaemia predicts glandular and extra-glandular damage in primary Sjögren's syndrome: results from the KISS cohort study.

OBJECTIVES: To investigate whether temporal changes in immunoglobulin (Ig) levels and persistent hypergammaglobulinaemia cause glandular and extra-glandular damage in patients with primary Sjögren's syndrome (pSS). METHODS: Cumulative demographics and clinical and serological data from pSS patients in the Korean Initiative pSS cohort were evaluated. Persistent hypergammaglobulinaemia was defined as mean IgG levels of ≥1600 mg/dL over 3 years. Salivary gland damage was assessed by measuring salivary flow impairment, and lacrimal gland damage was assessed by examining ocular structural abnormalities. Solid organ damage included neurological and pleuropulmonary damage, renal impairment and lymphoproliferative disease. Independent predictors of glandular and extra-glandular damage in the third year were identified by logistic regression. RESULTS: Of 256 patients with pSS (median age, 55 years; 98% female), 47% had hypergammaglobulinaemia at baseline. IgG levels fell during the first 2 years in patients with hypergammaglobulinaemia at baseline, but not in those with normal IgG levels. Changes in IgG levels were associated with hydroxychloroquine and glucocorticoids. In the third year of follow-up, salivary flow impairment and solid organ damage were present in 71% and 9% of patients, respectively. After adjusting for age and medication use, persistent hypergammaglobulinaemia was associated with salivary flow impairment and solid organ damage in the third year. Patients in whom IgG fell by more than 80 mg/dL from baseline over 2 years showed less solid organ damage. CONCLUSIONS: Persistent hypergammaglobulinaemia was associated with salivary gland and solid organ damage. Decreased IgG may attenuate progression to solid organ dysfunction.

Development of the 8-Item Phlegm Pattern Questionnaire (PPQ-8) Using Rasch Analysis.

The 25-item Phlegm Pattern Questionnaire (PPQ) has been widely used to examine the relationship between the phlegm pattern (PP), quality of life, tongue colour, vocal qualities, and dysfunctional breathing. However, the concerns of response burden and differences in the respondent's abilities or item difficulty for the original version of the PPQ have not been sufficiently addressed. This study aimed to develop a short-form PPQ using Rasch analysis, an item response theory. Based on the retrospective data, the response order, differential item functioning (DIF), dimensionality, reliability, concurrent validity, and fitting errors were examined for 291 normal participants and 61 inpatients. The discriminative ability of the short-form PPQ was examined using receiver operating characteristic curve analysis. Along with Rasch analysis, another short-form PPQ was developed using equidiscriminative item-total correlation (EITC) analysis and the results between the two short-form PPQs were compared accordingly. Rasch analysis results suggested a 6-point response category for the PPQ, and finally, 8 items without fitting errors or DIF variability were selected for the PPQ (PPQ-8). The PPQ-8 had satisfactory reliability (person separation index = 2.23), unidimensionality (unexplained variance in the first contrast = 1.598), fitting levels (infit mean square, 0.80-1.39; outfit mean square, 0.79-1.34), sensitivity (70.5%), and specificity (76.5%). The PPQ-8 had a moderate discriminative ability of the PP (area under the curve = 0.759), and the cut-off point was 23. Although the 8-item PPQ developed using EITC analysis showed similar levels of reliability, validity, and discriminative ability of the PP to the PPQ-8, it could not present the information of item hierarchy and differences in the respondents' abilities. In conclusion, the PPQ-8 by Rasch analysis is recommended for future use to evaluate the clinical severity of PP.