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The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers the maturation of interleukin-1β (IL-1β) and is implicated in the pathogenesis of various inflammatory diseases. Urolithin A, a gut microbial metabolite of ellagic acid, reportedly exerts antiinflammatory effects in vitro and in vivo. However, whether urolithin A suppresses NLRP3 inflammasome activation is unclear. In this study, urolithin A inhibited the cleavage of NLRP3 inflammasome agonist-induced caspase-1, maturation of IL-1β, and activation of pyroptosis in lipopolysaccharide-primed mouse bone marrow-derived macrophages. Urolithin A reduced generation of intracellular and mitochondrial reactive oxygen species (ROS) and restricted the interaction between thioredoxin-interacting protein and NLRP3, which attenuated NLRP3 inflammasome activation. Urolithin A administration prevented monosodium urate-induced peritonitis in mice. Collectively, these findings indicate that urolithin A suppresses NLRP3 inflammasome activation, at least partially, by repressing the generation of intracellular and mitochondrial ROS.Graphical AbstractSchematic diagram of the suppressive effect of urolithin A on NLRP3 inflammasome activation in macrophages.

The effect of exercise habits on the increased incidence of lifestyle-related diseases among residents of the evacuation area in Fukushima Prefecture after the Great East Japan Earthquake is not well characterized. This study examined the influence of exercise habits on the frequency of new onset of lifestyle-related diseases in the aftermath of the earthquake using data from the Fukushima Health Management Survey (FHMS). Of the 32 289 individuals (14 004 men and 18 285 women) aged 40–90 years who underwent one or more health examinations in both 2011–12 and 2014–15, those who knew whether they had any lifestyle diseases and who responded to a questionnaire about their exercise and physical activity habits were included (dyslipidemia, 8017; hypertension, 7173; and diabetes mellitus, 13140 individuals). The association between the frequency of new onset of lifestyle-related diseases in 2014–15 and the presence or absence of persistent exercise and physical activity habits (active lifestyle) was examined using the FHMS data. The frequency of new onset of dyslipidemia was significantly lower in the active lifestyle group than in the sedentary lifestyle group (P= 0.008). On univariate and multivariate logistic regression analyses, the presence of active lifestyle, obesity and the experience of evacuation showed a significant association with new onset of dyslipidemia, independent of age, sex or follow-up period. Thus maintaining physical activity and exercise habits may help prevent the new onset of dyslipidemia among residents of the evacuation area in the Fukushima Prefecture after the earthquake.

Potassium iodide (KI), initially derived from seaweed in the early 19th century, is used for treating sporotrichosis in dermatological practice. KI has also been used to treat several noninfectious inflammatory skin diseases. However, the mechanisms underlying the improvement in such skin diseases remain unknown, and KI is not used widely. Thus, although KI is an old drug, physicians may not prescribe it frequently because they lack knowledge about it. Although KI is very inexpensive and causes few side effects, it has been superseded by new powerful and expensive drugs, such as biological agents. We applied 3% KI topically to areas of inflammation induced by SDS in mice. The levels of IL-1and TNF-αgene expression were reduced, whereas that of IL-10gene expression was increased. Small interfering RNA that was designed to reduce IL-10gene expression levels was injected into the same mice, and the anti-inflammatory effects of KI were not observed. Thus, the pharmacologic action of KI is based on its anti-inflammatory effects caused by the increase in IL-10 levels. This information would increase dermatologists’ awareness of KI as an efficacious and cost-effective treatment.

In Parkinson’s disease (PD) patients, the factors related to weight loss remain unclear. To investigate determinants of low body mass index (BMI) in PD patients. We identified factors associated with low BMI in PD patients in a multicenter case-control study. A total of 435 PD patients and 401 controls were included. The mean BMI was significantly lower in PD patients than in controls (22.0±3.4 kg/m2vs. 25.4±4.3 kg/m2), with an adjusted odds ratio (AOR) of 3.072 (95% CI, 2.103–4.488; p < 0.001) for low BMI (<22 kg/m2) in PD. Compared to the high-BMI PD group (>22 kg/m2), the low-BMI PD group (<22 kg/m2) had more women; a longer disease duration; higher revised Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) II and IV scores; an increased levodopa equivalent dose (LED); and increased constipation, visual hallucination, dysphagia, dyskinesia and wearing off rates. There were no between-group differences in depression, anhedonia, apathy, sleep problems and daytime sleepiness. Multivariable analysis showed that visual hallucination (AOR, 2.408; 95% CI, 1.074–5.399; p = 0.033) and the MDS-UPDRS IV (AOR, 1.155; 95% CI, 1.058–1.260; p = 0.001) contributed to low BMI after controlling for clinical factors. In a second model, visual hallucination (AOR, 2.481; 95% CI, 1.104–5.576; p = 0.028) and dyskinesia (sum of the MDS-UPDRS 4.3–4.6) (AOR, 1.319; 95% CI, 1.043–1.668; p = 0.021) significantly contributed to low BMI. PD patients were 3 times more likely than healthy controls to have a low BMI. Motor complications, particularly dyskinesia, and visual hallucination were significantly associated with low BMI in PD patients.

Chronic kidney disease (CKD) is an important health problem for which risk equations have been developed for Western populations. This study aimed to develop and validate a risk prediction equation for CKD in a Japanese population.

The aim of this study was to examine the attribution of each cardiovascular risk factor in combination with abdominal obesity (AO) on Japanese health expenditures.

We sought to clarify the association between the personal utilization of general health checkups (GHCs) and medical expenditures (MEs) in a middle-aged Japanese population.

The Great East Japan Earthquake and subsequent Fukushima Daiichi Nuclear Power Plant accident caused residents to switch from their normal lives to lives focused on evacuation. We evaluated liver function before and after this disaster to elucidate the effects of evacuation on liver function.

Objective.Cigarette smoking may be associated with increased risk of systemic lupus erythematosus (SLE), whereas the role of alcohol consumption is unknown. We examined the association between SLE risk and smoking or drinking.Methods.We investigated the relationship of smoking and drinking compared to SLE risk among 171 SLE cases and 492 healthy controls in female Japanese subjects. Unconditional logistic regression was used to compute OR and 95% CI, with adjustments for several covariates.Results.Compared with nonsmoking, current smoking was significantly associated with increased risk of SLE (OR 3.06, 95% CI 1.86–5.03). The higher the level of exposure to cigarette smoke, the higher the risk of SLE. Inhalation was also associated with increased SLE risk (OR 3.73, 95% CI 1.46–9.94 for moderate inhalation; OR 3.06, 95% CI 1.81–5.15 for deep inhalation). In contrast, light/moderate alcohol consumption had a protective effect on SLE risk (OR 0.38, 95% CI 0.19–0.76). As for beer, the risks for non-beer drinkers and beer drinkers were similar. This also applies to alcoholic beverages other than beer.Conclusion.Our results suggest that smoking was positively associated with increased SLE risk whereas light/moderate alcohol consumption was inversely associated with SLE risk, irrespective of the type of alcoholic beverage. Additional studies are warranted to confirm these findings.

We sought to examine occupational disparities in tumor grade and cytosolic expression of high‐mobility group box‐1 (HMGB1) among renal cell cancer (RCC) patients. This retrospective study included 318 RCC patients with complete information on occupation and pathology in Kanagawa Cancer Registry (KCR). Longest‐held occupations were grouped into manual workers (e.g., manufacturing, construction) versus “others.” Odds ratios (OR) and 95% confidence intervals (CI) for high‐grade histology were estimated by logistic regression, adjusted for age and sex. We also examined a sub‐sample of 74 low‐grade RCC inpatients to estimate the OR for positive cytosolic HMGB1 expression in manual workers, adjusting for age, sex, and other available covariates. High‐grade tumors were more prevalent in manual workers compared to other occupations: 23.0% (14/61) versus 10.9% (28/257, p= .01) with an adjusted OR of 2.28 (95% CI, 1.11–4.69). In the sub‐sample of low‐grade RCCs, positive cytosolic HMGB1 expression was more prevalent in manual workers compared to other occupations: 71.4% (10/14) versus 38.3% (23/60, p= .03) with a sex‐ and age‐adjusted OR of 3.76 (95% CI, 1.03–13.7). Manual workers are associated with increased risks of high‐grade renal cell tumors and cytosolic HMGB1 expression.

Multiple chemical sensitivity (MCS) is a form of chemical intolerance in which various systemic symptoms are triggered by exposure to a variety of chemical substances. Although migraine has been associated with central sensitivity syndrome, the relationship between MCS and migraine has not been studied. We assessed the frequency of MCS and its related factors in patients with migraine. We performed a cross‐sectional study that included 95 patients (14 M/81 F; age, 45.4 ± 12.4 years) out of 100 consecutive patients with migraine from our outpatient headache clinic. MCS was defined as having a combination of Q1 ≥ 30, Q3 ≥ 13, and Q5 ≥ 17 on the quick environment exposure sensitivity inventory (QEESI; Japanese version). Central sensitization inventory‐A scores >40 were considered an indication of central sensitization. Headache‐related disability and psychological distress were evaluated with the Migraine Disability Assessment score (MIDAS) and Kessler Psychological Distress Scale (K6), respectively. MCS was identified in 20% of patients with migraine; however, none had previously been diagnosed with MCS. The MCS‐positive group had higher rates of photophobia, osmophobia, visual aura, sensory aura, and central sensitization and higher MIDAS and K6 scores than the MCS‐negative group. A logistic regression analysis showed that osmophobia, sensory aura, and central sensitization were significant contributors to MCS. We showed that MCS was observed in 20% of patients with migraine, and our study results may indicate a possible association of MCS with central sensitization and hypersensitivity‐related symptoms in patients with migraine.

OBJECTIVE: Recent studies have identified signal transducer and activator of transcription 4 (STAT4) as a susceptibility gene for systemic lupus erythematosus (SLE) in different populations. Similarly, tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B) has been reported to be associated with SLE risk in Japanese populations. Along with environmental factors such as smoking, both polymorphisms may modulate an individual’s susceptibility to SLE. We investigated these relationships in a case-control study to evaluate risk factors for SLE among Japanese women. METHODS: We investigated the relationship of the STAT4 rs7574865 and TNFRSF1B rs1061622 polymorphisms to SLE risk with special reference to their combination and interaction with cigarette smoking among 152 SLE cases and 427 controls. RESULTS: The TT genotype of STAT4 rs7574865 was significantly associated with increased risk of SLE (OR 2.21, 95% CI 1.10–4.68). Subjects with at least one G allele of TNFRSF1B rs1061622 had an increased risk of SLE (OR 1.56, 95% CI 0.99–2.47). The attributable proportion due to the interaction between the TNFRSF1B rs1061622 genotypes and smoking was estimated to be 0.49 (95% CI 0.07–0.92), indicating that 49% of the excess risk for SLE in smokers with at least one G allele was due to an additive interaction. A lack of significant associations of STAT4 with smoking was observed. No significant gene-gene interactions were found among polymorphisms of STAT4 and TNFRSF1B. CONCLUSION: Our findings suggest that the association between cigarette smoking and SLE could be differentiated by the TNFRSF1B rs1061622 T allele among female Japanese subjects. This preliminary exploratory result should be confirmed in a larger study.

The relation between dietary habits and the risk of ossification of the posterior longitudinal ligaments of the spine (OPLL) was investigated in a case-control study conducted in Japan from 1998 to 2001. Prevalent OPLL cases ( n = 69) were identified and individually matched by age and sex with community controls ( n = 138) randomly selected from the general population in Hokkaido. A self-administered food-frequency questionnaire was used to assess habitual dietary intake. The odds ratio (OR) and its 95% confidence interval (CI) were estimated, using conditional logistic regression models to compute the OR adjusted for a history of diabetes mellitus. We found that frequent consumption of pickles (salted products) was significantly associated with an increased risk of OPLL, with an adjusted OR of 1.6 (95% CI, 1.1 to 2.2). The adjusted OR for nondaily consumers of rice was 3.0 (95% CI, 2.4 to 3.7). Frequent consumption of chicken (adjusted OR, 0.5; 95% CI, 0.3 to 0.98) and soy foods (adjusted OR, 0.4; 95% CI, 0.2 to 0.7) was significantly associated with a decreased risk of OPLL. Our findings suggest that dietary habits may constitute independent risk factors for OPLL. Further studies will be needed to prospectively determine the relationship between dietary habits and OPLL risk.

In order to determine whether maternal smoking before or during pregnancy, or both, is associated with a reduced risk for preeclampsia in Japanese subjects, we conducted a case-control study that took other risk factors for preeclampsia into consideration. Seventy-one preeclampsia patients were matched with 142 controls for parity and age. Information from a self-administered questionnaire and clinical data such as maternal age, parity, family history of hypertension, prepregnancy body mass index (BMI), and pregnancy outcomes were analyzed. No significant difference was found between the groups in smoking rates before and during pregnancy (38.0 and 18.3% in preeclampsia patients and 38.0 and 16.9% in controls, respectively). However, classification of the subjects according to the presence of "prepregnancy high body mass (BMI ≥ 24)" revealed a significant association between maternal smoking before pregnancy and preeclampsia in women with a prepregnancy high body mass (a smoking rate of 47.6% in patients with preeclampsia and 7.1% in controls, p &lt; 0.05). This result suggests that there is a clear racial difference in the manifestation of preeclampsia with respect to the effect of smoking and that early intervention, particularly before pregnancy, to get obese women to stop smoking may be effective for preventing preeclampsia.

We sought to perform a tree-based analysis of lifestyle risk factors for hypertension in pregnancy (HP) with univariate and multivariate analyses. Seventy-eight HP patients and 199 normal controls were recruited from primiparous women 20 to 34 years of age. Data from angiotensinogen (AGT) genotyping and data from a self-administered questionnaire about lifestyle were subjected to univariate and multivariate analyses. By dividing the subjects into two subgroups-those who possessed "the TT genotype of AGT" and "body mass index (BMI) &lt; 24" and those who did not-we were able to examine the acquired risk factors for HP during pregnancy in these two groups. Multivariate analysis selected "mentally stressful condition" and "no antenatal training during pregnancy" in the former group, and "poorly balanced diet" in the latter group. Determination of factors obvious before pregnancy, such as genotype or prepregnancy BMI, may be useful for devising effective individualized strategies for preventing HP.

PROBLEM: The aims of this study were to investigate the efficacy of massive intravenous immunoglobulin (MIVIg) treatment for women with recurrent spontaneous abortion (RSA) of unexplained etiology, and to investigate changes in peripheral natural killer (NK) cell activity and subsets.
 METHOD OF STUDY: MIVIg treatment was performed in 18 pregnancies from 15 women with 4 or more consecutive RSA of unexplained etiology. NK cell activity and subsets were assessed in 8 of the pregnancies.
 RESULTS: 14 pregnancies resulted in live births and 4 resulted in abortions with chromosome abnormality. The pre‐infusion NK cell activity (mean±SD, 40.9±17.0%) at 4.4±0.5 weeks of gestation (GW) decreased to 15.0±7.9% at post‐infusion status (5.4±0.5 GW). Pre‐infusion percentages of CD56+CD16−cells (3.5±2.1%) and CD56+CD16−cells (16.8±8.8%) decreased to 3.0±2.2% and 11.1±6.9%, respectively, after MIVIg treatment.
 CONCLUSIONS: MIVIg treatment was effective in all 14 pregnancies from RSA women of unexplained etiology, excluding 4 abortions with chromosome abnormality. Peripheral NK cell activity and subsets were suppressed by MIVIg treatment.

Hypertension in pregnancy (HP), including preeclampsia, is known to be a multifactorial disease. Recently, a Glu298Asp variant of the endothelial nitric oxide synthase gene (NOS3) was identified as being associated with coronary spasm and myocardial infarction, whereas it has been reported that endothelial nitric oxide synthase plays a role in HP. We therefore performed an association study of the Glu298Asp variant with HP among 152 HP patients and 335 normal pregnant control individuals, in the context of other risk factors before pregnancy. The frequency of the variant GA+AA NOS3 genotypes was significantly higher in the patients (0.23) than in the controls (0.12) (P &lt; 0.01). Multivariate analysis revealed that family history of hypertension, TT genotype of the angiotensinogen gene (AGT), GA+AA NOS3 genotype, and prepregnancy body mass index ≥ 24 were independent potent risk factors, after adjustment for maternal age and parity. The odds ratios of the factors were 2.7, 2.3, 2.2, and 2.1, respectively. Our results suggested that the Asp298 of NOS3 is a potent, independent risk factor for HP. © 2001 Wiley-Liss, Inc.

PROBLEM: The aim of this study was to assess the role of natural killer (NK) cells in pregnant women with a history of recurrent spontaneous abortion (RSA). 
METHOD OF STUDY: Consecutive 66 pregnant women with a history of RSA were prospectively assessed for peripheral NK cell activity, percentage of the NK cell subsets, and subsequent pregnancy outcome. 
RESULTS: NK cell activity in women with subsequent live birth (group I) at 4–5 gestational weeks (GW) (mean±SD, 32.5±12.3%) significantly decreased at 6–7 GW (28.1±12.1%) and at 8–9 GW (28.0±11.8%). NK cell activity in women with subsequent abortion with normal chromosomes (group II) at 6–7 GW (41.2±19.0%) was significantly higher than that in group I women, while NK cell activity at 6–7 GW in women with subsequent abortion with abnormal chromosomes (group III) was the same as the level in group I women. 
CONCLUSIONS: High NK cell activity at 6–7 GW correlates with subsequent abortion with normal chromosomes.

Objective:The aim of this study was to assess the role of NK cells in nonpregnant women with a history of spontaneous abortion. Study Design:113 nonpregnant women with a history of spontaneous abortion were assessed for peripheral NK cell activity and percentage of NK cell subsets, in relation to the cause of abortions, the number of spontaneous abortions, and subsequent pregnancy outcome (n = 56). Results:Neither NK cell activity nor subsets showed a significant difference in relation to the cause or number of spontaneous abortions. NK cell activity in nonpregnant women who later experienced subsequent abortion with normal chromosomes (n = 10) (mean ± SD: 42.8 ± 15.8%) was relatively higher than that in women with subsequent live birth (control, n = 39) (32.1 ± 13.7%) (p = 0.099). NK cell activity in women who later experienced subsequent abortion with abnormal chromosomes (n = 7) (28.7 ± 21.4%) was the same as the level in the control. Conclusion:Peripheral NK cell activity or subsets during nonpregnant status were not related to the cause or number of previous spontaneous abortions. A relation between preconceptional NK cell activity and later experiencing abortion with normal chromosomes should be further studied.

The aim of this study was to evaluate the insulin dynamics of patients with gestational diabetes mellitus (GDM) and to compare perinatal outcomes according to the insulin response patterns. Twenty-two out of 925 consecutive women examined were diagnosed as having GDM. One hundred and ten women who experienced a normal pregnancy were used as controls. Plasma glucose levels and insulin responses were evaluated by a 2-hour 75-gram oral glucose tolerance test (OGTT). Immunoreactive insulin (IRI), the area under the curve (AUC) of glucose (AUCg) and insulin (AUCi), and the insulinogenic index (II = ΔIRI 30 min/ΔBS 30 min) were measured. The GDM patients were divided into three subgroups, consisting of hyper-, normo- and hypoinsulinemic groups, according to the mean ± 2 SD of the AUCi obtained from the controls. Clinical and laboratory findings were compared among the GDM subgroups and controls. The GDM patients showed impaired insulin secretion to glucose stimuli, with low plasma insulin levels (at 30 min) and reduced insulin/glucose ratios (at 30 and 60 min) early in the 75-gram OGTT. The II and AUCi/AUCg values of GDM patients were reduced as compared with those of controls. These reduced insulin responses were remarkable in hypo- and normoinsulinemic GDM patients, but were not detected in hyperinsulinemic GDM patients. The number of babies large for their gestational age in normo- and hypoinsulinemic GDM patients was significantly higher than that in hyperinsulinemic GDM patients or controls. Hyperinsulinemic GDM patients had a high frequency of pregnancy-induced hypertension (40%). The body mass index prior to pregnancy of hyperinsulinemic GDM patients was significantly higher than that of normoinsulinemic GDM patients or controls. It was demonstrated that not only insulin secretion, but also perinatal clinical characteristics, differed among the GDM subgroups. The heterogeneity of the disease was thus confirmed.

An association between preeclampsia (PE) and a common missense mutation of the methylenetetrahydrofolate reductase gene (MTHFR), a C to T substitution at nucleotide 677 (C677T), which converts an alanine to a valine residue, has been reported in Italian and Japanese populations. We examined 101 cases of hypertension in pregnancy (HP), including 73 cases of PE, and 215 normal pregnancy controls to confirm the association in Japanese women. No significant differences of the frequency of the T677 allele frequency or percentage of T677 homozygotes were detected among the various types of cases: HP (0.38, 12%, respectively), severe HP (0.40, 12%), PE (0.38, 11%), severe PE (0.41, 11%), primiparous HP (0.40, 12%), primiparous PE (0.44, 18%), nonelderly HP (0.39, 13%), nonelderly PE (0.40, 14%), nonobese HP (0.38, 12%), nonobese PE (0.39, 10%), HP without homozygous T235 of the angiotensinogen gene (TT of AGT) (0.38, 15%), PE without TT of AGT (0.38, 15%), and controls (0.38, 15%). The results indicate that T677 of MTHFR may not be a risk factor for PE in Japanese population. Am. J. Med. Genet. 93:122–125, 2000. © 2000 Wiley-Liss, Inc.

Congenital thrombophilia is known to cause significant maternal complications, and possibly has an adverse effect on normal fetal development. The aim of this study was to assess the prevalence of factor XII (FXII) deficiency in women with a history of recurrent miscarriage. Two hundred and forty-one consecutive Japanese women with a history of two or more recurrent miscarriages were prospectively assessed for their etiology by conventional screening methods. Seven women were found to have reduced FXII activity (19.2–46.1%) and prolonged activated partial thromboplastin time (33.3–51.3 s). Of these 7 women, 6 had experienced early pregnancy losses, while 1 woman had experienced repeated mid-trimester fetal losses with coincidental gestational thrombocytopenia. In 241 women with a history of recurrent miscarriage, the prevalence of FXII deficiency was 2.9%.

PROBLEM: The aim of this study was to elucidate fetomaternal risks in systemic lupus erythematosus (SLE)‐complicated pregnancy.

The contribution of genetic factors to hypertension in pregnancy, including pre-eclampsia, has been well documented. The association with a common molecular variant of the angiotensinogen (AGT) gene, in which methionine (M235) is substituted for threonine (T235) at residue 235, has been reported in both Caucasians and Japanese. In the present study, we examined 115 cases of pure type of hypertension in pregnancy (PHP) and 381 normal pregnant controls in order to look for subgroups in which the AGT gene is the major factor in the PHP pathogenesis. By classification of PHP cases according to the clinical diagnosis, gravidity, and maternal age, we found significantly higher frequencies of T235 in both all PHP patients and preeclampsia/eclampsia patients than in normal controls. These results are discordant with those reported for Caucasian subjects where only a group of preeclamptic primigravidae was associated with the AGT variant, possibly indicating the existence of a racial difference. We also found that the variant frequency was significantly higher in the PHP subgroup with maternal age of 20–34 years (0.93) than in a subgroup of multigravid PHP patients age 35 years or older (0.77, P &lt; 0.05) or in normal controls of age 20–34 years (0.76, P &lt; 0.001). The result indicates that the AGT variant plays a significant role in hypertension in the age group 20–34 years. Am. J. Med. Genet. 86:232–236, 1999. © 1999 Wiley-Liss, Inc.

Background. The role of central sensitization in refractory pain-related diseases has not yet been clarified. Methods. We performed a multicenter case-controlled study including 551 patients with various neurological, psychological, and pain disorders and 5,188 healthy controls to investigate the impact of central sensitization in these patients. Symptoms related to central sensitization syndrome (CSS) were assessed by the Central Sensitization Inventory (CSI) parts A and B. Patients were categorized into 5 groups based on CSI-A scores from subclinical to extreme. The Brief Pain Inventory (BPI), addressing pain severity and pain interference with daily activities, and the Patient Health Questionnaire (PHQ)-9, assessing depressive symptoms, were also administered. Results. CSI-A scores and CSI-B disease numbers were significantly greater in patients than in controls (p<0.001). Medium effect sizes (r = 0.37) for CSI-A scores and large effect sizes (r = 0.64) for CSI-B disease numbers were found between patients and control groups. Compared with the CSI-A subclinical group, the CSI-A mild, moderate, severe, and extreme groups had significantly higher BPI pain interference and severity scores, PHQ-9 scores, and CSS-related disease numbers based on ANCOVA. Greater CSI-B numbers resulted in higher CSI-A scores (p<0.001) and a higher odds ratio (p for trend <0.001). CSS-related symptoms were associated with pain severity, pain interference with daily activities, and depressive symptoms in various pain-related diseases. Conclusions. Our findings suggest that CSS may participate in these conditions as common pathophysiology.