Urolithin A suppresses NLRP3 inflammasome activation by inhibiting the generation of reactive oxygen species and prevents monosodium urate crystal-induced peritonitis.

The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome triggers the maturation of interleukin-1ß (IL-1ß) 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-1ß, and activation of pyroptosis in lipopolysaccharide-primed mouse bone marrow-derived macrophages. Urolithin A reduced generation of intracellular and mitochondrial reactive oxygen species 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 reactive oxygen species.

The COVID-19 pandemic affects pregnancy complications and delivery outcomes in Japan: a large-scale nationwide population-based longitudinal study.

The impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnancy outcomes in Japan at the national level is unclear. This study aimed to assess the impact of the pandemic on pregnancy complications and delivery outcomes in Japan using nationwide population-based longitudinal data. Secondary data from the Japan Society of Obstetrics and Gynecology from 2016 to 2020 were analyzed. Obstetric information, pregnancy complications, and delivery information of pregnant women over 22 weeks of gestation were compared before and during the pandemic. The trends of hypertensive disorder of pregnancy, fetal growth restriction, and APGAR < 7 increased, whereas those of preterm birth and low birth weight decreased during the COVID-19 pandemic. Pregnancy complications and delivery outcomes have worsened during the COVID-19 pandemic in Japan. Social changes caused by unprecedented situations may have massively influenced pregnancy in several ways. Our findings suggest that even in mild lockdowns like those in Japan, the introduction of social fear during the pandemic might negatively impact pregnancy outcomes.

Vascular endothelial growth factor isoforms are expressed in the uterus during estrous cycle of golden hamsters (Mesocricetus auratus).

We investigated VEGF expression in the uterus during the estrous cycle in the golden hamster (Mesocricetus auratus). Reverse transcription polymerase chain reaction of genes expressed in the uterus revealed the presence of at least three different VEGF isoforms (hamster VEGF188, VEGF164, and VEGF120). They were highly homologous to the respective mouse and human isoforms. Furthermore, VEGF164 and VEGF120 were predominantly expressed in the hamster uterus during the estrous cycle. In situ hybridization revealed that VEGF is expressed only in the luminal and glandular epithelium of the endometrium but not in the stromal cells or myometrium. The positive reaction of luminal and glandular epithelial cells on day 4 of the estrous cycle (day 1 = day of ovulation) was a little stronger than that of other days of the cycle. These findings suggest that VEGF molecules are secreted by endometrial epithelial cells and play an important role in the maintenance of blood vessels in the endometrial stroma. These results also suggest that uterine changes, such as edema, observed from day 4 to day 1 of the estrous cycle, are expected to occur primarily through the action of VEGF secreted by the uterine endometrial epithelium in preparation for subsequent embryo implantation.

A large-scale population-based epidemiological study on the prevalence of central sensitization syndromes in Japan.

A cross-sectional study of 21,665 Japanese residents was performed to investigate the prevalence of central sensitization syndromes (CSS). CSS were assessed using the Central Sensitization Inventory (CSI-A). CSS were defined as a CSI-A score of 40 or higher. Age, sex, district, 10 CSS-related diseases (CSI-B), lifestyle, and mental factors were rated in a self-reported survey. The prevalence of CSS and its relationship with potential factors were examined by sex using descriptive and logistic regression models. The prevalence of CSS was 4.2% in all participants and was significantly higher in women (4.9%) than in men (2.7%). Adjusted odds ratios correlated with CSS for an age of 80-97 years versus 60-79 years (2.07 and 2.89), one or more CSI-B diseases (3.58 and 3.51), few sleeping hours (2.18 and 1.98), high perceived stress (5.00 and 4.91), low (2.94 and 2.71) and high (0.45 and 0.66) resilience versus moderate resilience, and exercise habits (0.68 and 0.55) in men and women (all P < 0.05). The relationship between CSS and age 20 and 59 years, ex-smokers, coffee intake, and alcohol intake differed by sex. The prevalence of CSS was estimated to be low in the healthy population. CSS correlated with CSS-related diseases and some positive and negative factors.

Central Sensitization in Neurological, Psychiatric, and Pain Disorders: A Multicenter Case-Controlled Study.

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.

Central sensitization in migraine is related to restless legs syndrome.

OBJECTIVE: We hypothesized that, in migraine patients, central sensitization (CS) could be associated with comorbid restless legs syndrome (RLS). METHODS: We conducted a case-control study including 186 migraine patients and 186 age- and sex-matched healthy controls. Symptoms related to CS syndrome were assessed by the Central Sensitization Inventory (CSI). Individuals with CSI Part A (CSI-A) scores ≥ 40 were defined as having CS. For patients with migraine, the Brief Pain Inventory (BPI) and Patient Health Questionnaire (PHQ)-9 were administered. In the patient group, RLS and migraine were diagnosed through face-to-face interviews. RESULTS: Among migraine patients, 26 (14.0%) suffered from chronic migraine. The mean disease duration was 23.7 ± 11.8 years. Migraine patients showed a higher rate of CS (21.0% vs. 8.6%) than healthy controls, with an adjusted odds ratio (AOR) of 3.039 (95% confidence interval (CI) 1.560-5.992; p = 0.001). Migraine patients in the CS group had higher rates of smoking, chronic migraine and RLS and higher BPI and PHQ-9 scores than migraine patients in the non-CS group. The use of acute and preventive treatment for migraine did not significantly differ between the CS and non-CS groups. Multivariable analysis identified the presence of RLS (AOR, 28.471; 95% CI 6.438-125.918; p < 0.001) and the BPI pain interference score (AOR, 1.398; 95% CI 1.061-1.843; p = 0.017) as the significant determinants of CS among migraine patients. CONCLUSION: Migraine patients were 3 times more likely to have CS than healthy controls. Our study results showed an association between RLS and CS in migraine patients.

Poor uterine contractility and postpartum hemorrhage among low-risk women: A case-control study of a large-scale database from Japan.

OBJECTIVE: To examine the association between the risk of postpartum hemorrhage (PPH) and poor uterine contractility, which is suggested by the characteristics of labor. METHODS: This case-control study used cases recorded in the Japan Perinatal Registry database during the period 2013-2016. After exclusion of women with specified known risk factors for PPH, we enrolled 174 082 primiparas who had a full-term live singleton vaginal birth. Participants were classified into four classes according to the diagnosis of abnormal labor patterns and use of uterotonics. χ2 tests were used to compare PPH cases with controls, and odds ratios (OR) were calculated by univariate and multivariate analyses. RESULTS: Among the enrolled women, 10 508 (6.0%) had PPH. Abnormal labor patterns were significantly associated with an increased risk of PPH. Compared with women without any abnormal labor patterns who had not used uterotonics, women with abnormal labor patterns were at a significantly increased risk for PPH regardless of whether they had used uterotonics (adjusted OR 1.23, 95% confidence interval [CI] 1.10-1.37) or not (adjusted OR 1.30, 95% CI 1.23-1.37). CONCLUSION: Our study suggests that among low-risk women with PPH, poor uterine contractility in labor could be a significant predisposing risk factor for PPH.

Recent Increasing Incidence of Early-Stage Cervical Cancers of the Squamous Cell Carcinoma Subtype among Young Women.

Few studies have reported on the increase in cervical cancer incidence in Japan. We aimed to determine the relevant trends in the metropolitan regions of Japan and to identify the population with the highest risk, based on histological subtype, cancer stage, and diagnostic processes. Using population-based data (2009-2013), we identified 2110 women, aged ≥20 years, with cervical cancer. We estimated the age-standardized and age-specific incidence rates of cervical cancer for the study period based on the 1985 national model population. The average annual percent change (AAPC) and 95% confidence interval (CI) were calculated using the joinpoint regression analysis. We stratified the analyses based on histological subtypes, stage, and diagnostic process via cancer screening. The increase in the overall age-standardized incidence was not significant. However, the increase was significant for women aged 30-39 years (AAPC 20.0%/year, 95% CI: 9.9-31.1), which was attributable to the increase in the incidence of the squamous cell carcinoma (SCC) subtype (AAPC 23.1%/year, 95% CI: 10.7-36.8). Among younger women, aged <50 years, further stratification showed an increase in the undiagnosed early-stage SCC subtype via cancer screening. In Japan, the incidence of HPV-related cervical cancer has been increasing in undiagnosed younger women.

Gestational Hypertension as Risk Factor of Hypertension in Middle-Aged and Older Women.

The association of gestational hypertension (GH) with future hypertension in Japanese women is unclear. Hence, this study aimed to examine the association between GH and the risk of future hypertension in middle-aged-to-older Japanese women. A case-control study was performed, including 62 hypertensive women (case) and 75 nonhypertensive women (control). GH during the first pregnancy was diagnosed on the basis of the Maternal and Child Health Handbook record. Hypertensive women were recruited from outpatients in the hospital and residents who completed an annual health check-up in a community. Hypertension was defined as blood pressure with systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg, or taking antihypertensive medications. The average age (SD) of the cases and controls at the time of recruitment was 63.1 (8.4) and 57.7 (9.4), respectively. The multivariable-adjusted odds ratio of GH for hypertension in middle-aged-to-older women was 4.2 (95% confidence interval, 1.0-17.5) after adjustment for potential confounding factors such as age and body-mass index (BMI) upon recruitment, prepregnancy BMI, and age at first delivery. In conclusion, GH can be an independent risk factor for future hypertension among Japanese women.

Association between Passive Smoking from the Mother and Pediatric Crohn's Disease: A Japanese Multicenter Study.

Smoking is a risk factor for adult-onset Crohn's disease (CD). Although passive smoking from family members is a major concern, especially in pediatric CD, the number of existing epidemiological studies is limited. This multicenter case-control study aimed to assess the effects of familial smoking on pediatric CD. We examined 22 pediatric CD cases and 135 controls. The subjects' mothers were given a self-administered questionnaire about family smoking before disease onset in the CD group or the corresponding period in the control group. Univariable logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), whereas dose-response relationship analyses were performed for more in-depth evaluations. Univariable analyses indicated that passive smoking from the mother (OR, 2.09; 95% CI, 0.61-7.10) was not a significant, but a candidate risk factor for developing pediatric CD. In contrast, the dose-response relationship analyses revealed that passive smoking from the mother (OR, 1.17; 95% CI, 1.04-1.31) was significantly associated with pediatric CD. Therefore, passive smoking from the mother may be predominantly associated with the development of pediatric CD. Further follow-up studies comprising environmental measurements of passive smoking exposure doses and genetic factors interaction analysis are necessary.

Lipid and Bile Acid Dysmetabolism in Crohn's Disease.

Crohn's disease is one of the systemic autoimmune diseases. It commonly affects the small intestine and colon but may involve any portion of the gastrointestinal tract from the mouth to the anus. The most affected area by Crohn's disease is the distal part of the small intestine, in which the bile acid molecules are most efficiently reabsorbed. Bile acids form mixed micelles together with fatty acids, which function as a transport vehicle to deliver fatty acids to the apical membrane of enterocytes for absorption. Therefore, if the terminal ileum is impaired, bile acid malabsorption may occur, which may cause congenital diarrhoea in Crohn's disease. Similarly, the impairment of the terminal ileum also induces fatty acid malabsorption, which may influence the role of fatty acids in Crohn's disease. In contrast, a recent study reported that multidrug resistance protein 1 (MDR1) regulated effector T-cell function in the ileum from bile acid-driven oxidative stress and MDR1 loss of function in a subset of patients with Crohn's disease. However, the role of consumption of fatty acids in Crohn's disease remains to be fully elucidated. This review is aimed at providing an overview of some recent developments in research of Crohn's disease from comprehensive perspective with a focus on the connection between disease location and behaviour, lipid diets, and bile acid malabsorption.

Use of Iodine-131 to Tellurium-132 Ratios for Assessing the Relationships between Human Inhaled Radioactivity and Environmental Monitoring after the Accident in Fukushima.

Significant differences in findings were seen between the intake amounts of iodine-131 that were derived from direct measurements and the estimated intake from environmental monitoring data at the Fukushima accident. To clarify these discrepancies, we have investigated the iodine-131 and tellurium-132 body burdens of five human subjects, who after being exposed to a radioactive plume, underwent 21.5 h whole body counter measurements at Fukui Prefectural Hospital, so clear intake scenario and thyroid counter measurement data were available. To determine the iodine-131 and tellurium-132 body burdens, we introduced a new method of whole body counter calibration composed of a self-consistent approach with the time-dependent correction efficiency factors concept. The ratios of iodine-131 to tellurium-132, ranging from 0.96 ± 0.05 to 2.29 ± 0.38, were consistent with results of the environmental measurements. The 24 h iodine uptake values ranging from 12.1-16.0% were within euthyroid range in Japanese people. These results suggest, even if the relatively low thyroid iodine uptake in the Japanese population was taken into consideration, that there is no doubt about the consistency between direct measurements and environmental monitoring data. Adequate intake scenario is suggested to be principally important to estimate the inhaled radioactivity in areas in or around nuclear accidents.

Chronic myocarditis with a long clinical course: Report of an autopsy case of probable autoimmune myocarditis.

The patient was a 54-year-old woman, who died of chronic cardiac insufficiency after a clinical course of 2 years and 4 months. She had complained of myalgia, muscle weakness, and blepharoptosis before the onset of cardiac symptoms, but there was no evidence of myasthenia gravis or collagen-vascular diseases. At autopsy, the heart (280 g) showed marked dilatation of the four chambers and thinning of the ventricular walls. Diffuse and intense lymphocytic infiltration and extensive fibrosis were noted, with the latter being accentuated in the subendocardial and subepicardial zones. Small foci of myocardial necrosis were scattered and a small number of multinucleated giant cells were found, but epithelioid cell granulomas, Aschoff's nodules, and viral inclusion bodies were not observed. Some cardiomyocytes showed the aberrant expression of the HLA-DR antigen. No viral genomes were detected in myocardial tissue using a multivirus real-time polymerase chain reaction. The protracted clinical course, presence of active inflammatory changes at autopsy, expression of the HLA-DR antigen on cardiomyocytes, and absence of viral genomes in myocardial tissue suggest that autoimmune mechanisms played an important role in the pathogenesis and persistence of myocarditis in this patient.

Maintaining of the Green Fluorescence Emission of 9-Aminoanthracene for Bioimaging Applications.

The green fluorescence emission of 9-aminoanthracence (9AA) was maintained by controlling the oxidation of 9AA with oxygen in the solid state and in solution. The solid-state fluorescence of 9AA was maintained for a longer time when lauric acid was used because the equilibrium between 9AA and 9-anthrylammonium salt (9AAH + ) inclines toward the right-hand side in the presence of an acid. A solution of 9AA in CDCl3, to which nitrogen had been bubbled through for 5 min, continued to emit green fluorescence for more than 3 days, whereas the fluorescence emission disappeared within 3 days for the solution that had been bubbled with oxygen for 5 min. 9AA is oxidized by oxygen in MeOH under dark conditions to give almost nongreen fluorescent anthraquinone monoimine (AQNH), whereas dimerization of 9AA occurs under UV irradiation at 365 nm, much faster than the generation of AQNH. These results suggest that 9AA is oxidized by the triplet rather than the singlet oxygen in MeOH. Some of the organic molecules, proteins, and biological tissues were successfully stained with 9AA on microscope slides within 10 min because the green fluorescence emission of 9AA was successfully maintained in the presence of an acid and under hypoxic conditions of the used materials.

A Study of Thyroid 131I Activity of Five Human Subjects Exposed to a Radioactive Plume at Tamura City in Fukushima.

Thyroid 131I activities were determined for five human subjects from a disaster medical assistance team of Fukui Prefectural Hospital. The team was dispatched to the Tamura City Sports Park, 40 km from the Fukushima Daiichi nuclear power plant. They were exposed to a radioactive plume on 15 March 2011. In vivo measurements at Fukui Prefectural Hospital were conducted around 17 h after the team left the park. A thyroid counter equipped with a 51-mm-diameter × 51-mm-thick NaI(Tl) detector with a 20-mm-thick lead collimator was used. Mock iodine (133Ba and 137Cs) with a thyroid uptake neck phantom was used for calibration. On 16 March 2011, at 11:30, thyroid activity of a member of the team age 53 y, who was never administered stable iodine, was 268 ± 38 Bq. The remaining four men, aged 49, 35, 34, and 27 y, ingested two stable iodine pills (a total of 100 mg of potassium iodide) approximately 36 h before being exposed to the plume. Their thyroid activity values were 249 ± 86 Bq, 676 ± 107 Bq, 569 ± 96 Bq, and 1,082 ± 119 Bq, respectively. An inverse relationship between age and thyroid activity was observed among those who ingested potassium iodide before exposure, indicating that stable iodine administration may have a protective effect. Thyroid 131I activity was reduced by approximately 70% in the oldest person. This can be explained by the iodine metabolism in the thyroid of younger individuals being significantly faster than that of older individuals.

A novel imprinted transgene located near a repetitive element that exhibits allelic imbalance in DNA methylation during early development.

A mouse line carrying a lacZ transgene driven by the human EEF1A1/EF1 alpha promoter was established. Although the promoter is known to show ubiquitous activity, only paternal transgene alleles were expressed, resulting in a transgene imprinting. At mid-gestation, the promoter sequence was differentially methylated, hypomethylated for paternal and hypermethylated for maternal alleles. In germline, the promoter was a typical differentially methylated region. After fertilization, however, both alleles were hypermethylated. Thus, the differential methylation of the promoter required for transgene imprinting was re-established during later embryonic development independently of the germline differential methylation. Furthermore, also a retroelement promoter closely-flanking imprinted transgene and its wild type counterpart displayed similar differential methylation during early development. The retroelement promoter was methylated differentially also in germline, but in an opposite pattern to the embryonic differential methylation. These results suggest that there might be an unknown epigenetic regulation inducing transgene imprinting independently of DNA methylation in the transgene insertion site. Then, besides CpG dinucleotides, non-CpG cytosines of the retroelement promoter were highly methylated especially in the transgene-active mid-gestational embryos, suggesting that an unusual epigenetic regulation might protect the active transgene against de novo methylation occurring generally in mid-gestational embryo.

Structural abnormalities of corpus callosum and cortical axonal tracts accompanied by decreased anxiety-like behavior and lowered sociability in spock3- mutant mice.

Spock3/Testican-3 is a nervous system-expressed heparan sulfate proteoglycan belonging to a subgroup of the BM-40/SPARC/osteonectin family, the role of which in brain development is unclear. Because Spock1, a member of the Spock family, inhibits their attachment to substrates and the neurite outgrowth of cultured neuronal cells, Spock3 is also thought to be similarly involved in the neuronal development. In the present study, we established a Spock3-mutant mouse harboring a deletion extending from the presumptive upstream regulatory region to exon 4 of the Spock3 locus and performed histological and behavioral studies on these mutant mice. In wild-type (WT) mice, all Spock members were clearly expressed during brain development. In adults, intense Spock1 and Spock2 expressions were observed throughout the entire brain; whereas, Spock3 expression was no longer visible except in the thalamic nuclei. Thus, Spock3 expression is mostly confined to the developmental stage of the brain. In adult mutant mice, the cells of all cortical layers were swollen. The corpus callosum was narrowed around the central region along the rostral-caudal axis and many small spaces were observed without myelin sheaths throughout the entire corpus callosum. In addition, the cortical input and output fibers did not form into thick bundled fibers as well as the WT counterparts did. Moreover, a subpopulation of corticospinal axonal fibers penetrated into the dorsal striatum with moderately altered orientations. Consistent with these modifications of brain structures, the mutant mice exhibited decreased anxiety-like behavior and lowered sociability. Together, these results demonstrate that Spock3 plays an important role in the formation or maintenance of major neuronal structures in the brain.

Myocardial expression level of neural cell adhesion molecule correlates with reduced left ventricular function in human cardiomyopathy.

BACKGROUND: Recently, we screened for cardiac genes induced by metabolic stress and identified neural cell adhesion molecule (NCAM) as a candidate. This study aimed to clarify the expression pattern of NCAM in human cardiomyopathy. METHODS AND RESULTS: A total of 64 cardiac tissue samples of patients with dilated cardiomyopathy were dichotomized according to the immunohistochemically determined signal intensity of NCAM staining (NCAM-high and NCAM-low groups). Clinical and hemodynamic data of the patients were compared between the 2 groups. Fibrosis area, left ventricular end-diastolic volume index, and left ventricular diastolic pressure were greater in the NCAM-high group (22.8% versus 11.6%, P<0.05; 130.3±57.6 versus 104.8±31.7 mL/m(2), P<0.05; 14.3±8.0 versus 8.8±4.7 mm Hg, P<0.005; respectively). Incidence of cardiac death and admission for worsening heart failure was higher in the NCAM-high group during a follow-up of 6.3 years (log-rank P<0.05). Another 18 tissue samples were analyzed to determine the relationships between expression level of NCAM and major metabolic genes as well as hemodynamic parameters. The mRNA level of NCAM correlated with the serum (r=0.58; P=0.01) and mRNA levels (r=0.61; P=0.008) of brain-derived natriuretic peptides. It was also correlated with the mRNA levels of proliferator-activated receptor-γ coactivator-1 α (r=0.69; P=0.002) and the nuclear respiratory factor 1 (r=0.74; P<0.001). CONCLUSIONS: Expression of NCAM was associated with worsening hemodynamic parameters and major metabolic genes. Together with our previous findings, these data support the involvement of NCAM in left ventricular remodeling, revealing new insights into the pathophysiology of heart failure.

Mast cells play a critical role in the pathogenesis of viral myocarditis.

BACKGROUND: Mast cells are powerful producers of multiple cytokines and chemical mediators playing a pivotal role in the pathogenesis of various cardiovascular diseases. We examined the role of mast cells in murine models of heart failure due to viral myocarditis, using 2 strains of mast cell-deficient mice. METHODS AND RESULTS: Two strains of mast cell-deficient mice, WBB6F1-Kit(W)/Kit(W-v) (W/W(V)) and WCB6F1-Kitl(Sl)/Kitl(Sl-d) (Sl/Sl(d)), were inoculated with 10 plaque-forming units of the encephalomyocarditis virus intraperitoneally. On day 14 after inoculation, survival of W/W(V) mice was significantly higher than that of their control littermates (77% versus 31%; P=0.03; n=13). On histological examination on day 7, myocardial necrosis and cellular infiltration were significantly less pronounced in W/W(V) and Sl/Sl(d) mice than in their control littermates (area of infiltration, 7.6+/-3.5% versus 29.3+/-15.6%; P=0.002; area of necrosis, 7.6+/-3.5% versus 30.0+/-17.2%; P=0.003; n=10). Histological examination showed more severe changes in mast cell-reconstituted than in -nonreconstituted W/W(V) and Sl/Sl(d) mice. The gene expressions of mast cell proteases were upregulated in the acute phase of viral myocarditis and rose further in the subacute phase of heart failure. Their activation coincided with the development of myocardial necrosis and fibrosis and correlated with the upregulation of gene expression of matrix metalloproteinase-9. The histamine H1-receptor antagonist bepotastine improved encephalomyocarditis viral myocarditis. CONCLUSIONS: These observations suggest that mast cells participate in the acute inflammatory reaction and the onset of ventricular remodeling associated with acute viral myocarditis and that the inhibition of their function may be therapeutic in this disease.