Prevalence and risk factors for medication-refractory reflux esophagitis in patients with systemic sclerosis in Japan.

BACKGROUNDS: Patients with systemic sclerosis (SSc) often have esophageal motility abnormalities and weak esophago-gastric junction (EGJ) barrier function, which causes proton pump inhibitor (PPI)-refractory reflux esophagitis (RE). The aims of this study were to clarify the current management of RE and prevalence and risk factors of medication-refractory RE in patients with SSc in Japan. METHODS: A total of 188 consecutive patients with SSc who underwent both esophageal high-resolution manometry (HRM) and esophagogastroduodenoscopy (EGD) were reviewed. The presence of RE and grades of the gastroesophageal flap valve (GEFV) were assessed. Esophageal motility was assessed retrospectively according to the Chicago classification v3.0. When RE was seen on a standard dose of PPI or any dose of vonoprazan (VPZ), it was defined as medication-refractory RE. RESULTS: Approximately 80% of patients received maintenance therapy with acid secretion inhibitors regardless of esophageal motility abnormalities. Approximately 50% of patients received maintenance therapy with PPI, and approximately 30% of patients received VPZ. Medication-refractory RE was observed in 30 patients (16.0%). In multivariable analyses, the number of EGD and absent contractility were significant risk factors for medication-refractory RE. Furthermore, combined absent contractility and GEFV grade III or IV had higher odds ratios than did absent contractility alone. CONCLUSIONS: Patients with persistent reflux symptoms and those with absent contractility and GEFV grade III or IV should receive maintenance therapy with strong acid inhibition to prevent medication-refractory RE.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Keratinocyte-Specific SOX2 Overexpression Suppressed Pressure Ulcer Formation after Cutaneous Ischemia-Reperfusion Injury via Enhancement of Amphiregulin Production.

Ischemia-reperfusion (I/R) injury is a key player in the pathogeneses of pressure ulcer formation. Our previous work demonstrated that inducing the transcription factor SOX2 promotes cutaneous wound healing through EGFR signaling pathway enhancement. However, its protective effect on cutaneous I/R injury was not well-characterized. We aimed to assess the role of SOX2 in cutaneous I/R injury and the tissue-protective effect of SOX2 induction in keratinocytes (KCs) in cutaneous I/R injury. SOX2 was transiently expressed in KCs after cutaneous I/R injury. Ulcer formation was significantly suppressed in KC-specific SOX2-overexpressing mice. SOX2 in skin KCs significantly suppressed the infiltrating inflammatory cells, apoptotic cells, vascular damage, and hypoxic areas in cutaneous I/R injury. Oxidative stress-induced mRNA levels of inflammatory cytokine expression were suppressed, and antioxidant stress factors and amphiregulin were elevated by SOX2 induction in skin KCs. Recombinant amphiregulin administration suppressed pressure ulcer development after cutaneous I/R injury in mice and suppressed oxidative stress-induced ROS production and apoptosis in vitro. These findings support that SOX2 in KCs might regulate cutaneous I/R injury through amphiregulin production, resulting in oxidative stress suppression. Recombinant amphiregulin can be a potential therapeutic agent for cutaneous I/R injury.

Transient receptor potential vanilloid 4 promotes cutaneous wound healing by regulating keratinocytes and fibroblasts migration and collagen production in fibroblasts in a mouse model.

BACKGROUND: Transient receptor potential vanilloid 4 (TRPV4), a cation ion channel, is expressed in different cells, and it regulates the development of different diseases. We recently found a high TRPV4 expression in the wounded skin area. However, the role of TRPV4 in cutaneous wound healing is unknown. OBJECTIVE: To investigate the role of TRPV4 in cutaneous wound healing in a mouse model. METHODS: Skin wound healing experiment and histopathological studies were performed between WT and TRPV4 KO mice. The effect of TRPV4 antagonist and agonist on cell migration, proliferation, and differentiation were examined in vitro. RESULTS: TRPV4 expression was enhanced in wounded area in the skin. TRPV4 KO mice had impaired cutaneous wound healing compared with the WT mice. Further, they had significantly suppressed re-epithelialization and formation of granulation tissue, amount of collagen deposition, and number of α-SMA-positive myofibroblasts in skin wounds. qPCR revealed that the KO mice had decreased mRNA expression of COL1A1 and ACTA2 in skin wounds. In vitro, treatment with selective TRPV4 antagonist suppressed migrating capacity, scratch stimulation enhanced the expression of phospho-ERK in keratinocytes, and TGF-ß stimulation enhanced the mRNA expression of COL1A1 and ACTA2 in fibroblasts. Selective TRPV4 agonist suppressed cell migration in keratinocytes, and did not enhance proliferation and migration, but promoted differentiation in fibroblasts. CONCLUSION: TRPV4 mediates keratinocytes and fibroblasts migration and increases collagen deposition in the wound area, thereby promoting cutaneous wound healing.

TRPV4 Regulates the Development of Psoriasis by Controlling Adenosine Triphosphate Expression in Keratinocytes and the Neuroimmune System.

TRPV4 is a calcium ion channel that is widely expressed in various cells. It is also involved in physiological and pathological processes. However, the role of TRPV4 in psoriasis remains unknown. We aimed to investigate the role of TRPV4 in psoriasis using human psoriasis skin samples and an imiquimod-induced psoriasis-like mouse model. Keratinocytes in human psoriasis skin had high TRPV4 expression. Trpv4-knockout mice had less severe dermatitis than wild-type mice in the imiquimod-induced mouse model. Knockout mice had significantly reduced epidermal thickness and a low number of infiltrated CD3+ T cells and CD68+ macrophages on the basis of histopathological studies and decreased mRNA expression of Il17a, Il17f, and Il23, as detected through qPCR. Furthermore, knockout mice had a significantly low expression of neuropeptides and the neuron marker PGP9.5. Adenosine triphosphate release was significantly suppressed by TRPV4 knockdown in both human and mouse keratinocytes in vitro. Finally, treatment with TRPV4 antagonist was significantly effective in preventing the progression of psoriasis-like dermatitis. In conclusion, TRPV4 mediates the expression of keratinocyte-derived adenosine triphosphate and increases the secretion of neuropeptides, resulting in the activation and amplification of IL-23/Th17 responses. Hence, TRPV4 can serve as a novel therapeutic target in psoriasis.

Renal dysfunction, malignant neoplasms, atherosclerotic cardiovascular diseases, and sarcopenia as key outcomes observed in a three-year follow-up study using the Werner Syndrome Registry.

Werner syndrome is an adult-onset progeria syndrome that results in various complications. This study aimed to clarify the profile and secular variation of the disease. Fifty-one patients were enrolled and registered in the Werner Syndrome Registry. Their data were collected annually following registration. A cross-sectional analysis at registration and a longitudinal analysis between the baseline and each subsequent year was performed. Pearson's chi-squared and Wilcoxon signed-rank tests were used. Malignant neoplasms were observed from the fifth decade of life (mean onset: 49.7 years) and were observed in approximately 30% of patients during the 3-year survey period. Regarding renal function, the mean estimated glomerular filtration rate calculated from serum creatinine (eGFRcre) and eGFRcys, which were calculated from cystatin C in the first year, were 98.3 and 83.2 mL/min/1.73 m2, respectively, and differed depending on the index used. In longitudinal analysis, the average eGFRcre for the first and fourth years was 74.8 and 63.4 mL/min/1.73 m2, showing a rapid decline. Secular changes in Werner syndrome in multiple patients were identified. The prevalence of malignant neoplasms is high, and renal function may decline rapidly. It is, therefore, necessary to carry out active and detailed examinations and pay attention to the type and dose of the drugs used.

Real-world effectiveness and safety of bosentan in Japanese patients with systemic sclerosis: A single-center retrospective study.

Patients with systemic sclerosis (SSc) develop various vascular disorders, including digital ulcers (DUs), which are sometimes intractable. Bosentan is a dual endothelin receptor antagonist expected to suppress the development of new DUs. The objective of this study was to analyze retrospectively Japanese SSc patients treated with bosentan and investigate its efficacy and safety. We analyzed 40 patients who visited our department from 2009 to 2022 and were treated with bosentan. Of the 25 patients who were able to continue bosentan, 64% (16 patients) were cured by 16 weeks . New DUs occurred in 5.9% (2/34) of patients and the number of new DUs per person was 0.1. Adverse events occurred in 45% (18/40), and hepatic dysfunction was occurred most frequently at 32.5% (13/40). In univariate analysis, hepatic dysfunction was significantly high in patients with low modified Rodnan total skin thickness score. Antimitochondria-antibody-positive patients were more likely to develop liver dysfunction. Hepatic dysfunction was improved without the reduction or discontinuation, dose reduction, discontinuation, or concomitant use of ursodeoxycholic acid. These results suggest that bosentan can be selected as an additional treatment for DU, which is difficult to treat with existing therapies, while carefully monitoring hepatic function.

Evaluation of Sleep Parameters and Sleep Staging (Slow Wave Sleep) in Athletes by Fitbit Alta HR, a Consumer Sleep Tracking Device.

Purpose: Sleep is an essential factor for athletes, and it is important to intervene in sleep to manage it. We need a device that can evaluate sleep easily and constantly. Consumer wearable devices can be useful tools for athletes. In order to use consumer wearable devices in clinical research, it is essential to conduct a validation study. Thus, we conducted a validation study to assess the Fitbit Alta HRTM (FBA)- a consumer wearable device with an accelerometer and a heart rate monitor to detect sleep stages and quality against electroencephalographic (EEG) studies in athletes. Patients and Methods: Forty college athletes participated in the study. EEG was applied to participants simultaneously while wearing FBA. Results: Regarding sleep parameters, there was a strong correlation between the total sleep time (TST)-EEG and the TST-Fitbit (r = 0.83; p < 0.001). Regarding the sleep stages, there was a modest correlation between the N3 sleep-EEG and the N3 sleep-Fitbit (r = 0.68; p < 0.001). In addition, there was a strong correlation between the percentage of N3 sleep in between sleep onset and initial rapid eye movement sleep-EEG and those on Fitbit (r = 0.73; p < 0.001). Conclusion: These results demonstrate that FBA facilitates sleep monitoring and exhibits acceptable agreement with EEG. Therefore, FBA is a useful tool in athletes' sleep management.

Glucocorticoid Induces Atrial Arrhythmogenesis via Modification of Ion Channel Gene Expression in Rats.

Excess psychological stress is one of the precipitating factors for paroxysmal atrial fibrillation (AF), although the involved mechanisms are still uncertain. To test a hypothesis that one of the stress-induced hormones, glucocorticoid, is involved in the pathogenesis of stress-induced AF, we investigated whether the glucocorticoid could alter the temporal profile of cardiac ion channels gene expression, thereby leading to atrial arrhythmogenesis.Dexamethasone (DEX, 1.0 mg/kg) was injected subcutaneously in Sprague-Dawley rats. At predetermined times after DEX injection (0, 1, 3, 6, 12, and 24 hours), the mRNA levels of cardiac ion channel genes (erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2, SUR2A, Kir6.2, Kir3.4, Kir3.1 Kir2.2, Kir2.1, SCN5A, and α1C) were determined using RNase protection assay. DEX induced immediate and transient increase in the mRNA level of Kv1.5 and Kir2.2 with peaks at 6 (5.0 fold) and 3 hours (3.3 fold) after DEX injection, respectively. Patch-clamp studies revealed a significantly increased current density of the corresponding current, IKur and IK1 at 6 hours after DEX injection. Simultaneously, electrophysiological study in isolated perfused hearts showed significantly increased number of repetitive atrial responses induced by single atrial extrastimulus (3.2 ± 2.4 to 26.7 ± 16.4, P = 0.004) with shorting of the refractory period (36.4 ± 4.6 to 27.4 ± 5.5 ms, P = 0.049) after DEX injection.Glucocorticoid immediately modified Kv1.5 and Kir2.2 gene expression at pretranslational levels, thus leading to effective refractory period shortening that could be arrhythmogenic. These results implied that transient glucocorticoid-induced biochemical modification of cardiac ion channels might be one of the mechanisms underlying the stress-induced paroxysmal AF.

Effects of Aging and Hypertension on the Antithrombotic Function of Atrial Endocardium in Rats.

We have previously reported that atrial endocardial remodeling is induced by atrial fibrillation (AF), and the endocardial dysfunction may be partly responsible for the thrombus formation in the left atrium associated with AF. However, the relationship between the endocardial dysfunction and the epidemiologically determined risk factors of AF-related strokes, including aging, hypertension, and diabetes mellitus, is yet to be elucidated.To test the hypothesis that aging, hypertension, and diabetes mellitus individually impair the atrial endocardial function in conjunction with AF, we have analyzed the expression of the tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) in the atrial endocardium in 30-week-old Wister-Kyoto (WKY), 60-week-old WKY, 30-week-old spontaneously hypertensive rats (SHR), and 30-week Goto-Kakizaki (GK) rats during normal sinus rhythm and after rapid atrial pacing at 1200 bpm for 8 hours, using Western blotting and immunohistochemical analysis. Even during sinus rhythm, the TFPI and TM expressions were noted to be remarkably downregulated in the atrial endocardium among 60-week-old WKY rats. In contrast, in SHR rats, only the TFPI expression has significantly decreased, while TM was preserved to the same level of control 30-week-old WKY rats. Rapid atrial pacing significantly reduced the TM and TFPI expression similarly in each model, thereby augmenting the endocardial dysfunction during normal sinus rhythm individually induced by the risk factors themselves prior to AF.Aging and hypertension, both of which are epidemiologically well-known risk factors for strokes in AF, have been associated with a specific atrial endocardial impairment prior to AF that could additionally disturb the antithrombotic function of the atrial endocardium.

Neutrophil elastase in the development of nephrogenic systemic fibrosis (NSF)-like skin lesion in renal failure mouse model.

Although neutrophil elastase (NE) may play a role in lung fibrosis and liver fibrosis, NE involvement in the development of nephrogenic systemic fibrosis has been unclear. We investigated the involvement of NE in the development of nephrogenic systemic fibrosis-like skin lesions post-injections of linear gadolinium-based contrast agents in renal failure mouse models. Renal failure mouse models were randomly divided into three groups: control group (saline), gadodiamide group, and gadopentetate group. Each solution was intravenously administered three times per week for three weeks. The mice were observed daily for skin lesions. Quantification of skin lesions, infiltrating inflammatory cells, and profibrotic cytokines in the affected skin was performed by immunostaining and reverse-transcription polymerase chain reaction (RT-PCR). Blood samples were collected from the facial vein to quantify NE enzymatic activity. The 158Gd concentrations in each sample were quantified using inductively coupled plasma mass spectrometry (ICP-MS). In the gadodiamide group, the mRNA expression of fibrotic markers was increased in the skin lesions compared to the control group. In the gadopentetate group, only collagen 1α and TGF-ß mRNA expression were higher than in the control group. The expression of CD3+, CD68+, NE cells and the NE activity in the blood serum were significantly higher in the gadodiamide and gadopentetate groups compared to the control group. Gadolinium concentration in the skin of the gadodiamide group was significantly higher than the gadopentetate group, while almost no traces of gadolinium were found in the control group. Although gadopentetate and gadodiamide affected the fibrotic markers in the skin differently, NE may be involved in the development of fibrosis linked to the GBCAs injections in renal failure mouse models.

Antifibrotic effects and mechanisms of mesenchymal stem cell-derived exosomes in a systemic sclerosis mouse model: Possible contribution of miR-196b-5p.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disorder characterized by the development of fibrosis in the skin and internal organs. Increasing evidence suggests that mesenchymal stem cells (MSCs) can be used to a treatment for fibrotic diseases. Recent studies have demonstrated that some of the biological effects of MSCs are due to the secretion of exosomes. However, the precise mechanisms underlying MSCs-derived exosomes in skin fibrosis are not well understood. OBJECTIVE: We aimed to elucidate the effect of MSCs-derived exosomes on skin fibrosis in SSc and the mechanism underlying their inhibitory action on fibrosis. METHODS: Exosome was collected from MSCs by ultracentrifugation method. We examined the suppressive effect of MSCs-derived exosome on skin fibrosis in bleomycin-induced SSc mouse model. Skin samples from the injected site were collected for further examination, and micro-RNA analysis of MSCs-derived exosome was performed. RESULTS: Injection of MSCs-derived exosomes significantly inhibited bleomycin-induced dermal fibrosis in mice. MSCs-derived exosomes significantly reduced the amount of collagen and the number of α-SMA+ myofibroblasts and CD68+ macrophages in lesional skin. They also reduced the expression of type I collagen and TGF-ß receptor 1 in fibroblasts in vitro. Moreover, micro-RNA analysis revealed that several microRNAs in MSCs-derived exosomes have antifibrotic potential. We confirmed that overexpression of miR-196b-5p in fibroblasts significantly suppressed collagen type I alpha 2 expression. CONCLUSION: This study demonstrated that inhibition of collagen type I expression by miR-196b-5p in exosomes might be one of the mechanisms by which MSCs suppress skin fibrosis in an SSc mouse model.

Inhibition of skin fibrosis in systemic sclerosis by botulinum toxin B via the suppression of oxidative stress.

Oxidative stress has been reported to play an important role in the pathogenesis of skin fibrosis in systemic sclerosis (SSc). We previously identified that botulinum toxin (BTX) injection suppresses pressure ulcer formation in a cutaneous ischemia-reperfusion injury mouse model by regulation of oxidative stress. However, the therapeutic possibility of BTX administration for preventing skin fibrosis in SSc is unclear. The objective of this study was to investigate the effect of BTX-B on skin fibrosis in a murine model of SSc and determine the underlying mechanism. We found that BTX-B injection significantly reduced dermal thickness and inflammatory cell infiltration in bleomycin-induced skin fibrosis lesion in mice. We also identified that the oxidative stress signal detected through bioluminescence in OKD48 mice after bleomycin injection in the skin was significantly decreased by BTX-B. Additionally, mRNA levels of oxidative stress associated factors (NOX2, HO-1, Trx2) were significantly decreased by BTX-B. Apoptotic cells in the lesional skin of bleomycin-treated mice were significantly reduced by BTX-B. Oxidant-induced intracellular accumulation of reactive oxygen species in SSc fibroblasts was also inhibited by BTX-B. In conclusion, BTX-B might improve bleomycin-induced skin fibrosis via the suppression of oxidative stress and inflammatory cells in the skin. BTX-B injection may have a therapeutic effect on skin fibrosis in SSc.

Changes in the proportion of clinical clusters contribute to the phenotypic evolution of Behçet's disease in Japan.

BACKGROUND: We hypothesized that Behçet's disease (BD) consists of several clinical subtypes with different severity, resulting in heterogeneity of the disease. Here, we conducted a study to identify clinical clusters of BD. METHODS: A total of 657 patients registered in the Yokohama City University (YCU) regional BD registry between 1990 and 2018, as well as 6754 patients who were initially registered in the Japanese Ministry of Health, Labour and Welfare (MHLW) database between 2003 and 2014, were investigated. The YCU registry data regarding the clinical manifestations of BD, human leukocyte antigen (HLA) status, treatments, and hospitalizations were analyzed first, followed by similar analyses of the MHLW for validation. A hierarchical cluster analysis was independently performed in both patient groups. RESULTS: A hierarchical cluster analysis determined five independent clinical clusters in the YCU cohort. Individual counterparts of the YCU clusters were confirmed in the MHLW registry. Recent phenotypical evolutions of BD in Japan, such as increased gastrointestinal (GI) involvement, reduced complete type according to the Japan Criteria, and reduced HLA-B51 positivity were associated with chronologically changing proportions of the clinical clusters. CONCLUSIONS: In this study, we identified independent clinical clusters among BD patients in Japan and found that the proportion of each cluster varied over time. We propose five independent clusters namely "mucocutaneous", "mucocutaneous with arthritis", "neuro", "GI", and "eye."

Plasma homocysteine levels are positively associated with interstitial lung disease in dermatomyositis patients with anti-aminoacyl-tRNA synthetase antibody.

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of central and peripheral vascular disorders, including carotid, coronary and peripheral arterial diseases, and Raynaud's phenomenon. Recently, associations of plasma homocysteine levels with autoimmune diseases such as systemic lupus erythematodes and systemic sclerosis have been reported. However, no study analyzed the association between plasma homocysteine levels and dermatomyositis (DM). The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with DM. Plasma homocysteine levels in 28 Japanese patients with DM and 22 healthy controls were examined. We found that the plasma homocysteine levels in DM patients were significantly higher than those in healthy individuals (15.8 ± 1.1 vs 8.5 ± 0.5 µmol/L, P < 0.01). Presence of mechanic's hand, complication of interstitial lung disease (ILD), high serum Krebs von den Lungen-6 (KL-6), surfactant protein-D and creatine kinase levels, and anti-aminoacyl-tRNA synthetase (ARS) antibody (Ab) positivity were significantly more prevalent among DM patients with elevated plasma homocysteine levels. The plasma homocysteine levels in DM patients with mechanic's hand, ILD and anti-ARS Ab were significantly higher than those in DM without those features. Furthermore, the plasma homocysteine levels were positively correlated with serum KL-6 levels. These results suggest that the pathogenesis of elevated plasma homocysteine levels may be associated with ILD in DM patients, especially with anti-ARS Ab, and further examination is required.

Clinical features of dermatomyositis associated with anti-MDA5 antibodies by age.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-positive and age at onset ≥60 years are poor prognosis factors in polymyositis (PM) and dermatomyositis (DM) associated with interstitial lung disease (ILD) among Japanese patients. However, the influence of age on the clinical features of anti-MDA5 autoantibody-positive patients with DM remains unclear. METHODS: We retrospectively examined 40 patients with DM and anti-MDA5 autoantibodies according to age. We compared patients aged <60 and ≥60 years with respect to clinical features including laboratory test findings, high-resolution lung computed tomography data, treatment content, and complications such as infections and prognosis. We also examined clinical features between surviving and deceased patients in the older patient group. RESULTS: Of 40 enrolled patients, 13 were classified as old and 27 as young. Older patients had significantly fewer clinical symptoms including arthralgia/arthritis (p < .01), skin ulceration (p = .02), and higher mortality than younger patients (p = .02) complicated with rapidly progressive ILD (RP-ILD), combination immunosuppressive therapy, and strictly controlled infections. CONCLUSION: Clinical features and mortality of anti-MDA5 autoantibody-positive DM patients were influenced by age. Patients aged ≥60 years had a worse prognosis, and combination immunosuppressive therapy was often ineffective for RP-ILD in older patients.

Suppression of neuropeptide by botulinum toxin improves imiquimod-induced psoriasis-like dermatitis via the regulation of neuroimmune system.

BACKGROUND: Psoriasis is a multifactorial disease arises from a complex interaction of genetics, immune system, and environmental aspects. IL-23/Th17 immune axis has been considered as a primary modulator in psoriasis. In addition, several findings imply that nervous system may take a part in the pathogenesis of psoriasis, suggesting that nervous system, through its neuropeptide, may interact with immune system and lead to the formation of psoriasis. OBJECTIVE: We aimed to ascertain the role of neuropeptides secreted from neurons in the pathogenesis of psoriasis in vivo. METHODS: The release of neuropeptide was inhibited by injecting Botulinum toxin B (BTX-B) on Imiquimod (IMQ)-induced psoriasis-like dermatitis mice model. Quantification of skin dermatitis, infiltrating inflammatory cells, and the production of cytokines at the lesional skin area were performed by PSI score, immunostaining, and real-time PCR. We also tested the effect of selective CGRP antagonist (CGRP8-37) on psoriasis-like dermatitis in IMQ-treated mice. RESULTS: BTX-B injection significantly suppressed PSI score and reduced the number of CD4+ T cells, CD11c+ dendritic cells, and the production of IL-17A/F in the lesional skin. The expressions of PGP9.5+ nerve fibers and neuropeptides (SP, CGRP) were also significantly reduced following BTX-B injection. Additionally, CGRP antagonist also suppressed the development of IMQ-induced psoriasis-like dermatitis in mice. CONCLUSION: The suppression of neuropeptide secretion in the skin by BTX injection might inhibit nerve elongation, the infiltration of immune cells, as well as IL-17 production, resulting in the improvement of psoriasis. Neuropeptide inhibitor could also be applied to the treatment of psoriasis.

Time gap between the onset and diagnosis in Werner syndrome: a nationwide survey and the 2020 registry in Japan.

Patients with Werner syndrome present with diverse signs of aging that begin in adolescence. A Japanese nationwide survey was conducted to establish a registry that could clarify the disease profile of patients with Werner syndrome. The questionnaires were sent to 7888 doctors. The survey identified 116 patients diagnosed with Werner syndrome based on the diagnosis criteria. Forty patients were enrolled in the registry. Data on clinical symptoms, treatment information, and laboratory examination from patients who provided informed consent were collected. The data at enrollment were analyzed. The patients' average age at enrollment was 50.1±7.5 years. The mean onset age was 26.1±9.5 years, but the mean age at diagnosis was 42.5±8.6 years. Average height and weight of the study patients were lower than those of Japanese individuals. Almost all patients experienced hair change and cataracts. More than 60% of patients presented with glycolipid abnormalities. Overall, 15% of patients had a history of foot amputation. Approximately 30% of the patients' parents had a consanguineous marriage. The average grip strength, walking speed, and skeletal muscle mass index met the diagnostic criteria for sarcopenia. The registry revealed that there are opportunities for early diagnosis and intervention; therefore, sensitization about the disease is needed.