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We conducted a Japanese GWAS for systemic sclerosis (SSc) comprising 1,428 cases and 112,599 controls, the largest Asian GWAS for SSc ever, and identified three novel signals. The lead SNP in FCGR/FCRL region had a strong effect size (OR 2.05, P = 4.9×10−11). The complete LD SNP, rs10917688, was found in a cis-regulatory element and a part of binding motifs for IRF8. IRF8 was a significant locus in the European GWAS and rs10917688 showed an association only in the presence of the risk allele of IRF8 in Japanese. rs10917688 was marked with H3K4me1 in primary B cells, and the heritability was enriched in active histone marks of primary B cells. A meta-analysis with the latest European GWAS found additional 30 significant loci including three novel signals. PRS constructed with the effect sizes of the meta-analysis indicated potential portability of genetic associations beyond populations (AUC: 0.593). The fitting of PRS was improved by further prioritizing the top 5% SNPs of IRF8 biding sites in B cells, underscoring common genetic architecture across populations and critical roles of B cells and IRF8 for SSc development.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrotic, inflammatory, and vascular dysfunction. Danger-associated molecular patterns (DAMPs)-mediated inflammasome activation has been reported to be involved in the pathogenesis of SSc. Cold-inducible RNA-binding protein (CIRP) is newly identified as a DAMP. Here we examined the clinical significance of serum levels of CIRP in 60 patients with SSc and 20 healthy control patients (HCs) using an enzyme-linked immunosorbent assay. Serum CIRP levels in diffuse cutaneous SSc (dcSSc) patients were significantly increased compared with limited cutaneous SSc (lcSSc) patients or HCs. When examining the relationship with SSc-specific parameters, serum CIRP levels with the presence of interstitial lung disease (ILD) were higher than those without ILD. In detail, serum CIRP levels correlated negatively with the percent predicted diffusing capacity for carbon monoxide and positively with levels of Krebs von den Lungen-6. In addition, elevated serum CIRP levels declined along with decreased SSc-ILD activity in patients who received immunosuppressive therapy. These results suggest that CIRP may play a role in the development of ILD in SSc. Moreover, CIRP could serve as a useful serological marker of SSc-ILD in terms of disease activity and therapeutic effects.

Photocatalytic proximity labeling has recently undergone significant advances as a valuable tool for understanding protein–protein and cell–cell interactions. This paper reports the first photocatalytic protein-labeling approach in which the reaction can be controlled using near-infrared (NIR) light (810 nm). Magnetic affinity beads with encapsulated sulfur-substituted silicon (IV) phthalocyanine, which produces singlet oxygen upon NIR irradiation, were prepared. We have developed a method in which the histidine residues of proteins bound to the ligands on the beads are selectively oxidized and labeled by the nucleophilic labeling reagent while minimizing nonspecific adsorption to the dye. Beads with aryl sulfamide, lactose, or CZC-8004 ligands immobilized on their surface can be used to label proteins that bind these ligands, as well as their protein–protein interaction partners.

Purpose The purpose of this study is to find out a simple cognitive intervention method to use MCI and suffering people with depression. As the elderly society increases around the world, the number of elderly people with diseases and dementia is increasing rapidly. Mild cognitive impairment (MCI), a pre-stage to dementia, is a critical treatment time to slow disease progression. However, there is currently no appropriate medication. Furthermore, MCI patients with depression are more difficult to treat. Design/methodology/approach To overcome these problems, the authors confirmed improvements and delayed effects in MCI patients in this study for three years through cognitive intervention, demonstrating its effectiveness. Cognitive interventions were conducted for memory retrieval and steadily stimulated the brain by performing tasks to solve problems during daily conversations. Findings As a result, the intervention group retained mini-mental state examination and Montreal cognitive assessment scores on the domains of cognitive function and also instrumental activities of daily living in the domain of motion compared to the non-intervention group. Moreover, significant improvements in geriatric depression scales-15 and quality-of-life scales enabled the patients to maintain stable living compared to before the intervention. In addition, the intervention group showed a change in patterns that allowed them to voluntarily devote time to going out at the end of the study. Research limitations/implications This study was originally planned to compare the rates of transmission from MCI to dementia by tracking over five years (2016–2021). However, due to the impact of COVID-19, which began to spread around the world in 2020, further face-to-face visits and cognitive intervention became impossible. Thus, only half of the data in the existing plans were collected. Although it is difficult to present accurate results for the rate of transmission from MCI to dementia, the tendency was confirmed, indicating sufficient implications as an intervention. Originality/value This study was originally planned to compare the rates of transmission from MCI to dementia by tracking three years (2016–2019). The authors had studied for long-term effect.

[Image: see text] The onset of neurodegenerative disorders (NDs), such as Alzheimer’s disease, is associated with the accumulation of aggregates of misfolded proteins. We previously showed that chemical knockdown of ND-related aggregation-prone proteins can be achieved by proteolysis targeting chimeras (PROTACs). However, hetero-bifunctional PROTACs generally show poor permeability into the central nervous system, where NDs are located. Here, we document the conversion of one of our PROTACs into hydrophobic tags (HyTs), another class of degraders bearing hydrophobic degrons. This conversion decreases the molecular weight and the number of hydrogen bond donors/acceptors. All the developed HyTs lowered the level of mutant huntingtin, an aggregation-prone protein, with potency comparable to that of the parent PROTAC. Through IAM chromatography analysis and in vivo brain penetration assay of the HyTs, we discovered a brain-permeable HyT. Our results and mechanistic analysis indicate that conversion of protein degraders into HyTs could be a useful approach to improve their drug-like properties.

Objectives The double-blind, parallel-group comparison, investigators initiated phase II clinical trial of IDEC-C2B8 (Rituximab) in patients with Systemic sclerosis (DesiReS) trial showed that rituximab is effective in treating skin sclerosis in SSc. However, which patient groups are likely to benefit from rituximab is unknown. Methods We performed post-hoc analysis of prospective data from 54 patients who received rituximab or placebo in the DesiReS trial. Twenty-seven baseline factors were used to investigate subpopulations with different magnitudes of rituximab effect on modified Rodnan skin score (mRSS) change at 24 weeks. Based on a machine-learning algorithm called the causal tree, we explored the combination of predictors needed to identify subpopulations that would respond to rituximab and have good treatment outcomes. Results Three factors were identified as branches of the decision tree: peripheral blood CD19-positive cell counts’, ‘mRSS’, and ‘serum surfactant protein D (SP-D) levels’. It was only in the subpopulation of patients with CD19-positive cell counts of Conclusion SSc patients who have high CD19-positive cell counts and high mRSS are expected to have greater improvement in mRSS with rituximab. When the patients with high CD19-positive cell counts show low mRSS, serum SP-D levels may modify the treatment effect. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT04274257 and UMIN-CTR; https://center6.umin.ac.jp, UMIN000030139.

Objectives SSc is an autoimmune disease characterized by excessive fibrosis in multiple organs, including the gastrointestinal (GI) tract. GI symptoms of SSc such as intestinal pseudo-obstruction (IPO) are often refractory to conventional intervention and can result in longer in-hospital stay or even increased mortality. We aimed to summarize the insights to date regarding the efficacy of IVIG against GI symptoms of SSc to unveil what we should focus on in future studies. Methods Herein we report the response of GI symptoms in three cases with SSc-myositis overlap who received IVIG administration. We also conducted a systematic literature review to summarize previous reports regarding the efficacy of IVIG upon the GI manifestations of SSc, according to the PRISMA 2020 guideline. Results The case series demonstrated remarkable and rapid improvement of GI symptoms, including IPO, after IVIG administration. The literature review revealed that previous reports also support the efficacy and safety of IVIG against GI manifestations of SSc. However, they were all retrospective studies and lacking description of the short-term outcome after IVIG administration with objective and quantitative metrics. Conclusion IVIG seems to be a promising therapeutic option for the management of GI symptoms in SSc, including IPO. Investigators should focus more on short-term outcomes to properly assess the therapeutic benefit of IVIG, ideally using reliable quantitative measures in a multicentre randomized placebo-controlled setting.

Artificial placenta therapy (APT) is an experimental care strategy for extremely preterm infants born at 21-24 weeks' gestation. In our previous studies, blood taken from the maternal ewe was used as the basis of priming solutions for the artificial placenta circuit. However, the use of maternal blood as a priming solution is accompanied by several challenges. We explored the use of synthetic red cells (hemoglobin vesicles; HbV) as the basis of a priming solution for APT used to manage extremely early preterm ovine fetuses.Six ewes with singleton pregnancies at 95 d gestation (term = 150 d) were adapted to APT and maintained with constant monitoring of key vital parameters. The target maintenance period was 72 h in duration. A synthetic red cell solution consisting of HbV, sheep albumin and electrolytes was used as priming solutions for the APT circuit. Fetuses were evaluated on gross appearance, physiological parameters and bleeding after euthanasia.Two out of six APT fetuses were successfully maintained for the targeted 72 h experimental period with controllable anemia (10 g/dl) and methemoglobinemia (10%) using an infusion of blood transfusion and nitroglycerin delivered1 h after APT commencement, a sufficient period of time to cross-match blood products and screen for viral agents of concern.Extremely preterm sheep fetuses were maintained for a period of up to 72 h using APT in combination with circuit priming using a synthetic red cell (HbV) preparation. Although significant further refinements are required, these findings demonstrated the potential clinical utility of synthetic blood products in the eventual clinical translation of artificial placenta technology to support extremely preterm infants.

Objective Following the case of a 10-month-old with Japanese encephalitis in Chiba in 2015, the Chiba Pediatric Association and Chiba Medical Association recommended that children receive the Japanese encephalitis vaccine at six months of age. In this study, we investigated early vaccinations and standard vaccinations of children in a patient outbreak area. Additionally, we examined changes in the timing of vaccination initiation and the acquisition and maintenance of protective immunity before and after the early vaccination recommendation.Methods With the cooperation of the medical institution designated for Type II Infectious Diseases, which treated affected children in 2015, the history and timing of vaccinations for children who visited the hospital between October 2018 and March 2020 were investigated, and serum samples were collected. The data obtained in this study and the Ministry of Health, Labour and Welfare's Community Health Service Report were used to investigate the timing of vaccinations. Neutralizing antibody titers in serum were quantified with the focus measurement method and examined with respect to the number of vaccinations, doses, and number of days since vaccination.Results A total of 154 samples were obtained, with 89 from the vaccinated group and 65 from the unvaccinated group. There was no difference in the percentage of children based on the age of first vaccination between Japan, Chiba Prefecture, and the study subjects until FY2015, but from FY2016 onward, the percentage of children vaccinated early was higher among the study subjects, as well as for children from Chiba Prefecture and Japan, in that order. The antibody possession rate by vaccination frequency was 9.2% for the unimmunized, 87.5% for those vaccinated once, 95.1% for those vaccinated twice, and 100% for those vaccinated three times. In the group vaccinated twice, antibody titers of children who received half the vaccine dose were significantly lower than those of children who received the normal dose.Conclusion In the districts targeted in this study, significantly more children under three years of age were vaccinated before the early vaccination recommendation, suggesting the effectiveness of that recommendation. In addition, the high rate of antibody positivity among unvaccinated children suggests that it is important to promote early vaccination in areas at high risk for Japanese encephalitis. In this study, there was no evidence of attenuation of antibody titers over time after early immunization, but the possibility remains that the children who completed early immunization received a booster due to pathogen exposure and maintained antibody titers, given that Japanese encephalitis was endemic in the target area.

Here we demonstrate that a guanine-to-adenine substitution within guanine repeat sequences in the MSH 5′-UTR weakens G-quadruplex stability, leading to increased protein synthesis. The abnormal pro...

OBJECTIVE We undertook this study to investigate the effect of B cell depletion on fibrosis in systemic sclerosis (SSc) and its mechanism of action. METHODS Mice with bleomycin-induced SSc (BLM-SSc) were treated with anti-CD20 antibody, and skin and lung fibrosis were histopathologically evaluated. T cells and macrophages were cocultured with B cells, and the effect of B cells on their differentiation was assessed by flow cytometry. We also cocultured B cells and monocytes from SSc patients and analyzed the correlation between fibrosis and profibrotic macrophage induction by B cells. RESULTS B cell depletion inhibited fibrosis in mice with BLM-SSc. B cells from mice with BLM-SSc increased proinflammatory cytokine-producing T cells in coculture. In mice with BLM-SSc, B cell depletion before BLM treatment (pre-depletion) inhibited fibrosis more strongly than B cell depletion after BLM treatment (post-depletion) (P < 0.01). However, the frequencies of proinflammatory T cells were lower in the post-depletion group than in the pre-depletion group. This discrepancy suggests that the effect of B cell depletion on fibrosis cannot be explained by its effect on T cell differentiation. On the other hand, profibrotic macrophages were markedly decreased in the pre-depletion group compared to the post-depletion group (P < 0.05). Furthermore, B cells from mice with BLM-SSc increased profibrotic macrophage differentiation in coculture (P < 0.05). In SSc patients, the extent of profibrotic macrophage induction by B cells correlated with the severity of fibrosis (P < 0.0005). CONCLUSION These findings suggest that B cell depletion inhibits tissue fibrosis via suppression of profibrotic macrophage differentiation in mice with BLM-SSc, providing a new rationale for B cell depletion therapy in SSc.

Squamous cell carcinoma antigen (SCCA) was originally isolated as tumour-specific antigens in uterine cervix carcinoma. These comprise two similar proteins, SCCA1 and SCCA2, and both are induced by type 2 cytokines such as interleukin (IL)-4 and IL-13. The involvement of these antigens in atopic dermatitis has been reported, however, the role in mycosis fungoides (MF) and Sézary syndrome (SS), which are also linked with type 2 cytokines, remains to be seen.This study investigated a possible association between SCCA1/2 and MF/SS.We compared serum levels of SCCA1/2 between MF/SS patients and healthy controls. We also examined the correlation between serum SCCA1/2 levels in MF/SS patients and clinical disease markers. The expression of SCCA1/2 in skin samples was examined by immunohistochemistry.The serum levels of SCCA1/2 in MF/SS patients were significantly higher than those in normal controls and correlated with clinical disease markers. Immunohistochemical staining showed upregulated expression of SCCA1/2 in MF/SS lesional skin.Enhanced SCCA1/2 expression may contribute to the progression of MF/SS. Measurement of serum SCCA1/2 levels may become a useful tool to evaluate the progression or therapeutic effects of MF/SS.

Background: Few studies have provided observational data on long-term trends in the incidence of stroke and its subtypes, and shown the urban–rural disparities of stroke incidence in Japan. Methods: A multiple-source, community-based stroke surveillance was performed since 1963/1964 to determine all first-ever stroke cases among Japanese residents aged ⩾40 years living in the Minami-Takayasu district in Yao city, an urban community, and Ikawa town, a rural community. Sex-specific, age-standardized incidence per 1000/year with 95% confidence intervals was calculated during seven periods of 1963/1964–1971 (urban population (% men): 3242 (47.3%); rural population (% men): 2311 (46.0%)), 1972–1979, 1980–1987, 1988–1995, 1996–2003, 2004–2011, and 2012–2018 (13,307 (46.7%); 3586 (44.8%)). Results: The age-standardized incidence of all strokes in the Japanese urban community decreased from 6.60 to 1.15 per 1000/year for men and 3.28 to 0.59 for women. In the rural community, the corresponding incidence decreased from 11.51 to 1.98 for men and 6.46 to 1.31 for women. Similar reductions were observed in the incidence of intracerebral hemorrhage, subarachnoid hemorrhage, ischemic stroke, and lacunar stroke. In the period of 2012–2018, the incidence ratios (95% confidence intervals) of all strokes for the rural compared to the urban community were 1.72 (1.08–2.75) for men and 2.23 (1.23–4.03) for women. Conclusion: The stroke incidence continued to decline in both urban and rural Japanese communities with the regional disparities over the past half century, whereas it remained higher than that in many Western countries.

Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

Bullous pemphigoid (BP) is an autoimmune disease characterized by autoantibody-mediated activation of immune cells and subepidermal blister formation. Excess amounts of extracellular DNA are produced in BP, however, it remains unclear how extracellular DNA contributes to BP pathogenesis. Here we show a possible mechanism by which interleukin (IL)-26 binds to extracellular DNA released from neutrophils and eosinophils to support DNA sensing. Patients with BP exhibited high circulating levels of IL-26, forming IL-26–DNA complexes in the upper dermis and inside the blisters. IL-26–DNA complexes played a dual role in regulating local immunity and blister formation. First, they enhanced the production of inflammatory cytokines in monocytes and neutrophils. Second, and importantly, the complexes augmented the production and activity of proteases from co-cultured monocytes and neutrophils, which induced BP180 cleavage in keratinocytes and dermal-epidermal separation in a modified human cryosection model. Collectively, we propose a model in which IL-26 and extracellular DNA synergistically act on immune cells to enhance autoantibody-driven local immune responses and protease-mediated fragility of dermal-epidermal junction in BP.

Leukoaraiosis, a common ischaemic lesion diagnosed using magnetic resonance imaging (MRI), can influence driving safety performance (DSP). Most older drivers with leukoaraiosis are unaware of their affliction. Japan is a super-aged country, where preventing accidents caused by older drivers is an urgent national issue. We investigated the subcortical and periventricular leukoaraiosis regions that were most involved in DSP decline. The driving skills of 101 drivers (51 men, 50 women; mean age, 77.88 ± 3.75 years) without dementia were assessed by official driving instructors, using actual vehicles on a closed-circuit course. Parietal and occipital (but not frontal or temporal) leukoaraiosis volumes were significantly correlated with decreased DSP scores regardless of age, especially when turning right at intersections, which needs more attention than turning left because left-side driving is legally enforced in Japan. Occipital leukoaraiosis was also involved via a decline in dynamic visual cognitive function. MRI-based assessment of leukoaraiosis volume and localisation may enable the identification of older drivers prone to DSP deterioration. Risk factors for leukoaraiosis include smoking and lifestyle-related diseases such as hypertension. Thus, brain healthcare in patients with MRI-diagnosed leukoaraiosis may be particularly useful for the risk management of traffic accidents caused by the elderly in Japan.

Systemic sclerosis (SSc) is a chronic autoimmune disease with a poor prognosis. Among the various complications of SSc, treatment options for the fibrotic lesions, skin sclerosis, and SSc-associated interstitial lung disease (SSc-ILD) have been limited. However, since 2019, the efficacy and safety of nintedanib, tocilizumab, and rituximab for SSc or SSc-ILD have been demonstrated in double-blind, randomized, placebo-controlled trials, respectively. The antifibrotic agent nintedanib was approved for SSc-ILD in all regions of the United States, Europe, and Japan after the SENSCIS study confirmed that it suppressed the reduction in forced vital capacity (FVC), a measure of SSc-ILD. Tocilizumab, an anti-interleukin-6 receptor antibody, was approved for the treatment of SSc-ILD in the United States after the FocuSSced study showed that it inhibited the decrease in FVC. Rituximab, an anti-CD20 antibody, showed improvement in both modified Rodnan skin score, a measure of skin sclerosis, and FVC in the DESIRES study, and was approved in Japan for the treatment of SSc itself. With the development of these three drugs, SSc treatment is entering a new era. This paper outlines the latest advances in SSc therapeutics, focusing on nintedanib, tocilizumab, and rituximab.

Bitter taste receptors (T2Rs) are G protein-coupled receptors involved in the perception of bitter taste on the tongue. In humans, T2Rs have been found in several sites outside the oral cavity. Although T2R38 has been reported to be expressed on peripheral lymphocytes, it is poorly understood whether T2R38 plays immunological roles in inflammatory skin diseases such as atopic dermatitis (AD). Then, we first confirmed that T2R38 gene expression was higher in lesional skin of AD subjects than healthy controls. Furthermore, skin T2R38 expression levels were correlated with serum thymus and activation-regulated chemokine and IgE levels in AD patients. In lesional skin of AD, section staining revealed that CD3+ T cells in the dermis were T2R38 positive. In addition, flow cytometry analysis showed T2R38 expression in skin T cells. Migration assays using T2R38-transduced Jurkat T cell leukemia cells revealed that T2R38 agonists exerted a dose-dependent migration inhibitory effect. Moreover, skin tissue extracts, as well as supernatants of cultured HaCaT keratinocytes, caused T2R38-dependent migration inhibition, indicating that there should be an endogenous ligand for T2R38 in the skin epidermis. These findings implicate T2R38 as a migratory inhibitory receptor on the skin-infiltrating lymphocytes and as a therapeutic target for allergic/inflammatory skin diseases.

This research examines the authenticity of digital news coverage in the mainstream media in Japan via a specific case study, namely ‘Doctoral Students Have Decreased by Half’. In research, ‘fake news’ comprises two elements, facticity and intentionality; this study focuses on facticity or misinformation. Studies regarding ‘fake news’ are abundant, but those focussing on the mainstream digital media and Japan are highly scarce. This study applied a gap analysis, a comparison between the expected original information and the actual news coverage in a reversed direction. The study first detected and examined the original governmental data and announcements on which a series of news reports were based. Next, it drew a compare and contrast between the news on selective mainstream media and the original information. The reported drop in the number of doctoral students could be a ‘false alarm’ for prospective target audiences, implying that digital news portals may disseminate misinformation. The analysis also revealed that the current structure of digital news making, segmented into multiformat comprising headlines, texts, videos, captions, and others, may make the information verification process more complex and obstructed for individuals. The study also points at the risk of spread of misinformation and of memory retention, amplified by the use of culture-specific symbolic numbers, which weakens our reasoning ability. The findings emphasise the importance of updating our digital media literacy and making collaborative efforts to make local research internationally sharable to advance the understanding of ‘fake news’ research in this multimedia era.

BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. AlthoughBiodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue.MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity.MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied.

In recent years, circulating cell-free DNA (cfDNA) has received a great attention as a biomarker for various cancers. Many reports have shown that serum cfDNA levels are elevated in cancer patients and their levels correlate with prognosis and disease activity. The aim of this study was to measure serum cfDNA levels in patients with cutaneous T-cell lymphoma (CTCL) and to evaluate their correlations with hematological and clinical findings. Serum cfDNA levels in CTCL patients were significantly higher than those in healthy controls, and their levels gradually increased with the progression of the disease stage. Positive correlations were detected between serum cfDNA levels and those of lactate dehydrogenase, thymus and activation-regulated chemokine and soluble IL-2 receptor as well as neutrophil and eosinophil count in peripheral blood and neutrophil-to-lymphocyte ratio. Furthermore, CTCL patients with higher serum cfDNA levels exhibited a significantly worse prognosis. Taken together, these results suggest the potential of cfDNA as a new biomarker reflecting prognosis and disease activity in CTCL. CfDNA levels may serve as an indicator for considering the intensity and timing of subsequent therapeutic intervention.

Palmoplantar pustulosis (PPP) is a disease that causes recurrent blisters and aseptic pustules on the palms and soles. It has been suggested that both innate and acquired immunity are involved. In particular, based on the tonsils and basic experiments, it has been assumed that T and B cells are involved in its pathogenesis. In addition, the results of clinical trials have suggested that IL-23 is closely related to the pathogenesis. This review describes PPP and the genetic background, the factors involved in the onset and exacerbation of disease and its relation to the molecular mechanism. In addition, we describe the usefulness of biological therapy and its implications in relation to the importance in pathology, the pathogenesis of PPP, the importance of the role of the IL-23–Th17 axis and IL-36 in PPP. Furthermore, we describe an animal experimental model of PPP, the efficacy and mechanism of action of guselkumab, an anti-IL-23 antibody, the latest research, and finally the possibility for it to be effective for other autoimmune diseases.

Objectives PsA is one of the most serious comorbidities associated with psoriasis. While the early intervention in PsA is demanded, risk factors of PsA development are not well-known. This is the first prospective study to evaluate the clinical significance of nailfold capillary (NFC) changes in patients with psoriasis. Methods We conducted a prospective cohort study in a population of 449 psoriasis patients who had not been treated with systemic therapy or topical finger therapy. NFCs were observed by dermoscopy and capillaroscopy, and the correlation of NFC abnormalities, including nailfold bleeding (NFB) and enlarged capillaries, with the prevalence of PsA, incidence of new PsA, and serum levels of TNF-a, IL-17A and IL-23 were analysed. Results Detailed examination at the time of inclusion revealed that of 449 patients, 236 had Psoriasis vulgaris (PsV) and 213 had PsA. Both NFB and enlarged capillaries were significantly more frequent in patients with PsA (34.7% vs 84.5%, P Conclusions NFC abnormalities were suggested to be a predictor of PsA in psoriasis patients, and at the same time, its degree could be an indicator of disease severity.

Introduction: Evaluation of the safety of taking lamotrigine (LTG) during lactation in breastfed infants varies according to the information sources. As it is possible that prescribers may avoid pr...

Background Psoriasis is a chronic inflammatory skin disease. Interleukin (IL)-17A plays a key role in the pathogenesis of psoriasis. Fingolimod, which is available for the treatment of multiple sclerosis, exerts anti-inflammatory effects by sequestrating inflammatory lymphocytes in secondary lymphoid tissues and the thymus. The effect of fingolimod on psoriasis has not been reported yet. Objective Our objectives were to investigate the effect of fingolimod on psoriasis utilizing mice with imiquimod (IMQ)-induced psoriasiform dermatitis, and explore the possibility of fingolimod as a therapeutic agent for psoriasis. Methods Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Fingolimod prepared in phosphate-buffered saline (PBS), or PBS alone as a control, was administered intraperitoneally daily from days 0 to 5. Results Fingolimod ameliorated IMQ-induced psoriasis dermatitis clinically and histologically. On day 6, the mRNA expression level of IL-17A was lower in the skin of fingolimod-treated mice than in that of PBS-treated mice, whereas it was higher in the inguinal lymph nodes of fingolimod-treated mice than in those of PBS-treated mice. Flow cytometric analyses revealed that fingolimod reduced IL-17A-producing ?d T cells infiltrating into the skin, whereas it increased these cells in the inguinal lymph nodes. Fingolimod inhibited egress of Langerhans cells from the skin to lymph nodes. Conclusion Our results demonstrated that fingolimod showed effectiveness for IMQ-induced psoriasiform dermatitis by hindering the emigration of IL-17A-producing ?d T cells from the lymph nodes to the skin, and suggest that fingolimod is a promising candidate for the treatment of psoriasis.