Publications by authors named "Shinichi Sato"

694 Publications

Serum levels of tissue factor pathway inhibitor: Potential association with Raynaud's phenomenon and telangiectasia in patients with systemic sclerosis.

J Dermatol 2021 Apr 13. Epub 2021 Apr 13.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Vasculopathy is a critical step of systemic sclerosis (SSc) development, bridging between autoimmune inflammation and tissue fibrosis. Impaired coagulation system is a part of SSc vasculopathy, but the role of tissue factor pathway inhibitor (TFPI), a critical regulator of the extrinsic coagulation pathway, remained unknown. Therefore, we evaluated the clinical correlation of serum TFPI levels in SSc patients. Serum TFPI levels were comparable between SSc and control participants, but SSc patients with Raynaud's phenomenon and telangiectasia had significantly lower serum TFPI levels than those without. Importantly, there was a significant positive correlation between serum TFPI levels and protein S activity. These results support the critical role of impaired coagulation system in SSc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15893DOI Listing
April 2021

Evaluation of the Safety of Taking Lamotrigine During Lactation Period.

Breastfeed Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan.

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 prescribing LTG despite of it being one of the essential drugs, more information needs to be accumulated to facilitate its use. We retrospectively compared the safety of LTG during the lactation period in 20 pairs of mothers and infants with 20 pairs as the control group. The mean dose of LTG in 20 mothers was 161.1 mg/day (range: 50-400 mg/day). None of the infants showed a neonatal withdrawal syndrome score of 2 or more up to 1 month after delivery. Although drowsiness ( = 3), skin rash ( = 11), jaundice ( = 8), heart murmur ( = 1), poor suckling ( = 1), and retractive breathing ( = 1) were observed in infants, none of these adverse events were serious and the infants recovered. Nineteen of 20 pairs could continue lactation until 1 month after delivery. One pair discontinued breastfeeding because of pain in the mother's nipples. All pairs could continue maternal medication. We then compared the results with those of the control group. There were no significant differences in the presence of adverse events between the LTG and control groups. These data suggest that taking low to moderate doses of LTG during the lactation period might be relatively safe, at least for a period of 1 month after delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/bfm.2020.0210DOI Listing
April 2021

Fibrosarcomatous dermatofibrosarcoma protuberans in a seven-year-old boy.

Eur J Dermatol 2021 Feb;31(1):106-107

Department of Dermatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/ejd.2020.3962DOI Listing
February 2021

Development of a prediction model of treatment response in patients with cutaneous arteritis: Insights from a cohort of 33 patients.

J Dermatol 2021 Mar 25. Epub 2021 Mar 25.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Cutaneous arteritis (CA) is necrotizing vasculitis invading the small- to medium-sized arteries of the skin. The majority of patients can be favorably managed by low- to medium-dose systemic corticosteroids (prednisolone, <0.5 mg/kg/day) or other oral medications such as non-steroidal anti-inflammatory drugs, dapsone, and azathioprine. Meanwhile, some patients require more intensive therapy including high-dose systemic corticosteroids (prednisolone, ≥0.5 mg/kg/day), i.v. immunoglobulin, and i.v. cyclophosphamide therapy. Although predicting such treatment response among CA patients is critical in clinical decision-making, prediction rules have not yet been established. Herein, we retrospectively reviewed 33 patients regularly visiting our clinic to reveal predictive factors of their treatment response. Clinical data were collected from electronic medical records. Association between each factor and treatment response was examined by logistic regression analysis. Progression-free time was calculated by Kaplan-Meier's method and analyzed by log-rank test and Cox progression hazard model. Potential predictive factors were selected, given 1 point for each, and integrated into a classification model. Discrimination of the model was examined by the receiver operating characteristic (ROC) curve analysis. In total, 33 CA patients were enrolled in our study. Of these, 11 patients required intensive therapy, classified as treatment non-responders. Logistic analyses revealed that treatment response was significantly associated with male sex, presence of skin ulcers, and elevated serum levels of C-reactive protein at the initial work-up. Kaplan-Meier analyses also demonstrated that those factors are predictive of progression-free time. The area under the ROC curve of our classification model was 0.92 (95% confidence interval, 0.83-1.00), which classified non-responders from the others with a sensitivity of 90.9% and specificity of 81.8% at the cut-off point of 2 or more. Collectively, treatment response of CA could be predictable by a combination of sex, presence of skin ulcers, and serum levels of C-reactive protein.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15868DOI Listing
March 2021

Association of serum CCL20 levels with pulmonary vascular involvement and primary biliary cholangitis in patients with systemic sclerosis.

Int J Rheum Dis 2021 Mar 22. Epub 2021 Mar 22.

Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: Systemic sclerosis (SSc) is a chronic autoimmune disease resulting in vasculopathy and fibrosis of the skin and major internal organs. Especially, interstitial lung disease and pulmonary arterial hypertension are the leading causes of mortality. C-C motif ligand 20 (CCL20) is known as a homeostatic and inflammatory chemokine, which is associated with fibrosis and angiogenesis and constantly expressed in organs involved in SSc. Therefore, we investigated the potential contribution of CCL20 to the development of SSc.

Method: We conducted cross-sectional analyses of 67 SSc patients and 20 healthy controls recruited in a single center for 9 years. Serum CCL20 levels were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed with the Mann-Whitney U test, the Kruskal-Wallis test followed by Dunn's multiple comparison test, Fisher's exact probability test and the Spearman's rank correlation coefficient.

Results: SSc patients had significantly higher serum CCL20 levels than healthy controls. In SSc patients, serum CCL20 levels correlated inversely with the percentage of predicated diffusion lung capacity for carbon monoxide and positively with mean pulmonary artery pressure (mPAP). In addition, SSc patients with increased serum CCL20 levels had anti-mitochondrial antibody M2 titer significantly elevated relative to those with normal levels, and SSc patients with asymptomatic primary biliary cholangitis (PBC) possessed higher serum CCL20 levels than those without. Importantly, serum CCL20 levels were associated positively with mPAP values and PBC presence by multivariate regression analysis.

Conclusion: Serum CCL20 levels may be involved in the development of pulmonary vascular involvement leading to pulmonary arterial hypertension and asymptomatic PBC in SSc patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1756-185X.14103DOI Listing
March 2021

A potential contribution of decreased serum galectin-10 levels to systemic inflammation and pulmonary vascular involvement in systemic sclerosis.

Exp Dermatol 2021 Mar 14. Epub 2021 Mar 14.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Objective: Galectin-10 (Gal-10) is a key molecule involved in eosinophil-mediated suppression of T-cell immune response. Systemic sclerosis (SSc) is characterized by T helper (Th) 2/Th17 immune response and impaired function of regulatory T cells, but the pathological role of Gal-10 has not been studied so far. Therefore, we investigated the clinical correlation of serum Gal-10 levels in SSc patients.

Methods: Serum Gal-10 levels were determined by enzyme-linked immunosorbent assay in 38 patients with diffuse cutaneous SSc (dcSSc), 30 with limited cutaneous SSc and 20 healthy controls. Clinical correlations of serum Gal-10 levels were examined.

Results: Serum Gal-10 levels were significantly lower in SSc patients than in healthy controls, especially in dcSSc patients, and inversely correlated with skin score, the percentage of predicted diffusion lung capacity for carbon monoxide and estimated right ventricular systolic pressure (RVSP). Furthermore, serum Gal-10 levels had negative correlations with leucocyte counts and inflammatory parameters. Multivariate regression analysis identified C-reactive protein and RVSP as explanatory parameters for serum Gal-10 levels.

Conclusion: Decreased serum Gal-10 levels may reflect the impairment of eosinophil-mediated regulatory system for T-cell immune response in SSc, possibly contributing to pulmonary vascular involvement leading to pulmonary arterial hypertension.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.14320DOI Listing
March 2021

Serum vasohibin-1 levels: A potential marker of dermal and pulmonary fibrosis in systemic sclerosis.

Exp Dermatol 2021 Mar 8. Epub 2021 Mar 8.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Vasohibin-1 (VASH-1) is a potent anti-angiogenic factor mainly produced by endothelial cells. In addition, VASH-1 prevents TGF-β-dependent activation of renal fibroblasts. Since systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy and fibrosis of multiple organs, VASH-1 may be involved in the development of this disease. In this study, we investigated the potential role of VASH-1 in SSc by evaluating the clinical correlation between serum VASH-1 levels and the expression of VASH-1 in SSc-involved skin. Serum VASH-1 levels were higher in SSc patients, especially those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, SSc patients with interstitial lung disease had significantly elevated levels of serum VASH-1 as compared to those without. Importantly, serum VASH-1 levels correlated inversely with both the percentage of predicted vital capacity and the percentage of predicted diffusion lung capacity for carbon monoxide and positively with serum KL-6 levels, but not serum surfactant protein D levels. In SSc-involved skin, VASH1 mRNA was remarkably upregulated compared with healthy control skin, but the major source of VASH-1 was not clear. Fli1 deficiency, a predisposing factor inducing SSc-like endothelial properties, did not affect VASH-1 expression in human dermal microvascular endothelial cells. Collectively, these results suggest that VASH-1 upregulation in the skin and sera is linked to dermal and pulmonary fibrotic changes in SSc, while the contribution of VASH-1 to SSc vasculopathy seems to be limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.14321DOI Listing
March 2021

Increased Regulatory T Cells and Decreased Myeloid-Derived Suppressor Cells Induced by High CCL17 Levels May Account for Normal Incidence of Cancers among Patients with Atopic Dermatitis.

Int J Mol Sci 2021 Feb 18;22(4). Epub 2021 Feb 18.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

The incidence of cancers in atopic dermatitis (AD) is not increased, although the Th2-dominant environment is known to downregulate tumor immunity. To gain mechanistic insights regarding tumor immunity in AD, we utilized CCL17 transgenic (TG) mice overexpressing CCL17, which is a key chemokine in AD. Tumor formation and lung metastasis were accelerated in CCL17 TG mice when melanoma cells were injected subcutaneously or intravenously. Flow cytometric analysis showed increases in regulatory T cells (Tregs) in lymph nodes in CCL17 TG mice with high mRNA levels of and in tumors, suggesting that Tregs attenuated tumor immunity. The frequency of myeloid-derived suppressor cells (MDSCs), however, was significantly decreased in tumors of CCL17 TG mice, suggesting that decreased MDSCs might promote tumor immunity. Expression of , a chemoattractant of MDSCs, was decreased in tumors of CCL17 TG mice. Depletion of Tregs by the anti-CD25 antibody markedly reduced tumor volumes in CCL17 TG mice, suggesting that tumor immunity was accelerated by the decrease in MDSCs in the absence of Tregs. Thus, CCL17 attenuates tumor immunity by increasing Tregs and Th2 cells, while it decreases MDSCs through reductions in CXCL17, which may work as a "safety-net" to reduce the risk of malignant tumors in the Th2-dominant environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22042025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922104PMC
February 2021

Serum TARC Levels in Patients with Systemic Sclerosis: Clinical Association with Interstitial Lung Disease.

J Clin Med 2021 Feb 9;10(4). Epub 2021 Feb 9.

Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Systemic sclerosis (SSc) is a multisystem fibrotic disorder with autoimmune background. Accumulating evidence has highlighted the importance of T helper (Th) 2 cells in the pathogenesis of SSc and its complications. Because thymus and activation-regulated chemokine (TARC) is a potent chemoattractant for Th2 cells, we measured serum TARC levels in SSc patients and analyzed their correlation with interstitial lung disease (ILD), a major complication of SSc. Serum TARC levels were significantly elevated in patients with SSc, especially in those with the diffuse subtype, compared with healthy controls. In particular, dcSSc patients with SSc-associated ILD (SSc-ILD) showed higher TARC levels than those without SSc-ILD. However, there was no significant correlation between serum TARC levels and pulmonary function in SSc patients. Serum TARC levels did not correlate with serum levels of interleukin-13, an important Th2 cytokine, either. Furthermore, in the longitudinal study, serum TARC levels did not predict the onset or progression of SSc-ILD in patients with SSc. These results were in contrast with those of KL-6 and surfactant protein D, which correlated well with the onset, severity, and progression of SSc-ILD. Overall, these results suggest that serum TARC levels are not suitable for monitoring the disease activity of SSc-ILD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10040660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915627PMC
February 2021

Mycosis fungoides and Sézary syndrome tumor cells express epidermal fatty acid-binding protein, whose expression decreases with loss of epidermotropism.

J Dermatol 2021 Feb 9. Epub 2021 Feb 9.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Fatty acid binding protein (FABP) is a family of transport proteins for fatty acid (FA). Epidermal FABP (E-FABP) is highly expressed by resident memory T cells (T ) in the skin. It supports the uptake of exogenous FA for long-term survival of skin T . Mycosis fungoides (MF) is regarded as malignancy of skin T . In this study, we investigated E-FABP expression in psoriasis vulgaris (PV), atopic dermatitis (AD), MF, and Sézary syndrome (SS). E-FABP mRNA levels in PV were much higher than those in healthy controls. E-FABP mRNA levels in AD and MF/SS lesional skin were also significantly higher than those of normal skin. By immunohistochemical staining, E-FABP was positive in MF/SS lesional skin. Interestingly, E-FABP was stained positive in epidermotropic lymphoid cells in patch, plaque, and erythrodermic lesions of MF/SS, suggesting that a part of tumor cells expressed E-FABP. In tumorous lesions, however, most dermal tumor cells were negative for E-FABP. Immunohistochemical staining using patch/plaque lesions and tumorous lesions from the same patients also revealed that E-FABP expression decreased in tumorous lesions. Our study has suggested that MF/SS tumor cells express E-FABP, whose expression decreases with loss of epidermotropism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15775DOI Listing
February 2021

A case of mycosis fungoides successfully treated with combination of bexarotene and mogamulizumab.

Dermatol Ther 2021 Mar 27;34(2):e14805. Epub 2021 Jan 27.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dth.14805DOI Listing
March 2021

Serum Calponin 3 Levels in Patients with Systemic Sclerosis: Possible Association with Skin Sclerosis and Arthralgia.

J Clin Med 2021 Jan 14;10(2). Epub 2021 Jan 14.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis and vasculopathy in various organs with a background of inflammation initiated by autoimmune abnormalities. Calponin 3 plays a role in the cell motility and contractibility of fibroblasts during wound healing in the skin. We aimed to evaluate serum calponin 3 levels in SSc patients and their association with clinical manifestations of SSc. Serum samples were collected from 68 patients with SSc and 20 healthy controls. Serum calponin 3 levels were examined using enzyme-linked immunosorbent assay kits, and their association with clinical features of SSc was statistically analyzed. The upper limit of the 95% confidence interval of serum calponin 3 levels in healthy controls was utilized as the cut-off value when dividing SSc patients into the elevated and normal groups. Serum calponin 3 levels were significantly higher in SSc patients than in healthy controls (mean (95% confidence interval), 15.38 (14.66-16.11) vs. 13.56 (12.75-14.38) ng/mL, < 0.05). The modified Rodnan total skin thickness score was significantly higher in the elevated serum calponin 3 level group than in the normal level group (median (25-75th percentiles), 10.0 (2.0-16.0) vs. 6.5 (3.25-8.75), < 0.05). Moreover, SSc patients with increased serum calponin 3 levels also had a higher frequency of arthralgia (40% vs. 9%, < 0.05). Elevated serum calponin 3 levels were associated with skin sclerosis and arthralgia in SSc patients. Serum calponin 3 levels might be a biomarker that reflects the severity of skin sclerosis and joint involvement in SSc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10020280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828654PMC
January 2021

A Case of Multiple Phleboliths on the Medial Side of the Right Mandible.

Case Rep Dent 2020 27;2020:6694402. Epub 2020 Dec 27.

Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

A 66-year-old female patient was admitted to the orthopedic department due to a left femoral neck fracture. She received perioperative oral management prior to femoral head replacement. Laboratory blood tests indicated an elevated D-dimer level, which suggested the presence of a venous malformation. Computed tomography, magnetic resonance imaging, and short TI inversion recovery indicated the presence of multiple phleboliths medial to the right mandibular ramus. No swelling, redness, or salivary colic pain was observed. Owing to the absence of clinical symptoms, the patient elected to undergo observation of the lesion, as opposed to surgical treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/6694402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785374PMC
December 2020

HMGB1-mediated chromatin remodeling attenuates gene expression for the protection from allergic contact dermatitis.

Proc Natl Acad Sci U S A 2021 Jan;118(1)

Department of Dermatology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced mRNA, expression was also augmented in the -deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the gene in the -deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2022343118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817117PMC
January 2021

Generalized Argyria Successfully Treated with Q-switched Alexandrite Laser: A Case Report.

Acta Derm Venereol 2020 Dec 14;100(19):adv00348. Epub 2020 Dec 14.

Department of Dermatology, Graduate School of Medicine, the University of Tokyo, 113-8655 Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3713DOI Listing
December 2020

A Case of Systemic Sclerosis Complicated With Portal Hypertension.

J Clin Rheumatol 2020 Dec 1. Epub 2020 Dec 1.

From the Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RHU.0000000000001633DOI Listing
December 2020

Association of serum CXCL12 levels with arthropathy in patients with systemic sclerosis.

Int J Rheum Dis 2021 Feb 30;24(2):260-267. Epub 2020 Nov 30.

Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Aim: Systemic sclerosis (SSc) is an autoimmune connective tissue disease, in which extensive fibrotic change and vasculopathy affect the skin and various internal organs. It also involves the joints, causing stiffness, arthralgia, and arthritis. Although arthropathy is commonly observed in SSc, its underlying mechanism remains unknown. CXCL12, also known as stromal cell derived factor 1, is associated with inflammation, mesenchymal cell recruitment, angiogenesis, and collagen production, and is implicated in the development of various joint diseases. To assess the potential contribution of CXCL12 to SSc development, we investigated the clinical association of serum CXCL12 levels in patients with SSc.

Method: We conducted a cross-sectional analysis of 68 patients with SSc and 20 healthy controls recruited in a single center over 9 years. Serum CXCL12 levels were measured by enzyme-linked immunosorbent assay.

Results: Serum CXCL12 levels were significantly higher in patients with SSc than in healthy controls (median 1554.0 pg/mL, 25th-75th centiles 1313.0-1914.0 pg/mL vs 967.4 pg/mL, 608.8-1271.0 pg/mL, P < 0.001). Patients with SSc with elevated CXCL12 levels had significantly more cases of arthropathy than those with normal CXCL12 levels (85.7% vs 25.0%, P = 0.01). Furthermore, patients with SSc with elevated CXCL12 levels showed an increased trend in the prevalence of limited range of motion of the finger joints compared with those with normal CXCL12 levels (60.0% vs 18.6%, P =0 .07). Moreover, serum CXCL12 levels were significantly correlated with the titers of rheumatoid factor in patients with SSc (r = .41, P = 0.001).

Conclusion: Elevated serum CXCL12 levels may be related to the development of SSc arthropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1756-185X.14037DOI Listing
February 2021

Diagnostic Specificity of Cerebral Magnetic Resonance Imaging for Punctate White Matter Lesion Assessment in a Preterm Sheep Fetus Model.

Reprod Sci 2021 Apr 25;28(4):1175-1184. Epub 2020 Nov 25.

Department of Veterinary Pathology, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan.

Recent studies, using magnetic resonance imaging (MRI) to assess white matter injury in preterm brains, increasingly recognize punctate white matter lesions (PWML) as the primary lesion type. There are some papers showing the relationship between the size and number of PWML and the prognosis of infants. However, the histopathological features are still unknown. In this study, we experimentally induced periventricular leukomalacia (PVL) in a sheep fetus model, aiming to find whether MRI can visualize necrotic foci (small incipient lesions of PVL) as PWML. Three antenatal insults were employed to induce PVL in preterm fetuses at gestational day 101-117: (i) hypoxia under intrauterine inflammation, (ii) restriction of artificial placental blood flow, and (iii) restriction of artificial placental blood flow after exposure to intrauterine inflammation. MRI was performed 3-5 days after the insults, and standard histological studies of the PVL validated its findings. Of the 89 necrotic foci detected in histological samples from nine fetuses with PVL, 78 were visualized as PWML. Four of the lesions detected as abnormal findings on MRI could not be histologically detected as corresponding abnormal findings. The diagnostic sensitivity and positive predictive values of histologic focal necrosis visualized as PWML were 0.92 and 0.95, respectively. The four lesions were excluded from these analyses. These data suggest that MRI can visualize PVL necrotic foci as PWML 3-5 days after the injury induction. PWML can spontaneously become obscure with time after birth, so their accurate diagnosis in the acute phase can prevent overlooking mild PVL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s43032-020-00401-5DOI Listing
April 2021

TLR2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation through Decrease in Regulatory T Cells and Impaired IL-10 Production.

Int J Mol Sci 2020 Nov 13;21(22). Epub 2020 Nov 13.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21228560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696365PMC
November 2020

COVID-19 pandemic highlighted the importance of telemedicine in the collagen disease of systemic sclerosis.

Clin Exp Rheumatol 2020 Nov 5. Epub 2020 Nov 5.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, and Systemic Sclerosis Center, The University of Tokyo Hospital, Tokyo, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
November 2020

Serum S100A12 levels: Possible association with skin sclerosis and interstitial lung disease in systemic sclerosis.

Exp Dermatol 2021 Mar 29;30(3):409-415. Epub 2020 Oct 29.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Damage-associated molecular patterns (DAMPs) have drawn much attention as a member of disease-associated molecules in systemic sclerosis (SSc). In this study, we investigated the potential contribution of S100A12, a member of DAMPs, to the development of SSc by evaluating S100A12 expression in the lesional skin and the clinical correlation of serum S100A12 levels. S100A12 expression was markedly elevated in the epidermis of SSc-involved skin at protein levels and in the bulk skin at mRNA levels. The deficiency of transcription factor Fli1, a predisposing factor of SSc, enhanced S100A12 expression and Fli1 occupied the S100A12 promoter in normal human keratinocytes. Serum S100A12 levels were higher in SSc patients, especially in those with diffuse cutaneous involvement, than in healthy controls and positively correlated with skin score. Furthermore, the presence of interstitial lung disease significantly augmented serum levels of S100A12. Importantly, serum S100A12 levels correlated inversely with both per cent forced vital capacity and per cent diffusing capacity for carbon monoxide and positively with serum levels of KL-6 and surfactant protein-D. Collectively, these results indicate a possible contribution of S100A12 to skin sclerosis and interstitial lung disease associated with SSc, further supporting the critical roles of DAMPs in the pathogenesis of this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/exd.14218DOI Listing
March 2021

Inhibitory role of interleukin-10 in the cutaneous reverse Arthus reaction.

J Dermatol 2021 Feb 15;48(2):219-222. Epub 2020 Oct 15.

Department of Dermatology, Tokyo University Graduate School of Medicine, Tokyo, Japan.

The formation and deposition of immune complexes (IC) containing immunoglobulin (Ig)G antibodies induces an acute inflammatory response with tissue injury. One of the experimental models of IC-related vasculitis is the cutaneous reverse passive Arthus reaction, in which IgG antibodies are injected i.d., followed immediately by the i.v. application of the corresponding antigen. This reaction is characterized by edema, hemorrhage and neutrophil infiltration. To assess the role of the anti-inflammatory cytokine interleukin (IL)-10 in IC-related vasculitis, we investigated the cutaneous Arthus reaction using IL-10 knockout (IL-10KO) mice. Edema, which was quantified macroscopically by measuring the vascular leakage of Evans blue dye at 4 h after IC challenge, was significantly increased in IL-10KO mice compared with wild-type mice. In addition, hemorrhage, which was assessed by the average diameter of purpuric spots at 8 h after IC challenge, was enhanced significantly in IL-10KO mice compared with wild-type mice. Histological examination showed that the number of extravascular neutrophils was significantly increased in IL-10KO mice compared with wild-type mice at 4 and 8 h after IC challenge. Analysis of pro-inflammatory cytokine mRNA expression showed that IL-6 mRNA levels were significantly increased in IL-10KO mice compared with wild-type mice at 4 and 8 h after IC challenge. These results showed that IC-induced inflammation and vascular damage were significantly enhanced in the absence of IL-10. Thus, IL-10 may limit tissue disruption by suppressing the excessive infiltration of neutrophils and cytokine expression in a mouse model of type III vasculitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15641DOI Listing
February 2021

A Case of Cytomegalovirus-Induced Oral Ulcer in an Older Adult Patient with Nephrotic Syndrome due to Membranous Nephropathy.

Case Rep Dent 2020 29;2020:8843816. Epub 2020 Sep 29.

Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, 4-1, Seiryo-machi, Aoba-Ku, Sendai 980-8575, Japan.

We report a case of cytomegalovirus- (CMV-) induced buccal ulcer in a patient with nephrotic syndrome. An 82-year-old man with membranous nephropathy was on immunosuppressive therapy presented with an ulcer in the oral cavity and was hospitalized. Intraoral examination revealed an inflamed and painful ulcer on the left buccal mucosa. Blood test results showed CMV positivity, and histopathological examination confirmed the diagnosis. Anti-CMV therapy (ganciclovir) was initiated from the third day of hospitalization. However, he developed dyspnea on the 14th day. Computed tomography images of the chest revealed the presence of ground-glass opacities, and noninvasive positive pressure ventilation was initiated under the provisional diagnosis of pneumocystis pneumonia caused by ganciclovir-associated myelosuppression and/or steroid-induced immunocompromised state. The patient died of pneumocystis pneumonia on the 21st day. The patient had received immunosuppressive therapy for renal dysfunction. Immunocompromised patients with CMV infection should be treated with caution, as drugs for CMV may themselves cause myelosuppression, deteriorating the prognosis of the patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8843816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542526PMC
September 2020

CX3CR1 Deficiency Attenuates DNFB-Induced Contact Hypersensitivity Through Skewed Polarization Towards M2 Phenotype in Macrophages.

Int J Mol Sci 2020 Oct 7;21(19). Epub 2020 Oct 7.

Department of Dermatology, the University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1 cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1-CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity using CX3CR1 mice. Ear swelling and dermal edema were attenuated after DNFB challenge in CX3CR1 mice. Expression of TNF-α, IL-6, and M1 macrophage markers was decreased in the ears of CX3CR1 mice, whereas expression of M2 macrophage markers including arginase-1 was increased. Decreased TNF-α and IL-6 expression and increased arginase-1 expression were found in peritoneal macrophages from CX3CR1 mice. Furthermore, ear swelling was attenuated by depleting dermal macrophages in wild-type mice to a similar level to CX3CR1 mice. These results suggest that CX3CR1 deficiency could induce skewed polarization towards M2 phenotype in macrophages, resulting in attenuation of contact hypersensitivity response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582565PMC
October 2020

G-quadruplex-proximity protein labeling based on peroxidase activity.

Chem Commun (Camb) 2020 Oct 1;56(78):11641-11644. Epub 2020 Sep 1.

Graduate School of Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka, Japan.

Peroxidase-proximity protein labeling was performed using a hemin-parallel G-quadruplex (G4) complex. A tyrosine labeling reaction using an N-methyl luminol derivative was accelerated in close proximity to the hemin with enhanced peroxidase activity by binding to parallel G4. The TERRA-hemin complex activated the labeling of many RNA-binding proteins, including heterogeneous nuclear ribonucleoproteins, in a HeLa cell lysate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0cc02571bDOI Listing
October 2020

Whole-exome sequencing and host cell reactivation assay lead to a diagnosis of xeroderma pigmentosum group D with mild ultraviolet radiation sensitivity.

J Dermatol 2021 Jan 24;48(1):96-100. Epub 2020 Sep 24.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

A case of xeroderma pigmentosum (XP) group D in a 39-year-old Japanese man is reported. The patient had suffered from moderate to severe solar sensitivity and freckle-like pigmented macules in sun-exposed areas since 6 years of age, and developed skin malignancies such as squamous cell carcinoma, actinic keratosis, Bowen's disease and basal cell carcinoma. The minimal erythema dose for ultraviolet (UV) radiation was decreased with a delayed peak reaction. The level of unscheduled DNA synthesis of fibroblasts from the patient was 70% of normal, while they expressed POLH, a gene product responsible for the XP variant. Whole-exome sequencing indicated that the patient harbored a homozygous mutation of c.1802G>T, p.Arg601Leu in ERCC2. A genetic complementation test was carried out by host cell reactivation assay, which showed that the patient's fibroblasts recovered only when they were transfected with XPD cDNA, confirming the diagnosis of XP-D. Arg601Leu mutation in ERCC2 may be related to mild UV radiation sensitivity and moderate skin lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15617DOI Listing
January 2021

Case of aquagenic urticaria: Case report and the results of histopathological examination.

J Dermatol 2021 Jan 17;48(1):88-91. Epub 2020 Sep 17.

Departments of, Department of, Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Aquagenic urticaria (AU) is a rare skin condition in which dermal contact with water serves as a trigger of urticaria and pruritus. To make a diagnosis, a water challenge test is useful. We herein report a 16-year-old Japanese boy diagnosed with AU by water provocation test. The induced skin lesion histologically showed prominent degranulation of mast cells and lymphocytic infiltration throughout the dermis. This is the second report documenting the histopathological features of AU.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15615DOI Listing
January 2021

Labeling of Peroxide-Induced Oxidative Stress Hotspots by Hemin-Catalyzed Tyrosine Click.

Chem Pharm Bull (Tokyo) 2020 ;68(9):885-890

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology.

Tyrosyl radical generation is one of the major factors for hemin/peroxide-induced oxidative stress. A method for trapping tyrosyl radical directly was developed using N-methyl luminol derivative, a tyrosine labeling reagent. N-Methyl luminol derivative selectively forms a covalent bond with a tyrosine residue under the single-electron oxidation condition. This reaction labels oxidative stress hotspots not only at the protein level but also at the level of tyrosine residues undergoing oxidation. Human serum albumin complexed with hemin was labeled at Tyr138, the tyrosine residue closest to the hemin binding site and most strongly subjected to oxidative stress caused by hemin/HO. Oxidatively damaged proteins were visualized in protein mixtures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/cpb.c20-00434DOI Listing
January 2020

Characteristics of Japanese patients with eosinophilic fasciitis: A brief multicenter study.

J Dermatol 2020 Dec 29;47(12):1391-1394. Epub 2020 Aug 29.

Department of Dermatology, Kumamoto University, Kumamoto, Japan.

Eosinophilic fasciitis is a relatively rare cutaneous fibrotic condition affecting the deep fascia of the extremities, with or without peripheral blood eosinophilia. To examine the characteristics of Japanese patients with eosinophilic fasciitis, we conducted a brief, multicenter, retrospective survey at seven university hospitals. In total, 31 patients were identified as having eosinophilic fasciitis, among whom 30 patients fulfilled the Japanese diagnostic criteria. The male : female ratio was 2.3:1, and the mean age was 47.7 years. Three of the patients were under 20 years old. The possible triggering factors included muscle training, sports, walking or sitting for a long time, physical work, insect bite and drug. Co-occurrence of morphea was observed in nine cases (29%), and malignancies were associated in three (two hematological malignancies and one internal malignancy). Immunological abnormalities in the serum showed positive antinuclear antibody, positive rheumatoid factor, increased aldolase levels and increased immunoglobulin G levels. The patients were treated with either monotherapy or combination therapy by oral prednisolone (20-80 mg/day), methotrexate (6-10 mg/week), cyclosporin (100-150 mg/day), mizoribine, infliximab and phototherapy. Methylprednisolone pulse therapy was performed in six cases. By contrast, spontaneous improvement due to resting only was observed in two cases, and skin hardening was improved by withdrawal of the anticancer drug in one case. This study suggests several characteristics of Japanese patients with eosinophilic fasciitis, namely male predominance, rare pediatric occurrence, immunological abnormalities and coexistence with morphea. Systemic prednisolone is the first-line therapy, but pulse therapy is occasionally required for severe cases. The triggering events of physical stress are not so frequent as have previously been reported, and various factors or even unknown factors may be associated with the induction of eosinophilic fasciitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15561DOI Listing
December 2020