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Background: In contrast to childhood minimal change disease (MCD), adult-onset MCD frequently recurs and requires prolonged immunosuppressive therapy. Accordingly, an investigation of the pathogenesis of adult MCD is required. MCD is usually accompanied by severe dyslipidaemia. Oxidized low-density lipoprotein (ox-LDL) is known to function in a damage-associated molecular pattern (DAMP) through CD36, triggering the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and programmed cell death called pyroptosis. However, the relationship between MCD pathogenesis and NLRP3 inflammasome/pyroptosis activation via CD36 is not fully understood., Methods: We conducted comprehensive histological and clinical evaluations by analysing renal biopsy (RBx) specimens and urine samples obtained from 26 patients with MCD. These samples were compared with control kidneys from 15 transplant donors and urine samples from 15 healthy volunteers., Results: The number of podocytes was lower in the MCD group than in the control group. Urinary ox-LDL levels were higher in the MCD group than in the control group. Immunofluorescence staining revealed that NLRP3 and CD36 were upregulated in MCD podocytes. Urinary interleukin (IL)-18 levels increased in patients with MCD. Steroid therapy performed before RBx appeared to maintain the podocyte number and reduce urinary ox-LDL and IL-18 levels., Conclusion: In MCD, the NLRP3 inflammasome and pyroptosis cascade seem to be activated via upregulation of CD36 in podocytes, associated with increased urinary ox-LDL. Elevated urinary IL-18 levels suggest that pyroptosis may occur in MCD. Further research is required to confirm the significance of the podocyte NLRP3 inflammasome/pyroptosis in MCD., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in the PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes, including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10. Short-term treatment of CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Background: Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential., Methods: The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting., Results: In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease., Conclusions: These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients., (© American Association for Clinical Chemistry 2020.)

Background: Since recombinant human soluble thrombomodulin (RH-TM) has anti-inflammatory properties through neutralizing high-mobility group box 1 protein (HMGB1), the protective effects of RH-TM were examined in anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in Wistar-Kyoto rats., Methods: Rats were injected with nephrotoxic serum (NTS) to induce anti-GBM GN on Day 0, and were given either RH-TM or vehicle from Day 0 to Day 6. Rats were sacrificed 7 days after NTS injection., Results: RH-TM-treated rats had decreased proteinuria and serum creatinine level. RH-TM significantly reduced the percentage of glomeruli with crescentic features and fibrinoid necrosis. In addition, RH-TM-treated rats had significantly reduced glomerular ED1+ macrophage accumulation as well as reduced renal cortical proinflammatory cytokine expression. Furthermore, RH-TM had a potent effect in reducing intercellular adhesion molecule-1 (ICAM-1) expression in kidneys and urine. RH-TM significantly reduced renal cortical mRNA levels for toll-like receptor -2 and -4, known as receptors for HMGB1, and their downstream adopter protein, myeloid differentiation primary respond protein 88 (MyD88)., Conclusions: We showed for the first time that anti-inflammatory effects, which were characterized by reduced glomerular macrophage influx concomitant with a marked reduction in proinflammatory cytokines, were involved in the mechanism of attenuating experimental anti-GBM GN by RH-TM. The observed effects might be attributable to the downregulation of ICAM-1 by reducing the HMGB1/TLR/MyD88 signaling pathway., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objective: To clarify the roles of mast cells (MCs) on the pathogenesis of lupus erythematosus (LE)-like skin lesions on MRL/lpr mice., Methods: MRL/lpr mice were mated with C57BL/6-Kit wsh/wsh mice and the heterozygous F1 mice were 10 times backcrossed with the parental MRL/lpr to generate MRL/lpr-Kit wsh/wsh mice. MC-deficient MRL/lpr-Kit wsh/wsh mice were compared with MRL/lpr-Kit +/+ and MRL/lpr-Kit wsh/+ mice with intact MCs., Results: MRL/lpr-Kit wsh/wsh mice developed skin lesions without infiltrating MCs. As similar skin lesions on MRL/lpr-Kit +/+ mice and MRL/lpr-Kit wsh/+ mice contain comparable number of MCs, these mice were collectively analyzed as MRL/lpr mice with MCs. Compared with MRL/lpr mice with MCs, skin lesions developed earlier and showed consistently higher severity, with significantly higher mRNA expressions of many inflammatory cytokines in the dorsal skin on MRL/lpr mice without MCs. Furthermore, survival rate was significantly lower in MRL/lpr mice without MCs. The number of infiltrating MCs significantly increased in association with the severity of skin lesions in MRL/lpr mice with MCs., Conclusions: These results demonstrated that MCs are infiltrated to suppress the progression of LE-like skin lesions in MRL/lpr mice.

Objectives: To evaluate the effect and safety of hydroxychloroquine (HCQ) on lupus erythematosus (LE)-like skin lesions in the MRL/lpr mouse, a model for systemic LE (SLE)., Methods: We divided the MRL/lpr mice into three groups that were given: (1) drinking water, (2) HCQ at a dose of 4 mg/kg/d, or (3) HCQ at a dose of 40 mg/kg/d. The HCQ was administered to examine the effect and safety of HCQ on skin lesions and the number of infiltrating cells including mast cells in the dermis., Results: Six of 13 mice in the group given drinking water, 3 of 11 mice in the group administered low-dose HCQ (4 mg/kg/d), and 1 of 10 mice in the group administered high-dose HCQ (40 mg/kg/d) presented the skin lesions. The average number of mast cells was 81, 50, and 12 (magnification, ×100), the mortality rate was 24%, 8%, and 9% and the mean body weight gain was 4.6 g, 8.0 g and 5.1 g, respectively., Conclusions: HCQ was demonstrated to decrease the appearance of LE-like lesions and the number of mast cells in the dermis. Furthermore, there were no obvious systemic adverse effects. This study provides evidence that suggests benefits in human patients.

Glucocorticoids (GCs) are widely used for the treatment of various diseases, particularly in dermatology. However, there have been few reports about the outcome of treatment for GC-induced osteoporosis in patients with dermatological conditions receiving oral GCs. The present study was undertaken to prospectively evaluate the usefulness of etidronate for preventing steroid-induced osteoporosis in patients on prolonged GC therapy as routine clinical management. In total, 110 patients receiving oral GC therapy were enrolled into the study. Of these, 87 patients were evaluated (44 patients with collagen diseases, 13 patients with autoimmune bullous dermatoses, 19 patients with chronic eczema/dermatitis, 2 patients with toxicoderma/drug eruption and 9 others). Urinary deoxypyridinoline (DPD) was evaluated as a marker of bone resorption, and serum bone-specific alkaline phosphatase (BAP) as a marker of bone formation. Significant increases in urinary DPD were seen in the control group after oral GC therapy had been continued for ≥ 1 year. Treatment with etidronate suppressed this increase. When the patients were stratified according to gender, this improvement was more obvious in women. No significant difference in serum BAP level was found between the two groups. These results suggest that bisphosphonates may be useful for preventing steroid-induced osteoporosis in dermatology patients (particularly women) receiving oral GC therapy., (© 2010 The Author(s). Journal compilation © 2010 British Association of Dermatologists.)

We report here the case of a 48-year-old Japanese woman showing plaque-forming scattered indurative papules on her face, buttock and extremities. Histological examination revealed a large amount of interstitial mucin deposition, and negative direct immunofluorescence was observed. The provocative phototesting reproduced the skin lesion, and the patient was diagnosed with lupus erythematosus tumidus (LET). A review of ten LET cases previously reported in Japan revealed that all of these cases had clinicopathological features similar to those reported for European cases, although not all of the former fully satisfied the European criteria.

Prostate-specific antigen (PSA) is a kallikrein-like serine proteinase (human kallikrein 3) produced by epithelial cells of both benign and malignant prostate tissue. In this study, PSA expression was histologically examined in tissue specimens from 34 patients with extramammary Paget's disease (EPD; 31 cases) and extramammary Paget's carcinoma (EPC; three cases), but no associated prostate carcinoma. Tumour cells positive for PSA were found in 17 of the 34 cases. Based on this finding, we examined serum PSA level in the three EPC cases. A high level of serum PSA was observed in one case of EPC, which was correlated with disease progression. Because some reports suggest that 50-80% cases of EPD/EPC express androgen receptor (AR), we also examined expression of AR. Immunohistological staining showed correlation of PSA and AR in expression. These results suggest that PSA and the androgen signalling pathway may be involved in the pathogenesis of EPD.

Background: Mortality statistics show rapid increase in the number of deaths from mesothelioma. However, population-based study of the incidence and the survival has never been conducted. Time-trends and regional differences in the incidence of mesothelioma in Osaka were examined together with their 5-year survival., Methods: Individual data for mesothelioma were retrieved from Osaka Cancer Registry during the period 1966-2001. Annual incidence rates were calculated for every 3 years from 1975 to 2001, and age-standardized rates were calculated with the Japanese model population of 1985. Standardized incidence ratios were also calculated by age-specific number of population of each municipality and the corresponding age-specific incidence rates of mesothelioma in Osaka Prefecture during the period 1981-2001. The survival analysis was performed with the Kaplan-Meier method, based on the newly reported cases diagnosed during the period 1975-1997., Results: Incidence rates of mesothelioma have increased rapidly both among males and females in Osaka during the past few decades. Geographical differences in the standardized incidence ratios were found to be remarkable in Osaka Prefecture. The result shows that the survival of malignant mesothelioma was very poor (5-year survival and median survival time: 5.1% and 6 months for males, 10.2% and 5 months for females)., Conclusions: Incidence of mesothelioma has increased remarkably in Osaka, Japan, during past few decades. Geographical variations in the incidence were also suggested. Five-year survival of the patients was very poor.

Treatment of hepatitis C virus (HCV) infection with interferon (IFN)- alpha and ribavirin combination therapy results in superior clinical antiviral responses than does monotherapy with IFN. To explore the virological basis of the effects of combination therapy, we analyzed the effects of IFN- alpha and ribavirin, singly and in combination, on intracellular HCV replication by use of an HCV replicon system. A new replicon that expressed a selectable chimeric reporter protein comprising firefly luciferase and neomycin phosphotransferase was constructed. The replicon was highly sensitive to IFN-alpha (50% inhibitory concentration [IC(50)], 0.5 U/mL). Therapy with ribavirin showed weak suppression of HCV replication at a lower concentration (IC(50), 126 mu mol/L). The nucleotide sequence diversity of the replicon was increased significantly by therapy with ribavirin, suggesting that error-prone HCV replication was induced by the drug. Importantly, use of a clinically achievable concentration of ribavirin (approximately 10 mu mol/L) in combination with IFN showed strong synergistic inhibitory effects on HCV replication. Our results suggest that the direct effects of ribavirin on the genetic stability of the HCV subgenome and its synergistic action combined, with IFN-alpha, may explain the improved clinical responses to combination therapy.

To analyze the influence of hepatitis C virus nonstructural protein 5A (NS5A) on apoptosis, we established Huh7 cells that stably express NS5A, and induced apoptosis using tumor necrosis factor (TNF)-alpha. The viability of control Huh7 cells was reduced to 40%, compared with untreated cells, after TNF-alpha treatment, whereas that of Huh7-NS5A cells was reduced only to 80%. DNA fragmentation also decreased to <50% in Huh7-NS5A compared with control cells. Nuclear factor-kappaB activation was the same in both cell types, whereas caspase-8, -9, and -3 activity was decreased in Huh7-NS5A cells, compared with control cells, which indicates that the inhibition of caspase-8 activation is responsible for the antiapoptotic effect of the NS5A protein. The coexpression of NS5A did not inhibit apoptosis induced by caspase-8 or Fas-associating death domain protein expression. These findings suggest that the NS5A protein inhibits the apoptotic effect of TNF-alpha upstream of caspase-8 in the apoptosis cascade.

Exposure to heavy particle radiation in the galacto-cosmic environment poses a significant risk in space exploration and the evaluation of radiation-induced genetic damage in tissues, especially in the central nervous system, is an important consideration in long-term manned space missions. We used a plasmid-based transgenic mouse model system, with the pUR288 lacZ transgene integrated in the genome of every cell of C57Bl/6(lacZ) mice, to evaluate the genetic damage induced by iron particle radiation. In order to examine the importance of genetic background on the radiation sensitivity of individuals, we cross-bred p53 wild-type lacZ transgenic mice with p53 nullizygous mice, producing lacZ transgenic mice that were either hemizygous or nullizygous for the p53 tumor suppressor gene. Animals were exposed to an acute dose of 1 Gy of iron particles and the lacZ mutation frequency (MF) in the brain was measured at time intervals from 1 to 16 weeks post-irradiation. Our results suggest that iron particles induced an increase in lacZ MF (2.4-fold increase in p53+/+ mice, 1.3-fold increase in p53+/- mice and 2.1-fold increase in p53-/- mice) and that this induction is both temporally regulated and p53 genotype dependent. Characterization of mutants based on their restriction patterns showed that the majority of the mutants arising spontaneously are derived from point mutations or small deletions in all three genotypes. Radiation induced alterations in the spectrum of deletion mutants and reorganization of the genome, as evidenced by the selection of mutants containing mouse genomic DNA. These observations are unique in that mutations in brain tissue after particle radiation exposure have never before been reported owing to technical limitations in most other mutation assays.