Cutaneous ischemia-reperfusion injury is exacerbated by IL-36 receptor antagonist deficiency.

BACKGROUND: Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear. OBJECTIVES: We investigated the role of IL36Ra in cutaneous I/R injury. METHODS: We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined. RESULTS: IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-ß, IL-1ß, IL-6 and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1ß, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1ß showed significantly increased CXCL1, TNF-α, IL-6, IL-36ß and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn-/- mice. CONCLUSIONS: This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

Granulocyte and monocyte apheresis can control juvenile generalized pustular psoriasis with mutation of IL36RN.

Patients with deficiency of interleukin-36 receptor antagonist (DITRA), due to mutation of IL36RN, exhibit psoriatic phenotypes, typically generalized pustular psoriasis (GPP). We report a paediatric patient with DITRA, whose cutaneous lesions varied from psoriasis vulgaris in infancy to annular pustular psoriasis with acute exacerbation to GPP at 13 years of age. Conventional systemic treatments for GPP, which include oral retinoids, ciclosporin and methotrexate, are controversial in paediatric cases, because of their adverse effects and uncertain long-term consequences. Granulocyte monocyte apheresis, a process associated with few adverse events, promptly controlled the GPP of our paediatric patient, and has potential as a suitable alternative treatment for paediatric patients with DITRA.

Case report of multiple pustules of the bilateral lower limbs caused by a granulocyte colony-stimulating factor-producing solid pseudopapillary tumour of the pancreas.

Here we report a rare case of neutrophilic dermatoses related to a granulocyte colony-stimulating factor (G-CSF)-producing solid pseudopapillary tumour (SPT). The patient was a 39-year-old woman presenting with scattered pustules and crusts of the palms, heels and thighs and plaques of the bilateral lower legs. The skin biopsy revealed dense neutrophil infiltration in the epidermis to the dermis. A pancreatic head tumour was detected using computed tomography. A pathological examination of the resected specimen suggested an SPT. As the skin eruption promptly disappeared after SPT resection, we hypothesized that SPT secretes growth factors including epidermal growth factor (EGF) and G-CSF. The SPT cells stained positive for both EGF and G-CSF tumour cells. The serum levels of interleukin (IL)-6 and IL-10 and tumour necrosis factor-α were within normal limits before and after the SPT resection. In contrast, the serum IL-8, EGF and G-CSF levels decreased after the SPT resection. This is a rare case of neutrophilic dermatoses related to a G-CSF-producing SPT. The present case suggests that physicians should be aware that a G-CSF-producing tumour is a differential diagnosis to consider in patients with unusual aseptic pustulosis.

Quantitative risk assessment of the introduction of rabies into Japan through the importation of dogs and cats worldwide.

Japan has been free from rabies since 1958. A strict import regimen has been adopted since 2004 consisting of identification of an animal with microchip, two-time rabies vaccination, neutralizing antibody titration test and a waiting period of 180 days. The present study aims to quantitatively assess the risk of rabies introduction into Japan through the international importation of dogs and cats and hence provide evidence-based recommendations to strengthen the current rabies prevention system. A stochastic scenario tree model was developed and simulations were run using @RISK. The probability of infection in a single dog or cat imported into Japan is estimated to be 2·16 × 10-9 [90% prediction interval (PI) 6·65 × 10-11-6·48 × 10-9]. The number of years until the introduction of a rabies case is estimated to be 49 444 (90% PI 19 170-94 641) years. The current import regimen is effective in maintaining the very low risk of rabies introduction into Japan and responding to future changes including increases in import level and rabies prevalence in the world. However, non-compliance or smuggling activities could substantially increase the risk of rabies introduction. Therefore, policy amendment which could promote compliance is highly recommended. Scenario analysis demonstrated that the waiting period could be reduced to 90 days and the requirement for vaccination could be reduced to a single vaccination, but serological testing should not be stopped.

Founder mutation in dystonin-e underlying autosomal recessive epidermolysis bullosa simplex in Kuwait.

Only two homozygous nonsense mutations in the epidermal isoform of the dystonin gene, DST-e, have been reported previously in autosomal recessive epidermolysis bullosa simplex (EBS); the affected pedigrees were Kuwaiti and Iranian. This subtype of EBS is therefore considered to be a rare clinicopathological entity. In this study, we identified four seemingly unrelated Kuwaiti families in which a total of seven individuals had predominantly acral trauma-induced blistering since infancy. All affected individuals were homozygous for the mutation p.Gln1124* in DST-e, the same mutation that was identified in the originally reported family from Kuwait. Haplotype analysis in the five pedigrees (including the previous case) revealed a shared block of ~60 kb of genomic DNA across the site of the mutation, consistent with a founder effect. Most heterozygotes had no clinical abnormalities although one subject had mild transient skin fragility during childhood, an observation noted in the previously reported Iranian pedigree, suggesting that the condition may also be semidominant in some pedigrees rather than purely autosomal recessive. Our study reveals propagation of a mutant ancestral allele in DST-e throughout Kuwait, indicating that this subtype of EBS may be more common in Kuwait, and perhaps other Middle Eastern countries, than is currently appreciated.

Magnetic resonance imaging findings are useful for evaluating the three-dimensional development and follow-up of linear lupus erythematosus profundus.

Lupus erythematosus profundus (LEP), which is a variant of chronic cutaneous lupus erythematosus (CLE), is seen in approximately 2∼3% of CLE patients, and only 10% to 20% of LEP patients present with systemic LE (SLE). LEP shows subcutaneous nodules with or without discoid LE (DLE). Linear LEP, a very rare variant of LEP, was first reported in 1991 in Japanese and in 1998 in English. Since LEP sometimes leaves skin depressions or scars as a result of atrophy of adipose tissue, early and adequate treatments are necessary. Here, we introduce an LEP case in which magnetic resonance imaging (MRI) was quite effective in evaluating a lesion that had been considered to be linear DLE.

Highly prevalent SERPINB7 founder mutation causes pseudodominant inheritance pattern in Nagashima-type palmoplantar keratosis.

BACKGROUND: Nagashima-type palmoplantar keratosis (NPPK) is a distinct autosomal recessive genodermatosis characterized by diffuse transgressive palmoplantar keratoderma (PPK). Very recently, putative loss-of-function mutations in SERPINB7, which encodes a member of the serine protease inhibitor superfamily and is abundantly expressed in the epidermis, have been identified as a cause of NPPK. OBJECTIVES: To confirm further the role of SERPINB7 mutations in the pathogenesis of NPPK. METHODS: We analysed 10 Japanese families with NPPK using Sanger and/or whole-exome sequencing. RESULTS: We identified one novel and three recurrent null mutations in SERPINB7. In all the families, the NPPK trait was inherited in an autosomal recessive manner; in one of the families, there was pseudodominant inheritance, which had not been described in NPPK. CONCLUSIONS: These data clearly provide further evidence that NPPK is caused by loss-of-function mutations in SERPINB7.

Sales of veterinary antimicrobial agents for therapeutic use in food-producing animal species in Japan between 2005 and 2010.

The use of veterinary antimicrobial agents in animals can result in the emergence and selection of resistant bacteria in food-producing animals. This study elucidated the use of veterinary antimicrobial agents in Japan in terms of milligrams of active ingredient sold per kilogram of biomass between 2005 and 2010. Data on sales of antimicrobial agents and on the biomass of the target animal species were compiled from statistics published bythe Japanese Ministry of Agriculture, Forestry and Fisheries. The quantities of antimicrobials used varied between animal species: the highest usage was observed in pigs (392 to 423 mg/ kg), followed by beef cattle (45 to 67 mg/kg), broiler chickens (44 to 63 mg/kg) and dairy cattle (33 to 49 mg/kg). For the animal species combined, usage of third- and fourth-generation cefalosporins, fluoroquinolones and macrolides ranged from 0.10 to 0.14 mg/kg biomass, 1.1 to 1.3 mg/kg biomass and 7.8 to 10.6 mg/kg biomass, respectively.

Ensuring continuous TB treatment across Asian borders.

BACKGROUND: Mid-treatment cross-border migration of patients with TB increases the risk of treatment interruption. OBJECTIVE: To establish a cross-border referral process for patients with TB in Japan, and enhance their access to health facilities and treatment outcomes. DESIGN: This prospective cohort study describes and assesses the process of foreign-born patients with TB who returned to their home countries during treatment, focusing on their access to healthcare facilities and treatment outcomes. RESULTS: We enrolled 135 foreign-born patients with TB, and confirmed that 112 (83.0%) were referred to and accessed healthcare facilities after returning to their home countries. Of 102 patients due to complete treatment as of July 2023, 87 (85.3%) completed their treatment. We did not identify significant differences in the treatment success rate among patient characteristics, except between the patients with confirmed access to a healthcare facility and those without (P < 0.001). We confirmed that 49/87 (56.3%) patients had completed treatment with official data. CONCLUSION: The access and treatment success rates of the cross-bordered patients with TB from Japan were >80%; however, we should further improve this proportion by confirming the treatment outcomes with official data.

CONTEXTE: La migration transfrontalière en milieu de traitement des patients atteints de TB augmente le risque d'interruption du traitement. OBJECTIF: Etablir un processus d'orientation transfrontalière pour les patients atteints de TB au Japon et à améliorer leur accès aux établissements de santé et les résultats de leur traitement. CONCEPTION: Cette étude de cohorte prospective décrit et évalue le processus des patients atteints de TB et nés à l'étranger qui sont retournés dans leur pays d'origine pendant le traitement, en se concentrant sur leur accès aux établissements de santé et sur les résultats du traitement. RÉSULTATS: Nous avons recruté 135 patients atteints de TB et nés à l'étranger et confirmé que 112 (83,0%) ont été orientés vers des établissements de santé et y ont accédé après leur retour dans leur pays d'origine. Des 102 patients qui devaient terminer leur traitement en juillet 2023, 87 (85,3%) l'ont terminé. Nous n'avons pas identifié de différences significatives dans le taux de réussite du traitement en fonction des caractéristiques des patients, sauf entre les patients ayant un accès confirmé à un établissement de santé et ceux qui n'en ont pas (P < 0,001). Nous avons confirmé que 49 (56,3%) des 87 patients avaient terminé leur traitement à l'aide des données officielles. CONCLUSION: Les taux d'accès et de réussite du traitement des patients transfrontaliers atteints de TB en provenance du Japon étaient >85% ; cependant, nous devrions encore améliorer cette proportion en confirmant les résultats du traitement à l'aide de données officielles.

Efficacy of porcine placental extract on shoulder stiffness in climacteric women.

OBJECTIVES: Some of the most common climacteric symptoms are somatic symptoms, such as muscle and joint pain, which cause limitations in performing daily tasks. This study aimed to assess whether oral porcine placental extract (PPE) affects patients with shoulder stiffness, one of the most common types of muscle-tendon stiffness, in climacteric women and postmenopausal women with hormone therapy (HT). METHODS: Sixty-six climacteric women (33 each in the control and study groups) with shoulder stiffness and 54 postmenopausal women (27 each in the control and study groups) with HT-resistant shoulder stiffness were enrolled into this open-label, randomized, controlled study. The control subjects received Toki-shakuyaku-san (TJ23; 7.5 g/day, daily per os), an oral herbal remedy used to alleviate climacteric symptoms, and study subjects received PPE orally for 24 weeks in climacteric women and for 12 weeks in postmenopausal women with HT. Changes in the degree of shoulder stiffness were evaluated by the Visual Analog Scale (VAS). RESULTS: Treatment with PPE was significantly effective in reducing the VAS score for shoulder stiffness during the study period compared with the control group in both climacteric and postmenopausal women with HT. The VAS score at the end of treatment was significantly reduced (p < 0.01 vs. baseline) by 76.4% for climacteric women and 64.8% for postmenopausal women with HT compared with baseline. CONCLUSIONS: PPE is useful as an oral supplement for shoulder stiffness in climacteric women without HT or in postmenopausal women with HT-resistant, long-term shoulder stiffness.

Efficacy of porcine placental extract on climacteric symptoms in peri- and postmenopausal women.

OBJECTIVES: Injections of human placental extract have long been used to treat menopausal symptoms. Recently, porcine placental extract (PPE), an oral supplement, has been developed for this purpose. The aim of this study was to assess whether PPE has an impact on climacteric symptoms in perimenopausal and postmenopausal women. METHODS: Seventy-six women with climacteric symptoms were enrolled into this open-label, randomized, controlled study. The control group (n = 38) underwent 24 weeks of open treatment with Toki-shakuyaku-san (TJ23), an oral herbal remedy used to alleviate climacteric symptoms. The PPE group (n = 38) received three capsules of PPE/day orally for the initial 12 weeks and six capsules/day for the next 12 weeks. Climacteric symptoms were evaluated in both groups using the Simplified Menopausal Index (SMI) score, Zung's Self-Rating Depression Scale (ZSDS) and the Spielberger State-Trait Anxiety Inventory (STAI) before commencing treatment, after 12 weeks of treatment and on completion of treatment. RESULTS: Treatment with PPE was significantly (p < 0.01) more effective in reducing the SMI, ZSDS and STAI measures at 12 and 24 weeks than TJ23 treatment alone. Treatment with PPE was also significantly effective (p < 0.01) in reducing the subscale scores of the SMI for items such as hot flushes, insomnia, irritability, depression, fatigue and joint pain. PPE treatment had no significant adverse effects. CONCLUSION: Oral PPE treatment is another possible option for treating perimenopausal and postmenopausal women with climacteric symptoms.

Prevalent founder mutation c.736T>A of LIPH in autosomal recessive woolly hair of Japanese leads to variable severity of hypotrichosis in adulthood.

BACKGROUND: Mutations in LIPH are a cause of autosomal recessive woolly hair (ARWH). Homozygous c.736T>A (p.Cys246Ser), and compound heterozygous c.736T>A and c.742C>A (p.His248Asn) have been reported in 5 and 7 Japanese children with ARWH respectively. The severity of hypotrichosis is known to be able to change in the clinical course, and the mutation patterns of LIPH do not always correlate with the severity of hypotrichosis in ARWH caused by other mutation sites of LIPH. However, all 12 Japanese children previously reported to have ARWH have shown similar severity of hypotrichosis. OBJECTIVE: In this study, we investigated the clinical features and molecular basis of ARWH in patients including three adults (three adults and two children) from five non-related Japanese families. METHODS: Five families of Japanese origin that presented with woolly hair were studied. The phenotype was confirmed by clinical examination. Direct automated DNA sequencing of the LIPH gene was performed to identify the mutations in our probands. RESULTS: All patients had had woolly hair since birth. Homozygous c.736T>A mutations were found in four patients, including three adult cases, and compound heterozygous c.736T>A and c.742C>A mutations were found in one child patient. The two adults and two children had only sparse scalp hair, although one adult woman had mild hypotrichosis with long hairs. CONCLUSION: Some patients with homozygous c.736T>A can have a mild hypotrichosis phenotype with long hairs in adulthood.