Solar urticaria: clinical characteristics, treatment effectiveness, long-term prognosis, and QOL status in 29 patients.

Introduction: Solar urticaria (SU), a relatively rare skin inflammatory and photosensitivity disease, is often resistant to standard urticaria treatment. Quality of life (QOL) among SU patients has not been extensively explored. This study was performed to clarify the clinical features and effectiveness of therapies (e.g., hardening therapy) for SU and to determine QOL among SU patients. Methods: The authors examined the characteristics, treatments, and QOL statuses of 29 Japanese SU patients using medical records and a questionnaire approach. Results: Among 29 patients, H1 antihistamine therapy (H1) was effective in 22 (75.8%) patients. H2 antihistamine therapy (H2) was effective in three of seven (42.9%) patients. Ultraviolet radiation A (UVA) hardening therapy was effective in eight of nine (88.9%) patients. Visible light (VL) hardening therapy was ineffective in three of three patients. In one patient who underwent both UVA and VL hardening therapy, only UVA hardening therapy was effective. In the questionnaire, 18 patients (90%) reported some improvement compared with disease onset (four had complete remission, six had completed treatment although mild symptoms persisted, and eight were receiving treatment with moderate symptoms), whereas two patients reported exacerbation. Patients in complete remission had a mean disease duration of 4 years, whereas patients not in remission had a mean disease duration of 8.8 years. The mean Dermatology Life Quality Index (DLQI) score for the current status was 7.4. There was a correlation between DLQI and symptom/treatment status. However, neither DLQI and action spectra nor DLQI and treatments exhibited significant differences. Discussion: The questionnaire revealed current QOL status and long-term prognosis in SU patients. Compared with disease onset, most patients showed improvement when assessed for this study. Both H1 and H2 should be attempted for all SU patients. UVA hardening therapy may be an option for SU patients with an action spectrum that includes UVA.

Dietary Intervention for Control of Clinical Symptom in Patients with Systemic Metal Allergy: A Single Center Randomized Controlled Clinical Study.

Patients with eczema with a systemic metal allergy, such as nickel (Ni), cobalt (Co), chromium (Cr), and tin (Sn), should pay attention to symptomatic exacerbation by excessive metal intake in food. However, dietary intervention for systemic metal allergy can be difficult. In this study, we evaluated the effect of dietary intervention by a registered dietitian on clinical symptoms in patients with a systemic metal allergy. Forty-four patients with cutaneous symptoms who were diagnosed with a metal allergy were randomly assigned to the dietary intervention group (DI group, n = 29) by a registered dietitian or the control group (C group, n = 15). The DI group was individually instructed by a registered dietitian how to implement a metal-restricted diet and then evaluated 1 month later. Dermatologists treated skin lesions of patients in both groups. Skin symptoms assessed by the Severity Scoring of Atopic Dermatitis (SCORAD) index, blood tests, and urinary metal excretion were evaluated. The DI group showed decreased Ni, Co, Cr, and Sn intake (all P ≤ 0.05), and an improved total SCORAD score, eczema area, erythema, edema/papulation, oozing/crust, excoriation, lichenization and dryness after 1 month of intervention compared with before the intervention (all P ≤ 0.05). However, the C group showed decreased Ni and Sn intake and an improved oozing/crust score (all P < 0.05). It showed the effective reduction of dietary metal intake controls dermatitis due to a metal allergy. In conclusion, dietary intervention by a registered dietitian is effective in improving skin symptoms with a reduction in metal intake.

Assessing the safety of new germicidal far-UVC technologies.

The COVID-19 pandemic underscored the crucial importance of enhanced indoor air quality control measures to mitigate the spread of respiratory pathogens. Far-UVC is a type of germicidal ultraviolet technology, with wavelengths between 200 and 235 nm, that has emerged as a highly promising approach for indoor air disinfection. Due to its enhanced safety compared to conventional 254 nm upper-room germicidal systems, far-UVC allows for whole-room direct exposure of occupied spaces, potentially offering greater efficacy, since the total room air is constantly treated. While current evidence supports using far-UVC systems within existing guidelines, understanding the upper safety limit is critical to maximizing its effectiveness, particularly for the acute phase of a pandemic or epidemic when greater protection may be needed. This review article summarizes the substantial present knowledge on far-UVC safety regarding skin and eye exposure and highlights research priorities to discern the maximum exposure levels that avoid adverse effects. We advocate for comprehensive safety studies that explore potential mechanisms of harm, generate action spectra for crucial biological effects and conduct high-dose, long-term exposure trials. Such rigorous scientific investigation will be key to determining safe and effective levels for far-UVC deployment in indoor environments, contributing significantly to future pandemic preparedness and response.

Loss of social independence in patients with neurofibromatosis type 2: a follow-up study using a national registry in Japan.

BACKGROUND: For patients with neurofibromatosis type 2 (NF2), maintaining an independent state of living is important. The present study aimed to examine the loss of social independence (i.e., a status that patients can work and go to school) and its contributing factors in patients with NF2 using data from a national registry in Japan. METHODS: This longitudinal study used a registry database containing information on patients with NF2 who had submitted initial claims to receive medical expense subsidies between 2004 and 2010. Patients with "employed," "studying," and "housekeeping" categories were classified as "socially independent." Patients who were socially independent at baseline were followed-up for up to nine years. The primary outcome of the present study was the loss of social independence during the follow-up period, which was defined as the change in status from being socially independent to socially dependent. First, we examined longitudinal associations between demographic variables and neurological symptoms at baseline and the loss of social independence. Second, we examined whether the occurrence of neurological symptoms is associated with a loss of social independence in patients. RESULTS: A total of 156 patients were included in the present study. During the follow-up period, 37 (23.7%) patients experienced a loss of social independence. In the first analysis, the multivariate logistic regression model showed that the loss of social independence was significantly more frequent among patients with spinal dysfunction than among patients without. In the second analysis, logistic regression analyses showed that neurological symptoms, including bilateral hearing loss, facial nerve palsy, cerebellar dysfunction, decreased facial sensation, speech dysfunction (dysphagia/dysarthria and aphasia), double vision, blindness, hemiparesis, and seizures, were significantly associated with loss of social independence. CONCLUSIONS: The occurrence of various neurological symptoms of NF2 can hinder social independence in the long term. Medical service providers need to observe patients while considering the risks, and provide appropriate support to address neurological symptoms that can restrict social independence, as this will lead to maintaining social engagement.

Implications of interleukin-17 in psoriatic lesions as Koebner phenomenon caused by recurrent occupational burns.

The Koebner phenomenon (KP) is the emergence of new lesions in an uninvolved skin area caused by different types of stimulations, including mechanical stress, chemical stress, trauma, or injury. KP affects patients with certain skin diseases and is frequently observed in patients with psoriasis. We report the case of a 43-year-old obese male welder who developed psoriatic lesions only in areas of repeated burns due to his occupation. He was repeatedly exposed to mild burns in his anterior neck and the periorbital region as he was welding without shield protection. Subsequently, erythema appeared in the same region. Skin appearance and skin biopsy suggested psoriasis vulgaris (PV), and immunohistochemical analysis of anti-interleukin (IL)-17, a crucial element in the development of PV, showed the positivestained cells. The anti-IL-17 staining was prominent around the thickened epidermis as psoriatic lesions. IL-17 produced by T helper 17 cells stimulates keratinized cells and promotes chemokine secretion involved in neutrophil migration. Our case showed that patients, even without a history of PV, may have a risk of developing KP and PV via the enhanced production of IL- 17 locally in the repeated burn area. No recurrence of skin symptoms was observed when the patient used a fully defensive shield during welding.

Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

Genomic mutation landscape of skin cancers from DNA repair-deficient xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) is a genetic disorder caused by mutations in genes of the Nucleotide Excision Repair (NER) pathway (groups A-G) or in Translesion Synthesis DNA polymerase η (V). XP is associated with an increased skin cancer risk, reaching, for some groups, several thousand-fold compared to the general population. Here, we analyze 38 skin cancer genomes from five XP groups. We find that the activity of NER determines heterogeneity of the mutation rates across skin cancer genomes and that transcription-coupled NER extends beyond the gene boundaries reducing the intergenic mutation rate. Mutational profile in XP-V tumors and experiments with POLH knockout cell line reveal the role of polymerase η in the error-free bypass of (i) rare TpG and TpA DNA lesions, (ii) 3' nucleotides in pyrimidine dimers, and (iii) TpT photodimers. Our study unravels the genetic basis of skin cancer risk in XP and provides insights into the mechanisms reducing UV-induced mutagenesis in the general population.

Whole Exome Sequencing of a Patient with a Milder Phenotype of Xeroderma Pigmentosum Group C.

A 17-year-old female Korean patient (XP115KO) was previously diagnosed with Xeroderma pigmentosum group C (XPC) by Direct Sanger sequencing, which revealed a homozygous nonsense mutation in the XPC gene (rs121965088: c.1735C > T, p.Arg579Ter). While rs121965088 is associated with a poor prognosis, our patient presented with a milder phenotype. Hence, we conducted whole-exome sequencing in the patient and her family members to detect coexisting mutations that may have resulted in a milder phenotype of rs121965088 through genetic interaction. Materials and Methods: the whole-exome sequencing analysis of samples obtained from the patient and her family members (father, mother, and brother) was performed. To identify the underlying genetic cause of XPC, the extracted DNA was analyzed using Agilent's SureSelect XT Human All Exon v5. The functional effects of the resultant variants were predicted using the SNPinfo web server, and structural changes in the XPC protein using the 3D protein modeling program SWISS-MODEL. Results: Eight biallelic variants, homozygous in the patient and heterozygous in her parents, were detected. Four were found in the XPC gene: one nonsense variant (rs121965088: c.1735C > T, p.Arg579Ter) and three silent variants (rs2227998: c.2061G > A, p. Arg687Arg; rs2279017: c.2251-6A > C, intron; rs2607775: c.-27G > C, 5'UTR). The remaining four variants were found in non-XP genes, including one frameshift variant [rs72452004 of olfactory receptor family 2 subfamily T member 35 (OR2T35)], three missense variants [rs202089462 of ALF transcription elongation factor 3 (AFF3), rs138027161 of TCR gamma alternate reading frame protein (TARP), and rs3750575 of annexin A7 (ANXA7)]. Conclusions: potential candidates for genetic interactions with rs121965088 were found. The rs2279017 and rs2607775 of XPC involved mutations in the intron region, which affected RNA splicing and protein translation. The genetic variants of AFF3, TARP, and ANXA7 are all frameshift or missense mutations, inevitably disturbing the translation and function of the resultant proteins. Further research on their functions in DNA repair pathways may reveal undiscovered cellular relationships within xeroderma pigmentosum.

Clinical trial on the efficacy and safety of NPC-15 for patients with xeroderma pigmentosum exaggerated sunburn reaction type: XP-1 study protocol for a multicentre, double-blinded, placebo-controlled, two-group crossover study followed by a long-term open study in Japan.

INTRODUCTION: Xeroderma pigmentosum (XP) is a rare intractable disease without a fundamental treatment, presenting with severe photosensitivity, freckle-like pigmented and depigmented maculae and numerous skin cancers before the age of 10 years without strict sun protection. About 70% of the patients exhibit extremely severe sunburn reactions and most of them develop neurological symptoms, including sensorineural hearing impairment and progressive peripheral and central nervous disorders beginning from childhood ages. In the preclinical study, we found that N-acetyl-5-methoxytryptamine was effective in suppressing skin tumour development in addition to improvement of auditory brainstem response in chronically ultraviolet-irradiated XP-A model mice. METHODS AND ANALYSIS: On the bases of the preclinical study, we conduct a clinical trial on the efficacy of NPC-15 for patients with XP with exaggerated sunburn reaction type by a multicentre, double-blinded placebo-controlled, two-group crossover study followed by a 52 weeks open study. ETHICS AND DISSEMINATION: Ethics approval is overseen by the Kobe University Institutional Review Board and Osaka Medical and Pharmaceutical University Institutional Review Board, and the study is conducted in accordance with the approved protocol. All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The data sets generated during the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: jRCTs051210181.

Cell migration is impaired in XPA-deficient cells.

Xeroderma pigmentosum (XP) is a hereditary disorder characterized by photosensitivity, predisposition to skin cancers, and neurological abnormalities including microcephaly and progressive neurodegeneration. A lack of nucleotide excision repair (NER) in patients with XP can cause hypersensitivity to the sun, leading to skin cancer, whereas the etiology of the neuronal symptoms of XP remains ambiguous. There are various neurological disorders that perturb neuronal migration, causing mislocalization and disorganization of the cortical lamination. Here, we investigated the role of the XP group-A (Xpa) gene in directed cell migration. First, we adopted an in utero electroporation method to transduce shRNA vectors into the murine embryonic cerebral cortex for the in vivo knockdown of Xpa. Xpa-knockdown neurons in the embryonic cerebral cortex showed abnormal cell migration, cell cycle exit, and differentiation. The genotype-phenotype relationship between the lack of XPA and cell migration abnormalities was confirmed using both a scratch assay and time-lapse microscopy in XP-A patient-derived fibroblasts. Unlike healthy cells, these cells showed impairment in overall mobility and the direction of motility. Therefore, abnormal cell migration may explain neural tissue abnormalities in patients with XP-A.

A case of Cockayne syndrome with unusually mild clinical manifestations.

We present a mild case of Cockayne syndrome that was referred to us with an extreme sunburn at the age of 3. In early teens, although her cutaneous symptoms alleviated without any medications, she developed tremor and dysarthria. Neurological examination and brain imaging suggested demyelination disorders. The patient's cells indicated a reduced recovery of RNA synthesis, which was partially restored by the introduction of CSB (Cockayne Syndrome B)-cDNA. In addition, her cells indicated a substantially reduced level of CSB protein. Despite the insidious progression of neurological symptoms, she gave birth to a child. Such mild cases of Cockayne syndrome may be misdiagnosed.

Biological Impact of Shorter Wavelength Ultraviolet Radiation-C†.

Life on earth has constantly coped with the impact of solar radiation, especially solar ultraviolet radiation (solar UV). Various biological mechanisms protect us from solar UV. New devices emitting shorter wavelengths UV-C, i.e. <254 nm emitted by conventional UV germicidal lamps, have emerged. These shorter wavelength UV-C emitting devices are useful for various purposes, including microorganism inactivation. However, as solar UV-C does not reach the earth surface, biological impacts of UV-C has been studied using 254 nm germicidal lamps, and those using shorter wavelength UV-C is rarely known. To balance the utility and risk of UV-C, the biological effect of these new UV-C emitting devices must be investigated. In addition, our knowledge of biological impacts of the wavelength-dependent entire UV (100-400 nm) must be enhanced. In this review, we briefly summarize the biological impacts of shorter wavelength UV-C. Mechanisms of UV-C-induced cellular damage and factors affecting the microorganism inactivation efficiency of UV-C have been discussed. In addition, we theoretically estimate the probable photocarcinogenic action spectrum of shorter wavelength UV-C. We propose that increasing the knowledge on UV-C will facilitate the adoption of shorter wavelength UV-C emitting new devices in an optimal and appropriate manner.

S-Palmitoylation of Tyrosinase at Cysteine500 Regulates Melanogenesis.

Palmitoylation is a lipid modification involving the attachment of palmitic acid to a cysteine residue, thereby affecting protein function. We investigated the effect of palmitoylation of tyrosinase, the rate-limiting enzyme in melanin synthesis, using a human three-dimensional skin model system and melanocyte culture. The palmitoylation inhibitor, 2-bromopalmitate, increased melanin content and tyrosinase protein levels in melanogenic cells by suppressing tyrosinase degradation. The palmitoylation site was Cysteine500 in the C-terminal cytoplasmic tail of tyrosinase. The nonpalmitoylatable mutant, tyrosinase (C500A), was slowly degraded and less ubiquitinated than wild-type tyrosinase. Screening for the Asp-His-His-Cys (DHHC) family of proteins for tyrosinase palmitoylation suggested that DHHC2, 3, 7, and 15 are involved in tyrosinase palmitoylation. Knockdown of DHHC2, 3, or 15 increased tyrosinase protein levels and melanin content. Determination of their subcellular localization in primary melanocytes revealed that DHHC2, 3, and 15 were localized in the endoplasmic reticulum, Golgi apparatus, and/or melanosomes, whereas only DHHC2 was localized in the melanosomes. Immunoprecipitation showed that DHHC2 and DHHC3 predominantly bind to mature and immature tyrosinase, respectively. Taken together, tyrosinase palmitoylation at Cysteine500 by DHHC2, 3, and/or 15, especially DHHC2 in trans-Golgi apparatus and melanosomes and DHHC3 in the endoplasmic reticulum and cis-Golgi apparatus, regulate melanogenesis by modulating tyrosinase protein levels.

Case report: Severe non-pigmenting fixed drug eruption showing general symptoms caused by chondroitin sulfate sodium.

Non-pigmenting fixed drug eruption (NPFDE) is a subtype of fixed drug eruption (FDE) in which repeated eruptions occur at the same site. Clinically, NPFDE disappears without pigmentation changes; however, it sometimes causes fever or arthralgia. Its histopathological characteristics reportedly include infiltrations of CD8-positive T cells with a paucity of melanocytes as compared to FDE. We present the first case of severe NPFDE exhibiting general symptoms caused by chondroitin sulfate sodium. The patient was a 44-year-old man. Intravenous injection of chondroitin sulfate sodium caused erythema in the affected area. A histopathological examination of the biopsy tissue revealed infiltration of CD3-positive lymphocytes (both CD4-positive and CD8-positive lymphocytes) into the epidermis, minimal liquefaction degeneration in the basal layer of the epidermis, and few dermal melanophages, which may be responsible for non-pigmentation.

Cross-sectional study of cholinergic urticaria subtypes and bronchial hyperresponsiveness.

Cholinergic urticaria (CholU) is classified into several subtypes: (1) conventional sweat allergy-type CholU (conventional SAT-CholU), (2) CholU with palpebral angioedema (CholU-PA), 3) CholU with acquired anhidrosis and/or hypohidrosis (CholU-Anhd); 1) and 2) include SAT based on pathogenesis. There have been no studies on differences in the prevalence of bronchial asthma among the subtypes. We analyzed bronchial responsiveness using the methacholine dose indicator Dmin, respiratory symptoms, and exhaled nitric oxide (FeNO). Median log10 Dmin (interquartile range) of patients with conventional SAT-CholU (n = 11), CholU-PA (n = 11), and CholU-Anhd (n = 11) was 0.381 (- 0.829, 1.079), 0.717 (0.249, 0.787), and 1.318 (0.121, 1.699), respectively (p = 0.516). Respiratory symptoms were less frequently observed in CholU-Anhd than in conventional SAT-CholU or CholU-PA. FeNO of patients with conventional SAT-CholU, CholU-PA, and CholU-Anhd was 23 (18.5, 65.0), 39 (32.0, 59.5), and 25 (19.0, 33.0) ppb, respectively (p = 0.237). Nine% of conventional SAT-CholU patients and more than half of CholU-PA patients required treatment for asthma. Log Dmin tended to be lower in patients with SAT-CholU than in those with CholU-Anhd. CholU-PA might be associated with asthma.

Clinical Reasoning: A 60-Year-Old Man With Ataxia, Chorea, and Mild Cognitive Impairment.

We describe the case of a 60-year-old man with a 16-year history of gait imbalance and a 15-year history of forgetfulness. The insidious onset and slow progression suggested that the disease was degenerative. Neurologic examination revealed cerebellar ataxia, chorea, and mild cognitive impairment. Brain MRI revealed prominent cerebellum atrophy and diffuse atrophy in the brainstem and cerebrum. Based on neurologic manifestations, an additional patient interview and skin examination were conducted. Photosensitivity and freckling in exposed areas, which the patient did not recognize as disease symptoms, were observed. Based on acute and chronic photosensitivity and DNA repair test results, a final diagnosis was made. In patients with cerebellar ataxia, chorea, and cognitive dysfunction of unknown etiology, clinicians should explore patients' history of photosensitivity and carefully examine the skin.

Severe and delayed-onset acneiform eruptions as an adverse reaction to regorafenib.

Regorafenib is an oral multikinase inhibitor targeting several tyrosine kinase receptors including BRAF and epidermal growth factor receptor (EGFR) and is approved as a third-line treatment for metastatic gastrointestinal stromal tumor (GIST). While acneiform eruptions have been observed in patients receiving other BRAF and EGFR inhibitors, the commonly reported adverse reactions to regorafenib are fatigue and palmar-plantar erythrodysesthesia. Herein, we report, to the best of our knowledge, the first case who presented with a severe acneiform eruption 24 months after beginning regorafenib for the treatment of GIST. A 61-year-old woman developed GIST with multiple liver metastases, and she was treated with imatinib and sunitinib. However, these therapies were discontinued, and regorafenib was administered. Twenty-four months after beginning regorafenib, she developed an acneiform eruption on her back. Histopathologic analysis of a skin biopsy from the back revealed neutrophilic suppurative folliculitis. Therefore, she postponed regorafenib administration for 2 months and was treated with topical application of clindamycin phosphate hydrate, which was effective. Consistent with reported evidence that the presence of acneiform eruption and the efficacy of EGFR inhibitors are positively associated, regorafenib had good anticancer activity in our patient. Ultimately, we found that although regorafenib- associated skin toxicities usually appear within 1 month of treatment, patients potentially can present with delayed-onset acneiform eruptions even 24 months later.