Bilateral leg ulcers secondary to dystrophic calcinosis in a patient with rheumatoid arthritis

Calcinosis cutis can be classified into four subtypes : dystrophic, metastatic, idiopathic, and iatrogenic. Of these subtypes, dystrophic calcinosis (DC) is the most common, and is most frequently associated with connective tissue disease, particularly dermatomyositis and systemic sclerosis, and less commonly with systemic lupus erythematosus. However, DC associated with rheumatoid arthritis (RA) is extremely rare. In this paper, we present a Japanese woman with RA, who suffered from bilateral leg ulcers secondary to DC. To the best of our knowledge, only two cases of DC associated with RA have been reported to date. Similar to this case, the DC lesions were observed in the extremities, including the buttocks in the other two cases. Although the ulcers on her left leg were gradually epithelialized after one year, they may easily recur due to whitish abnormal underlying tissues, and a large ulcer remains on her right leg. Thus, it is important for physicians to identify DC when encountering non-healing leg ulcers associated with connective tissue diseases

コウレイシャ ノ ヒフ シュヨウ

Skin tumors in aged patients consist of benign tumors, precancerous lesions or carcinomas in situ, and skin cancers. We reviewed the clinical characteristic and treatment for each of them, and the molecular pathogenesis and protection for skin cancers. Exposure to ultra-violet (UV) radiation is the most common cause of skin cancers. In particular, UV-B radiation is mainly involved in the mutagenesis in the skin by two major photoproducts of a cyclobutane pyrimidine dimer and a (6-4) photoproduct. Recently, the ozone layer of the earth has been destroyed, and the increase in UV-B radiation on the earth surface can be expected in the next years. Therefore, we should add special attention to patients with skin cancers that are predicted to increase in number, and UV protection by sunscreens from childhood should be essential for the prevention against skin cancers in the 21st century

スイホウセイ シッカン

Some autoimmune bullous disorders are not uncommon among elderly people. We reaported 2 cases of autoimmune bullous disorders of elderly people with complications. Case 1 was a 64 year-old man with pemphigus vulgaris. He was complicated with acquired hemophilia A due to factor VIII inhibitor. Case 2 was an 80 year-old man with bullous pemphigoid. He had huge liver tumor. We should keep in mind that autoimmune bullous disorders in elderly persons may be complicated with other systemic disease, especially internal malignancy

ターゲットエクソーム解析および染色体マイクロアレイ解析を用いた母斑性基底細胞癌症候群の遺伝子診断

Background: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder mainly caused by heterozygous mutations of PTCH1. In addition to characteristic clinical features, detection of a mutation in causative genes is reliable for the diagnosis of NBCCS; however, no mutations have been identified in some patients using conventional methods. Objective: To improve the method for the molecular diagnosis of NBCCS. Methods: We performed targeted exome sequencing (TES) analysis using a multi-gene panel, including PTCH1, PTCH2, SUFU, and other sonic hedgehog signaling pathway-related genes, based on next-generation sequencing (NGS) technology in 8 cases in whom possible causative mutations were not detected by previously performed conventional analysis and 2 recent cases of NBCCS. Subsequent analysis of gross deletion within or around PTCH1 detected by TES was performed using chromosomal microarray (CMA). Results: Through TES analysis, specific single nucleotide variants or small indels of PTCH1 causing inferred amino acid changes were identified in 2 novel cases and 2 undiagnosed cases, whereas gross deletions within or around PTCH1, which are validated by CMA, were found in 3 undiagnosed cases. However, no mutations were detected even by TES in 3 cases. Among 3 cases with gross deletions of PTCH1, deletions containing the entire PTCH1 and additional neighboring genes were detected in 2 cases, one of which exhibited atypical clinical features, such as severe mental retardation, likely associated with genes located within the 4.3 Mb deleted region, especially. Conclusion: TES-based simultaneous evaluation of sequences and copy number status in all targeted coding exons by NGS is likely to be more useful for the molecular diagnosis of NBCCS than conventional methods. CMA is recommended as a subsequent analysis for validation and detailedmapping of deleted regions, which may explain the atypical clinical features of NBCCS cases

The Common Genetic Variant rs944289 on Chromosome 14q13.3 Associates with Risk of Both Malignant and Benign Thyroid Tumors in the Japanese Population

Background: Several single nucleotide polymorphisms (SNP) have been identified to be associated with the risk for differentiated thyroid cancer in populations of distinct ethnic background. The relationship of these genetic markers to a benign tumor of the thyroid, follicular adenoma (FA), is not well established. Methods: In a multicenter retrospective case-control study, five thyroid cancer-related SNPs - rs966513 (9q22.33, FOXE1), rs944289 (14q13.3, PTCSC3), rs2439302 (8p12, NRG1), rs1867277 (9q22.23, FOXE1), and rs6983267 (8q24, POU5F1B) - were genotyped in 959 cases of histologically verified FA, 535 papillary thyroid carcinomas (PTC), and 2766 population controls. Results: A significant association was found between FA and rs944289 (p=0.002; OR 1.176 [CI 1.064-1.316]), and suggestively with rs2439302 (p=0.033; OR 1.149 [CI 1.010-1.315]). In PTC, significant associations were confirmed for rs965513 (p=4.21E-04; OR 1.587 [CI 1.235-2.000]) and rs944289 (p=0.003; OR 1.234 [CI 1.075-1.408]), newly found for rs2439302 (p=0.003; OR 1.266 [CI 1.087-1.493]) and rs1867277 (p=1.17E-04; OR 1.492 [CI 1.235-1.818]), and was not replicated for rs6983267 (p=0.082; OR 1.136 [CI 0.980-1.316]) in this series. A significant correlation between rs2439302 genotype and relative expression of NRG1 was detected in normal and tumor counterparts of PTC (about 10% decrease per each risk allele). NRG1 expression also significantly correlated with that of PTCSC3. Conclusions: Association of rs944289, which was previously known to confer risk for thyroid cancer, with FA, and the correlation between PTCSC3 and NRG1 expression demonstrates that predisposing genetic factors are partly common for benign and malignant thyroid tumors, and imply broader roles of the pathways they underlie in thyroid tumorigenesis, not limited to carcinogenesis

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Pathogenic Role of Iron Deposition in Reticuloendothelial Cells during the Development of Chronic Hepatitis C

Aim. Chronic hepatitis C (CHepC) is frequently associated with hepatic iron overload, yet mechanisms underlying iron-induced liver injury have not been elucidated. We examined the significance of iron deposition in hepatocytes (HC) and reticuloendothelial cells (REC) in CHepC. Methods. Stainable hepatic iron was scored according to the iron deposition pattern in 373 patients. The levels of serum soluble TNF-α receptor (sTNFR2) and hepatic hepcidin mRNA and the efficacy of phlebotomy were compared among patients with different iron deposition patterns. Results. Serum transaminase levels and hepatic scores of stage, grade, and steatosis were higher in patients with REC iron staining than in those without. REC iron scores were independently associated with advanced stage. Serum sTNFR2 levels were significantly higher in patients with REC iron than in those without. REC iron scores were independently correlated with sTNFR2 levels. Compared with patients without stainable iron, those with iron overload had decreased ratios of hepcidin mRNA to serum ferritin. The efficacy of phlebotomy was greater in patients with REC iron than in those without REC iron. Conclusions. The present results show the importance of REC iron for the development of CHepC and the therapeutic effect of phlebotomy in CHepC

Clinical Outcomes of Digital Cholangioscopy-Guided Procedures for the Diagnosis of Biliary Strictures and Treatment of Difficult Bile Duct Stones: A Single-Center Large Cohort Study

Although Spy DS (SpyGlass DS Direct Visualization System) is considered to be useful for the diagnosis of bile duct strictures and the treatment of bile duct stones, there is limited data to date validating its efficacy. We hence retrospectively evaluated the clinical outcomes of the use of Spy DS in a large number of patients. A total of 183 patients who underwent Spy DS-guided procedures for indeterminate bile duct strictures (n = 93) and bile duct stones (n = 90) were analyzed retrospectively. All patients (93/93) with bile duct strictures successfully underwent visual observation, and 95.7% (89/93) of these patients successfully underwent direct biopsy. The sensitivity, specificity, and overall accuracy were 94.7%, 83.3%, and 90.3%, respectively, for visual impression; 80.9%, 100%, and 89.2%, respectively, for histopathological analysis of a direct biopsy; and 96.5%, 91.7%, and 94.6%, respectively, for visual impression combined with biopsy. Successful visualization of the stones was achieved in 98.9% (89/90) of the patients, and complete stone removal was achieved in 92.2% (83/90) of the patients, with an average of 3.3 procedures. The adverse events rate was 17.5% (32/183; cholangitis in 15 patients, fever the following day in 25, pancreatitis in 1, hemorrhage in 1, and gastrointestinal perforation in 1). No administration of antibiotics before the procedure was found to be a statistically significant risk factor for the development of fever after the procedure (p < 0.01). Spy DS-guided procedures are effective for the diagnosis and treatment of bile duct lesions and can be performed with a low risk of serious adverse events