Comprehensive analyses of the cysteine thiol oxidation of PKM2 reveal the effects of multiple oxidation on cellular oxidative stress response.

Redox regulation of proteins via cysteine residue oxidation is involved in the control of various cellular signal pathways. Pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis, is critical for the metabolic shift from glycolysis to the pentose phosphate pathway under oxidative stress in cancer cell growth. The PKM2 tetramer is required for optimal pyruvate kinase (PK) activity, whereas the inhibition of inter-subunit interaction of PKM2 induced by Cys358 oxidation has reduced PK activity. In the present study, we identified three oxidation-sensitive cysteine residues (Cys358, Cys423 and Cys424) responsible for four oxidation forms via the thiol oxidant diamide and/or hydrogen peroxide (H2O2). Possibly due to obstruction of the dimer-dimer interface, H2O2-induced sulfenylation (-SOH) and diamide-induced modification at Cys424 inhibited tetramer formation and PK activity. Cys423 is responsible for intermolecular disulfide bonds with heterologous proteins via diamide. Additionally, intramolecular polysulphide linkage (-Sn-, n ≧ 3) between Cys358 and an unidentified PKM2 Cys could be induced by diamide. We observed that cells expressing the oxidation-resistant PKM2 (PKM2C358,424A) produced more intracellular reactive oxygen species (ROS) and exhibited greater sensitivity to ROS-generating reagents and ROS-inducible anti-cancer drugs compared with cells expressing wild-type PKM2. These results highlight the possibility that PKM2 inhibition via Cys358 and Cys424 oxidation contributes to eliminating excess ROS and oxidative stress.

Symposium on disaster-related deaths after the Fukushima Daiichi Nuclear Power Plant accident.

Disaster deaths can be classified into direct and indirect deaths. Direct deaths are those caused by the direct physical effects of disasters, such as earthquakes, tsunamis, and radiation exposure. Indirect deaths are those caused by secondary health effects such as emergency evacuation, relocation, evacuation environment, disruption of health care delivery services, and psychosocial effects. In addition, in Japan, the term disaster-related deaths refers to indirect deaths in accordance with the disaster condolence payments system, which provides relief for bereaved families. On 11 March 2011, the Great East Japan Earthquake exposed several issues related to disaster-related deaths in Japan. Therefore, on 1 February 2022, a symposium on disaster-related deaths hosted by this study was held on the website. The symposium discussed the issues and challenges associated with disaster-related deaths for future disaster preparedness. The authors introduced the concept of 'shaking' at the symposium by defining 'shaking' as 'the repeated changes in the social and living environment that worsen health conditions, regardless of the disaster'. It was also pointed out that vulnerable populations are more likely to experience more pronounced health effects. This generalised concept of 'shaking' associated with disaster-related deaths suggests that it is important to anticipate disasters before they occur to take specific preventive measures, targeted at vulnerable populations. This study found that disaster-related deaths in Japan create several problems in terms of future radiation disaster preparedness and medical countermeasures. In the future, there will be a need to examine the relevance of the issues of disaster-related deaths identified as a result of this symposium for future radiation disaster preparedness.

A case of spontaneous autoimmune skin disease in a cynomolgus monkey (Macaca fascicularis).

Pemphigus is an autoimmune blistering disease characterized by lesions on the skin and mucous membranes. To date, no spontaneous cases of this disease have been reported in cynomolgus monkeys. This report describes the histopathological characteristics of spontaneous pemphigus in a cynomolgus monkey. Macroscopically, redness and scaling with pruritus were observed on the skin of the entire body. Histopathologically, the epidermis showed intercellular edema, and eosinophils and mononuclear cells infiltrated the epidermis. There was no obvious acantholysis in the epidermis. The perivascular area showed edema, and eosinophils and mononuclear cells infiltrated the vessels in the dermis. Immunohistochemically, the intercellular area in the epidermis was positive for Immunoglobulin G and Complement component 3. Serologically, anti-desmoglein 1 and desmoglein 3 antibodies in the serum were negative. From these findings, this case was diagnosed as an autoimmune skin disease, suspected to be pemphigus, and concluded as lesions being similar to those in human "pemphigus herpetiformis".

Efficacy and safety of sclerotherapy with polidocanol in children with internal hemorrhoids.

BACKGROUND: Hemorrhoids are an extremely rare condition in children, and data on its incidence and treatment in the pediatric population remains scarce. We retrospectively reviewed children who underwent sclerotherapy for internal hemorrhoids, and analyzed patients' characteristics and outcomes. METHODS: A total of 14 pediatric patients who underwent sclerotherapy were included. Patients' ages and the required amount of polidocanol, depending on the grade of hemorrhoids, and the correlation between age and volume of sclerosant, were statistically analyzed. RESULTS: Patients had a male predominance with a ratio of 2.5:1 (grade 2:6 patients, grade 3:8 patients). Four children had underlying conditions including portal hypertension and Klippel-Trenaunay syndrome. Of the 14 patients, 43% had constipation requiring medication or enema. Only one minor complication, a perianal ulceration, was found to be associated with sclerotherapy. Patients with grade 3 hemorrhoids required a significantly larger amount of polidocanol than those with grade 2 hemorrhoids. Two patients with grade 3 hemorrhoids required a second session of treatment for recurrence. The success rate of sclerotherapy with polidocanol was 86%. CONCLUSIONS: Sclerotherapy with polidocanol is a safe, effective, and less invasive treatment option for internal hemorrhoids in children. Further studies are needed to investigate this treatment approach.

Japanese clinical practice guidelines for allied disorders of Hirschsprung's disease, 2017.

BACKGROUND: Despite the presence of ganglion cells in the rectum, some patients have symptoms similar to those of Hirschsprung's disease. A consensus has yet to be established regarding the terminology for these diseases. We defined this group of diseases as "allied disorders of Hirschsprung's disease" and compiled these guidelines to facilitate accurate clinician diagnosis and provide appropriate treatment strategies for each disease. METHODS: These guidelines were developed using the methodologies in the Medical Information Network Distribution System (MINDS). Of seven allied disorders, isolated hypoganglionosis; megacystis-microcolon-intestinal hypoperistalsis syndrome; and chronic idiopathic intestinal pseudo-obstruction were selected as targets of clinical questions (CQ). In a comprehensive search of the Japanese- and English-language articles in PubMed and Ichu-Shi Web, 836 pieces of evidence related to the CQ were extracted from 288 articles; these pieces of evidence were summarized in an evidence table. RESULTS: We herein outline the newly established Japanese clinical practice guidelines for allied disorders of Hirschsprung's disease. Given that the target diseases are rare and intractable, most evidence was drawn from case reports and case series. In the CQ, the diagnosis, medication, nutritional support, surgical therapy, and prognosis for each disease are given. We emphasize the importance of full-thickness intestinal biopsy specimens for the histopathological evaluation of enteric ganglia. Considering the practicality of the guidelines, the recommendations for each CQ were created with protracted discussions among specialists. CONCLUSIONS: Clinical practice recommendations for allied disorders of Hirschprung's disease are given for each CQ, along with an assessment of the current evidence. We hope that the information will be helpful in daily practice and future studies.

Congenital hyperinsulinism treated by surgical resection of the hyperplastic lesion which had been preoperatively diagnosed by 18F-DOPA PET examination in Japan: a nationwide survey.

PURPOSE: Congenital hyperinsulinism is a rare disease, and the newly developed 18 fluoro-L-dihydroxyphenylalanine-positron emission tomography (18F-DOPA PET) examination can detect hyperplastic lesions. Our purpose was to report the results of a nationwide survey on surgical treatment of congenital hyperinsulinism in Japan. METHODS: A questionnaire was sent to the 159 accredited and affiliated training institutes certified as pediatric surgical institutes by the Japanese Association of Pediatric Surgeons, asking if they had encountered patients who underwent surgical treatment for congenital hyperinsulinism after 18F-DOPA PET examination from 2000 to 2017. Six institutes answered that they had treated such cases, and the total number of cases was 14. RESULTS: 18F-DOPA PET examination detected the focal lesion in 12 of the 14 cases. 18F-DOPA PET examination could accurately determine the site of the hyperplastic lesion in the pancreas in 11 (91.7%) of the 12 cases. All cases underwent surgical resection of the hyperplastic lesion at under 2 years of age. CONCLUSION: Surgical resection of a focal hyperplastic lesion in the pancreas was a safe and effective treatment if the hyperplastic lesion was a focal lesion. However, it is necessary to check the exact distribution of the lesion by intraoperative pathologic examination of frozen sections.

Resolution of liver disease in transient abnormal myelopoiesis with fish oil emulsion.

Neonates with Down syndrome are at risk of developing transient abnormal myelopoiesis (TAM), which is characterized by transient clonal myeloproliferation of the blast cells. TAM can resolve spontaneously, but some patients die at an early age due to organ failure. Liver fibrosis in TAM is a life-threatening condition, but treatment options have not yet been established. Here, we report on the case of an infant with TAM complicated by liver disease, whose hyperbilirubinemia was successfully ameliorated with omega-3 fatty acid (ω3FA) lipid emulsion. Timely ω3FA lipid emulsion may be a feasible treatment for liver disease in TAM before serious liver damage develops.

Anal Canal Carcinoma in a Child With Disorders of Sex Development.

Squamous cell carcinoma of the anal canal in children is rare. To date, the etiology and outcome of this condition have been not fully understood. Here, we report an 11-year-old child with anal canal cancer who had concomitant disorders of sex development. Radiotherapy followed by salvage surgery achieved disease-free survival of 3 years. Since overexpression of cell cycle regulatory protein p16 was immunohistochemically evident in tumor tissue, human papillomavirus infection was considered as a causative factor in the carcinogenesis.