Targeted gene panel analysis of Japanese patients with maturity-onset diabetes of the young-like diabetes mellitus: Roles of inactivating variants in the ABCC8 and insulin resistance genes.

AIMS/INTRODUCTION: To investigate the genetic background of Japanese patients with suspected maturity-onset diabetes of the young (MODY). MATERIALS AND METHODS: On 340 proband patients referred from across Japan, genomic variants were analyzed using a targeted multigene panel analysis combined with the multiplex ligation probe amplification (MLPA) analysis, mitochondrial m.3243A > G analysis and methylation-specific polymerase chain reaction of the imprinted 6q24 locus. Pathogenic/likely pathogenic variants were listed according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Additionally, variants with a population frequency <0.001 and Combined Annotation Dependent Depletion score >20 (CS >20) were listed as rare variants of uncertain significance-CS >20. RESULTS: A total of 157 pathogenic/likely pathogenic variants and 44 rare variants of uncertain significance-CS >20 were identified. In the pathogenic/likely pathogenic variants, alterations in the GCK gene were the most common (82, 52.2%) followed by HNF1A (29, 18.5%), HNF4A (13, 8.3%) and HNF1B (13, 8.3%). One patient was a 29.5% mosaic with a truncating INSR variant. In the rare variants of uncertain significance-CS >20, 20 (45.5%) were in the genes coding for the adenosine triphosphate-sensitive potassium channel, KCNJ11 or ABCC8, and four were in the genes of the insulin-signaling pathway, INSR and PIK3R1. Four variants in ABCC8 were previously reported in patients with congenital hyperinsulinism, suggesting the inactivating nature of these variants, and at least two of our patients had a history of congenital hyperinsulinism evolving into diabetes. In two patients with INSR or PIK3R1 variants, insulin resistance was evident at diagnosis. CONCLUSIONS: Causative genomic variants could be identified in at least 46.2% of clinically suspected MODY patients. ABCC8-MODY with inactivating variants could represent a distinct category of MODY. Genes of insulin resistance should be included in the sequencing panel for MODY.

[A Study of Sustainable End-of-Life Care in a Depopulating Society].

In facing a society characterized by a decreasing population, I think that sustainability of end-of-life medical care needs to prevent death in isolation, offer optimal allocation of medical care providers, and ensure the centralization of urban functions. How do leading practitioners who actually practice advanced medical care view my hypotheses ?My survey showed that my hypotheses turned out to be unsupported, but on the other hand, it also indicated the concerns and resolve of leading medical practitioners and their views on venturing into unknown domains.

[A Discussion of Involvement of Pharmacists in Home Medical Care in Foreign Countries and International Comparison of Medical Care System].

In an aging society, the sustainability of the public medical system is the most important factor. I surveyed leading cases in Japan, as well as corresponding cases overseas. I also conducted interviews in Britain, North America, and Europe, and these indicated the current trends and issues. The UK has a universal insurance system and, facing a declining birthrate and an aging population, they have adopted a policy of immigration, which has various problems. However, the GP system is highly regarded by the OECD. Denmark has also introduced a similar medical system and they are implementing social security policies based on ICT. Sweden managed to cover an extreme shortage of pharmacists by adopting several policies. The U. S., under the pressures of their current health insurance system, is now shifting to preventive and early intervention by cultivating public consciousness in this area. In comparison, there is no country like Japan, which has a serious problem of an increasingly aging population, and where pharmacists play important roles in home care. However, leading overseas cases are worth learning from.

[Significance of the Pharmacist in Inter-Professional Cooperation].

Two points are considered effective in preventing the exhaustion of the various medical professions involved in home care as we look at the challenges to be confronted in 2025: increasing participation parameters and streamlining business operations. In order to increase participation parameters, the number of participating professions must be increased and the base of existing professional staff must be broadened.In order to streamline business operations, it has been determined that it is important to better understand the functions of each profession and accurately and speedily promote the contents of business operations with staffing that places the right people in the right job.The results of this verification concluded that it is efficient for various professions to each take on roles in their specialties in order to support home care in the community, and to train young people in line with the concept of the Learning Pyramid, with each profession incorporating better functional differentiation and a mentor system, in order to broaden the base of staff.The results also concluded that it is effective to promote information sharing among areas, job types, and related professions.

Pediatric myeloid/NK cell precursor lymphoma/leukemia expressing T/NK immunophenotype markers.

Myeloid/NK cell precursor lymphoma/leukemia has been suggested to be of precursor NK origin. We report a 1-year-old boy with myeloid/NK cell precursor lymphoma/leukemia who presented with a skin nodule. Biopsy of the skin nodule specimen revealed CD45(+), CD56(+), myeloid antigen(+), CD7(-), CD3(-), CD19(-), CD34(-), CD4(-) by flow cytometry and myeloperoxidase (MPO)(+), TdT(+), cytoplasmic CD3(+) by immunohistochemistry. He received acute myeloid leukemia-oriented combination chemotherapy. Although his skin nodule disappeared, regrowth was observed; a biopsy was performed again, showing that the immunophenotype was CD56(+), myeloid antigen(+), HLA-DR(+), MPO(-), CD3(+) and TCRgammadelta(+). Being refractory to chemotherapy, he underwent stem cell transplantation from his father. However, he relapsed again and died from septic shock. Although myeloid/NK cell precursor acute leukemia is characterized by CD7(+), CD56(+), CD3(-), CD34(+) and myeloid antigen(+) phenotype, the blast cells of our patients lacked CD34 and CD7 expression while expressing myeloid antigens. Furthermore, CD94 1A transcripts were predominantly expressed rather than CD94 1B, implying their origin in immature NK cells. After acute myeloid leukemia-oriented combination chemotherapy, his blasts acquired stable CD3 expression and TCRgammadelta rearrangement at recurrence. The blast cells possessed features overlapping both myeloid/NK precursor acute leukemia and blastic NK/precursor acute lymphoma/leukemia. These observations suggest that two subclones originated from common precursors.