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To investigate the prevalence and background of children with medical complexity (CMC) and its secular trend in Japan.CMC were defined as patients under the age of 20 years requiring medical care and devices. The patients were enrolled using the national health insurance claims data of three hospitals and two rehabilitation centers in Tottori Prefecture. The study period was divided into three periods: Period 1, 2007-2010; Period 2, 2011-2014; and Period 3, 2015-2018.A total of 378 CMC were enrolled. The prevalence of CMC was 1.88 per 1000 population among subjects aged20 years in 2018, and it increased by approximately 1.9 times during the study period. The number of CMC who presented with severe motor and intellectual disabilities did not change from Period 1 to Period 3. Meanwhile, the number of CMC who had relatively preserved motor and intellectual abilities increased from 58 to 98. The proportion of CMC who required respiratory management and oxygen therapy increased by 1.3 and 1.8 times, respectively. By contrast, the proportion of CMC who need tube feeding decreased significantly between periods 1 and 3 (P 0.05).The prevalence of CMC increased almost twice during the 12-year study period; however, the increase in the number of patients with relatively preserved motor and intellectual abilities was pronounced. This study showed that the need for medical care and devices differed based on the underlying disorders and severity of CMC; therefore, individualized medical, welfare, and administrative services and education about the various types of CMC must be provided.

We describe a Japanese brother and sister with Martsolf syndrome. They had short stature, severe mental retardation, cataract, hypogonadism, craniofacial dysmorphism, and bone and joint symptoms including scoliosis, lax finger joints, and talipes valgus. Previously undescribed findings included proximal femoral epiphyseal dysplasia reminiscent of Legg-Calve-Perthes disease in both patients, and Klippel-Feil malformation and osteopathia striata in one patient. Brain MRI showed mild frontal and temporal lobe atrophy, and mild ventricular enlargement. Severe GH deficiency was demonstrated after insulin tolerance and glucagon/propranolol tolerance tests. No responses to serum LH and FSH after a gonadotropin-releasing hormone (GnRH) test suggested secondary hypogonadism, that is, hypogonadotropic hypogonadism, due to hypothalamus-pituitary axis insufficiency in both patients.

高Ca尿症を合併し尿路結石を反復した偽性低アルドステロン症II型の1例を経験した。症例は14歳女性。5歳，14歳時に尿路結石をきたした。平成7年7月高血圧，高K血症，高Cl性代謝性アシドーシスを指摘され，精査により，本症と診断された。また高Ca尿症を合併しており，尿路結石との関連が疑われた。サイアザイド系利尿剤投与により，代謝性アシドーシス，高K血症は改善した。高Ca尿症と反復した尿路結石を合併した症例は過去に報告がなく貴重な症例と考えられるので報告する。

非IgA型びまん性メサンギウム増殖を伴うネフローゼ症候群の4例を経験し，臨床病理像とステロイド治療に対する反応性を検討した。全例幼児期発症で，全例血尿，変形赤血球，赤血球円柱，硝子円柱を，2例に明らかな肉眼的血尿を認めた。4例中3例はメサンギウム細胞の増殖が中等度以上であったがステロイドに対し良好な反応性を示した。残りの1例は，メサンギウム細胞の増殖の程度が軽度にもかかわらずステロイドに対する反応性は不良であり，プレドニン投与4週の時点で寛解が得られないためエンドキサンを併用した。全例寛解後のプレドニン減量，あるいは中止によって蛋白尿の増悪やネフローゼの再発を認めなかった。非IgA型メサンギウム増殖を伴うネフローゼ症候群に対するステロイドに対する反応性は必ずしも肉眼的血尿やメサンギウム増殖の程度には関係せず，免疫抑制剤の併用を必要とする症例は存在するもののおおむね良好と思われた。

特発性ネフローゼ症候群 (以下，ネ症) の中には緩徐な経過でネ症に至る症例や病初期にはネ症の診断基準を満たすが，経過観察のみで自然に軽快する非典型的な経過をとる症例がみられる。鳥取県では平成3年より鳥取県小児腎疾患患者登録を実施しており，平成3年～5年の3年間にネ症は25例登録された。その中に，非典型ネ症は4例含まれていた。ステロイド剤 (以下，ス剤) を3日間服用しただけで軽快した症例が1例，緩徐な経過の症例が1例，いったん自然に尿蛋白が消失した後に再燃した症例が2例であった。全例ス剤に感受性があり，1例のみ再発したが，すべて経過は順調である。非典型的ネ症は言い換えれば軽症のネ症と考えられ，ス剤長期投与の副作用を考慮すればネ症診断直後より早期にス剤を開始すべきではなく，一定期間の観察期間をおき，ス剤を必要としない症例を発見する努力が必要と考えられる。

Immunoglobulin A (IgA) nephropathy progresses without apparent signs. The only available means of knowing the precise incidence of this disease in children is to analyze data from the school urinary screening system. Students between 6 and 15 years old with IgA nephropathy detected by school urinary screening from 1983 to 1999 in Yonago City, Japan, were examined. In addition, two hospitals with pediatric care units administered a questionnaire and patients with pediatric IgA nephropathy detected by means other than the school urinary screening program were recruited. Of 270,902 children examined by the school urinary screening system, 29 demonstrated suspected chronic nephritis on the basis of abnormal urinalysis and underwent renal biopsy procedures. Among the 29 children, 14 cases of IgA nephropathy were confirmed. During the same period, of the children examined by means other than the school screening program, 20 demonstrated suspected renal disease and underwent renal biopsies. Among these 20 children, 6 cases of IgA nephropathy were diagnosed. In all, 20 cases of pediatric IgA nephropathy were detected over the past 17 years. The incidence rate of pediatric IgA nephropathy was 4.5 cases/year per 100,000 children under 15 years. The incidence of pediatric IgA nephropathy is higher than that of idiopathic nephrotic syndrome.

A single intravenous injection of adriamycin (ADR) results in marked proteinuria and glomerular morphological changes that are similar to minimal-change disease in humans. We examined the effect of superoxide dismutase (SOD) on ADR-induced proteinuria. ADR in a dose of 7.5 mg/kg body weight significantly increased urinary protein by day 14; proteinuria rapidly increased thereafter. Concurrent administration of SOD (50 mg/kg) over 30 min prior to and 30 min following ADR injection markedly reduced proteinuria. Twenty-one days after the treatment with SOD, the amount of urinary protein was 108.6 +/- 43.1 mg/24 h in the experimental animals, while it was 221.6 +/- 102.9 mg/24 h in the ADR control group (p less than 0.05). There were also less severe glomerular morphologic changes in the SOD group versus ADR controls. The protective effects of SOD provide indirect evidence that oxygen free radicals are important mediators of ADR-induced proteinuria.

The serpin proteinase inhibitor 9 (PI-9) protects cells from serine protease granzyme B (GrB)/perforin-induced apoptosis and cytotoxicity, which is one of the important mechanisms in immunotherapy against tumors. However, the role of PI-9, which specifically inhibits GrB, in tumor immune escape is still under debate. Graft-versus-leukemia (GVL) effect and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) are the reciprocal aspects the established immunotherapeutic approach in hematopoietic malignancies, and are thought to be caused at least partly through apoptotic molecules GrB and perforin produced by the donor-derived cytotoxic T cells (CTLs) and natural killer cells. However, the role of PI-9 in GVHD and GVL is unknown. In this study we analyzed the role of PI-9 in GVHD and GVL after HSCT through expression of PI-9 relative to GrB and perforin. First, we analyzed the expressions of PI-9 and three apoptosis-related molecules GrB, perforin and Fas ligand by quantitative RT-PCR in leukocytes of five patients with chronic GVHD and six patients without obvious GVHD, from whom a written informed consent was obtained. The level of GrB expression was significantly increased in three of the patients with GVHD and two of them exhibited elevation both in GrB/perforin and FasL. One of the cases with GVHD showed an isolated high expression of FasL. However, significantly, the expression of PI-9 was prominently decreased in all of the cases with GVHD relative to those without GVHD. None of the patients with GVHD who were positive for any of the apoptosis-related molecules relapsed. Two of the six patients without GVHD showed an elevated expression of GrB and perforin. The one of these two patients suffered from relapsed leukemic infiltration into various tissues and the other from herpes zoster reactivation. Thus, the expression of these molecules was thought to reflect the recipients’ protective reactions against the intrinsic diseases. We observed a tendency that the ratio of GrB and PI-9 expressions were higher in patients with GVHD. Next, human CTL and natural killer cell (YT-N10) lines were analyzed to check the time course of PI-9 and GrB expressions in vitro. The CTL line had been established by immortalization of normal T cells with herpesvirus saimiri. The stimulation of these cells with phorbol 12-myristate 13 acetate (PMA) resulted in the prior peak of expression of PI-9 within 3 hours followed by the late expression of GrB peaked after 8 hours. The co-stimulation of these cells with IL-2 and IL-12 showed similar results. These results have indicated that the earlier synthesis of PI-9 might be important for escaping autolysis of immunocompetent cells and that the expressions of PI-9 and the apoptosis-related molecules may be controlled in a different manner. The low expression of PI-9 relative to GrB/perforin in patients who received HSCT may indicate that the balance between the expressions of PI-9 and GrB/perforin could monitor the activity of CTLs in patients with post-transplantation GVHD (and possibly with various other immune disorders) and predict the prognosis of these diseases. It could also be correlated with the GVL activity and hence predict the probability of relapses.