Overexpression of osteoactivin protects skeletal muscle from severe degeneration caused by long-term denervation in mice

We have previously shown that osteoactivin, a type I membrane glycoprotein expressed in myofibers, upregulated expression of matrix metalloprotease (MMP)-3 and MMP-9 in fibroblasts infiltrated denervated skeletal muscle in mice. To address whether osteoactivin-mediated increase in MMPs in skeletal muscle is useful for regeneration of denervated skeletal muscle, we subjected osteoactivin-transgenic mice to long-term denervation for 70 or 90 days. Long-term denervation caused severe degeneration of myofibers and fibrosis in skeletal muscle of wild-type mice. However, overexpression of osteoactivin protected skeletal muscle from such changes. Infiltration of fibroblast-like cells and collagen deposition were sustained at low levels after long-term denervation in skeletal muscle of osteoactivin-transgenic mice. This cytoprotective effect of osteoactivin was supported by the expression of regeneration/degeneration-associated genes in the gastrocnemius muscle during denervation. Denervation significantly upregulated the expression of anti-fibrotic genes, such as glypican-1 and decorin-1, in the gastrocnemius muscle of osteoactivin-transgenic mice, compared with wild-type mice. In contrast, overexpression of osteoactivin caused a significant reduction in denervation-induced expression of elongation factor 1A-1, an indicator for the persistence of degenerated cells. Our results suggest that an osteoactivin-mediated increase in MMPs in skeletal muscle might be useful for protecting injured muscle from fibrosis, leading to full regeneration after denervation

A case report on refractory ulcerative stomatitis associated with acute lymphoblastic leukemia

症例は難治性潰瘍性口内炎を契機に判明した急性リンパ性白血病の 1 例である．患者は 60 歳台，女性．下口唇に難治性潰瘍を認め紹介となった．血液検査にて汎血球減少を認めたため，血液疾患を疑った．骨髄検査にて，Ph 染色体陰性急性 B 細胞性リンパ性白血病と診断され，初診の 4 日後からステロイド療法が開始された．なお，下口唇生検の病理組織には明らかな白血病細胞の浸潤は認めなかった．口腔症状が白血病の初発症状となることがあり，これを主訴に受診した白血病患者を早期診断することは大変重要である．しかし，口腔病変の原因は多彩であり，さまざまな科が対応することが多く，各科が連携して診療にあたることが重要と考える．We herein report a case on refractory ulcerative stomatitis associated with acute lymphoblastic leukemia. The female patient in her 60s showed refractory ulcer on her lower lip ; and the referral was made. Since pancytopenia was found by a blood test, hematologic disease was suspected. Bone marrow examination presented the diagnosis of Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia. Based on this diagnosis, steroid therapy had been initiated from four days after the first visit. On biopsy of lower lip, the pathological tissue did not show obvious infiltration of leukemia cells. Since oral manifestation may sometimes be an initial symptom of leukemia, an early diagnosis on leukemia patient with main complaint of oral symptom is critically important. Oral lesions, however, have various causes, and it thus often requires care of various clinical department. Based on this, it is considered to be important to implement treatment with cooperation among each clinical department

Low-grade B-cell lymphoma presenting primarily in the bone marrow

Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma

A Proposal for Practical Diagnosis of Renal Hypouricemia : Evidenced from Genetic Studies of Nonfunctional Variants of URAT1/SLC22A12 among 30,685 Japanese Individuals

Background: Renal hypouricemia (RHUC) is characterized by a low serum uric acid (SUA) level and high fractional excretion of uric acid (FEUA). Further studies on FEUA in hypouricemic individuals are needed for a more accurate diagnosis of RHUC. Methods: In 30,685 Japanese health-examination participants, we genotyped the two most common nonfunctional variants of URAT1 (NFV-URAT1), W258X (rs121907892) and R90H (rs121907896), in 1040 hypouricemic individuals (SUA ≤ 3.0 mg/dL) and 2240 individuals with FEUA data. The effects of NFV-URAT1 on FEUA and SUA were also investigated using linear and multiple regression analyses. Results: Frequency of hypouricemic individuals (SUA ≤ 3.0 mg/dL) was 0.97% (male) and 6.94% (female) among 30,685 participants. High frequencies of those having at least one allele of NFV-URAT1 were observed in 1040 hypouricemic individuals. Furthermore, NFV-URAT1 significantly increased FEUA and decreased SUA, enabling FEUA and SUA levels to be estimated. Conversely, FEUA and SUA data of hypouricemic individuals are revealed to be useful to predict the number of NFV-URAT1. Conclusions: Our findings reveal that specific patterns of FEUA and SUA data assist with predicting the number of nonfunctional variants of causative genes for RHUC, and can also be useful for practical diagnosis of RHUC even before genetic tests

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10–8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci—TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A—are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients

Objectives Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years. Methods Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. Results In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. Conclusions Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia

チテキ ショウガイ ジ ニ オケル オンセツ チュウシュツ カダイ ト シリトリ カダイ ノ シュウトク ケイカ ニ カンスル ジレイ ケンキュウ

知的障害児を対象としたかな文字の読み書き学習では、音節抽出課題の指導が重要である。本研究では、音節抽出課題に先だって「かな文字カードにより単語を呈示した後、隠す」という手続きを利用して音節抽出の支援課題を設定し、その支援効果に関して検討することを目的とした。対象は、知的障害児2名（知的障害特別支援学校小学部4年生、語彙年齢4歳および7歳）とした。指導前において両対象児は、かな文字読みについてほぼ達成を示したが、音節抽出課題未達成を示した。7月から11月にかけての音節抽出指導の結果、対象児Ａ、Ｂ共に支援がない条件で、2、3音節単語の音節抽出課題の正答率が増加し、課題達成を確認できた。また、2から4音節単語の音節抽出が達成された段階の後に、しりとり課題の流暢な遂行が可能になった。これより音節抽出の支援課題の有効性を指摘できる

Duodenal Tube Feeding: An Alternative Approach for Effectively Promoting Weight Gain in Children with Gastroesophageal Reflux and Congenital Heart Disease

We tested whether duodenal tube feeding effectively improves the clinical symptoms and body weight gain in children with congenital heart disease (CHD) and gastroesophageal reflux (GER). In the retrospective analysis of 17 consecutive children with CHD who were treated with duodenal tube feeding for symptomatic GER, we found that clinical symptoms of persistent emesis or respiratory wheezing after feeding disappeared with duodenal tube feeding in all patients. Duodenal tube feeding facilitated a stable nutritional supply, resulting in marked improvement of weight gain from 6 to 21 g/day (). In a patient with trisomy 21 and persistent pulmonary hypertension after the closure of a ventricular septal defect, duodenal tube feeding ameliorated pulmonary hypertension, as evidenced by the improvement of the pressure gradient of tricuspid regurgitation from 77 to 41 mm Hg. In 14 of the 17 patients, the duodenal tube was successfully removed, with the spontaneous improvement of GER (median duration of duodenal tube feeding: 7 months). In conclusion, duodenal tube feeding improves the weight gain of infants with GER who need treatment for CHD-associated heart failure. It also allows for the improvement of pulmonary hypertension