Uncultured Autogenous Adipose-derived Regenerative Cells Promote Bone Formation During Distraction Osteogenesis in Rats

13301甲第4174号博士（医学）金沢大学博士論文本文Full 以下に掲載：Clinical Orthopaedics and Related Research® 472(12) pp.3798-3806 2014. springer. 共著者：Issei Nomura, Koji Watanabe, Hidenori Matsubara, Katsuhiro Hayashi, Naotoshi Sugimoto, Hiroyuki Tsuchiy

Salvage surgery with a tumor prosthesis for femoral condylar nonunion at the very advanced age of 90 years

We report an unusual case of multifragmentary condylar femoral nonunion with severe synovitis and bone loss in a 90-year-old woman. Initially, conservative treatment of the condylar femoral fracture was indicated because the fracture was severely comminuted and the patient was very advanced in age. The fracture failed to heal. Salvage surgery with a total knee tumor endoprosthetic replacement was performed. Four years postoperatively, the patient was walking without knee pain using a walker. We believe that the present results justify the use of a megaprosthesis in the treatment of benign conditions even in very elderly patients. © 2012

Correction of a Severe Poliomyelitic Equinocavovarus Foot Using an Adjustable External Fixation Frame

One-stage surgical correction of severe equinocavovarus deformity can result in complications ranging from skin necrosis to tibial nerve palsy. Fewer complications have been reported when severe deformities were treated by gradual correction using external frames such as the Ilizarov external fixator or the Taylor Spatial FrameTM. We describe a case of a 64-year-old female patient with severe poliomyelitic equinocavovarus whose deformity required her to ambulate using the dorsum of her right foot as a weightbearing surface. We treated the deformity with gradual correction using a Taylor Spatial FrameTM, followed by ankle arthrodesis. At the most recent postoperative evaluation, 20 months after the initial surgery, the patient was pain free and ambulating on the sole of her right foot. © 2014 American College of Foot and Ankle Surgeons

Over 10-year follow-up of functional outcome in patients with bone tumors reconstructed using distraction osteogenesis

Background: The aim of this study was to investigate the long-term functional capabilities of patients who underwent bone distraction for the treatment of bone defects caused by bone tumor excision. Methods: Bone distraction was indicated for patients with stage IIB malignant bone tumors when chemotherapy was judged to be effective and an epiphysis could be preserved or for patients with low-grade or aggressive benign bone tumors. Twenty-two patients who underwent reconstruction with bone distraction and were followed up for at least 10 years were retrospectively investigated. Patients included 8 males and 14 females, with a mean age of 25.3 years. Tumor types included seven osteosarcomas, two osteofibrous dysplasias, one Ewing\u27s sarcoma, five low-grade osteosarcomas, two adamantinomas, and five giant cell tumors. Chemotherapy was performed during bone distraction in 8 cases. Bone transport was used in 17 cases, while shortening distraction was used in 5 cases. Results: The mean distraction length was 8.1 cm, and the mean external fixation period was 301 days. The average Musculoskeletal Tumor Society score (used to measure functional outcome) was 91.5 % at mean follow-up of 202 months. Fourteen patients were able to play sports without any difficulty. Conclusions: Epiphyseal preservation and reconstruction by bone distraction require both time and effort, but can provide excellent long-term outcomes, resulting in a stable reconstruction that functionally restores the natural limb. © 2012 The Japanese Orthopaedic Association

Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis

肉芽腫形成に特異的な代謝経路の発見 --ペントースリン酸回路の制御による新規治療--. 京都大学プレスリリース. 2023-12-01.More than skin-deep: Kyoto researchers discover metabolic pathway specific to granuloma formation in patients. 京都大学プレスリリース. 2023-12-07.Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2–positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1, 6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis

Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction

心房細動の遺伝的基盤を解明 --大規模ゲノムデータによる病態解明と遺伝的リスクスコア構築--. 京都大学プレスリリース. 2023-01-20.Atrial fibrillation (AF) is a common cardiac arrhythmia resulting in increased risk of stroke. Despite highly heritable etiology, our understanding of the genetic architecture of AF remains incomplete. Here we performed a genome-wide association study in the Japanese population comprising 9, 826 cases among 150, 272 individuals and identified East Asian-specific rare variants associated with AF. A cross-ancestry meta-analysis of >1 million individuals, including 77, 690 cases, identified 35 new susceptibility loci. Transcriptome-wide association analysis identified IL6R as a putative causal gene, suggesting the involvement of immune responses. Integrative analysis with ChIP-seq data and functional assessment using human induced pluripotent stem cell-derived cardiomyocytes demonstrated ERRg as having a key role in the transcriptional regulation of AF-associated genes. A polygenic risk score derived from the cross-ancestry meta-analysis predicted increased risks of cardiovascular and stroke mortalities and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide new biological and clinical insights into AF genetics and suggest their potential for clinical applications

Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury

Background: The sympathetic nervous system regulates immune cell dynamics. However, the detailed role of sympathetic signaling in inflammatory diseases is still unclear because it varies according to the disease situation and responsible cell types. This study focused on identifying the functions of sympathetic signaling in macrophages in LPS-induced sepsis and renal ischemia-reperfusion injury (IRI).Methods: We performed RNA sequencing of mouse macrophage cell lines to identify the critical gene that mediates the anti-inflammatory effect of β2-adrenergic receptor (Adrb2) signaling. We also examined the effects of salbutamol (a selective Adrb2 agonist) in LPS-induced systemic inflammation and renal IRI. Macrophage-specific Adrb2 conditional knockout (cKO) mice and the adoptive transfer of salbutamol-treated macrophages were used to assess the involvement of macrophage Adrb2 signaling.Results: In vitro, activation of Adrb2 signaling in macrophages induced the expression of T cell Ig and mucin domain 3 (Tim3), which contributes to anti-inflammatory phenotypic alterations. In vivo, salbutamol administration blocked LPS-induced systemic inflammation and protected against renal IRI; this protection was mitigated in macrophage-specific Adrb2 cKO mice. The adoptive transfer of salbutamol-treated macrophages also protected against renal IRI. Single-cell RNA sequencing revealed that this protection was associated with the accumulation of Tim3-expressing macrophages in the renal tissue.Conclusions: The activation of Adrb2 signaling in macrophages induces anti-inflammatory phenotypic alterations partially via the induction of Tim3 expression, which blocks LPS-induced systemic inflammation and protects against renal IRI