Angiomyofibroblastoma of the vulva: a large pedunculated mass formation.

Angiomyofibroblastoma is a rare, usually small benign mesenchymal tumor that occurs in vulvar lesions of premenopausal women. A case of angiomyofibroblastoma that arose as a unique pedunculated and particularly large mass in the left vulva of a 48-year-old woman is presented herein. The patient had been aware of a gradually enlarged mass of 7 years duration without any other gynecological symptoms or signs. The maximum dimension of the tumor measured 11 cm. The resected tumor was well circumscribed with a bulging and glistening cut surface. Histological examination revealed an admixture of irregularly distributed hypercellular and hypocellular areas with spindled, plump spindled, or plasmacytoid stromal cells and abundant venular or capillary-sized vessels. Stromal cells characteristically cluster around delicate vessels within an edematous to collagenous matrix. In the present case, intralesional adipose tissue was present throughout the tumor. There was no significant nuclear atypia, and mitotic figures were very sparse. There was little stromal mucin throughout the tumor. Immunohistochemically, the stromal cells were characterized by strong reactivity for vimentin and CD34, with focal reactivity for desmin and alpha smooth muscle actin. Both estrogen and progesterone receptors were diffusely expressed in the stromal cells. These histological findings are consistent with angiomyofibroblastoma and support the hypothesis that angiomyofibroblastoma originates from perivascular stem cells with a capacity for myofibroblastic and fatty differentiation

豊田法による無カテーテル尿管皮膚痩術の成績

最近9年間に, 43症例67尿管に対し豊田法により無カテーテル尿管皮膚瘻術を行った.対象患者は男性30例, 女性13例, 平均年齢は61.4歳で, そのほとんどが膀胱, 直腸, 前立腺, 子宮の悪性腫瘍であった.両側性の場合は, 原則として左右尿管を一ヵ所に出す二連銃式尿管皮膚吻合術(double barrel ureterostomy)を行った.術前術後の腎盂像の推移をIVPで追求できた60尿管についてみると, 単側性の場合は20尿管中4尿管を除けばほぼ満足すべき結果を得ている.Double barrel法40尿管について, stoma側では中等度以上の腎盂拡張が20尿管中3尿管であったが, stomaと反対側では腎機能に影響が出ることが多く, 20尿管中3尿管に中等度の腎盂拡張が, また5尿管に高度の腎盂拡張または腎機能喪失があった.術後間もなく汎血管内凝固症候群で死亡した1例を除き, 結果的にはstoma付近が強い炎症性肉芽に覆われた1例と尿管の狭窄を生じた2例を除いた42例中39例(92.8%)をtubelessの尿管皮膚瘻としえたTubeless cutaneous ureterostomy by Toyoda's method was conducted in 67 ureters from 43 patients during the last 9 years. Subjects included 30 males and 13 females, with an average age of 61.4 years. Most of them were afflicted with malignant tumors in the bladder, rectum, prostate, or uterus. For bilateral ureterostomy, the double-barrel method was performed in which the stoma was made at the same site in both the right and left ureters. Among 60 ureters in which pre- and postoperative changes in the renal pelvis could be traced by IVP, satisfactory results were obtained in 16 of 20 ureters treated by unilateral surgery. Of the 40 ureters treated by the double-barrel method, moderate or severe pyeloectasis was observed in 3 of the 20 ureters on the side of the stoma, while moderate pyeloectasis was seen in 3 of 20 ureters of the side opposite the stoma, and severe pyeloectasis or loss of renal function was noted in 5. Thus, renal function on the side opposite the stoma was frequently influenced by the procedure. A patient who died of disseminated intravascular coagulation syndrome soon after the operation was excluded from analysis. Tubeless cutaneous ureterostomy could be conducted in 39 of 42 patients (92.8%), excluding one whose stoma and its periphery were covered with severe inflammatory granulation and 2 with ureteral constriction

The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus.

Because a rank-ordered recruitment of motor units occurs during isometric contraction of jaw-closing muscles, jaw-closing motoneurons (MNs) may be recruited in a manner dependent on their soma sizes or input resistances (IRs). In the dorsolateral part of the trigeminal motor nucleus (dl-TMN) in rats, MNs abundantly express TWIK (two-pore domain weak inwardly rectifying K channel)-related acid-sensitive-K(+) channel (TASK)-1 and TASK3 channels, which determine the IR and resting membrane potential. Here we examined how TASK channels are involved in IR-dependent activation/recruitment of MNs in the rat dl-TMN by using multiple methods. The real-time PCR study revealed that single large MNs (>35 μm) expressed TASK1 and TASK3 mRNAs more abundantly compared with single small MNs (15-20 μm). The immunohistochemistry revealed that TASK1 and TASK3 channels were complementarily distributed in somata and dendrites of MNs, respectively. The density of TASK1 channels seemed to increase with a decrease in soma diameter while there were inverse relationships between the soma size of MNs and IR, resting membrane potential, or spike threshold. Dual whole-cell recordings obtained from smaller and larger MNs revealed that the recruitment of MNs depends on their IRs in response to repetitive stimulation of the presumed Ia afferents. 8-Bromoguanosine-cGMP decreased IRs in small MNs, while it hardly changed those in large MNs, and subsequently decreased the difference in spike-onset latency between the smaller and larger MNs, causing a synchronous activation of MNs. These results suggest that TASK channels play critical roles in rank-ordered recruitment of MNs in the dl-TMN

A Method for Generating Program Specification from Source Program: Analysis by Transforming Program Structure and Argument Manipulation

本論文では，ソースプログラムからプログラム仕様を自動生成するための変形解析法を提案し，この手法を実装したシステムAPSG/I（Automatic Program Specification Generator I）について述べている．変形解析法では，Prologのリスト処理プログラムの類似性に注目し，類推の枠組みを利用することによって，典型的なリスト処理プログラムとその仕様から与えられたプログラムに対する仕様の生成を行っている．まず，プログラムが入力されると，あらかじめ定義した典型的なプログラムと比較して，①命令の有無や実行順序などで規定される構造，②データの受け渡しなどで規定される引数の組合せ，の2点について差異を求める．次に，求めた差異によって，あらかじめ定義したプログラム仕様を変換し，入力されたプログラムの仕様を生成する．変形解析法で生成される仕様は，①プログラム仕様と，仕様を変換する規則を自然語で定義しているため自然言語文になる，②形式が統一され，かつ細部に関する情報についても十分に含んでいるなどの特徴を有している．本研究の一部は，文部省科学研究費（重点領域研(2)02249204）による

Undifferentiated Sarcoma of the Salivary Gland in a Mongolian Gerbil (Meriones unguiculatus)

A subcutaneous mass was found in the lower ventral neck region of a 55-week-old male Mongolian gerbil (Meriones unguiculatus). Histopathologically, the mass involved salivary glands and featured diffuse proliferation of pleomorphic neoplastic cells with large necrotic foci. The lesion was well demarcated from the surrounding tissue, although invasive growth to fibrous septa was occasionally observed. The neoplastic cells were mainly arranged in irregular sheets with severe cellular atypia, round to oval nuclei and varying amounts of eosinophilic cytoplasm. Mitotic figures and multinucleated giant cells were frequent. Immunohistochemical analysis revealed that the neoplastic cells were strongly positive for vimentin and S-100 and negative for NSE, cytokeratin, α-SMA, c-kit, factor VIII, CD34, α-1-antitrypsin, lysozyme and MSR-A. Based on the results, the mass was diagnosed as an undifferentiated sarcoma of the salivary gland. To the best of our knowledge, this is the first report of such a tumor in Mongolian gerbils

Regulation of NR4A nuclear receptors by p38

In Drosophila, the melanization reaction is an important defense mechanism against injury and invasion of microorganisms. Drosophila tyrosine hydroxylase (TH, also known as Pale) and dopa decarboxylase (Ddc), key enzymes in the dopamine synthesis pathway, underlie the melanin synthesis by providing the melanin precursors dopa and dopamine, respectively. It has been shown that expression of Drosophila TH and Ddc is induced in various physiological and pathological conditions, including bacterial challenge; however, the mechanism involved has not been fully elucidated. Here, we show that ectopic activation of p38 MAPK induces TH and Ddc expression, leading to upregulation of melanization in the Drosophila cuticle. This p38-dependent melanization was attenuated by knockdown of TH and Ddc, as well as by that of Drosophila HR38, a member of the NR4A family of nuclear receptors. In mammalian cells, p38 phosphorylated mammalian NR4As and Drosophila HR38 and potentiated these NR4As to transactivate a promoter containing NR4A-binding elements, with this transactivation being, at least in part, dependent on the phosphorylation. This suggests an evolutionarily conserved role for p38 MAPKs in the regulation of NR4As. Thus, p38-regulated gene induction through NR4As appears to function in the dopamine synthesis pathway and may be involved in immune and stress responses

Super-responder to pirfenidone therapy in IPF

Background : Pirfenidone (PFD), an anti-fibrosis drug for idiopathic pulmonary fibrosis (IPF), suppresses disease progression and delays decline of forced vital capacity. However, this drug rarely makes marked improvement of pulmonary function, chest high-resolution computed tomography (HRCT) findings and hypoxia. Case presentation : A 59 year-old-man, who was a former smoker and had a history of alcoholic liver cirrhosis, developed exertional dyspnea and was referred to our hospital. HRCT showed honeycomb changes with surrounding ground-glass opacity (GGO) in a predominantly basal and subpleural distribution. He was diagnosed with IPF and the treatment with PFD was started. At 16 months after the start of treatment, the predicted forced vital capacity value markedly improved from 82.9% to 98.6%. His resting-state partial pressure of arterial oxygen while breathing room air increased from a minimum of 54.7 mmHg (at 2 months treatment) to 72.5 mmHg. The GGO observed at diagnosis disappeared in HRCT. But after 32 months of treatment, his general condition got worse gradually, and he died from chronic progression of IPF after 48 months of treatment. Conclusion : Our case suggests that a complication of chronic liver disease and the existence of GGO may be characteristics of super-responder to PFD treatment for IPF patients

Gradient-based parameter optimization method to determine membrane ionic current composition in human induced pluripotent stem cell-derived cardiomyocytes

Premature cardiac myocytes derived from human induced pluripotent stem cells (hiPSC-CMs) show heterogeneous action potentials (APs), probably due to different expression patterns of membrane ionic currents. We developed a method for determining expression patterns of functional channels in terms of whole-cell ionic conductance (Gx) using individual spontaneous AP configurations. It has been suggested that apparently identical AP configurations can be obtained using different sets of ionic currents in mathematical models of cardiac membrane excitation. If so, the inverse problem of Gx estimation might not be solved. We computationally tested the feasibility of the gradient-based optimization method. For a realistic examination, conventional 'cell-specific models' were prepared by superimposing the model output of AP on each experimental AP recorded by conventional manual adjustment of Gxs of the baseline model. Gxs of 4–6 major ionic currents of the 'cell-specific models' were randomized within a range of ± 5–15% and used as an initial parameter set for the gradient-based automatic Gxs recovery by decreasing the mean square error (MSE) between the target and model output. Plotting all data points of the MSE–Gx relationship during optimization revealed progressive convergence of the randomized population of Gxs to the original value of the cell-specific model with decreasing MSE. The absence of any other local minimum in the global search space was confirmed by mapping the MSE by randomizing Gxs over a range of 0.1–10 times the control. No additional local minimum MSE was obvious in the whole parameter space, in addition to the global minimum of MSE at the default model parameter

CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs

サイクリン依存性キナーゼCDK8/19阻害はヒトiPS細胞からの膵島様細胞への分化誘導において重要な役割を果たす. 京都大学プレスリリース. 2023-02-27.A safer method of generating pancreatic islet-like cells from human iPS cells by inhibiting cyclin-dependent kinase CDK8/19. 京都大学プレスリリース. 2023-03-08.[Background] Transplantation of differentiated cells from human-induced pluripotent stem cells (hiPSCs) holds great promise for clinical treatments. Eliminating the risk factor of malignant cell transformation is essential for ensuring the safety of such cells. This study was aimed at assessing and mitigating mutagenicity that may arise during the cell culture process in the protocol of pancreatic islet cell (iPIC) differentiation from hiPSCs. [Methods] We evaluated the mutagenicity of differentiation factors used for hiPSC-derived pancreatic islet-like cells (iPICs). We employed Ames mutagenicity assay, flow cytometry analysis, immunostaining, time-resolved fluorescence resonance energy transfer-based (TR-FRET) cell-free dose–response assays, single-cell RNA-sequencing and in vivo efficacy study. [Results] We observed a mutagenic effect of activin receptor-like kinase 5 inhibitor II (ALK5iII). ALK5iII is a widely used β-cell inducer but no other tested ALK5 inhibitors induced β-cells. We obtained kinase inhibition profiles and found that only ALK5iII inhibited cyclin-dependent kinases 8 and 19 (CDK8/19) among all ALK5 inhibitors tested. Consistently, CDK8/19 inhibitors efficiently induced β-cells in the absence of ALK5iII. A combination treatment with non-mutagenic ALK5 inhibitor SB431542 and CDK8/19 inhibitor senexin B afforded generation of iPICs with in vitro cellular composition and in vivo efficacy comparable to those observed with ALK5iII. [Conclusion] Our findings suggest a new risk mitigation approach for cell therapy and advance our understanding of the β-cell differentiation mechanism