Senescence-accelerated mice (SAMP1/TA-1) treated repeatedly with lipopolysaccharide develop a condition that resembles hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is a life-threatening systemic hyperinflammatory disorder with primary and secondary forms. Primary hemophagocytic lymphohistiocytosis is associated with inherited defects in various genes that affect the immunological cytolytic pathway. Secondary hemophagocytic lymphohistiocytosis is not inherited, but complicates various medical conditions including infections, autoinflammatory/autoimmune diseases, and malignancies. When senescence-accelerated mice (SAMP1/TA-1) with latent deterioration of immunological function and senescence-resistant control mice (SAMR1) were treated repeatedly with lipopolysaccharide, SAMP1/TA-1 mice displayed the clinicopathological features of hemophagocytic lymphohistiocytosis such as hepatosplenomegaly, pancytopenia, hypofibrinogenemia, hyperferritinemia, and hemophagocytosis. SAMR1 mice showed no features of hemophagocytic lymphohistiocytosis. Lipopolysaccharide induced upregulation of proinflammatory cytokines such as interleukin-1β, interleukin-6, tumor necrosis factor-α, and interferon-γ, and interferon-γ-inducible chemokines such as c-x-c motif chemokine ligands 9 and 10 in the liver and spleen in both SAMP1/TA-1 and SAMR1 mice. However, upregulation of proinflammatory cytokines and interferon-γ-inducible chemokines in the liver persisted for longer in SAMP1/TA-1 mice than in SAMR1 mice. In addition, the magnitude of upregulation of interferon-γ in the liver and spleen after lipopolysaccharide treatment was greater in SAMP1/TA-1 mice than in SAMR1 mice. Furthermore, lipopolysaccharide treatment led to a prolonged increase in the proportion of peritoneal M1 macrophages and simultaneously to a decrease in the proportion of M2 macrophages in SAMP1/TA-1 mice compared with SAMR1 mice. Lipopolysaccharide appeared to induce a hyperinflammatory reaction and prolonged inflammation in SAMP1/TA-1 mice, resulting in features of secondary hemophagocytic lymphohistiocytosis. Thus, SAMP1/TA-1 mice represent a useful mouse model to investigate the pathogenesis of bacterial infection-associated secondary hemophagocytic lymphohistiocytosis

Thioredoxin-1 maintains mechanistic target of rapamycin (mTOR) function during oxidative stress in cardiomyocytes

Thioredoxin 1 (Trx1) is a 12-kDa oxidoreductase that catalyzes thiol-disulfide exchange reactions to reduce proteins with disulfide bonds. As such, Trx1 helps protect the heart against stresses, such as ischemia and pressure overload. Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth, metabolism, and survival. We have shown previously that mTOR activity is increased in response to myocardial ischemia-reperfusion injury. However, whether Trx1 interacts with mTOR to preserve heart function remains unknown. Using a substrate-trapping mutant of Trx1 (Trx1C35S), we show here that mTOR is a direct interacting partner of Trx1 in the heart. In response to H2O2 treatment in cardiomyocytes, mTOR exhibited a high molecular weight shift in non-reducing SDS-PAGE in a 2-mercaptoethanol-sensitive manner, suggesting that mTOR is oxidized and forms disulfide bonds with itself or other proteins. The mTOR oxidation was accompanied by reduced phosphorylation of endogenous substrates, such as S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) in cardiomyocytes. Immune complex kinase assays disclosed that H2O2 treatment diminished mTOR kinase activity, indicating that mTOR is inhibited by oxidation. Of note, Trx1 overexpression attenuated both H2O2-mediated mTOR oxidation and inhibition, whereas Trx1 knockdown increased mTOR oxidation and inhibition. Moreover, Trx1 normalized H2O2-induced down-regulation of metabolic genes and stimulation of cell death, and an mTOR inhibitor abolished Trx1-mediated rescue of gene expression. H2O2-induced oxidation and inhibition of mTOR were attenuated when Cys-1483 of mTOR was mutated to phenylalanine. These results suggest that Trx1 protects cardiomyocytes against stress by reducing mTOR at Cys-1483, thereby preserving the activity of mTOR and inhibiting cell death

A Case of Endoscopic Mucosal Resection of Carcinoma in Adenoma at the Minor Duodenal Papilla

Here, we describe a case of minor papillary adenocarcinoma in adenoma that was treated with endoscopic mucosal resection (EMR). In a 67-year-old woman, sigmoid colon cancer was incidentally detected on preoperative upper gastrointestinal endoscopy. Endoscopy revealed a slightly elevated lesion at the minor duodenal papilla. The findings of a histopathologic examination were suggestive of adenocarcinoma. Computed tomography and magnetic resonance images identified a minute tumor, whereas endoscopic ultrasonography revealed that the tumor did not spread to the pancreas. We performed EMR of this lesion. There were no complications, and relapse has not occurred in 3 years. Cases of minor papillary adenocarcinoma treated with EMR are quite rare

Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity

Neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism, involve altered synaptic transmission and plasticity. Functional characterization of their associated genes is vital for understanding physio-pathological brain functions. LGI3 is a recently recognized ID-associated gene encoding a secretory protein related to an epilepsy-gene product, LGI1. Here, we find that LGI3 is uniquely secreted from oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons, forming nanoscale subclusters. Proteomic analysis using epitope-tagged Lgi3 knockin mice shows that LGI3 uses ADAM23 as a receptor and selectively co-assembles with Kv1 channels. A lack of Lgi3 in mice disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. Collectively, this study identifies an extracellular organizer of juxtaparanodal Kv1 channel clustering for finely tuned synaptic transmission. Given the defective secretion of the LGI3 missense variant, we propose a molecular pathway, the juxtaparanodal LGI3-ADAM23-Kv1 channel, for understanding neurodevelopmental disorders.<br/

In vitro expansion of CD34+CD38- cells under stimulation with hematopoietic growth factors on AGM-S3 cells in juvenile myelomonocytic leukemia

advance online publication, August 8, 2014 [Epub ahead of print]ArticleLEUKEMIA. 29(3):606-614 (2015)journal articl

脾動脈瘤３例の検討

今回当科で経験した脾動脈瘤３例について報告する．年齢は17歳から76歳（平均49.3歳）で、女性；１例、男性；２例であった．１例は破裂症例で緊急開腹，それ以外の２例は血管内治療を施行し,全て術後経過は良好であった．緊急開腹術を行った１例は２cm 未満の嚢状瘤であり，術前瘤径にとらわれず治療適応を考える必要がある．治療の第一選択として低侵襲な血管内治療を考慮する必要がある．We report 3 cases of splenic artery aneurysm (2 males,1 female; median age, 49.3 years; age range, 17-76 years).We performed splenectomy (included aneurysm) in emergency surgery for one ruptured case and performed endovascular therapy for two unruptured cases. The postoperative progress of all cases was satisfactory.Emergency case was saccular aneurysm under 2cm of size. Indication for treatment of intraabdominal aneurysm may be considered even in small size of aneurysm.All cases are still alive. It is necessary to take into account minimally invasive endovascular therapy in first-line

Gastric function preserving esophagectomy for esophageal cancer

Although, the gastric roll is widely used for reconstruction after an esophagectomy for esophageal cancer, adverse effects such as the post operative disturbance of oral intake and the reflux of gastric juice have been reported. A function preserving surgical procedure, which is similar to that for stomach and colon cancer, has been developed for esophageal cancer. Gastric function can be preserved by using the intestine as the reconstructive organ after an esophagectomy. In this report, we described the procedure for an esophagectomy with pedunculated jejunal or right colonic interposition, collectively termed as a gastric function preserving esophagectomy (GPE). We believe that this procedure is minimally invasive with a low risk of postoperative digestive symptoms and weight loss