Dexmedetomidine improves acute lung injury by activating autophagy in a rat hemorrhagic shock and resuscitation model

Dexmedetomidine (DEX) can reduce lung injury in a hemorrhagic shock (HS) resuscitation (HSR) model in rats by inhibiting inflammation. Here, we aimed to investigate if these effects of DEX are due to autophagy activation. Therefore, we established HSR rat models and divided them into four groups. HS was induced using a blood draw. The rats were then resuscitated by reinjecting the drawn blood and saline. The rats were sacrificed 24 h after resuscitation. Lung tissues were harvested for histopathological examination, determination of wet/dry lung weight ratio, and detection of the levels of autophagy-related marker proteins LC3, P62, Beclin-1, and the ATG12-ATG5 conjugate. The morphological findings of hematoxylin and eosin staining in lung tissues and the pulmonary wet/dry weight ratio showed that lung injury improved in HSR + DEX rats. However, chloroquine (CQ), an autophagy inhibitor, abolished this effect. Detecting the concentration of autophagy-related proteins showed that DEX administration increased LC3, ATG12-ATG5, and Beclin-1 expression and decreased P62 expression. The expression levels of these proteins were similar to those in the HSR group after CQ + DEX administration. In summary, DEX induced autophagic activation in an HSR model. These findings suggest that DEX administration partially ameliorates HSR-induced lung injury via autophagic activation

A non-obese, diet-induced animal model of nonalcoholic steatohepatitis in Wistar/ST rats compared to Sprague-Dawley rats

Background: Non-alcoholic steatohepatitis (NASH), a subtype of non-alcoholic fatty liver disease (NAFLD), is a potentially progressive liver disease that can lead to cirrhosis. Obesity increases the risk of NAFLD/NASH, but this disease can also be observed in non-obese individuals. Methods: We investigated the metabolic and histopathological changes in 13 obesity-resistant Slc:Wistar/ST rats fed a high-fat and high-cholesterol (HFC) diet for 9 weeks, and also retrospectively compared the results of 41 Sprague-Dawley (SD) rats that were previously fed with the same protocol to the results of the Slc:Wistar/ST rats. Results: Of the 13 Slc:Wistar/ST rats fed an HFC diet containing 1.25% or 2.5% cholesterol, 11 (84.6%) developed histologically proven NASH without obesity, an increased visceral fat volume, insulin resistance, histopatological severe lobular inflammation and severe hepatic fibrosis. The HFC diets significantly increased the levels of mRNA encoding collagen type I alpha 1 (COL1A1), transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). The SD rats also developed NASH without obesity, an increased visceral fat volume and insulin resistance, but the metabolic and histopathological effects, such as lower serum adiponectin levels, higher serum leptin levels, histopatological severe lobular inflammation and hepatic fibrosis, seemed to be more pronounced in the SD rats than in the Slc:Wistar/ST rats. Conclusions: These two rat models may reflect the human etiology of NASH that is influenced by dietary factors, and the obesity-resistant Slc:Wistar/ST rat model may be particularly useful for elucidating the pathophysiological mechanism of the so-called “lean NASH”

BdWRKY38 is required for the incompatible interaction of Brachypodium distachyon with the necrotrophic fungus Rhizoctonia solani

Rhizoctonia solani is a soil‐borne necrotrophic fungus that causes sheath blight in grasses. The basal resistance of compatible interactions between R. solani and rice is known to be modulated by some WRKY transcription factors (TFs). However, genes and defense responses involved in incompatible interaction with R. solani remain unexplored, because no such interactions are known in any host plants. Recently, we demonstrated that Bd3‐1, an accession of the model grass Brachypodium distachyon, is resistant to R. solani and, upon inoculation with the fungus, undergoes rapid induction of genes responsive to the phytohormone salicylic acid (SA) that encode the WRKY TFs BdWRKY38 and BdWRKY44. Here, we show that endogenous SA and these WRKY TFs positively regulate this accession‐specific R. solani resistance. In contrast to a susceptible accession (Bd21), the infection process in the resistant accessions Bd3‐1 and Tek‐3 was suppressed at early stages before the development of fungal biomass and infection machinery. A comparative transcriptome analysis during pathogen infection revealed that putative WRKY‐dependent defense genes were induced faster in the resistant accessions than in Bd21. A gene regulatory network (GRN) analysis based on the transcriptome dataset demonstrated that BdWRKY38 was a GRN hub connected to many target genes specifically in resistant accessions, whereas BdWRKY44 was shared in the GRNs of all three accessions. Moreover, overexpression of BdWRKY38 increased R. solani resistance in Bd21. Our findings demonstrate that these resistant accessions can activate an incompatible host response to R. solani, and BdWRKY38 regulates this response by mediating SA signaling

Parental legacy and regulatory novelty in Brachypodium diurnal transcriptomes accompanying their polyploidy

Polyploidy is a widespread phenomenon in eukaryotes that can lead to phenotypic novelty and has important implications for evolution and diversification. The modification of phenotypes in polyploids relative to their diploid progenitors may be associated with altered gene expression. However, it is largely unknown how interactions between duplicated genes affect their diurnal expression in allopolyploid species. In this study, we explored parental legacy and hybrid novelty in the transcriptomes of an allopolyploid species and its diploid progenitors. We compared the diurnal transcriptomes of representative Brachypodium cytotypes, including the allotetraploid Brachypodium hybridum and its diploid progenitors Brachypodium distachyon and Brachypodium stacei. We also artificially induced an autotetraploid B. distachyon. We identified patterns of homoeolog expression bias (HEB) across Brachypodium cytotypes and time-dependent gain and loss of HEB in B. hybridum. Furthermore, we established that many genes with diurnal expression experienced HEB, while their expression patterns and peak times were correlated between homoeologs in B. hybridum relative to B. distachyon and B. stacei, suggesting diurnal synchronization of homoeolog expression in B. hybridum. Our findings provide insight into the parental legacy and hybrid novelty associated with polyploidy in Brachypodium, and highlight the evolutionary consequences of diurnal transcriptional regulation that accompanied allopolyploidy

成人発症の難治性胞巣型横紋筋肉腫に対する Vincristine Irinotecan Temozolomide 療法を用いた治療経験

　成人発症の胞巣型横紋筋肉腫は，まれであり，再発しやすく予後が悪いと言われている．さまざまな化学療法が試されているが効果的な報告は少ない．我々は，難治性胞巣型横紋筋肉腫に対してVincristine Irinotecan Temozolomide（VITA）療法を施行し，長期完全奏効（Complete Response：CR）を維持している症例を経験したため報告する．症例は20歳代の男性で，トルコ鞍斜台に腫瘍を認め，摘出生検を施行し胞巣型横紋筋肉腫と診断された．残存腫瘤に対して放射線治療を施行し，CT 検査で病変の消失を確認した．術後３か月後に右頸部リンパ節腫大が出現し，リンパ節郭清術を施行した．その２か月後に左頸部リンパ節腫大が出現したため，Childrens Oncology Group ARST0431レジメン（VI 療法とVDC/IE 交代療法およびVAC 療法によるブロックから構成される計54週間の治療）を施行し，PET/CT でFDG 集積の消失を確認し，CT でもリンパ節腫大病変は消失した．しかし，１年後に左頸部リンパ節腫大が再度出現．再発と判断し，VITA 療法を開始した．６コース施行しCT にてCR を確認した．以後，外来で経過観察中でありCR を維持している．難治性胞巣型横紋筋肉腫に対してVITA 療法は有用であると考えられ，治療法の選択枝の一つとして考慮すべきである．　Adult onset alveolar rhabdomyosarcoma is rare, but recurrence is common and prognosis is poor. Various types of chemotherapy regimens have been attempted, but few studies have reported information on efficacy. Here, we report our experience with a patient who received Vincristine Irinotecan Temozolomide (VITA) therapy and in whom long-term (complete response: CR) was maintained. The patient was a 20-year-old man who developed alveolar rhabdomyosarcoma in the clivus of the sella turcica. Following enucleation and postoperative radiotherapy, lesion disappeared by CT was achieved. However, right cervical lymphadenopathy was soon apparent, and a lymphadenectomy was performed. Because left cervical lymphadenopathy was apparent after 2 months, the Children\u27s Oncology Group ARST0431 regimen (54 weeks of therapy: blocks of therapy with VI, interval compression with VDC/IE and VAC) was initiated, negative PET imaging and lesion disappeared by CT was achieved. However, reappearance of left cervical lymphadenopathy was noted after 1 year. Recurrence was diagnosed in the patient, and VITA therapy was initiated again. CR was achieved after 6 courses, and subsequent outpatient follow-up has revealed that CR has been maintained. Hence, VITA therapy may be useful for treatment-resistant alveolar rhabdomyosarcoma and should be considered as a treatment option

臍帯血移植後発症した early lesion of PTLD の剖検例

移植後リンパ増殖性疾患（post-transplant lymphoproliferative disorders, PTLD）は，同種造血幹細胞移植後の生命を脅かす予後不良な合併症の一つである．臨床症状は非特異的であるが，PTLD を疑った場合はPCR 法による血中EB（Epstein-Barr）ウイルス-DNA 量を測定し，高値を示した場合はPTLD と判断する必要がある．今回，造血幹細胞移植後に高EB ウイルス血症を認め，急激な病状の悪化により死亡した症例を経験したため剖検所見を含め報告する．症例は，40歳代男性でフィラデルフィア染色体陽性急性リンパ性白血病を発症し，治療にて寛解を得た後に臍帯血移植を施行した．移植後280日に高熱が出現し，胸部CT 検査から細菌性肺炎と診断し入院．抗菌薬治療を開始するも効果不良であり，呼吸状態の悪化と，意識障害が出現した．血液，肺胞洗浄液と髄液から，EB ウイルス-DNA 異常高値が検出された．PTLD と判断したが，急激に呼吸状態が悪化し死亡した．剖検では，肺胞内出血を認め，急激に悪化した原因と考えられた．そして，肺門部リンパ節や肺にはEBER（EBV-encoded small RNA）陽性細胞を多数認め，一部では大型多核細胞も散見され，early lesion of PTLD と判断された．Early lesion of PTLD であっても，本症例のように肺病変を認めた場合，出血による呼吸状態の悪化から急激な経過をたどることがあり，早期の対応が必要と考えられた．Post-transplant lymphoproliferative disorder (PTLD), a life-threatening condition with poor prognosis, can arise after allogeneic hematopoietic stem cell transplantation. The clinical symptoms are non-specific, but if PTLD is suspected, the blood levels of Epstein-Barr (EB) virus DNA are measured using PCR. Here, we report our experience with a patient who showed high levels of EB virus DNA in the blood and a rapidly worsening condition resulting in death, after undergoing hematopoietic stem cell transplantation. The patient was male and in his 40s; he had developed Philadelphia chromosome-positive acute lymphoid leukemia and achieved remission with treatment, and he later underwent umbilical cord blood transplantation. A high fever appeared 280 days after transplantation, and he was hospitalized and diagnosed with bacterial pneumonia following a thoracic CT examination. He was initiated on antimicrobial therapy, but responded poorly, exhibiting a worsening respiratory condition and disturbance of consciousness. Abnormally high EB virus DNA levels were detected in his blood, bronchoalveolar lavage fluid, and cerebrospinal fluid. He was diagnosed with PTLD, but his respiratory condition deteriorated rapidly and he died. The autopsy revealed alveolar hemorrhage, which was thought to be the cause of the rapid deterioration. A large number of EBER (EBV-encoded small RNA)- positive cells were also found in hilar lymph nodes and lungs, which were deemed to be early lesions of PTLD. Therefore, timely action is crucial if lesions are presents as even early PTLD lesions can progress rapidly owing to bleeding that can result in the deterioration of the respiratory condition

クリプトコッカス髄膜炎を発症したCD4リンパ球減少症の２例

　クリプトコッカス感染症はCryptococcus neoformans による真菌感染症であり，免疫不全患者に発症しやすい．今回，我々はCD4リンパ球減少を認め，クリプトコッカス髄膜炎を発症した２例を経験したので報告する．症例１は，40歳代男性で不明熱のため受診した．血液検査でリンパ球930/μL，髄膜刺激症状はなかったが，髄液検査にてクリプトコッカス菌体が検出され，血液培養からも検出された．CD4 72.5/μL と低値であり，HIV 抗体陽性であった．クリプトコッカス髄膜炎を発症したAIDS 患者と診断した．症例２は，20歳代女性で不明熱のため受診した．血液検査でリンパ球510/μL，髄膜刺激症状はなかったが，髄液検査にてクリプトコッカス菌体が検出され，血液培養からも検出された．CD4 19.4/μL と低値であったが，HIV 抗体陰性で原発性免疫不全症や他の免疫不全となる原因は認められなかった．Idiopathic CD4 lymphocytopenia（ICL）に発症したクリプトコッカス髄膜炎と診断した．AIDS とICL がそれぞれ原因となったクリプトコッカス髄膜炎であった．前者での本症併発は2.4 %，後者での併発は19.7 % と報告されている．HIV非感染のクリプトコッカス髄膜炎をみた際にはICL によるCD4リンパ球減少症を考える必要がある．死に至ることもまれではないクリプトコッカス髄膜炎であるが，治療が奏効し１年以上経過しているため報告する．　Cryptococcal infections are fungal infections caused by Cryptococcus neoformans. This infection develops more commonly in immunocompromised patients. We report two cases of cryptococcal meningitis that developed as a result of CD4 lymphocytopenia. Case 1 was a man in his 40s who presented with a fever of unknown origin. A blood test revealed a lymphocyte count of 930/μL, with no meningeal irritation; however, examination of his cerebrospinal fluid detected cryptococcal bodies, which was also confirmed by blood culture. In addition, the patient had a low CD4 count of 72.5/μL, and was HIV antibodypositive. We thus diagnosed him as an AIDS patient who developed cryptococcal meningitis. Case 2 was a woman in her 20s who also presented with a fever of unknown origin. A blood test revealed a lymphocyte count of 510/μL, with no meningeal irritation; however, examination of her cerebrospinal fluid detected cryptococcal bodies, which was confirmed by blood culture. Despite the patient having a low CD4 count of 19.4/μL, she was HIV antibody-negative, and there was no evidence of primary immunodeficiency or any other causes of immune deficiency. Accordingly, we diagnosed this patient as cryptococcal meningitis that developed as a result of idiopathic CD4 lymphocytopenia (ICL). In the above cases, cryptococcal meningitis developed as a result of AIDS and ICL, respectively. The incidence rates of this complication are reported as 2.4% for the former and 19.7% for the latter. When cryptococcal meningitis without HIV infection is observed, it is necessary to consider the possibility of CD4 lymphocytopenia due to ICL. Although cryptococcal meningitis can be fatal, treatment was successful in both cases, and more than one year has elapsed since their initial presentation

リツキシマブ併用ベンダムスチン療法が奏効した腸管monomorphic PTLD

　移植後リンパ増殖性疾患（PTLD）は，造血幹細胞移植後に免疫抑制剤を使用した結果として，Ｔ細胞機能が低下して生じる異常なリンパ球，または形質細胞の増殖で，移植領域において最も致死的で注意を要する合併症の一つである．PTLD は４つのカテゴリーに分類され，その中のmonomorphic PTLD は、悪性リンパ腫の形態を呈する．Monomorphic PTLD の治療には，免疫抑制剤減量，リツキシマブ（Ｒ）単独療法やR-CHOP 療法があるが，予後は不良である．今回，難治性PTLD に対してリツキシマブ併用ベンダムスチン療法が奏効し寛解をえることができた症例を経験したので報告する．症例は50歳代男性で、骨髄異形成症候群に対して臍帯血移植を施行し，GVHD 予防にタクロリムスを使用した．移植後，消化管GVHD を発症し，プレドニゾロンで治療中，monomorphic PTLD（びまん性大細胞型Ｂ細胞リンパ腫）を発症した．免疫抑制剤中止後，リツキシマブ（Ｒ）単独療法，R-CHOP like 療法を施行したが効果不良であった．リツキシマブ併用ベンダムスチン療法に変更し４コース施行後，消化管内視鏡検査で病変は消失し，CT 検査で完全奏効を確認した．治療終了し約１年経過しているが，現在も症状増悪なく経過できており，難治性monomorphic PTLD に対してリツキシマブ併用ベンダムスチン療法が有効であった．Post-transplantation lymphoproliferative disorder (PTLD) occurs as a result of the use of immunosuppressants following hematopoietic stem cell transplantation, which causes the emergence of abnormal lymphocytes owing to the decline in T-cell function and the proliferation of plasma cells. It is thus one of the most fatal complications and the biggest concern for transplantation cases. PTLD is classified into 4 categories, and monomorphic PTLD takes the form of a malignant lymphoma. Immunosuppressant dose reduction, rituximab (R) monotherapy, and R-CHOP therapy are used to treat monomorphic PTLD, but the prognosis is poor for these forms of treatment. This report describes the experience of a patient with refractory PTLD who went into remission after responding to combination therapy with rituximab and bendamustine. A 50-year-old man underwent cord blood transplantation because of a myelodysplastic syndrome. Tacrolimus was used for GVHD prevention. After transplantation, symptoms of GVHD of the gastrointestinal tract developed, and during treatment using prednisolone, symptoms of monomorphic PTLD (diffuse large B-cell lymphoma) emerged. Once immunosuppressant use was discontinued, the patient underwent R monotherapy and R-CHOPlike treatment, but the response was poor. The treatment was then changed to combination therapy with rituximab and bendamustine; after 4 courses of treatment, gastrointestinal endoscopy revealed that the pathological abnormality had disappeared, and a complete response was confirmed. One year has passed since the completion of treatment, and at present, the patient’s symptoms have not worsened, suggesting that combination therapy with rituximab and bendamustine is effective for treating monomorphic PTLD

形態学的に骨髄腫細胞との鑑別に苦慮した plasmacytoid な形態を示した膀胱癌の多発骨転移の１例

　尿路上皮癌には，腫瘍細胞が形質細胞に酷似した形態を呈することがある．今回，形態学的に骨髄腫細胞との鑑別に苦慮したplasmacytoid な形態を示した膀胱癌の骨髄転移の一例を経験したので報告する．　症例は80歳代男性で，20XX 年10月に蛋白尿と腎機能障害が出現し，精査にて多発性骨髄腫（IgG-λ），ISS Ⅱ期と診断され，BD 療法（bortezomib+dexamethasone）を開始した．効果は良好で，３コース施行後にはVGPR（very good partial response）に到達した．20XX ＋１年２月間歇的に認めていた血尿の精査を行い，細胞診や膀胱鏡検査から膀胱癌の併発を確認した．骨髄腫治療は中断し，膀胱癌治療を優先した．PET/CT 検査ではリンパ節やその他臓器への転移は認めず，６月に膀胱全摘術が施行された．術後は経過良好であったため，全身状態の回復を待ち，骨髄腫治療を再開する予定であった．しかし，９月末頃から腰痛が出現し，10月には腰痛の増強を認めたため再度PET/CT 検査を施行したところ，多発する骨髄病変を認めた．骨髄腫の増悪を疑い骨髄検査を施行した．骨髄穿刺塗沫標本では，形質細胞様の異形細胞を多数認め，骨髄腫の増悪を推測させる所見であった．しかし同時に施行された骨髄腫関連検査では，IgG やその他の免疫グロブリンは正常であり，蛋白分画や免疫固定法でもM 蛋白は検出されなかった．骨髄生検の病理組織学的検査の結果，形質細胞様の異形細胞は尿路上皮系の腫瘍細胞であり，膀胱癌の骨転移と診断された．PET/CT 検査での多発骨髄病変は，多発性骨髄腫の増悪ではなく，膀胱癌の多発骨転移であった．　膀胱全摘後の再発は，遠隔転移が20～50% と遠隔転移が多く，遠隔転移部位として骨，リンパ節，肺，肝の順に多いと報告されている．そのため，骨髄塗抹標本検鏡の際，遭遇する可能性があり，骨髄腫細胞と見誤らないためには，免疫染色を含めた組織学的な検討，血清・尿の蛋白解析が必須と考えられた．　Urothelial cancer cells may appear similar to plasma cells. We present a case of plasmacytoid bladder cancer with bone marrow metastasis and difficult morphological differentiation from myeloma. A male in his 80s presented with proteinuria and renal dysfunction in October 20XX. Detailed examination led to a diagnosis of International Staging System Stage II multiple myeloma (IgG-λ), and BD (bortezomib + dexamethasone) therapy was started. Three courses of treatment resulted in a very good partial response. Intermittent hematuria was observed in February 20XX+1, and cytodiagnosis and cystoscopy confirmed bladder cancer. Myeloma treatment was discontinued, and treatment of bladder cancer was prioritized. There was no metastasis to lymph nodes or other organs on positron emission tomography-computed tomography (PET/CT) and cystectomy was performed in June. The postoperative course was good, and myeloma treatment was to resume once the patient had improved. However, in late September, he developed lower back pain that intensified in October. Repeat PET/ CT confirmed multiple bone marrow lesions. Exacerbation of myeloma was suspected. Bone marrow aspiration confirmed multiple plasma cell-like atypical cells, indicating exacerbation of myeloma. However, other myeloma-related tests performed at the same time, including IgG and immunoglobulins, were normal, and M protein was not detected on protein fractionation or immunofixation. Histopathological examination of a bone marrow biopsy showed that plasma cell-like atypical cells were urothelial tumor cells, and bone metastasis from bladder cancer was diagnosed. Multiple bone marrow lesions found on PET/CT were not an exacerbation of multiple myeloma but instead were multiple bone metastases from bladder cancer.　Recurrence following cystectomy has a high prevalence of distant metastasis (20 to 50%), and distant metastasis sites include bones, lymph nodes, lungs, and liver in the order of prevalence. Therefore, bone marrow aspiration and histological examination with immunostaining, in addition to serum and urine protein analysis are essential to prevent confusion with myeloma cells

JASMINE: Near-infrared astrometry and time-series photometry science

The Japan Astrometry Satellite Mission for INfrared Exploration (JASMINE) is a planned M-class science space mission by the Institute of Space and Astronautical Science, the Japan Aerospace Exploration Agency. JASMINE has two main science goals. One is Galactic archaeology with a Galactic Center survey, which aims to reveal the Milky Way’s central core structure and formation history from Gaia-level (∼25 ${\mu}$as) astrometry in the near-infrared (NIR) Hw band (1.0–1.6 ${\mu}$m). The other is an exoplanet survey, which aims to discover transiting Earth-like exoplanets in the habitable zone from NIR time-series photometry of M dwarfs when the Galactic Center is not accessible. We introduce the mission, review many science objectives, and present the instrument concept. JASMINE will be the first dedicated NIR astrometry space mission and provide precise astrometric information on the stars in the Galactic Center, taking advantage of the significantly lower extinction in the NIR. The precise astrometry is obtained by taking many short-exposure images. Hence, the JASMINE Galactic Center survey data will be valuable for studies of exoplanet transits, asteroseismology, variable stars, and microlensing studies, including discovery of (intermediate-mass) black holes. We highlight a swath of such potential science, and also describe synergies with other missions