齋藤 邦明

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT_1A receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635—a 5-HT_1A receptor antagonist—antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT_1A receptors in prenatal VPA mice.

High salt (HS) intake induces hypertension and cognitive impairment. Preventive strategies include against dietary supplements. Soybean lecithin is a widely used phospholipid supplement. Lysolecithin is important in cell signaling, digestion, and absorption. This study aimed to investigate the effects of lysophosphatidylcholine containing >70% of the total phospholipids (LPC70), on hypertension and cognitive impairment induced in mice by HS intake. Mice were provided with HS solution (2% NaCl in drinking water) with or without LPC70 for 12 weeks. Blood pressure, cognitive function, and inflammatory response of intestine were determined. Hypertension and impaired object recognition memory induced by HS intake were implicated with increased inducible nitric oxide synthase in the small intestine and tau hyperphosphorylation in the prefrontal cortex. LPC70 treatment prevented cognitive impairment by suppressing inducible nitric oxide synthase and tau hyperphosphorylation. LPC70 may be valuable as a functional food component in preventing HS-induced cognitive impairment.

BACKGROUND: Secondary carnitine deficiency in patients with anorexia nervosa has been rarely reported. This study aimed to investigate the occurrence of carnitine deficiency in severely malnourished patients with eating disorders during refeeding and assess its potential adverse effects on treatment outcomes. METHOD: In a cohort study of 56 female inpatients with eating disorders at a single hospital from March 2010 to December 2020, we measured plasma free carnitine (FC) levels and compared to those of a healthy control group (n = 35). The patients were categorized into three groups based on FC levels: FC deficiency (FC< 20 µmol/L), FC pre-deficiency (20 µmol/L ≤ FC< 36 µmol/L), and FC normal (36 µmol/L ≤ FC). RESULTS: Upon admission, the patients had a median age of 26 years (interquartile range [IQR]: 21-35) and a median body mass index (BMI) of 13.8 kg/m2 (IQR: 12.8-14.8). Carnitine deficiency or pre-deficiency was identified in 57% of the patients. Hypocarnitinemia was associated with a decline in hemoglobin levels during refeeding (odds ratio [OR]: 0.445; 95% confidence interval [CI]: 0.214-0.926, p = 0.03), BMI at admission (OR: 0.478; 95% CI: 0.217-0.874, p = 0.014), and moderate or greater hepatic impairment at admission (OR: 6.385; 95% CI: 1.170-40.833, p = 0.032). CONCLUSIONS: Hypocarnitinemia, particularly in cases of severe undernutrition (BMI< 13 kg/m2 at admission) was observed in severely malnourished patients with eating disorders during refeeding, a critical metabolic transition phase. Moderate or severe hepatic impairment at admission was considered a potential indicator of hypocarnitinemia. Although hypocarnitinemia was not associated with any apparent adverse events other than anemia during refeeding, the possibility that carnitine deficiency may be a risk factor for more serious complications during sudden increases in energy requirements associated with changes in physical status cannot be denied. Further research on the clinical significance of hypocarnitinemia in severely malnourished patients with eating disorders is warranted.

近年,大規模言語モデル(large language models;LLM)が世界的に様々な分野で注目を集めている。LLMとは,非常に巨大なデータセットとディープラーニング技術を用いて構築された言語モデルである。LLMは,人間に近い流暢な会話が可能であら,自然言語を用いたさまざまな処理を高精度で行えることから,世界中で注目を集めている。本研究では,LLMであるOpenAI社が開発したChatGPTの異なる2つのモデル(GPT-3.5,GPT-4)にて,過去3年間の臨床検査技師国家試験におけるChatGPTの正答率について評価を行った。GPT-3.5による正答率の平均は51.4%であった。一方,GPT-4では79.8%の正答率結果が得られた。本結果より,ChatGPTはこの先医療現場における有効なアドバイザーとして進化する可能性をもつことが示唆された。しかし,今回不正解となった20%の中には,患者を診断する際に誤診につながりかねない回答が含まれており,今後のChatGPTの精度向上は必須と考えられる。今回の検証は,LLMにおけるChatGPTの臨床検査領域での多様な応用の進展に寄与すると考えられ,この先の発展に期待したい。(著者抄録)

Abstract Stressful life events contribute to the onset of major depressive disorder (MDD). We recently demonstrated abnormalities in ubiquitination in the pathophysiology of MDD. However, the underlying molecular mechanisms remain unclear. We investigated the involvement of the ubiquitination system‐mediated glutamatergic dysfunction in social impairment induced by chronic social defeat stress (CSDS). Adult C57BL/6J mice were exposed to aggressor ICR male mice for 10 consecutive days. Social impairment was induced by CSDS in the social interaction test 1 days after the last stress exposure. In terms of brain microdialysis, CSDS reduced depolarization‐evoked glutamate release in the prefrontal cortex (PFC), which was reversed by a glutamate transporter 1 (GLT‐1) inhibitor. Interestingly, the expression of ubiquitinated, but not total GLT‐1, was decreased in the PFC of mice exposed to CSDS. The expression of neural precursor cells expressing developmentally downregulated gene 4‐like (Nedd4L: E3 ligase for GLT‐1), and ubiquitin‐conjugating enzyme E2D2 (Ube2d2: E2 ubiquitin‐conjugating enzyme for Nedd4L) was also reduced in CSDS mice. Furthermore, the downregulation of the Nedd4L‐GLT‐1 ubiquitination pathway decreased SIT ratio, but up‐regulation increased it even in non‐CSDS mice. Taken together, the decrease in GLT‐1 ubiquitination may reduce the release of extracellular glutamate induced by high‐potassium stimulation, which may lead to social impairment, while we could not find differences in GLT‐1 ubiquitination between susceptible and resistant CSDS mice. In conclusion, GLT‐1 ubiquitination could play a crucial role in the pathophysiology of MDD and is an attractive target for the development of novel antidepressants.

Indoleamine 2,3-dioxygenase 2 (IDO2) is an enzyme of the tryptophan-kynurenine pathway that is constitutively expressed in the brain. To provide insight into the physiological role of IDO2 in the brain, behavioral and neurochemical analyses in IDO2 knockout (KO) mice were performed. IDO2 KO mice showed stereotyped behavior, restricted interest and social deficits, traits that are associated with behavioral endophenotypes of autism spectrum disorder (ASD). IDO2 was colocalized immunohistochemically with tyrosine-hydroxylase-positive cells in dopaminergic neurons. In the striatum and amygdala of IDO2 KO mice, decreased dopamine turnover was associated with increased α-synuclein level. Correspondingly, levels of downstream dopamine D1 receptor signaling molecules such as brain-derived neurotrophic factor and c-Fos positive proteins were decreased. Furthermore, decreased abundance of ramified-type microglia resulted in increased dendritic spine density in the striatum of IDO2 KO mice. Both chemogenetic activation of dopaminergic neurons and treatment with methylphenidate, a dopamine reuptake inhibitor, ameliorated the ASD-like behavior of IDO2 KO mice. Sequencing analysis of exon regions in IDO2 from 309 ASD samples identified a rare canonical splice site variant in one ASD case. These results suggest that the IDO2 gene is, at least in part, a factor closely related to the development of psychiatric disorders.

プログラニュリン(PGRN)の測定方法の確立を目的として新たに開発されたPGRN測定試薬の基礎的検討をおこなった。未治療の関節リウマチ(RA)患者50例と変形性ひざ関節症(OA)患者37例,健常者100例についてPGRN測定試薬を用いて測定した。さらにRA治療薬のTNF関連生物学的製剤Infliximab(IFX)投与患者5例について経時変を観察した。再現性は2濃度の併行精度4.4%,4.2%,5日間の室内再現精度8.7%,7.8%であった。健常者のPGRN(Mean±SDng/mL)は男性37.9±8.9ng/ml,女性40.5±8.7ng/mlであった。RA患者は62.9±12.4ng/ml,OA患者55.1±12.0ng/mlでありRA患者が有意に高値であった。またIFX治療患者では治療前から約1年後のPGRNは軽度(約20%)の上昇が認められた。本試薬の基礎的検討は良好であり,RA患者ではOA患者,健常者対照に比べて有意に高く従来の報告と一致していた。(著者抄録)

Objective The objective of this study was to estimate the humoral immune response evaluated by immunoglobulin G (IgG) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD-IgG) following the third mRNA COVID-19 vaccination in patients with kidney disease who received immunosuppressive treatment. Methods The primary outcome was RBD-IgG levels after the third SARS-CoV-2 vaccination. The primary comparison was the RBD-IgG levels between patients with kidney disease who received immunosuppressive treatment (n=124) and those who did not (n=33). Results The RBD-IgG levels were significantly lower in the patients with kidney disease who received immunosuppressive treatment than in those who did not receive immunosuppressive treatment. The RBD-IgG levels were lower in patients treated with glucocorticoid monotherapy than in those who did not receive immunosuppressive treatment. Even in patients who received ≤ 5 mg prednisolone, the RBD-IgG levels were significantly lower. Nine of the 10 patients who received rituximab within one year before the first vaccination did not experience seroconversion after the third vaccination. Meanwhile, all nine patients who received rituximab only after the second vaccination experienced seroconversion, even if B cell recovery was insufficient. Patients treated with mycophenolate mofetil plus glucocorticoid plus belimumab had significantly lower RBD-IgG levels than those treated with mycophenolate mofetil plus glucocorticoid. Conclusions The RBD-IgG levels were lower in patients with kidney disease who received immunosuppressive treatment than in those who did not receive immunosuppressive treatment. Low-dose glucocorticoid monotherapy affected the humoral immune response following the third mRNA COVID-19 vaccination.

PET/CT can scan low-dose computed tomography (LDCT) images with morphological information and PET images with functional information. Because the whole body is targeted for imaging, PET/CT examinations are important in cancer diagnosis. However, the several images obtained by PET/CT place a heavy burden on radiologists during diagnosis. Thus, the development of computer-aided diagnosis (CAD) and technologies assisting in diagnosis has been requested. However, because FDG accumulation in PET images differs for each organ, recognizing organ regions is essential for developing lesion detection and analysis algorithms for PET/CT images. Therefore, we developed a method for automatically extracting organ regions from PET/CT images using U-Net or DenseUNet, which are deep-learning-based segmentation networks. The proposed method is a hybrid approach combining morphological and functional information obtained from LDCT and PET images. Moreover, pre-training using ImageNet and RadImageNet was performed and compared. The best extraction accuracy was obtained by pre-training ImageNet with Dice indices of 94.1, 93.9, 91.3, and 75.1% for the liver, kidney, spleen, and pancreas, respectively. This method obtained better extraction accuracy for low-quality PET/CT images than did existing studies on PET/CT images and was comparable to existing studies on diagnostic contrast-enhanced CT images using the hybrid method and pre-training.

Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. However, irrespective of its potent anticancer properties and efficacy, nephrotoxicity is the dose-limiting factor of cisplatin treatment. Cisplatin infiltrates renal tubular cells in the kidneys and is metabolized by cysteine conjugate-beta lyase 1 (CCBL1) to form highly reactive thiol-cisplatin; this may mediate cisplatin's nephrotoxicity. Therefore, CCBL1 inhibition may prevent cisplatin-induced nephrotoxicity. Using a high-throughput screening assay, we identified 2',4',6'-trihydroxyacetophenone (THA) as an inhibitor of CCBL1. THA inhibited human CCBL1 β-elimination activity in a concentration-dependent manner. We further investigated the preventive effect of THA on cisplatin-induced nephrotoxicity. THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells (LLC-PK1 cells) but had no effect on cisplatin-induced reduction of proliferation in the tumor cell lines (LLC and MDA-MB-231). THA pretreatment significantly attenuated cisplatin-induced increases in blood urea nitrogen, creatinine, cell damage score, and apoptosis of renal tubular cells in mice in a dose-dependent manner. Furthermore, THA pretreatment attenuated cisplatin-induced nephrotoxicity without compromising its antitumor activities in mice bearing subcutaneous syngeneic LLC tumors. THA could help prevent cisplatin-induced nephrotoxicity and may provide a new strategy for cisplatin-inclusive cancer treatments.

OBJECTIVES: We evaluated the applicability of a machine learning based Low-density lipoprotein-cholesterol (LDL-C) estimation method and the influence of the characteristics of the training datasets. METHODS: Three training datasets were chosen from training datasets: health check-up participants at the Resource Center for Health Science (N = 2664), clinical patients at Gifu University Hospital (N = 7409), and clinical patients at Fujita Health University Hospital (N = 14842). Nine different machine learning models were constructed through hyperparameter tuning and 10-fold cross-validation. Another test dataset of another 3711 clinical patients at Fujita Health University Hospital was selected as the test set used for comparing and validating the model against the Friedewald formula and the Martin method. RESULTS: The coefficients of determination of the models trained on the health check-up dataset produced coefficients of determination that were equal to or inferior to those of the Martin method. In contrast, the coefficients of determination of several models trained on clinical patients exceeded those of the Martin method. The means of the differences and the convergences to the direct method were higher for the models trained on the clinical patients' dataset than for those trained on the health check-up participants' dataset. The models trained on the latter dataset tended to overestimate the 2019 ESC/EAS Guideline for LDL-cholesterol classification. CONCLUSION: Although machine learning models provide valuable method for LDL-C estimates, they should be trained on datasets with matched characteristics. The versatility of machine learning methods is another important consideration.

Cisplatin is a chemotherapeutic agent used to treat many types of malignant tumors. However, irrespective of its potent anticancer properties and efficacy, nephrotoxicity is the dose-limiting factor of cisplatin treatment. Cisplatin infiltrates renal tubular cells in the kidneys and is metabolized by cysteine conjugate-beta lyase 1 (CCBL1) to form highly reactive thiol-cisplatin; this may mediate cisplatin's nephrotoxicity. Therefore, CCBL1 inhibition may prevent cisplatin-induced nephrotoxicity. Using a high-throughput screening assay, we identified 2',4',6'-trihydroxyacetophenone (THA) as an inhibitor of CCBL1. THA inhibited human CCBL1 beta-elimination activity in a concentration-dependent manner. We further investigated the preventive effect of THA on cisplatin-induced nephrotoxicity. THA attenuated the effect of cisplatin on the viability of confluent renal tubular cells (LLC-PK1 cells) but had no effect on cisplatin-induced reduction of proliferation in the tumor cell lines (LLC and MDA-MB-231). THA pre-treatment significantly attenuated cisplatin-induced increases in blood urea nitrogen, creatinine, cell damage score, and apoptosis of renal tubular cells in mice in a dose-dependent manner. Furthermore, THA pre-treatment attenuated cisplatin-induced nephrotoxicity without compromising its anti-tumor activities in mice bearing subcutaneous syngeneic LLC tumors. THA could help prevent cisplatin-induced nephrotoxicity and may provide a new strategy for cisplatin-inclusive cancer treatments.

Sepsis is a systemic inflammatory disease caused by a bacterial infection that leads to severe mortality, especially in elderly patients, because of an excessive immune response and impaired regulatory functions. Antibiotic treatment is widely accepted as the first-line therapy for sepsis; however, its excessive use has led to the emergence of multidrug-resistant bacteria in patients with sepsis. Therefore, immunotherapy may be effective in treating sepsis. Although CD8+ regulatory T cells (Tregs) are known to have immunomodulatory effects in various inflammatory diseases, their role during sepsis remains unclear. In this study, we investigated the role of CD8+ Tregs in an LPS-induced endotoxic shock model in young (8-12 wk old) and aged (18-20 mo old) mice. The adoptive transfer of CD8+ Tregs into LPS-treated young mice improved the survival rate of LPS-induced endotoxic shock. Moreover, the number of CD8+ Tregs in LPS-treated young mice increased through the induction of IL-15 produced by CD11c+ cells. In contrast, LPS-treated aged mice showed a reduced induction of CD8+ Tregs owing to the limited production of IL-15. Furthermore, CD8+ Tregs induced by treatment with the rIL-15/IL-15Rα complex prevented LPS-induced body wight loss and tissue injury in aged mice. In this study, to our knowledge, the induction of CD8+ Tregs as novel immunotherapy or adjuvant therapy for endotoxic shock might reduce the uncontrolled immune response and ultimately improve the outcomes of endotoxic shock.

BACKGROUND AND PURPOSE: High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well-known that angiotensin II (Ang II)-AT1 and prostaglandin E2 (PGE2)-EP1 systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS-mediated hypertension and emotional and cognitive impairments remains unclear. EXPERIMENTAL APPROACH: Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II-AT1 and PGE2-EP1 systems in HS-induced hypertension and neuronal and behavioral impairments was examined by treatment with losartan, an AT1 receptor blocker (ARB), or EP1 gene knockout. KEY RESULTS: We demonstrated that hypertension and impaired social behavior and object recognition memory following HS intake could be associated with tau hyperphosphorylation, decreased phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP1 gene knockout. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that the interaction of Ang II-AT1 and PGE2-EP1 systems could be novel therapeutic targets for hypertension-induced cognitive impairment.

The monoamine hypothesis has been common hypotheses for the pathophysiology of major depressive disorder (MDD). Since mainstream antidepressants are selective serotonin (5-HT) reuptake inhibitors, hypo-serotonergic function has been implicated in the MDD. However, one-third of patients are refractory to the treatment with antidepressants. Tryptophan (TRP) is metabolized via the kynurenine (KYN) and 5-HT pathways. Indoleamine 2,3-dioxygenase 1 (IDO1) is the first metabolizing enzyme in the TRP-KYN pathway which is inducible by pro-inflammatory cytokines, involved depression-like behavior via 5-HT depletion due to decreased level of TRP in the 5-HT pathway. Kynurenine 3-monooxygenase (KMO) is the enzyme in the metabolism of KYN to 3-hydroxykynurenine. KMO deficiency increases level of kynurenic acid (KA), a KYN metabolite by kynurenine aminotransferases (KATs) and induces depression-like behavior. Interestingly, Chronic unpredictable mild stress (CUMS) is associated with a disruption of the hypothalamus-pituitary-adrenocortical (HPA) system and increases KA level with decreased KMO expression in the prefrontal cortex. The decrease of KMO may be related to the reduction in expression of microglia, since KMO is mainly found in microglia in the nervous system. CUMS increases KA level via alternation of enzymes from KMO to KAT. KA is α7 nicotinic acetylcholine receptor (α7nAChR) antagonist. Activation of α7nAChR by nicotine or galantamine attenuates CUMS-induced depression-like behaviors. Taken together, depletion of 5-HT by induction of IDO1 and α7nAChR antagonism by KA via decreased KMO expression cause depression-like behavior, suggesting that metabolic alterations in TRP-KYN pathway are highly involved in the pathophysiology of MDD. Therefore, TRP-KYN pathway is expected to be an attractive target for the development of novel diagnosis of MDD and antidepressants.

厚生労働省より承認された重症急性呼吸器症候群コロナウイルス-2(SARS-CoV-2)抗原検査キットのうち6種の性能比較を行った。その結果,1キットのみが突出した検出感度を有していることが観察されRT-PCRのCt値28.0までの検体が検出可能であった。それ以外はほぼ同等の結果であり,Ct値25.0の検体の検出が16.7～100%で可能であった。SARS-CoV-2抗原検査キットは検出感度に若干の差異があるため,導入にあたっては検査キットの性能特性や操作性を踏まえて選定する必要がある。(著者抄録)

厚生労働省より承認された重症急性呼吸器症候群コロナウイルス-2(SARS-CoV-2)抗原検査キットのうち6種の性能比較を行った。その結果,1キットのみが突出した検出感度を有していることが観察されRT-PCRのCt値28.0までの検体が検出可能であった。それ以外はほぼ同等の結果であり,Ct値25.0の検体の検出が16.7～100%で可能であった。SARS-CoV-2抗原検査キットは検出感度に若干の差異があるため,導入にあたっては検査キットの性能特性や操作性を踏まえて選定する必要がある。(著者抄録)

The partial loss of liver due to liver transplantation or acute liver failure induces rapid liver regeneration. Recently, we reported that the selective inhibition of indoleamine 2,3‑dioxygenase (Ido) 1 promotes early liver regeneration. However, the role of Ido2 in liver regeneration remains unclear. Wild‑type (WT) and Ido2‑deficient (Ido2‑KO) mice were subjected to 70% partial hepatectomy (PHx). Hepatocyte growth was measured using immunostaining. The mRNA expression of inflammatory cytokines and production of kynurenine in intrahepatic mononuclear cells (MNCs) were analyzed using reverse transcription‑quantitative PCR and high‑performance liquid chromatography. The activation of NF‑κB was determined by both immunocytochemistry and western blotting analysis. The ratio of liver to body weight and the frequency of proliferation cells after PHx were significantly higher in Ido2‑KO mice compared with in WT mice. The expression of IL‑6 and TNF‑α in MNCs were transiently increased in Ido2‑KO mice. The nuclear transport of NF‑κB was significantly higher in peritoneal macrophages of Ido2‑KO mice compared with WT mice. These results suggested that Ido2 deficiency resulted in transiently increased production of inflammatory cytokines through the activation of NF‑kB, thereby promoting liver regeneration. Therefore, the regulation of Ido2 expression in MNCs may play a therapeutic role in liver regeneration under injury and disease conditions.

うつ病の病態にはモノアミン仮説が提唱されており，抗うつ薬の主流が選択的セロトニン（5-HT）再取り込み阻害薬であることから，特に5-HT神経系の機能低下が広く受け入れられている．しかし，患者の約1/3は既存の抗うつ薬に対して難治性であるため，新しい創薬ターゲットに対する新規抗うつ薬の開発が求められている．トリプトファン（TRP）は5-HT経路だけでなくキヌレニン（KYN）経路においても代謝される．インドールアミン2,3-ジオキシゲナーゼ1（IDO1）は，TRP-KYN経路の代謝を行う最初の律速酵素である．IDO1は炎症性サイトカインによって強く誘導され，TRPを代謝し，5-HT経路で代謝されるTRPレベルを低下させ，その結果，5-HT合成を抑制し，うつ様行動を惹起する．下流のキヌレニン-3-モノオキシゲナーゼ（KMO）は，KYNを3-ヒドロキシキヌレニンに代謝する重要な酵素である．KMOが欠損すると，キヌレニンアミノトランスフェラーゼ（KAT）によりKYNが代謝され，キヌレン酸（KA）が増加し，うつ様行動が惹起される．一方，慢性予測不能軽度ストレス（CUMS）は視床下部－下垂体－副腎皮質（HPA）系を破綻させ，前頭前野におけるKMOの発現が低下し，KAを増加させる．これにはCUMSによるKMOを主に発現するミクログリアの減少を伴っている．KAはα7ニコチン性アセチルコリン受容体（α7nAChR）アンタゴニスト作用を有する．ニコチンやガランタミンによるα7nAChRの活性化により，CUMS誘発のうつ病様行動が減弱される．IDO1の誘導による5-HT合成抑制と，KMO発現低下を介したKAレベルの増加によるα7nAChR拮抗作用はうつ様行動を引き起こすことから，TRP-KYN経路の代謝的変化がうつ病の病態に深く関与していると考えられる．TRP-KYN経路は，うつ病の新規診断方法や抗うつ薬の開発に向けた魅力的なターゲットになることが期待される．

Interstitial pneumonia of uncertain cause is referred to as idiopathic interstitial pneumonia (IIP). Among the various types of IIPs, the prognosis of cases of idiopathic pulmonary fibrosis (IPF) is extremely poor, and accurate differentiation between IPF and non-IPF pneumonia is critical. In this study, we consider deep learning (DL) methods owing to their excellent image classification capabilities. Although DL models require large quantities of training data, collecting a large number of pathological specimens is difficult for rare diseases. In this study, we propose an end-to-end scheme to automatically classify IIPs using a convolutional neural network (CNN) model. To compensate for the lack of data on rare diseases, we introduce a two-step training method to generate pathological images of IIPs using a generative adversarial network (GAN). Tissue specimens from 24 patients with IIPs were scanned using a whole slide scanner, and the resulting images were divided into patch images with a size of 224 × 224 pixels. A progressive growth GAN (PGGAN) model was trained using 23,142 IPF images and 7817 non-IPF images to generate 10,000 images for each of the two categories. The images generated by the PGGAN were used along with real images to train the CNN model. An evaluation of the images generated by the PGGAN showed that cells and their locations were well-expressed. We also obtained the best classification performance with a detection sensitivity of 97.2% and a specificity of 69.4% for IPF using DenseNet. The classification performance was also improved by using PGGAN-generated images. These results indicate that the proposed method may be considered effective for the diagnosis of IPF.

Abstract Artificial intelligence (AI) applications in medical imaging continue facing the difficulty in collecting and using large datasets. One method proposed for solving this problem is data augmentation using fictitious images generated by generative adversarial networks (GANs). However, applying a GAN as a data augmentation technique has not been explored, owing to the quality and diversity of the generated images. To promote such applications by generating diverse images, this study aims to generate free-form lesion images from tumor sketches using a pix2pix-based model, which is an image-to-image translation model derived from GAN. As pix2pix, which assumes one-to-one image generation, is unsuitable for data augmentation, we propose StylePix2pix, which is independently improved to allow one-to-many image generation. The proposed model introduces a mapping network and style blocks from StyleGAN. Image generation results based on 20 tumor sketches created by a physician demonstrated that the proposed method can reproduce tumors with complex shapes. Additionally, the one-to-many image generation of StylePix2pix suggests effectiveness in data-augmentation applications.

In computed tomography colonography (CTC), an electric cleansing technique is used to mix barium with residual fluid, and colon residue is removed by image processing. However, a nonhomogenous mixture of barium and residue may not be properly removed. We developed an electronic cleansing method using CycleGAN, a deep learning technique, to assist diagnosis in CTC. In this method, an original computed tomography (CT) image taken during a CTC examination and a manually cleansed image in which the barium area was manually removed from the original CT image were prepared and converted to an image in which the barium was removed from the original CT image using CycleGAN. In the experiment, the electric cleansing images obtained using the conventional method were compared with those obtained using the proposed method. The average barium cleansing rates obtained by the conventional and proposed methods were 72.3% and 96.3%, respectively. A visual evaluation of the images showed that it was possible to remove only barium without removing the intestinal tract. Furthermore, the extraction of colorectal polyps and early stage cancerous lesions in the colon was performed as in the conventional method. These results indicate that the proposed method using CycleGAN may be useful for accurately visualizing the colon without barium.

The COVID-19 vaccine will be safe and effective in solid organ transplant recipients (SOTs). However, the blunted antibody responses were also of concern. Few studies have reported prolonged serologic follow-up after 2 doses of BNT162b2 vaccine in SOTs. We performed a single-center, prospective observational study of 78 SOTs who received 2 doses of BNT162b2 vaccine. We identified the trajectory of antibody titers after vaccination among SOTs with or without mycophenolate mofetil (MMF) or withdrawn from MMF. We found low seroconversion rates (29/42: 69%) and low antibody titers in SOTs treated with MMF. An inverse linear relationship between neutralizing antibody titers and MMF concentration was confirmed in restricted cubic spline plots (P for effect < .01, P for nonlinearity = .08). For the trajectory of antibody responses, seroconversion and improved antibody titers were observed after withdrawal from MMF in SOTs who showed seronegative or low antibody titers at the first visit after 2 doses of vaccine (P for effect < .01, P for nonlinearity < .05, and P for interaction < .01). We identified increased B-cell counts after withdrawal from MMF (P < .01). The recovery of antibody responses was seen in SOTs withdrawn from MMF. The trajectories of antibody responses were modified by MMF administration.

Objectives High concentrations of low-density lipoprotein cholesterol (LDL-C) are a risk factor for cardiovascular disease. We validated the efficacy of the Martin method is useful in the estimation of LDL-C concentrations was validated in Japanese populations and derived a modified Martin method for easy laboratory information system applications. Methods We created 3 subject groups, including 2664 health check-up participants registered with the Resource Center for Health Science, 29,806 clinical patients (A) in the Gifu University Hospital, and 113,716 clinical patients (B) in the Fujita Health University Hospital. Each method to estimate serum LDL-C concentrations (Friedewald formula, Martin method and modified Martin method) was validated by correlation analysis with serum LDL-C concentrations measured using a direct method Results The correlation coefficients with the direct method in terms of the Friedewald formula, Martin method, and modified Martin method were 0.963, 0.972 and 0.970 in the health check-up participants; 0.946, 0.962 and 0.961 in clinical patients A; and 0.961, 0.979 and 0.978 in clinical patients B, respectively. Concordance ratios with using the direct method in the Friedewald formula, Martin method and modified Martin method were 82.8%, 85.5% and 85.3% in the health check-up participants; 76.4%, 80.5% and 80.2% in clinical patients A; and 76.1%, 82.6% and 82.6% in clinical patients B, respectively. Conclusion Our results show that the Martin and modified Martin methods display good performance in terms of the estimation of LDL-C concentrations among triglyceride concentrations of a wide range, and they may thus be useful for estimating LDL-C concentrations.

OBJECTIVES: High concentrations of low-density lipoprotein cholesterol (LDL-C) are a risk factor for cardiovascular disease. We validated the efficacy of the Martin method is useful in the estimation of LDL-C concentrations was validated in Japanese populations and derived a modified Martin method for easy laboratory information system applications. METHODS: We created 3 subject groups, including 2664 health check-up participants registered with the Resource Center for Health Science, 29,806 clinical patients (A) in the Gifu University Hospital, and 113,716 clinical patients (B) in the Fujita Health University Hospital. Each method to estimate serum LDL-C concentrations (Friedewald formula, Martin method and modified Martin method) was validated by correlation analysis with serum LDL-C concentrations measured using a direct method. RESULTS: The correlation coefficients with the direct method in terms of the Friedewald formula, Martin method, and modified Martin method were 0.963, 0.972 and 0.970 in the health check-up participants; 0.946, 0.962 and 0.961 in clinical patients A; and 0.961, 0.979 and 0.978 in clinical patients B, respectively. Concordance ratios with using the direct method in the Friedewald formula, Martin method and modified Martin method were 82.8%, 85.5% and 85.3% in the health check-up participants; 76.4%, 80.5% and 80.2% in clinical patients A; and 76.1%, 82.6% and 82.6% in clinical patients B, respectively. CONCLUSION: Our results show that the Martin and modified Martin methods display good performance in terms of the estimation of LDL-C concentrations among triglyceride concentrations of a wide range, and they may thus be useful for estimating LDL-C concentrations.

Endoscopy is widely applied in the examination of gastric cancer. However, extensive knowledge and experience are required, owing to the need to examine the lesion while manipulating the endoscope. Various diagnostic support techniques have been reported for this examination. In our previous study, segmentation of invasive areas of gastric cancer was performed directly from endoscopic images and the detection sensitivity per case was 0.98. This method has challenges of false positives and computational costs because segmentation was applied to all healthy images that were captured during the examination. In this study, we propose a cascaded deep learning model to perform categorization of endoscopic images and identification of the invasive region to solve the above challenges. Endoscopic images are first classified as normal, showing early gastric cancer and showing advanced gastric cancer using a convolutional neural network. Segmentation on the extent of gastric cancer invasion is performed for the images classified as showing cancer using two separate U-Net models. In an experiment, 1208 endoscopic images collected from healthy subjects, 533 images collected from patients with early stage gastric cancer, and 637 images from patients with advanced gastric cancer were used for evaluation. The sensitivity and specificity of the proposed approach in the detection of gastric cancer via image classification were 97.0% and 99.4%, respectively. Furthermore, both detection sensitivity and specificity reached 100% in a case-based evaluation. The extent of invasion was also identified at an acceptable level, suggesting that the proposed method may be considered useful for the classification of endoscopic images and identification of the extent of cancer invasion.