Nodeless electron pairing in CsV3Sb5-derived kagome superconductors.

The newly discovered kagome superconductors represent a promising platform for investigating the interplay between band topology, electronic order and lattice geometry1-9. Despite extensive research efforts on this system, the nature of the superconducting ground state remains elusive10-17. In particular, consensus on the electron pairing symmetry has not been achieved so far18-20, in part owing to the lack of a momentum-resolved measurement of the superconducting gap structure. Here we report the direct observation of a nodeless, nearly isotropic and orbital-independent superconducting gap in the momentum space of two exemplary CsV3Sb5-derived kagome superconductors-Cs(V0.93Nb0.07)3Sb5 and Cs(V0.86Ta0.14)3Sb5-using ultrahigh-resolution and low-temperature angle-resolved photoemission spectroscopy. Remarkably, such a gap structure is robust to the appearance or absence of charge order in the normal state, tuned by isovalent Nb/Ta substitutions of V. Our comprehensive characterizations of the superconducting gap provide indispensable information on the electron pairing symmetry of kagome superconductors, and advance our understanding of the superconductivity and intertwined electronic orders in quantum materials.

Overexpression of JNK-associated leucine zipper protein induces chromosomal instability through interaction with dynein light intermediate chain 1.

The c-Jun N-terminal kinase-associated leucine zipper protein (JLP), a scaffold protein of mitogen-activated protein kinase signaling pathways, is a multifunctional protein involved in a variety of cellular processes. It has been reported that JLP is overexpressed in various types of cancer and is expected to be a potential therapeutic target. However, whether and how JLP overexpression affects non-transformed cells remain unknown. Here, we aimed to investigate the effect of JLP overexpression on chromosomal stability in human non-transformed cells and the mechanisms involved. We found that aneuploidy was induced in JLP-overexpressed cells. Moreover, we established JLP-inducible cell lines and observed an increased frequency of chromosome missegregation, reduced time from nuclear envelope breakdown to anaphase onset, and decreased levels of the spindle assembly checkpoint (SAC) components at the prometaphase kinetochore in cells overexpressing the wild-type JLP. In contrast, we observed that a point mutant JLP lacking the ability to interact with dynein light intermediate chain 1 (DLIC1) failed to induce chromosomal instability. Our results suggest that overexpression of the wild-type JLP facilitates premature SAC silencing through interaction with DLIC1, leading to aneuploidy. This study provides a novel insight into the mechanism through which JLP overexpression is associated with cancer development and progression.

Effect of levodopa on pathological gait in Dravet syndrome: A randomized crossover trial using three-dimensional gait analysis.

OBJECTIVE: Individuals with Dravet syndrome (DS) exhibit progressive gait disturbance. No quantitative studies have been conducted to evaluate the effectiveness of medication for gait disturbance. Therefore, the aim of this study was to evaluate the effectiveness of levodopa for pathological gait in people with DS using three-dimensional gait analysis (3DGA). METHODS: Nine individuals with DS, ages 6-20 years, participated in a crossover study of levodopa and were randomly assigned to the levodopa precedence or no levodopa precedence group. Levodopa/carbidopa hydrate was prescribed at a dose of 5 mg/kg/day (body weight <60 kg) or 300 mg/day (body weight ≥60 kg). The medication was taken for 4-6 weeks (4-week washout period). 3DGA was performed three times before the study, with and without levodopa. A mixed-effects model was used to evaluate the effectiveness of levodopa. The primary outcome was the change in the Gait Deviation Index (GDI). In addition, spatiotemporal gait parameters, 6-minute walking distance (6MD), and balance were evaluated. The correlation between the effectiveness of levodopa and age or gait performance before starting levodopa was analyzed. RESULTS: Levodopa improved the GDI by 4.2 points, (p = .029), 6MD by 52 m (p = .002), and balance test result by 4.1 mm (p = .011) in participants with DS. No severe adverse events were observed, with the exception of one participant, who exhibited fever and consequently stopped taking levodopa. Levodopa was more effective in younger participants with a higher baseline gait performance. SIGNIFICANCE: Our randomized crossover trial showed that levodopa has the potential to improve gait disturbance in people with DS.

Collagen XIII Is the Key Molecule of Neurovascular Junctions in the Neuroendocrine System.

INTRODUCTION: Axons of magnocellular neurosecretory cells project from the hypothalamus to the posterior lobe (PL) of the pituitary. In the PL, a wide perivascular space exists between the outer basement membrane (BM), where nerve axons terminate, and the inner BM lining the fenestrated capillaries. Hypothalamic axon terminals and outer BMs in the PL form neurovascular junctions. We previously had found that collagen XIII is strongly localized in the outer BMs. In this study, we investigated the role of collagen XIII in the PL of rat pituitaries. METHODS: We first studied the expression of Col13a1, the gene encoding the α1 chains of collagen XIII, in rat pituitaries via quantitative real-time polymerase chain reaction and in situ hybridization. We observed the distribution of COL13A1 in the rat pituitary using immunohistochemistry and immunoelectron microscopy. We examined the expression of Col13a1 and the distribution of COL13A1 during the development of the pituitary. In addition, we examined the effects of water deprivation and arginine vasopressin (AVP) signaling on the expression of Col13a1 in the PL. RESULTS: Col13a1 was expressed in NG2-positive pericytes, and COL13A1 signals were localized in the outer BM of the PL. The expression of Col13a1 was increased by water deprivation and was regulated via the AVP/AVPR1A/Gαq/11 cascade in pericytes of the PL. CONCLUSION: These results suggest that pericytes surrounding fenestrated capillaries in the PL secrete COL13A1 and are involved in the construction of neurovascular junctions. COL13A1 is localized in the outer BM surrounding capillaries in the PL and may be involved in the connection between capillaries and axon terminals.

Development of UTX-143, a selective sodium-hydrogen exchange subtype 5 inhibitor, using amiloride as a lead compound.

NHE5, an isoform of the Na+/H+ exchanger (NHE) protein, is an ion-transporting membrane protein that regulates intracellular pH and is highly expressed in colorectal adenocarcinoma. Therefore, we hypothesized that NHE5 inhibitors can be used as anticancer drugs. However, because NHE1 is ubiquitously expressed in all cells, it is extremely important to demonstrate its selective inhibitory activity against NHE5. We used amiloride, an NHE non-selective inhibitor, as a lead compound and created UTX-143, which has NHE5-selective inhibitory activity, using a structure-activity relationship approach. UTX-143 showed selective cytotoxic effects on cancer cells and reduced the migratory and invasive abilities of cancer cells. These results suggest a new concept wherein drugs exhibit cancer-specific cytotoxic effects through selective inhibition of NHE5 and the possibility of UTX-143 as a lead NHE5-selective inhibitor.

The membrane-linked adaptor FRS2ß fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis.

Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2ß, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2ß deficiency in mouse mammary tumor virus (MMTV)-ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2ß-deficient premalignant tissues. We found that colocalization of FRS2ß and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor-κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB-induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2ß contain more stroma. The elucidation of the FRS2ß-NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.

m6A RNA methylation regulates the transcription factors JUN and JUNB in TGF-ß-induced epithelial-mesenchymal transition of lung cancer cells.

N6-methyladenosine (m6A) is the most common internal chemical modification of mRNAs involved in many pathological processes including various cancers. In this study, we investigated the m6A-dependent regulation of JUN and JUNB transcription factors (TFs) during transforming growth factor-beta-induced epithelial-mesenchymal transition (EMT) of A549 and LC2/ad lung cancer cell lines, as the function and regulation of these TFs within this process remains to be clarified. We found that JUN and JUNB played an important and nonredundant role in the EMT-inducing gene expression program by regulating different mesenchymal genes and that their expressions were controlled by methyltransferase-like 3 (METTL3) m6A methyltransferase. METTL3-mediated regulation of JUN expression is associated with the translation process of JUN protein but not with the stability of JUN protein or mRNA, which is in contrast with the result of m6A-mediated regulation of JUNB mRNA stability. We identified the specific m6A motifs responsible for the regulation of JUN and JUNB in EMT within 3'UTR of JUN and JUNB. Furthermore, we discovered that different m6A reader proteins interacted with JUN and JUNB mRNA and controlled m6A-dependent expression of JUN protein and JUNB mRNA. These results demonstrate that the different modes of m6A-mediated regulation of JUN and JUNB TFs provide critical input in the gene regulatory network during transforming growth factor-beta-induced EMT of lung cancer cells.

Caveolae-mediated endocytosis pathway regulates endothelial fenestra homeostasis in the rat pituitary.

Endothelial fenestrae are transcellular pores separated by diaphragms formed by plasmalemma vesicle-associated proteins (PLVAP) and function as channels for peptide hormones and other substances. Caveola, a key regulator of clathrin-independent endocytosis, may be involved in the invagination and fusion of plasma membranes, which are essential for fenestra formation. In this study, we first found that caveolin-1 and -2, the major components of caveolae, was localized in fenestrated endothelial cells in the anterior lobe of the rat pituitary by immunohistochemistry. As we also observed caveolae in the endothelial cells of the anterior lobe of the rat pituitary by transmission electron microscopy, we studied the relationship between the caveolae-mediated endocytosis pathway and fenestrae structure in cultured endothelial cells isolated from the anterior lobe of the rat pituitary (CECAL) by immunofluorescence staining and scanning electron microscopy. The inhibition of caveolae-mediated endocytosis by genistein enlarged the PLVAP-positive oval-shaped structure that represented the sieve plate and induced the formation of a doughnut-shaped bulge around the fenestra in CECAL. In contrast, the acceleration of caveolae-mediated endocytosis by okadaic acid induced the diffusion of PLVAP-positive signals in the cytoplasm and reduced the number of fenestrae in CECAL. These results indicate that the caveolae-mediated endocytosis pathway is involved in the fenestra homeostasis in the fenestrated endothelial cells of the rat pituitary.

ASH2L, a COMPASS core subunit, is involved in the cell invasion and migration of triple-negative breast cancer cells through the epigenetic control of histone H3 lysine 4 methylation.

ASH2L (Absent-Small-Homeotic-2-Like protein) is a core subunit of the COMPASS (COMplex of Proteins ASsociated with Set1) complex, the most notable writer of the methylation of histone H3 lysine 4 (H3K4). The COMPASS complex regulates active promoters or enhancers for gene expression, and its dysfunction is associated with aberrant development and disease. Here, we demonstrated that ASH2L mediated the cell invasion and migration activity of triple-negative breast cancer cells through the interaction with the COMPASS components and the target genomic regions. Transcriptome analysis indicated a potential correlation between ASH2L and the genes involved in inflammatory/immune responses. Among them, we found that the intrinsic expression of IL1B (interleukin 1 beta), an essential proinflammatory gene, was directly regulated by ASH2L. These results revealed a novel role of ASH2L on the maintenance of breast cancer malignancy possibly through H3K4 methylation of the target inflammatory/immune responsive genes.

Potential biomarker proteins for aspiration pneumonia detected by shotgun proteomics using buccal mucosa samples: a cross-sectional case-control study.

BACKGROUND: Aspiration pneumonia (AP), which is a major cause of death in the elderly, does present with typical symptoms in the early stages of onset, thus it is difficult to detect and treat at an early stage. In this study, we identified biomarkers that are useful for the detection of AP and focused on salivary proteins, which may be collected non-invasively. Because expectorating saliva is often difficult for elderly people, we collected salivary proteins from the buccal mucosa. METHODS: We collected samples from the buccal mucosa of six patients with AP and six control patients (no AP) in an acute-care hospital. Following protein precipitation using trichloroacetic acid and washing with acetone, the samples were analyzed by liquid chromatography and tandem mass spectrometry (LC-MS/MS). We also determined the levels of cytokines and chemokines in non-precipitated samples from buccal mucosa. RESULTS: Comparative quantitative analysis of LC-MS/MS spectra revealed 55 highly (P values < 0.10) abundant proteins with high FDR confidence (q values < 0.01) and high coverage (> 50%) in the AP group compared with the control group. Among the 55 proteins, the protein abundances of four proteins (protein S100-A7A, eukaryotic translation initiation factor 1, Serpin B4, and peptidoglycan recognition protein 1) in the AP group showed a negative correlation with the time post-onset; these proteins are promising AP biomarker candidates. In addition, the abundance of C-reactive protein (CRP) in oral samples was highly correlated with serum CRP levels, suggesting that oral CRP levels may be used as a surrogate to predict serum CRP in AP patients. A multiplex cytokine/chemokine assay revealed that MCP-1 tended to be low, indicating unresponsiveness of MCP-1 and its downstream immune pathways in AP. CONCLUSION: Our findings suggest that oral salivary proteins, which are obtained non-invasively, can be utilized for the detection of AP.

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan.

BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

[A Case of Laparoscopic Repair for Hiatal Hernia Occurred Five Years after Esophagectomy for Esophageal Cancer].

A 70s man underwent minimally invasive esophagectomy and gastric conduit reconstruction via the posterior mediastinal route for early esophageal cancer 5 years ago. Three days prior to hospital visit, he presented with abdominal fullness, left chest pain, and vomiting. A CT revealed a postoperative hiatal hernia, and emergency surgery was performed laparoscopically. The laparoscopic findings showed that the transverse colon had prolapsed into the left thoracic cavity through the esophageal hiatus on the left side of the gastric conduit. The transverse colon had no sign of necrosis. The diaphragmatic defect was closed with unabsorbable suture. Increased bowel motility due to postoperative fat loss in the mesentery and intra-abdominal pressure are thought to be causes of the hernia. In addition, decreased adhesion formation due to endoscopic surgery may be a contributing factor. Although there is no unanimous opinion regarding the suture fixation of the conduit to the diaphragm after esophagectomy, it should be performed to prevent a herniation. Postoperative hiatal hernia occurs more than 5 years after the surgery is relatively rare, but its occurrence should be noted.

KDM2B is involved in the epigenetic regulation of TGF-ß-induced epithelial-mesenchymal transition in lung and pancreatic cancer cell lines.

Polycomb repressive complex-1 (PRC1) induces transcriptional repression by regulating monoubiquitination of lysine 119 of histone H2A (H2AK119) and as such is involved in a number of biological and pathological processes including cancer development. Previously we demonstrated that PRC2, which catalyzes the methylation of histone H3K27, has an essential function in TGF-ß-induced epithelial-mesenchymal transition (EMT) of lung and pancreatic cancer cell lines. Since the cooperative activities of PRC1 and PRC2 are thought to be important for transcriptional repression in EMT program, we investigated the role of KDM2B, a member of PRC1 complex, on TGF-ß-induced EMT in this study. Knockdown of KDM2B inhibited TGF-ß-induced morphological conversion of the cells and enhanced cell migration and invasion potentials as well as the expression changes of EMT-related marker genes. Overexpression of KDM2B influenced the expression of several epithelial marker genes such as CDH1, miR200a, and CGN and enhanced the effects of TGF-ß. Mechanistic investigations revealed that KDM2B specifically recognized the regulatory regions of CDH1, miR200a, and CGN genes and induced histone H2AK119 monoubiquitination as a component of PRC1 complex, thereby mediating the subsequent EZH2 recruitment and histone H3K27 methylation process required for gene repression. Studies using KDM2B mutants confirmed that its DNA recognition property but not its histone H3 demethylase activity was indispensable for its function during EMT. This study demonstrated the significance of the regulation of histone H2A ubiquitination in EMT process and provided the possibility to develop novel therapeutic strategies for the treatment of cancer metastasis.

Very low prevalence of ultrasound-detected tenosynovial abnormalities in healthy subjects throughout the age range: OMERACT ultrasound minimal disease study.

OBJECTIVES: This study aimed to determine the prevalence of ultrasound-detected tendon abnormalities in healthy subjects (HS) across the age range. METHODS: Adult HS (age 18-80 years) were recruited in 23 international Outcome Measures in Rheumatology ultrasound centres and were clinically assessed to exclude inflammatory diseases or overt osteoarthritis before undergoing a bilateral ultrasound examination of digit flexors (DFs) 1-5 and extensor carpi ulnaris (ECU) tendons to detect the presence of tenosynovial hypertrophy (TSH), tenosynovial power Doppler (TPD) and tenosynovial effusion (TEF), usually considered ultrasound signs of inflammatory diseases. A comparison cohort of patients with rheumatoid arthritis (RA) was taken from the Birmingham Early Arthritis early arthritis inception cohort. RESULTS: 939 HS and 144 patients with RA were included. The majority of HS (85%) had grade 0 for TSH, TPD and TEF in all DF and ECU tendons examined. There was a statistically significant difference in the proportion of TSH and TPD involvement between HS and subjects with RA (HS vs RA p<0.001). In HS, there was no difference in the presence of ultrasound abnormalities between age groups. CONCLUSIONS: Ultrasound-detected TSH and TPD abnormalities are rare in HS and can be regarded as markers of active inflammatory disease, especially in newly presenting RA.

Regulation of fenestra formation via actin-dynamin2 interaction in rat pituitary endothelial cells.

Endothelial fenestrae are transcellular pores divided by a diaphragm consisting of plasmalemma vesicle-associated protein (PLVAP). They function as a channel for peptide hormones and other substances. Invagination of the plasma membrane is necessary for the fenestra formation. The actin cytoskeleton is essential for scission of endocytic vesicles from the invaginated plasma membrane. Therefore, we examined the involvement of the actin cytoskeleton in fenestra formation in cultured endothelial cells isolated from the anterior lobe (AL) of the rat pituitary, using immunofluorescence and scanning electron microscopy. Inhibition of polymerization and depolymerization of the actin cytoskeleton by latrunculin A and jasplakinolide, respectively, remarkably increased the PLVAP-positive sieve plate area and number of fenestrae. Jasplakinolide significantly affected the arrangement of the fenestra on the cell surface, resulting in parallel serpentine furrows of the fenestra. These results suggest that the actin cytoskeleton not only induces fenestra formation but also regulates cell arrangement. Dynamin is a scission protein of the invaginated plasma membrane and interacts with the actin cytoskeleton. We found that dynamin2 is mainly expressed in the endothelial cells of the rat AL. We then investigated the function of dynamin2 by the treatment with dyngo-4a, a potent inhibitor of dynamin1 and dynamin2, on the fenestra formation. As a result, the PLVAP-positive area is significantly increased by the treatment. These results show that the actin-dynamin2 interaction is essential for the control of the fenestra formation in endothelial cells of rat AL. In conclusion, the actin cytoskeleton and dynamin2 function as regulators of endothelial fenestra formation.

Improvement of recombinant miraculin production in transgenic tomato by crossbreeding-based genetic background modification.

An important optimization step in plant-based recombinant protein production systems is the selection of an appropriate cultivar after a potential host has been determined. Previously, we have shown that transgenic tomatoes of the variety 'Micro-Tom' accumulate incredibly high levels of miraculin (MIR) due to the introduction of MIR gene controlled by a CaMV35S promoter and a heat-shock protein terminator. However, 'Micro-Tom' is unsuitable for commercial production of MIR as it is a dwarf cultivar characterized by small-sized fruit and poor yield. Here, we used the crossbreeding approach to transfer the high MIR accumulation trait of transgenic 'Micro-Tom' tomatoes to 'Natsunokoma' and 'Aichi First', two commercial cultivars producing medium and large fruit sizes, respectively. Fruits of the resultant crossbred lines were larger (~ 95 times), but their miraculin accumulation levels (~ 1,062 µg/g fresh mass) were comparable to the donor cultivar, indicating that the high miraculin accumulation trait was preserved regardless of fruit size or cultivar. Further, the transferred trait resulted in a 3-4 fold increase in overall miraculin production than that of the previously reported line 5B. These findings demonstrate the effectiveness of crossbreeding in improving MIR production in tomatoes and could pave the way for a more efficient production of recombinant proteins in other plants.

Epstein-Barr virus tegument protein BGLF2 in exosomes released from virus-producing cells facilitates de novo infection.

BACKGROUND: Viruses must adapt to the environment of their host cells to establish infection and persist. Diverse mammalian cells, including virus-infected cells, release extracellular vesicles such as exosomes containing proteins and miRNAs, and use these vesicles to mediate intercellular communication. However, the roles of exosomes in viral infection remain unclear. RESULTS: We screened viral proteins to identify those responsible for the exosome-mediated enhancement of Epstein-Barr virus (EBV) infection. We identified BGLF2 protein encapsulated in exosomes, which were released by EBV-infected cells. BGLF2 protein is a tegument protein that exists in the space between the envelope and nucleocapsid, and it is released into the cytoplasm shortly after infection. BGLF2 protein-containing exosomes enhanced viral gene expression and repressed innate immunity, thereby supporting the EBV infection. CONCLUSIONS: The EBV tegument protein BGLF2 is encapsulated in exosomes and released by infected cells to facilitate the establishment of EBV infection. These findings suggest that tegument proteins support viral infection not only between the envelope and nucleocapsid, as well as in extraviral particles such as exosomes. Video abstract.

Effect of Rapid Centrifugation Using High Centrifugal Force on Procoagulant Activity in Plasma Samples.

BACKGROUND: International guidelines for plasma preparation are not always observed because high-speed centrifugation reduces turnaround times. This study assessed the effect of rapid centrifugation on sample quality and clotting time. METHODS: Blood samples were obtained from five healthy volunteers. Normal blood samples were spiked with unfractionated heparin to produce abnormal samples. The normal and abnormal coagulation ability samples were centrifuged at 1,500 x g for 15 minutes, 2,000 x g for 10 minutes (both according to international guidelines), or 3,500 x g for 7 minutes (rapid centrifugation). Microparticle procoagulant activity (MP activity), prothrombin time (PT), and activated partial thromboplastin time (APTT) were measured in the supernatant plasma. RESULTS: Rapid centrifugation caused a significant increase in MP activity compared to the two recommended conditions and significantly shortened clotting times, particularly APTT in the abnormal samples. CONCLUSIONS: Rapid centrifugation should not be used for routine processing of blood samples for coagulopathy screening and monitoring patients on anticoagulant therapy.

Simultaneous occurrence of accelerated nodulosis in lungs, liver, and kidneys, and acute exacerbation of interstitial pneumonia in a patient with rheumatoid arthritis: an autopsy case report.

BACKGROUND: Accelerated nodulosis (ARN) is a rare variant of rheumatoid nodules (RNs) that is characterized by a rapid onset or the worsening of RNs. It generally develops at the fingers in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). Few case reports have described ARN at an extracutaneous location. CASE PRESENTATION: An elderly patient with long-standing RA was admitted to our hospital with acute respiratory failure. Computed tomography upon admission showed diffuse ground-glass opacities superimposed with subpleural reticular shadowing and honeycombing and multiple nodules in the lungs and liver. Despite the discontinuation of MTX and introduction of an immunosuppressive regimen with pulse methylprednisolone followed by a tapering dose of prednisolone and intravenous cyclophosphamide, the patient died due to the acute exacerbation (AE) of RA-related interstitial lung disease (ILD) following the parallel waxing and waning of a diffuse interstitial shadow and pulmonary and liver nodules. At autopsy, RNs were scattered throughout both lung fields in addition to extensive interstitial changes. RNs were also detected in the liver and kidneys. The foci of cryptococcosis were mainly identified in alveolar spaces. Based on the clinical and pathological findings, these nodules were most consistent with ARN because of acute increases in the size and number of previously detected pulmonary nodules. CONCLUSION: The present case is noteworthy because ARN was concurrently detected in multiple internal organs and may be associated with the AE of RA-related ILD.

Effects of Thoracic Epidural Anesthesia on Systemic and Local Inflammatory Responses in Patients Undergoing Lung Cancer Surgery: A Randomized Controlled Trial.

OBJECTIVE: Inflammatory responses play major roles in the development of acute lung injury following lung cancer surgery. The authors tested the hypothesis that thoracic epidural anesthesia (TEA) during surgery could attenuate both systemic and local inflammatory cytokine productions in patients undergoing lung cancer surgery. DESIGN: A prospective randomized controlled trial. SETTING: At Keio University Hospital, Tokyo, Japan. PARTICIPANTS: Patients scheduled for lung cancer surgery. INTERVENTIONS: Sixty patients were randomly allocated into two groups (n = 30 each group): the epidural group (group E), in which anesthesia was maintained with propofol, fentanyl, rocuronium, and epidural anesthesia with 0.25% levobupivacaine; or the remifentanil group (group R), in which a remifentanil infusion was used as a potent analgesia instead of epidural anesthesia. MEASUREMENTS AND MAIN RESULTS: The lung epithelial lining fluid (ELF) and blood sampling were collected prior to one-lung ventilation (OLV) initiation (T1) and at 30 minutes after the end of OLV (T2). The concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the ELF at T2 were increased significantly compared with those at T1 in both groups. The ELF concentration of IL-6 in group E was significantly lower than that in group R at T2 (median [interquartile range]: 39.7 [13.8-80.2] versus 76.1 [44.9-138.2], p = 0.008). Plasma IL-6 concentrations at T2, which increased in comparison to that at T1, were not significantly different between the two groups. The plasma concentrations of TNF-α did not change in both groups. CONCLUSIONS: This randomized clinical trial suggested that TEA could attenuate local inflammatory responses in the lungs during lung cancer surgery.