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Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) with ST8/SCCmecIV threatens human health. However, its pathogenesis remains unclear. ST8 CA-MRSA (CA-MRSA/J) with SCCmecIVl, which carries the large LPXTG-motif–containing putative adhesin gene, spj, has emerged in Japan. We present the first reported case of death from CA-MRSA/J. The patient was a 64-year-old woman with iliopsoas abscesses complicated by septic pulmonary embolism and multiorgan abscesses. Vancomycin, arbekacin, daptomycin and rifampicin were ineffective. CA-MRSA/J was resistant to erythromycin, clindamycin and antiseptics and was invasive in a HEp-2 cell assay, in contrast to skin-derived villous-adherent CA-MRSA/J. This suggests the strongly invasive pathotype of CA-MRSA/J. Keywords: Community-associated methicillin-resistant Staphylococcus aureus, iliopsoas abscess, pathotype, septic pulmonary embolism, ST8/SCCmecIVl

Background: Selective serotonin reuptake inhibitors (SSRIs) are used for the treatment of several conditions including anxiety disorders, but the basic neurobiology of serotonin function remains unclear. The amygdala and prefrontal cortex are strongly innervated by serotonergic projections and have been suggested to play an important role in anxiety expression. However, serotonergic function in behaviour and SSRI-mediated neurobiological changes remain incompletely understood., Aims: To investigate the neural correlates of subchronic antidepressant administration., Methods: We investigated whether the 2- to 3-week administration of a highly selective SSRI (escitalopram) would alter brain activation on a task robustly shown to recruit the bilateral amygdala and frontal cortices in a large healthy volunteer sample. Participants performed the task during a functional magnetic resonance imaging acquisition before ( n  = 96) and after subchronic escitalopram ( n  = 46, days of administration mean (SD) = 15.7 (2.70)) or placebo ( n  = 40 days of administration mean (SD) = 16.2 (2.90)) self-administration., Results: Compared to placebo, we found an elevation in right amygdala activation to the task after escitalopram administration without significant changes in mood. This effect was not seen in the left amygdala, the dorsomedial region of interest, the subgenual anterior cingulate cortex or the right fusiform area. There were no significant changes in connectivity between the dorsomedial cortex and amygdala or the subgenual anterior cingulate cortex after escitalopram administration., Conclusions: To date, this most highly powered study of subchronic SSRI administration indicates that, contrary to effects often seen in patients with anxiety disorders, subchronic SSRI treatment may increase amygdala activation in healthy controls. This finding highlights important gaps in our understanding of the functional role of serotonin., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: OJR held an MRC-Proximity to discovery award with Roche (who provide in-kind contributions and have sponsored travel for ACP) regarding work on heart-rate variability and anxiety. He also has completed consultancy work for Peak, IESO digital health, Roche and BlackThorn therapeutics. OJR sat on the committee of the British Association for Psychopharmacology until 2022. ACP sits on the Council for the British Association for Psychopharmacology and has received funding from the Wellcome Trust and Academy of Medical Sciences for unrelated projects. TM is currently employed by the Wellcome Trust. The other authors declare no competing interests.

Background and Objectives: Some reports suggest that older patients with traumatic brain injury (TBI) are more likely to experience acute intracranial hemorrhage, resulting in poor outcomes. However, the association between precise chronological age and use of antithrombotic agents with acute intracranial hemorrhage in these patients remains unknown. The aim of this study was to determine factors associated with acute intracranial hemorrhage and poor outcomes in patients with TBI, including chronological age and use of antithrombotic agents., Methods: Patients hospitalized for TBI between January 2006 and December 2021 were included. Patients were categorized by age groups of <65 years, 65 to 74 years, 75 to 84 years, and ≥85 years. Associations between each age group and acute intracranial hemorrhage, a poor outcome at discharge, and in-hospital mortality were evaluated., Results: The cohort included 1086 patients, with 713 (65.7%) in the ≥65 age group. Although chronological age was associated with acute intracranial hemorrhage in patients aged <65 years (odds ratio [OR] 1.02; 95% CI 1.01-1.03), it was not associated with patients aged ≥65 years. None of the antithrombotic agents investigated were associated with acute intracranial hemorrhage in the group aged ≥65 years. Although chronological age was associated with a poor outcome in patients aged <65 years (OR 1.03; 95% CI 1.01-1.07), it was not associated in those aged ≥65 years. The ≥85 year age group (OR 2.30; 95% CI 1.18-4.51) compared with <65 years were significantly associated with a poor outcome. None of the antithrombotic agents investigated were associated with a poor outcome in the group aged ≥65 years., Conclusion: Our findings confirmed the lack of an association of chronological age and antithrombotic agents with acute intracranial hemorrhage in the group of older adults with TBI. Our findings suggest that antithrombotic agents may be safely used, even in older adults., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Anxiety involves the anticipation of aversive outcomes and can impair neurocognitive processes, such as the ability to recall faces encoded during the anxious state. It is important to precisely delineate and determine the replicability of these effects using causal state anxiety inductions in the general population. This study therefore aimed to replicate prior research on the distinct impacts of threat-of-shock-induced anxiety on the encoding and recognition stage of emotional face processing, in a large asymptomatic sample ( n  = 92). We successfully replicated previous results demonstrating impaired recognition of faces encoded under threat-of-shock. This was supported by a mega-analysis across three independent studies using the same paradigm ( n  = 211). Underlying this, a whole-brain fMRI analysis revealed enhanced activation in the posterior cingulate cortex (PCC), alongside previously seen activity in the anterior cingulate cortex (ACC) when combined in a mega-analysis with the fMRI findings we aimed to replicate. We further found replications of hippocampus activation when the retrieval and encoding states were congruent. Our results support the notion that state anxiety disrupts face recognition, potentially due to attentional demands of anxious arousal competing with affective stimuli processing during encoding and suggest that regions of the cingulate cortex play pivotal roles in this., Competing Interests: Competing interestsThe authors declare the following competing interests: Oliver J. Robinson (O.J.R.) ran an investigator-initiated trial with medication donated by Lundbeck (escitalopram and placebo, no financial contribution). He also held an MRC-Proximity to discovery award with Roche and has completed consultancy work for Peak, IESO digital health, Roche and BlackThorn therapeutics. O.J.R. sat on the committee of the British Association of Psychopharmacology until 2022. All other authors declare no competing interests., (© The Author(s) 2024.)

Anginosus group streptococci (AGS) are opportunistic pathogens that reside in the human oral cavity. The β-hemolytic strains of Streptococcus anginosus subsp. anginosus (SAA) produce streptolysin S (SLS), a streptococcal peptide hemolysin. In recent clinical scenarios, AGS, including this species, have frequently been isolated from infections and disorders beyond those in the oral cavity. Consequently, investigating this situation will reveal the potential pathogenicity of AGS to ectopic infections in humans. However, the precise mechanism underlying the cellular response induced by secreted SLS and its relevance to the pathogenicity of AGS strains remain largely unknown. This study aims to elucidate the mechanism underlying the host cellular response of the human acute monocytic leukemia cell line THP-1 to secreted SLS. In THP-1 cells incubated with the culture supernatant of β-hemolytic SAA containing SLS as the sole cytotoxic factor, increased Ca 2+ influx and elevated expression of proinflammatory cytokines were observed. Significantly reduced expression of SLS-dependent upregulated cytokine genes under Ca 2+ -chelating conditions suggests that Ca 2+ influx triggers SLS-dependent cellular responses. Furthermore, SLS-dependent enhanced expression of IL-8 was also implicated in the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. The findings presented in this study are crucial for a comprehensive understanding of the real pathogenicity of SLS-producing β-hemolytic AGS in the latest clinical situations., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Atsushi Tabata reports financial support was provided by Japan Society for the Promotion of Science. Kazuto Ohkura reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (© 2024 The Authors.)

An angiotensin receptor/neprilysin inhibitor (ARNI), a heart failure treatment, is a combination drug made up of sacubitril, a neprilysin inhibitor, and valsartan, a vascular receptor blocker. No human or veterinary studies regarding the effect of ARNI on renal haemodynamics in the absence of cardiac or renal issues exist. Therefore, we investigated the effect of ARNI on renal haemodynamics in five healthy dogs. ARNI was administered to all five dogs at an oral dose of 20 mg/kg twice daily for 4 weeks. Renal haemodynamics were assessed on the day before ARNI administration (BL), on Day 7, and on Day 28. The glomerular filtration rate (GFR) significantly increased on Day 28 compared to BL and Day 7, whereas renal plasma flow increased on Day 7 and Day 28 compared to BL. Systolic blood pressure significantly decreased between BL and Day 28. Plasma atrial natriuretic peptide (ANP) concentrations increased on Day 7 compared to BL. Additionally, ANP concentrations increased on Day 28 in three of the five dogs. Different ANP concentrations were observed in the remaining two dogs. Both urine output volume and heart rate remained relatively stable and did not exhibit significant change. In conclusion, ARNI may enhance renal haemodynamics in healthy dogs. ARNI could be a valuable drug for treating both heart and kidney disease in dogs.

There is a growing focus on the computational aspects of psychiatric disorders in humans. This idea also is gaining traction in nonhuman animal studies. Commenting on a new comprehensive overview of the benefits of applying this approach in translational research by Neville et al. (Cognitive Affective & Behavioral Neuroscience 1-14, 2024), we discuss the implications for translational model validity within this framework. We argue that thinking computationally in translational psychiatry calls for a change in the way that we evaluate animal models of human psychiatric processes, with a shift in focus towards symptom-producing computations rather than the symptoms themselves. Further, in line with Neville et al.'s adoption of the reinforcement learning framework to model animal behaviour, we illustrate how this approach can be applied beyond simple decision-making paradigms to model more naturalistic behaviours., (© 2024. The Author(s).)

We herein report a case of severe fever with thrombocytopenia syndrome (SFTS) with Pasteurella multilocida bacteremia in a 65-year-old man with alcoholic cirrhosis who was admitted to our hospital with anorexia and severe fatigue. Laboratory tests revealed pancytopenia and liver and kidney dysfunction. After admission, he developed impaired consciousness, mucosal hemorrhaging, and septic shock. SFTS virus was detected on polymerase chain reaction testing of blood and throat swabs, and Pasteurella multocida was detected on blood culture. Despite being treated with invasive mechanical ventilation, vasopressors, and antibiotics, the patient's condition progressively deteriorated, and he died four days after admission.

Information on structures of protein-ligand complexes, including comparisons of known and putative protein-ligand-binding pockets, is valuable for protein annotation and drug discovery and development. To facilitate biomedical and pharmaceutical research, we developed PoSSuM (https://possum.cbrc.pj.aist.go.jp/PoSSuM/), a database for identifying similar binding pockets in proteins. The current PoSSuM database includes 191 million similar pairs among almost 10 million identified pockets. PoSSuM drug search (PoSSuMds) is a resource for investigating ligand and receptor diversity among a set of pockets that can bind to an approved drug compound. The enhanced PoSSuMds covers pockets associated with both approved drugs and drug candidates in clinical trials from the latest release of ChEMBL. Additionally, we developed two new databases: PoSSuMAg for investigating antibody-antigen interactions and PoSSuMAF to simplify exploring putative pockets in AlphaFold human protein models.

Although avoidance is a prevalent feature of anxiety-related psychopathology, differences in the measurement of avoidance between humans and non-human animals hinder our progress in its theoretical understanding and treatment. To address this, we developed a novel translational measure of anxiety-related avoidance in the form of an approach-avoidance reinforcement learning task, by adapting a paradigm from the non-human animal literature to study the same cognitive processes in human participants. We used computational modelling to probe the putative cognitive mechanisms underlying approach-avoidance behaviour in this task and investigated how they relate to subjective task-induced anxiety. In a large online study (n = 372), participants who experienced greater task-induced anxiety avoided choices associated with punishment, even when this resulted in lower overall reward. Computational modelling revealed that this effect was explained by greater individual sensitivities to punishment relative to rewards. We replicated these findings in an independent sample (n = 627) and we also found fair-to-excellent reliability of measures of task performance in a sub-sample retested 1 week later (n = 57). Our findings demonstrate the potential of approach-avoidance reinforcement learning tasks as translational and computational models of anxiety-related avoidance. Future studies should assess the predictive validity of this approach in clinical samples and experimental manipulations of anxiety., Competing Interests: YY No competing interests declared, OR OJR's MRC senior fellowship is partially in collaboration with Cambridge Cognition Ltd (who plan to provide in-kind contribution) and he is running an investigator-initiated trial with medication donated by Lundbeck (escitalopram and placebo, no financial contribution). He also holds an MRC-Proximity to discovery award with Roche (who provide in-kind contributions and have sponsored travel for ACP) regarding work on heart-rate variability and anxiety. He also has completed consultancy work for Peak, IESO digital health, Roche and BlackThorn therapeutics. OJR sat on the committee of the British Association of Psychopharmacology until 2022, JR Senior editor, eLife, (© 2023, Yamamori et al.)

Background: Motivational symptoms such as apathy and anhedonia are common in Parkinson's disease (PD), respond poorly to treatment, and are hypothesised to share underlying neural mechanisms. Striatal dopaminergic dysfunction is considered central to motivational symptoms in PD but the association has never been examined longitudinally. We investigated whether progression of dopaminergic dysfunction was associated with emergent apathy and anhedonia symptoms in PD., Methods: Longitudinal cohort study of 412 newly diagnosed patients with PD followed over 5 years as part of the Parkinson's Progression Markers Initiative cohort.Apathy and anhedonia were measured using a composite score derived from relevant items of the 15-item Geriatric Depression Scale (GDS-15) and part I of the MDS-Unified Parkinson's Disease Rating Scale. Dopaminergic neurodegeneration was measured using repeated striatal dopamine transporter (DAT) imaging., Results: Linear mixed-effects modelling across all contemporaneous data points identified a significant negative relationship between striatal DAT specific binding ratio (SBR) and apathy/anhedonia symptoms, which emerged as PD progressed (interaction:β=-0.09, 95% CI (-0.15 to -0.03), p=0.002). Appearance and subsequent worsening of apathy/anhedonia symptoms began on average 2 years after diagnosis and below a threshold striatal DAT SBR level. The interaction between striatal DAT SBR and time was specific to apathy/anhedonia symptoms, with no evidence of a similar interaction for general depressive symptoms from the GDS-15 (excluding apathy/anhedonia items) (β=-0.06, 95% CI (-0.13 to 0.01)) or motor symptoms (β=0.20, 95% CI (-0.25 to 0.65))., Conclusions: Our findings support a central role for dopaminergic dysfunction in motivational symptoms in PD. Striatal DAT imaging may be a useful indicator of apathy/anhedonia risk that could inform intervention strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Anginosus group streptococci (AGS) are opportunistic human pathogens of the oral cavity. The β-hemolytic subgroup of Streptococcus anginosus subsp. anginosus secretes streptolysin S (SLS) and exhibits not only hemolytic activity but also cytotoxicity toward cultured human cell lines. However, the detailed mechanism of action of SLS and the cellular responses of host cells have not yet been fully clarified. To determine the pathogenic potential of SLS-producing β-hemolytic S. anginosus subsp. anginosus, the SLS-dependent response induced in the human oral squamous cell carcinoma HSC-2 cells was investigated to determine the pathogenic potential of SLS-producing β-hemolytic S. anginosus subsp. anginosus. This study revealed that the Ca 2+ influx and the expression of immediate early genes (IEGs) encoding transcription factors such as early growth responses (EGRs) and activator protein-1 (AP-1) were greatly increased in HSC-2 cells incubated with the culture supernatant of SLS-producing β-hemolytic S. anginosus subsp. anginosus. Moreover, this SLS-dependent increase in expression was significantly suppressed by Ca 2+ chelation, except for jun. These results suggest that SLS caused Ca 2+ influx into the cells following greatly enhanced expression of IEG-encoding transcription factors. The results of this study may help in understanding the pathogenicity of SLS-producing AGS., (© 2023. Springer Nature Limited.)

Mitochondrial β-barrel proteins are essential for the transport of metabolites, ions and proteins. The sorting and assembly machinery (SAM) mediates their folding and membrane insertion. We report the cryo-electron microscopy structure of the yeast SAM complex carrying an early eukaryotic β-barrel folding intermediate. The lateral gate of Sam50 is wide open and pairs with the last β-strand (β-signal) of the substrate-the 19-β-stranded Tom40 precursor-to form a hybrid barrel in the membrane plane. The Tom40 barrel grows and curves, guided by an extended bridge with Sam50. Tom40's first β-segment (β1) penetrates into the nascent barrel, interacting with its inner wall. The Tom40 amino-terminal segment then displaces β1 to promote its pairing with Tom40's last β-strand to complete barrel formation with the assistance of Sam37's dynamic α-protrusion. Our study thus reveals a multipoint guidance mechanism for mitochondrial β-barrel folding., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Fear and anxiety are adaptive emotions that serve important defensive functions, yet in excess, they can be debilitating and lead to poor mental health. Computational modelling of behaviour provides a mechanistic framework for understanding the cognitive and neurobiological bases of fear and anxiety, and has seen increasing interest in the field. In this brief review, we discuss recent developments in the computational modelling of human fear and anxiety. Firstly, we describe various reinforcement learning strategies that humans employ when learning to predict or avoid threat, and how these relate to symptoms of fear and anxiety. Secondly, we discuss initial efforts to explore, through a computational lens, approach-avoidance conflict paradigms that are popular in animal research to measure fear- and anxiety-relevant behaviours. Finally, we discuss negative biases in decision-making in the face of uncertainty in anxiety., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Protein-protein interactions (PPIs), such as protein-protein inhibitor, antibody-antigen complex, and supercomplexes play diverse and important roles in cells. Recent advances in structural analysis methods, including cryo-EM, for the determination of protein complex structures are remarkable. Nevertheless, much room remains for improvement and utilization of computational methods to predict PPIs because of the large number and great diversity of unresolved complex structures. This review introduces a wide array of computational methods, including our own, for estimating PPIs including antibody-antigen interactions, offering both historical and forward-looking perspectives., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Background: As the global population ages, the incidence of traumatic brain injury (TBI) is increasing. Whereas mild TBI can impair the cognitive function of older adults, the cause and background of mild TBI-induced cognitive impairment remain unclear, and the evaluation of risk factors for cognitive impairment after mild TBI remains open for consideration, especially in the aging population. This study aimed to evaluate the risks associated with cognitive impairment following mild TBI., Methods: Between January 2006 and December 2018, a total of 2209 patients with TBI required hospitalization in Shimane Prefectural Central Hospital. Mild TBI was defined as a Japan Coma Scale ≤10 at admission. Patients' cognitive function was measured with the Hasegawa Dementia Rating Scale-Revised or Mini-Mental State Examination at least twice during the patients' hospital stays. The odds ratio (OR) and 95% confidence interval (CI) of each considered risk factor was calculated with multivariable logistic regression analysis after univariate analysis., Results: Among 1674 patients with mild TBI, 172 patients underwent cognitive function examinations, of whom 145 (84.3%) were found to have cognitive impairment at discharge. Significant risk factors for cognitive impairment included age (P = 0.008) and hypertension (P = 0.013) in univariate analysis; and age (OR, 1.04: 95% CI, 1.01-1.07) and hypertension (OR, 5.81: 95% CI, 1.22-27.68) by multivariable analysis., Conclusions: Older patients with hypertension displayed a significantly higher risk for cognitive impairment after even mild TBI. These patients warrant careful management after even mild TBI., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Cannabidiol (CBD) and Δ 9 -tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity., Aims: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor)., Method: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach., Results: Study 1 ( N  = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 ( N  = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks., Outcomes: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

Rationale: There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown., Objectives: We sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety., Methods: We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during functional magnetic resonance imaging) and cognitive (emotional appraisal) measures as well as subjective response to experimentally induced anxiety., Results: CBD did not produce effects on brain responses to emotional faces and cognitive measures of emotional processing, or modulate experimentally induced anxiety, relative to placebo., Conclusions: Given the rising popularity of CBD for its putative medical benefits, these findings question whether further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders., (© 2022. The Author(s).)

Translocator assembly and maintenance 41 (Tam41) catalyses the synthesis of cytidine diphosphate diacylglycerol (CDP-DAG), which is a high-energy intermediate phospholipid critical for generating cardiolipin in mitochondria. Although Tam41 is present almost exclusively in eukaryotic cells, a Firmicutes bacterium contains the gene encoding Tam41-type CDP-DAG synthase (FbTam41). FbTam41 converted phosphatidic acid (PA) to CDP-DAG using a ternary complex mechanism in vitro. Additionally, FbTam41 functionally substituted yeast Tam41 in vivo. These results demonstrate that Tam41-type CDP-DAG synthase functions in some prokaryotic cells. We determined the crystal structure of FbTam41 lacking the C-terminal 18 residues in the cytidine triphosphate (CTP)-Mg2+ bound form at a resolution of 2.6 Å. The crystal structure showed that FbTam41 contained a positively charged pocket that specifically accommodated CTP-Mg2+ and PA in close proximity. By using this structure, we constructed a model for the full-length structure of FbTam41 containing the last a-helix, which was missing in the crystal structure. Based on this model, we propose a molecular mechanism for CDP-DAG synthesis in bacterial cells and mitochondria., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Application of cryo-electron microscopy (cryo-EM) is crucially important for ascertaining the atomic structure of large biomolecules such as ribosomes and protein complexes in membranes. Advances in cryo-EM technology and software have made it possible to obtain data with near-atomic resolution, but the method is still often capable of producing only a density map with up to medium resolution, either partially or entirely. Therefore, bridging the gap separating the density map and the atomic model is necessary. Herein, we propose a methodology for constructing atomic structure models based on cryo-EM maps with low-to-medium resolution. The method is a combination of sensitive and accurate homology modeling using our profile-profile alignment method with a flexible-fitting method using molecular dynamics simulation. As described herein, this study used benchmark applications to evaluate the model constructions of human two-pore channel 2 (one target protein in CASP13 with its structure determined using cryo-EM data) and the overall structure of Enterococcus hirae V-ATPase complex.

DNA damage is increased in Alzheimer's disease (AD), while the underlying mechanisms are unknown. Here, we employ comprehensive phosphoproteome analysis, and identify abnormal phosphorylation of 70 kDa subunit of Ku antigen (Ku70) at Ser77/78, which prevents Ku70-DNA interaction, in human AD postmortem brains. The abnormal phosphorylation inhibits accumulation of Ku70 to the foci of DNA double strand break (DSB), impairs DNA damage repair and eventually causes transcriptional repression-induced atypical cell death (TRIAD). Cells under TRIAD necrosis reveal senescence phenotypes. Extracellular high mobility group box 1 (HMGB1) protein, which is released from necrotic or hyper-activated neurons in AD, binds to toll-like receptor 4 (TLR4) of neighboring neurons, and activates protein kinase C alpha (PKCα) that executes Ku70 phosphorylation at Ser77/78. Administration of human monoclonal anti-HMGB1 antibody to post-symptomatic AD model mice decreases neuronal DSBs, suppresses secondary TRIAD necrosis of neurons, prevents escalation of neurodegeneration, and ameliorates cognitive symptoms. TRIAD shares multiple features with senescence. These results discover the HMGB1-Ku70 axis that accounts for the increase of neuronal DNA damage and secondary enhancement of TRIAD, the cell death phenotype of senescence, in AD., (© 2021. The Author(s).)

Over the past three decades, functional magnetic resonance imaging (fMRI) has become crucial to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (N = 272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (N = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared with full in-person psychiatric screening), recruited at least partly from convenience samples (compared with community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias., (© The Author(s) 2021. Published by Oxford University Press.)

Aim: The rapid response system (RRS) is an in-hospital medical safety system. To date, not much is known about patient disposition after RRS activation, especially discharge home. This study aimed to investigate the prevalence, characteristics, and outcomes of patients with adverse events who required RRS activation., Methods: Retrospective data from the In-Hospital Emergency Registry in Japan collected from April 2016 to November 2020 were eligible for our analysis. We divided patients into Home Discharge, Transfer, and Death groups. The primary outcome was the prevalence of direct discharge home, and independently associated factors were determined using multivariable logistic regression., Results: We enrolled 2,043 patients who met the inclusion criteria. The prevalence of discharge home was 45.7%; 934 patients were included in the Home Discharge group. Age (adjusted odds ratio [AOR] 0.96; 95% confidence interval [CI], 0.95-0.97), malignancy (AOR 0.69; 95% CI, 0.48-0.99), oxygen administration before RRS (AOR 0.49; 95% CI, 0.36-0.66), cerebral performance category score on admission (AOR 0.38; 95% CI, 0.26-0.56), do not attempt resuscitation order before RRS (AOR 0.17; 95% CI, 0.10-0.29), RRS call for respiratory failure (AOR 0.50; 95% CI, 0.34-0.72), RRS call for stroke (AOR 0.12; 95% CI, 0.03-0.37), and intubation (AOR 0.20; 95% CI, 0.12-0.34) were independently negative, and RRS call for anaphylaxis (AOR 15.3; 95% CI, 2.72-86.3) was positively associated with discharge home., Conclusion: Less than half of the in-hospital patients under RRS activation could discharge home. Patients' conditions before RRS activation, disorders requiring RRS activation, and intubation were factors that affected direct discharge home., Competing Interests: Approval of the research protocol: The study protocol for this research project was approved by a suitably constituted ethics committee at our institution (registration no. 201201), and it conforms to the provisions of the Declaration of Helsinki. Informed consent: Informed consent was waived. Animal studies: N/A. Conflict of interest: None., (© 2021 The Authors. Acute Medicine & Surgery published by John Wiley & Sons Australia, Ltd on behalf of Japanese Association for Acute Medicine.)

The most common symptom following the accidental ingestion of a soap is lip edema. Although most cases are asymptomatic or exhibit mild symptoms, in some cases, aspiration pneumonia, oropharyngeal edema, and bronchial obstruction may be fatal., Competing Interests: Not declared., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Purpose: Improving the safety of general wards is a key to reducing serious adverse events in the postoperative period. We investigated the characteristics, treatment, and outcomes of postoperative patients managed by a rapid response system (RRS) in Japan to improve postoperative management., Methods: This retrospective study analyzed cases requiring RRS intervention that were included in the In-Hospital Emergency Registry in Japan. We analyzed data reported by 34 Japanese hospitals between January 2014 and March 2018, mainly focusing on postoperative patients for whom the RRS was activated within 7 days of surgery. Non-postoperative patients, for whom the RRS was activated in all other settings, were used for comparison as necessary., Results: There were 609 (12.7%) postoperative patients among the total patients in the registry. The major criteria were staff concerns (30.2%) and low oxygen saturation (29.7%). Hypotension, tachycardia, and inability to contact physicians were observed as triggers significantly more frequently in postoperative patients when compared with non-postoperative patients. Among RRS activations within 7 days of surgery, 68.9% of activations occurred within postoperative day 3. The ordering of tests (46.8%) and fluid bolus (34.6%) were major interventions that were performed significantly more frequently in postoperative patients when compared with non-postoperative patients. The rate of RRS activations resulting in ICU care was 32.8%. The mortality rate at 1 month was 16.2%., Conclusion: Approximately, 70% of the RRS activations occurred within postoperative day 3. Circulatory problems were a more frequent cause of RRS activation in the postoperative group than in the non-postoperative group.

The mitochondrial outer membrane contains so-called β-barrel proteins, which allow communication between the cytosol and the mitochondrial interior 1-3 . Insertion of β-barrel proteins into the outer membrane is mediated by the multisubunit mitochondrial sorting and assembly machinery (SAM, also known as TOB) 4-6 . Here we use cryo-electron microscopy to determine the structures of two different forms of the yeast SAM complex at a resolution of 2.8-3.2 Å. The dimeric complex contains two copies of the β-barrel channel protein Sam50-Sam50a and Sam50b-with partially open lateral gates. The peripheral membrane proteins Sam35 and Sam37 cap the Sam50 channels from the cytosolic side, and are crucial for the structural and functional integrity of the dimeric complex. In the second complex, Sam50b is replaced by the β-barrel protein Mdm10. In cooperation with Sam50a, Sam37 recruits and traps Mdm10 by penetrating the interior of its laterally closed β-barrel from the cytosolic side. The substrate-loaded SAM complex contains one each of Sam50, Sam35 and Sam37, but neither Mdm10 nor a second Sam50, suggesting that Mdm10 and Sam50b function as placeholders for a β-barrel substrate released from Sam50a. Our proposed mechanism for dynamic switching of β-barrel subunits and substrate explains how entire precursor proteins can fold in association with the mitochondrial machinery for β-barrel assembly.

Background: Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback., Hypotheses: We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback., Methods: We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions., Results: The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo., Discussion: Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.

Background: Cannabidiol (CBD) is being investigated as a potential treatment for several medical indications, many of which are characterised by altered memory processing. However, the mechanisms underlying these effects are unclear., Aims: Our primary aim was to investigate how CBD influences cerebral blood flow (CBF) in regions involved in memory processing. Our secondary aim was to determine if the effects of CBD on CBF were associated with differences in working and episodic memory task performance., Methods: We used a randomised, crossover, double-blind design in which 15 healthy participants were administered 600 mg oral CBD or placebo on separate days. We measured regional CBF at rest using arterial spin labelling 3 h after drug ingestion. We assessed working memory with the digit span (forward, backward) and n-back (0-back, 1-back, 2-back) tasks, and we used a prose recall task (immediate and delayed) to assess episodic memory., Results: CBD increased CBF in the hippocampus (mean (95% confidence intervals) = 15.00 (5.78-24.21) mL/100 g/min, t 14 = 3.489, Cohen's d = 0.75, p = 0.004). There were no differences in memory task performance, but there was a significant correlation whereby greater CBD-induced increases in orbitofrontal CBF were associated with reduced reaction time on the 2-back working memory task ( r = -0.73, p = 0.005)., Conclusions: These findings suggest that CBD increases CBF to key regions involved in memory processing, particularly the hippocampus. These results identify potential mechanisms of CBD for a range of conditions associated with altered memory processing, including Alzheimer's disease, schizophrenia, post-traumatic stress disorder and cannabis-use disorders.

Cysteine-rich transmembrane bone morphogenetic protein regulator 1 (CRIM1) is a type I transmembrane protein involved in the organogenesis of many tissues via its interactions with growth factors including BMP, TGF-β, and VEGF. In this study, we used whole-exome sequencing and linkage analysis to identify a novel Crim1 mutant allele generated by ENU mutagenesis in mice. This allele is a missense mutation that causes a cysteine-to-serine substitution at position 140, and is referred to as Crim1 C140S . In addition to the previously reported phenotypes in Crim1 mutants, Crim1 C140S homozygous mice exhibited several novel phenotypes, including dwarfism, enlarged seminal vesicles, and rectal prolapse. In vitro analyses showed that Crim1 C140S mutation affected the formation of CRIM1 complexes and decreased the amount of the overexpressed CRIM1 proteins in the cell culture supernatants. Cys140 is located in the internal region 1 (IR1) of the N-terminal extracellular region of CRIM1 and resides outside any identified functional domains. Inference of the domain architecture suggested that the Crim1 C140S mutation disturbs an intramolecular disulfide bond in IR1, leading to the protein instability and the functional defects of CRIM1. Crim1 C140S highlights the functional importance of the IR1, and Crim1 C140S mice should serve as a valuable model for investigating the functions of CRIM1 that are unidentified as yet.

Energetics was analyzed for the aggregation of an 11-residue peptide. An all-atom molecular dynamics simulation was conducted with explicit solvent, and the energy-representation theory of solution was employed to compute the solvation free energies of the peptide and its aggregates. The aggregation in the pure-water solvent was observed to be inhibited by the solvation. The driving force of aggregate formation is the interactions among the peptide molecules, and the sum of the intra-aggregate and solvation terms per monomer is more favorable for larger aggregates. The effect of the cosolvent was then examined by focusing on the mixtures of water with urea and dimethyl sulfoxide (DMSO). It was actually shown that the derivative of the excess chemical potential of a flexible solute species with respect to the cosolvent concentration is determined exactly by the corresponding derivative of the free energy of solvation. The cosolvent effect on the equilibrium of aggregate formation can thus be addressed by comparing the solvation free energies with and without the cosolvent, and both the urea and DMSO cosolvents were found to inhibit the aggregation. The cosolvent-induced change in the solvation free energy was further decomposed into the contributions from the cosolvent and water. Their dependencies on the degree of aggregation were seen to be weak for large aggregates, and the roles of the electrostatic, van der Waals, and excluded-volume components in the solvation energetics were discussed.

Background: Bacillus cereus is a gram-positive rod bacterium that is responsible for food poisoning. It is naturally widely distributed, and thus often contaminates cultures. Although it is rarely considered responsible, it can cause serious infections under certain conditions. However, lethal infections, especially in immunocompetent patients, are rare., Case Presentation: A healthy 60-year-old man developed community-acquired B. cereus pneumonia and alveolar hemorrhage unveiled by abrupt chest pain and hemoptysis with no other advance symptoms. B. cereus induced silent alveolar destruction without any local or systemic inflammatory response. Although the lesion resembled lung anthrax, there was no evidence of Bacillus anthracis toxin., Conclusions: Some isolates of B. cereus can cause anthrax-like fulminant necrotizing pneumonia in immunocompetent patients. If this type of B. cereus were used as a means of bioterrorism, it may be quite difficult to recognize as bioterrorism. We should keep B. cereus in mind as a potential pathogen of fulminant human infectious disease.

Background: Psoas abscess and pyogenic spondylitis are intractable diseases that require long-term treatment, but the clinical characteristics and causative organisms have not been fully investigated. Herein, we describe the clinical characteristics of these diseases and evaluate the factors associated with in-hospital mortality and the presence of gram-negative rods as causative microorganisms., Methods: All patients diagnosed with pyogenic spondylitis or psoas abscesses at a tertiary hospital were included. We retrieved the clinical data (age, sex, outcome, length of hospital stay, disease, bacteria, medication, comorbidities, and treatment status), vital signs (blood pressure, heart rate, and body temperature), and laboratory test results (blood cell count, liver function, renal function, electrolytes, blood sugar, and C-reactive protein) of all patients. The outcomes were in-hospital deaths and positive cultures of gram-negative rods., Results: We analyzed 126 patients consisting of 69 (55%) men with a population mean age of 72 years. Seventy-two patients had pyogenic spondylitis and 54 had psoas abscesses. Eleven patients (8.3%) died during admission. The causative bacteria were gram-positive cocci in 63 patients (50%) and gram-negative bacteria in 19 patients (15%). The multivariate logistic model showed that blood urea nitrogen (BUN) (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.02-1.06) and cardiovascular diseases (OR 7.02, 95% CI 1.55-31.8) were associated with in-hospital mortality. Platelets less than 150,000/μL (OR 3.14, 95% CI 1.02-9.65) and higher aspartic aminotransferase (OR 1.02, 95% CI 1.00-1.03) were associated with gram-negative rods., Conclusions: Patients with suspected psoas abscesses or pyogenic spondylitis having a high BUN level and a history of cardiovascular diseases have a higher risk of mortality.

Toward identifying the driving force of protein folding, energetics was analyzed in water for Trp-cage (20 residues), protein G (56 residues), and ubiquitin (76 residues) at their native (folded) and heat-denatured (unfolded) states. All-atom molecular dynamics simulation was conducted, and the hydration effect was quantified by the solvation free energy. The free-energy calculation was done by employing the solution theory in the energy representation, and it was seen that the sum of the protein intramolecular (structural) energy and the solvation free energy is more favorable for a folded structure than for an unfolded one generated by heat. Probabilistic arguments were then developed to determine which of the electrostatic, van der Waals, and excluded-volume components of the interactions in the protein-water system governs the relative stabilities between the folded and unfolded structures. It was found that the electrostatic interaction does not correspond to the preference order of the two structures. The van der Waals and excluded-volume components were shown, on the other hand, to provide the right order of preference at probabilities of almost unity, and it is argued that a useful modeling of protein folding is possible on the basis of the excluded-volume effect.

The effects of urea and its alkylated derivatives on the structure of T4-lysozyme were analyzed from the standpoint of energetics. Molecular dynamics simulations were conducted with explicit solvent, and the energy-representation method was employed to compute the free energy of transfer of the protein from pure-water solvent to the mixed solvents of water with urea, methylurea, 1,1-dimethylurea, and isopropylurea. Through the decomposition of the transfer free energy into the cosolvent and water contributions, it was observed that the former is partially cancelled by the latter and governs the total free energy of transfer. To determine the interaction component responsible for the transfer energetics, the correlations of the transfer free energy were also examined against the change in the solute-solvent interaction energy upon transfer and the corresponding changes in the electrostatic, van der Waals, and excluded-volume components. It was then found over the set of protein structures ranging from native to (partially) unfolded ones that the transfer free energy changes in parallel with the van der Waals component even when the cosolvent is alkylated. The electrostatic and excluded-volume components play minor roles in the structure modification of the protein, and the denaturing ability of alkylurea is brought by the van der Waals interaction.

Energetics was analyzed for cytochrome c in pure-water solvent and in a urea-water mixed solvent to elucidate the solvation effect in the structural variation of the protein. The solvation free energy was computed through all-atom molecular dynamics simulation combined with the solution theory in the energy representation, and its correlations were examined over sets of protein structures against the electrostatic and van der Waals components in the average interaction energy of the protein with the solvent and the excluded-volume component in the solvation free energy. It was observed in pure-water solvent that the solvation free energy varies in parallel to the electrostatic component with minor roles played by the van der Waals and excluded-volume components. The effect of urea on protein structure was then investigated in terms of the free-energy change upon transfer of the protein solute from pure-water solvent to the urea-water mixed solvent. The decomposition of the transfer free energy into the contributions from urea and water showed that the urea contribution is partially canceled by the water contribution and governs the total free energy of transfer. When correlated against the change in the solute-solvent interaction energy upon transfer and the corresponding changes in the electrostatic, van der Waals, and excluded-volume components, the transfer free energy exhibited strong correlations with the total change in the solute-solvent energy and its van der Waals component. The solute-solvent energy was decomposed into the contributions from the protein backbone and side chain, furthermore, and neither of the contributions was seen to be decisive in the correlation to the transfer free energy.

Streptococcal toxic shock syndrome is a severe infectious disease. We report a Japanese case of Streptococcal toxic shock syndrome caused by a highly mucoid strain of Streptococcus pyogenes. A 31-year old female with shock vital sign presented at a tertiary medical center. Her left breast was necrotizing and S. pyogenes was detected by Immunochromatographic rapid diagnostic kits. Intensive care, including administration of antibiotics and skin debridement, was performed. After 53 days in our hospital, she was discharged. The blood cultures and skin swab cultures all grew S. pyogenes which displayed a highly mucoid morphology on culture media. In her course of the disease, the Streptococcus strain had infected two other family members. All of the strains possessed the T1 and M1 antigens, as well as the emm1.0 gene. As for fever genes, the strains were all positive for speA, speB, and speF, but negative for speC. All of the strains exhibited and the same pattern in PFGE with the SfiI restriction enzyme. The strain might have spread in the local area by the data from the Japanese Infectious Disease Surveillance Center. Immunochromatographic rapid diagnostic kits are very useful for detecting S. pyogenes. However, they can not be used to diagnose severe streptococcul disease by highly mucoid strain alone. Careful observation of patients and colony morphology are useful methods for diagnosing severe streptococcal disease by highly mucoid strain., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

A new and efficient conformational sampling method, MuSTAR MD (Multi-scale Sampling using Temperature Accelerated and Replica exchange Molecular Dynamics), is proposed to calculate the free energy landscape on a space spanned by a set of collective variables. This method is an extension of temperature accelerated molecular dynamics and can also be considered as a variation of replica-exchange umbrella sampling. In the MuSTAR MD, each replica contains an all-atom fine-grained model, at least one coarse-grained model, and a model defined by the collective variables that interacts with the other models in the same replica through coupling energy terms. The coarse-grained model is introduced to drive efficient sampling of large conformational space and the fine-grained model can serve to conduct more accurate conformational sampling. The collective variable model serves not only to mediate the coarse- and fine-grained models, but also to enhance sampling efficiency by temperature acceleration. We have applied this method to Ala-dipeptide and examined the sampling efficiency of MuSTAR MD in the free energy landscape calculation compared to that for replica exchange molecular dynamics, replica exchange umbrella sampling, temperature accelerated molecular dynamics, and conventional MD. The results clearly indicate the advantage of sampling a relatively high energy conformational space, which is not sufficiently sampled with other methods. This feature is important in the investigation of transition pathways that go across energy barriers. MuSTAR MD was also applied to Met-enkephalin as a test case in which two Gō-like models were employed as the coarse-grained model.

We report a case of rapidly progressive necrotizing soft tissue infection and sepsis followed by a patient's death. We suspected Vibrio vulnificus infection because the patient's underlying disease was cirrhosis and the course extremely rapid. No microbe had been detected at death. We extracted DNA from a blood culture bottle. SYBR green I real-time PCR was conducted but could not detect V. vulnificus vvh in the DNA sample. Aeromonas hydrophila was cultured and identified in blood and necrotized tissue samples. Real-time PCR was conducted to detect A. hydrophila ahh1, AHCYTOEN and aerA in the DNA sample extracted from the blood culture bottle and an isolated necrotized tissue strain, but only ahh1 was positive. High-mortality in necrotizing soft tissue infections makes it is crucial to quickly detect V. vulnificus and A. hydrophila. We found real-time PCR for vvh, ahh1, AHCYTOEN, and aerA useful in detecting V. vulnificus and A. hydrophila in necrotizing soft tissue infections.

Pyogenic liver abscess caused by Klebsiella pneumoniae is an emerging disease worldwide, and we know the serotype K1 strain to be the most virulent strain. We report a Japanese case of septic pyogenic liver abscess caused by K. pneumoniae genetic serotype K1. A 60-year old man presented at our hospital in a state of cardiopulmonary arrest. From the patient's chief complaint of chest pain, we suspected acute coronary syndrome, i.e., acute myocardial infarction. We used extracorporeal circulation and checked coronary angiography, but the 75% stenosis by itself could not adequately account for the patient's critical condition. The patient's laboratory data indicated multiple organ failure. The patient's condition did not improve while in intensive care and he died 20 h after the onset of the cardiopulmonary arrest. Pathological autopsy later showed colliquative necrosis in the deltoid and left greater pectoral muscles, as well as liver abscesses. The patient's blood, gastric juice, and stool cultures all grew a Gram-negative bacillus identified as Klebsiella pneumoniae. We also performed capsular polysaccharide synthesis (cps) genotyping by polymerase chain reaction for the detection of K serotype-specific alleles at the wzx and wzy loci. The result indicated that wzx&#95;K1 and wzy&#95;K1 were positive. This is the first reported Japanese case of septic pyogenic liver abscess caused by K. pneumoniae genetic serotype K1.

Background: Hepatic resection is prone to significant blood loss. Adverse effects of blood loss and transfusion mandate improvements in surgical techniques to reduce blood loss and transfusion., Methods: We retrospectively analyzed the present status of intraoperative blood transfusion practice of 42 hepatic resections in National Kure Medical Center for the year of 2000., Results: Median values for blood loss were 1355, 1708, 1415, and 2298 ml for nonanatomic, subsegmental, segmental and extended right resections, respectively. Crossmatched to transfused blood (C/T) ratios were 1.76, 1.19, 2.31, and 0.90 for nonanatomic, subsegmental, segmental and extended right resections, respectively., Conclusion: In general, C/T ratio of 1.5 to 2.5 has been recommended but own C/T ratios are 1.19 and 0.9 for subsegmental and extended right hepatic resection, which are lower than recommended values. It was estimated that inappropriate prediction of blood loss by several surgeons and unused maximum surgical blood order schedule (MSBOS) or type and screen (T&S) decreased these values of C/T ratio in the present analysis. We therefore conclude that MSBOS and T&S could be improved by avoiding such in appropriate prediction.

We report four patients with advanced Borrmann type IV gastric carcinoma, in whom intraperitoneal chemotherapy with low-dose CDDP and 5-FU plus MMC via a peritoneal port was effective against peritoneal metastasis. However, none of the four patients survived for a long period. During treatment, they were followed on an outpatient basis and received intraperitoneal chemotherapy biweekly with good control of peritoneal metastasis. The ratio of the outpatient follow-up period was more than 50% in all these patients. Intraperitoneal chemotherapy may be effective for controlling peritoneal metastasis of advanced Borrmann type IV gastric carcinoma, and contribute to maintaining the patient's quality of life.