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Abstract Current differentiation protocols for human induced pluripotent stem cells (hiPSCs) produce heterogeneous cardiomyocytes (CMs). Although chamber-specific CM selection using cell surface antigens enhances biomedical applications, a cell surface marker that accurately distinguishes between hiPSC-derived atrial CMs (ACMs) and ventricular CMs (VCMs) has not yet been identified. We have developed an approach for obtaining functional hiPSC-ACMs and -VCMs based on CD151 expression. For ACM differentiation, we found that ACMs are enriched in the CD151low population and that CD151 expression is correlated with the expression of Notch4 and its ligands. Furthermore, Notch signaling inhibition followed by selecting the CD151low population during atrial differentiation leads to the highly efficient generation of ACMs as evidenced by gene expression and electrophysiology. In contrast, for VCM differentiation, VCMs exhibiting a ventricular-related gene signature and uniform action potentials are enriched in the CD151high population. Our findings enable the production of high-quality ACMs and VCMs appropriate for hiPSC-derived chamber-specific disease models and other applications.

Summary: Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are studied herein. Under glucose starvation, lysosomal protein expression decreased, leading to the accumulation of damaged lysosomes. Subsequently, cell death occurred via ferroptosis and iron accumulation due to DMT1 degradation. GPX4, a key factor in ferroptosis inhibition located on the outer membrane of lysosomes, accumulated in lysosomes, especially under glucose starvation, to protect cells from ferroptosis. ALDOA, GAPDH, NAMPT, and PGK1 are also located on the outer membrane of lysosomes and participate in lysosomal function. These enzymes did not function effectively under glucose starvation, leading to lysosomal dysfunction and ferroptosis. These findings may facilitate the treatment of lysosomal-related diseases.

Abstract Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose-starved conditions. Therefore, this study aimed to develop a mitochondria-targeted treatment to achieve normal glucose conditions. This study used U87MG (U87), U373, and patient-derived stem-like cells as well as chloramphenicol (CAP) and 2-deoxy-d-glucose (2-DG). We investigated whether CAP and 2-DG inhibited the growth of cells under normal and high glucose concentrations. In U87 cells, 2-DG and long-term CAP administration were more effective under normal glucose than high-glucose conditions. In addition, combined CAP and 2-DG treatment was significantly effective under normal glucose concentration in both normal oxygen and hypoxic conditions; this was validated in U373 and patient-derived stem-like cells. 2-DG and CAP acted by influencing iron dynamics; however, deferoxamine inhibited the efficacy of these agents. Thus, ferroptosis could be the underlying mechanism through which 2-DG and CAP act. In conclusion, combined treatment of CAP and 2-DG drastically inhibits cell growth of glioblastoma cell lines even under normal glucose conditions; therefore, this treatment could be effective for glioblastoma patients.

Abstract Glioblastoma is a difficult-to-cure disease owing to its malignancy. Under normal circumstances, cancer is dependent on the glycolytic system for growth, and mitochondrial oxidative phosphorylation (OXPHOS) is not well utilized. Here, we investigated the efficacy of mitochondria-targeted glioblastoma therapy in cell lines including U87MG, LN229, U373, T98G, and two patient-derived stem-like cells. When glioblastoma cells were exposed to a glucose-starved condition (100 mg/l), they rely on mitochondrial OXPHOS for growth, and mitochondrial translation product production is enhanced. Under these circumstances, drugs that inhibit mitochondrial translation, called antimicrobial agents, can cause mitochondrial dysfunction and thus can serve as a therapeutic option for glioblastoma. Antimicrobial agents activated the nuclear factor erythroid 2-related factor 2–Kelch-like ECH-associated protein 1 pathway, resulting in increased expression of heme oxygenase-1. Accumulation of lipid peroxides resulted from the accumulation of divalent iron, and cell death occurred via ferroptosis. In conclusion, mitochondrial OXPHOS is upregulated in glioblastoma upon glucose starvation. Under this condition, antimicrobial agents cause cell death via ferroptosis. The findings hold promise for the treatment of glioblastoma.

Background: Fibromyalgia (FM) is a chronic pain syndrome characterized by widespread pain, tenderness, and fatigue. Patients with FM have no effective medication so far, and their activity of daily living and quality of life are remarkably impaired. Therefore, new therapeutic approaches are awaited. Recently, exercise therapy has been gathering much attention as a promising treatment for FM. However, the underlying mechanisms are not fully understood, particularly, in the central nervous system, including the brain. Therefore, we investigated functional connectivity changes and their relationship with clinical improvement in patients with FM after exercise therapy to investigate the underlying mechanisms in the brain using resting-state fMRI (rs-fMRI) and functional connectivity (FC) analysis. Methods: Seventeen patients with FM participated in this study. They underwent a 3-week exercise therapy on in-patient basis and a 5-min rs-fMRI scan before and after the exercise therapy. We compared the FC strength of sensorimotor regions and the mesocortico-limbic system between two scans. We also performed a multiple regression analysis to examine the relationship between pre-post differences in FC strength and improvement of patients’ clinical symptoms or motor abilities. Results: Patients with FM showed significant improvement in clinical symptoms and motor abilities. They also showed a significant pre-post difference in FC of the anterior cingulate cortex and a significant correlation between pre-post FC changes and improvement of clinical symptoms and motor abilities. Although sensorimotor regions tended to be related to the improvement of general disease severity and depression, brain regions belonging to the mesocortico-limbic system tended to be related to the improvement of motor abilities. Conclusion: Our 3-week exercise therapy could ameliorate clinical symptoms and motor abilities of patients with FM, and lead to FC changes in sensorimotor regions and brain regions belonging to the mesocortico-limbic system. Furthermore, these changes were related to improvement of clinical symptoms and motor abilities. Our findings suggest that, as predicted by previous animal studies, spontaneous brain activities modified by exercise therapy, including the mesocortico-limbic system, improve clinical symptoms in patients with FM.

IntroductionPerspectives regarding the disease state often differ between patients with rheumatoid arthritis (RA) and physicians. The aim of the present longitudinal cohort study was to investigate the impact of the discordance in global assessments between patients and physicians on 9-year pain-related outcomes in patients with rheumatoid arthritis.MethodSixty-eight consecutive outpatients with rheumatoid arthritis on their first visit to a tertiary center were included. Baseline measurements included demographic data, drugs used, disease activity, and a modified Health Assessment Questionnaire (mHAQ). Discordance in global assessment between patients and physicians at baseline was defined as 10 mm higher in the patient global assessment (PGA) than in the physician global assessment. A 9-year follow-up assessment included pain intensity, the European Quality of Life 5 Dimensions 3 Level (EQ-5D-3L) scale, Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), Pain Disability Assessment Scale (PDAS), and Pain Self-Efficacy Questionnaire (PSEQ).ResultsThe number of patients with discordance was 26 (38%) in 68 patients. Patients with a 10 mm higher PGA than the physician global assessment at baseline measurements had significantly worse pain intensity, PCS score, PSEQ score, and EQ-5D-3L score measurements at the 9-year follow-up than those with concordance. A higher mHAQ score and 10 mm higher PGA at baseline were significantly independently associated with the EQ-5D-3L scale score and pain intensity at the 9-year follow-up.ConclusionThis longitudinal cohort study suggested that discordance in global assessment between patients and physicians modestly predicted worse 9-year pain-related outcomes in patients with rheumatoid arthritis.

Photochemical ozone (O _3 ) is an important chemical component in the atmosphere as an indicator of air pollution. Anthropogenic sources, such as domestic automobiles and industries, have been considered a main source of O _3 especially in urban areas; however, recent emission regulations have led to declining trends in anthropogenic sources. Therefore, other sources, such as biogenic emissions, could be important in the near future. In addition, increasing temperatures caused by global warming will relate to increasing biogenic emissions. In this study, the role of biogenic volatile organic compounds (BVOC) on O _3 concentration was focused. The target period was a hot summer in 2018 in Japan, and O _3 concentration by simulating with and without biogenic emissions over the Tokyo metropolitan area was analyzed. The result clarified that around 20% (up to 63%) of O _3 was produced from biogenic sources at high temperatures, even in the Tokyo metropolitan area. This study suggested that the biogenic sources should be paid attention to and taken into account in the regulation of anthropogenic emissions.

IntroductionThe proportion of neck injuries due to traffic accidents is increasing. Little is known about high-cost patients with acute whiplash-associated disorder (WAD). The present study aimed to investigate whether time to first visit for conventional medicine, multiple doctor visits, or alternative medicine could predict high-cost patients with acute WAD in Japan.MethodsData from a compulsory, no-fault, government automobile liability insurance agency in Japan between 2014 and 2019 were used. The primary economic outcome was the total cost of healthcare per person. Treatment-related variables were assessed based on the time to first visit for conventional and alternative medicine, multiple doctor visits, and visits for alternative medicine. Patients were categorized according to total healthcare cost (low, medium, and high cost). The variables were subjected to univariate and multivariate analysis to compare high-cost and low-cost patients.ResultsA total of 104,911 participants with a median age of 42 years were analyzed. The median total healthcare cost per person was 67,366 yen. The cost for consecutive medicine, for consecutive and alternative medicine, and total healthcare costs were significantly associated with all clinical outcomes. Female sex, being a homemaker, a history of WAD claim, residential area, patient responsibility in a traffic accident, multiple doctor visits, and visits for alternative medicine were identified as independent predictive factors for a high cost in multivariate analysis. Multiple doctor visits and visits for alternative medicine showed large differences between groups (odds ratios 2673 and 694, respectively). Patients with multiple doctor visits and visits for alternative medicine showed a significantly high total healthcare cost per person (292,346 yen) compared to those without (53,587 yen).ConclusionsA high total healthcare cost is strongly associated with multiple doctor visits and visits for alternative medicine in patients with acute WAD in Japan.

Abstract Although automated pollen monitoring networks using laser optics are well-established in Japan, it is thought that these methods cannot distinguish between pollen counts when evaluating various pollen taxa. However, a method for distinguishing the pollen counts of two pollen taxa was recently developed. In this study, we applied such a method to field evaluate the data of the two main allergens in Japan, Chamaecyparis obtusa and Cryptomeria japonica. We showed that the method can distinguish between the pollen counts of these two species even when they are simultaneously present in the atmosphere. This result indicates that a method for automated and simple two pollen taxa monitoring with high spatial density can be developed using the existing pollen network.

The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.

Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERRγ agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.

Abstract Background Fibromyalgia is characterized by chronic widespread pain, and more than half of patients with fibromyalgia report that weather-related variables aggravate their symptoms. However, the differences in actual symptoms have not been measured between those with and without weather sensitivity. The present study aimed to investigate whether weather sensitivity associated with the minimal clinically important difference values of quality of life in patients with fibromyalgia, between those with and without weather sensitivity. Methods Sixty-four consecutive outpatients with fibromyalgia on their first visit to our tertiary center were included. Weather sensitivity was measured using self-perceived symptoms. Pain intensity was measured using the 0–10 Numerical Rating Scale (NRS). Quality of life was measured using the Euro Quality of life-5 Dimensions-3 level (EQ-5D-3L) scale. The variables were subjected to univariable and multivariable analysis using the EQ-5D-3L scale. Results The mean age of the patients was 50 years. Forty-eight patients (75%) were women. The mean EQ-5D-3L score was 0.55. Thirty-seven patients (58%) reported weather sensitivity. In univariable analysis, the welfare recipient, weather sensitivity, and NRS values were associated with EQ-5D-3L scale scores. In multivariable analysis, NRS value and weather sensitivity were independently associated with EQ-5D-3L scale scores. The NRS and EQ-5D-3L scale scores were significantly worse in those with weather sensitivity than those without weather sensitivity. The difference in NRS values was less than 1.5 points between groups. The differences in EQ-5D-3L scale scores were 0.16 points between groups. Conclusions Weather sensitivity was significantly associated with quality of life in patients with fibromyalgia. There was an association with weather sensitivity and the minimal clinically important difference values of quality of life in patients with fibromyalgia. The presence of weather sensitivity could have a key role in the quality of life in patients with fibromyalgia.

Gastric endoscopy is a golden standard in the clinical process that enables medical practitioners to diagnose various lesions inside a patient's stomach. If a lesion is found, a success in identifying the location of the found lesion relative to the global view of the stomach will lead to better decision making for the next clinical treatment. Our previous research showed that the lesion localization could be achieved by reconstructing the whole stomach shape from chromoendoscopic indigo carmine (IC) dye-sprayed images using a structure-from-motion (SfM) pipeline. However, spraying the IC dye to the whole stomach requires additional time, which is not desirable for both patients and practitioners. Our objective is to propose an alternative way to achieve whole stomach 3D reconstruction without the need of the IC dye. We generate virtual IC-sprayed (VIC) images based on image-to-image style translation trained on unpaired real no-IC and IC-sprayed images, where we have investigated the effect of input and output color channel selection for generating the VIC images. We validate our reconstruction results by comparing them with the results using real IC-sprayed images and confirm that the obtained stomach 3D structures are comparable to each other. We also propose a local reconstruction technique to obtain a more detailed surface and texture around an interesting region. The proposed method achieves the whole stomach reconstruction without the need of real IC dye using SfM. We have found that translating no-IC green-channel images to IC-sprayed red-channel images gives the best SfM reconstruction result. Clinical impact We offer a method of the frame localization and local 3D reconstruction of a found gastric lesion using standard endoscopy images, leading to better clinical decision.

Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, themechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here, we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1a expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis. [ABSTRACT FROM AUTHOR]

Studies have indicated that chronic low back pain (LBP) should be approached according to its morphological basis and in consideration of biopsychosocial interventions. This study presents an updated review on available psychological assessments and interventions for patients with chronic LBP. Psychosocial factors, including fear-avoidance behavior, low mood/withdrawal, expectation of passive treatment, and negative pain beliefs, are known as risk factors for the development of chronic LBP. The Örebro Musculoskeletal Pain Questionnaire, STarT Back Screening Tool, and Brief Scale for Psychiatric Problems in Orthopaedic Patients have been used as screening tools to assess the development of chronicity or identify possible psychiatric problems. The Pain Catastrophizing Scale, Pain Self-Efficacy Questionnaire, and Injustice Experience Questionnaire are also widely used to assess psychosocial factors in patients with chronic pain. With regard to interventions, the placebo effect can be enhanced by preferable patient-clinician relationship. Reassurance to patients with non-specific pain is advised by many guidelines. Cognitive behavioral therapy focuses on restructuring the negative cognition of the patient into realistic appraisal. Mindfulness may help improve pain acceptance. Self-management strategies with appropriate goal setting and pacing theory have proved to improve long-term pain-related outcomes in patients with chronic pain.

Gastric endoscopy is a common clinical practice that enables medical doctors to diagnose various lesions inside a stomach. In order to identify the location of a gastric lesion such as early cancer and a peptic ulcer within the stomach, this work addresses to reconstruct the color-textured 3D model of a whole stomach from a standard monocular endoscope video and localize any selected video frame to the 3D model. We examine how to enable structure-from-motion (SfM) to reconstruct the whole shape of a stomach from endoscope images, which is a challenging task due to the texture-less nature of the stomach surface. We specifically investigate the combined effect of chromo-endoscopy and color channel selection on SfM to increase the number of feature points. We also design a plane fitting-based algorithm for 3D point outliers removal to improve the 3D model quality. We show that whole stomach 3D reconstruction can be achieved (more than 90% of the frames can be reconstructed) by using red channel images captured under chromo-endoscopy by spreading indigo carmine (IC) dye on the stomach surface. In experimental results, we demonstrate the reconstructed 3D models for seven subjects and the application of lesion localization and reconstruction. The methodology and results presented in this paper could offer some valuable reference to other researchers and also could be an excellent tool for gastric surgeons in various computer-aided diagnosis applications.

Abstract Aim To explore the characteristics of psychiatric morbidity in chronic pain patients who present with or without fibromyalgia. Methods Patients are referred to our chronic pain clinic from primary medical institutions, as we are a secondary medical institution. Although some patients have chronic pain, they have no clear organic disorder such as rheumatoid arthritis to account for the pain. Among the 367 new patients seen during the period from March 2009 to August 2012, 347 patients underwent psychiatric evaluation in face‐to‐face interviews with mental health specialists before a physical examination. Results Of the 347 patients examined, at least one psychiatric diagnosis was made for 94.6%. The average number of DSM‐IV‐TR diagnoses was 1.46 in the 330 chronic pain patients who had at least one psychiatric diagnosis. The breakdown of the number of psychodiagnoses was one in 60.8%, two in 27.1%, three in 4.9%, and more than three in 2.3% chronic pain patients with or without fibromyalgia. In fibromyalgia patients, the highest relative frequencies were found for somatoform disorders (76%), followed by dysthymic disorder (17%) and major depressive disorder (15%). In patients without fibromyalgia, the highest relative frequencies were found for somatoform disorders (64%), followed by major depressive disorder (15%) and dysthymic disorder (14%). Psychiatric disorders were found in 96.9% of fibromyalgia patients, and in 93.5% of chronic pain patients without fibromyalgia in Japan (no significant difference using chi‐square test). Conclusion Results show that chronic pain patients with or without fibromyalgia are extremely likely to be diagnosed with a psychiatric disorder.

Aim: Intracranial metastases from uterine leiomyosarcoma, particularly solitary skull metastases, are very rare, with only five cases reported to date. In this study, we present our experience with the treatment of these lesions, along with a review of the previously reported cases. To the best of our knowledge, this represents the first review of cases of skull metastasis from uterine leiomyosarcoma. Material and Methods: We examined three patients with skull metastases from uterine leiomyosarcomas. Planning their treatment was challenging because of the lack of literature on such cases. Results: Gross tumor resection with a 1-cm surgical margin was performed in all three cases. One of the patients also received postoperative radiation therapy. In two cases, there was no recurrence until the 15-month follow-up. The third patient developed two recurrences within a short period, and after two operations, she was treated with nivolumab. Genomic analysis was also performed in one case. Conclusions: Due to the lack of effective chemotherapy, skull metastasis from uterine leiomyosarcoma has a poor prognosis. However, in cases where genomic analysis does not indicate a poor prognosis, surgical treatment may be effective and is recommended.

INTRODUCTION:This study aimed to investigate the differences in the Injustice Experience Questionnaire (IEQ) scores during the early period after the diagnosis of Whiplash-associated disorder (WAD) between Japanese and Canadian samples, and the associations between the IEQ scores and treatment terms in Japanese patients with acute WAD. METHODS:We used secondary data for the IEQ scores of Canadian patients with acute WAD. In Japan, we collected data from 85 consecutively enrolled patients with acute WAD, and their treatment terms were collected; these referred to the number of days between the date of injury and the closure date of the insurance claim and the number of treatment visits. Before treatment, the Numeric Rating Scale, Neck Disability Index, Hospital Anxiety and Depression Scale, IEQ, and Euro Quality of Life five-dimensional questionnaire were administered. The variables were subjected to multivariate analysis with each treatment term. RESULTS:The IEQ scores were higher in Japan than in Canada. Through multiple regression analysis, IEQ scores were independently correlated with treatment terms. The optimal cutoff point of the IEQ scores for a prolonged treatment term was 21 and 22 points, respectively. CONCLUSIONS:The IEQ scores were associated with treatment terms in patients with acute WAD in Japan.

Brasil posee el mayor parque de reactores anaerobios del mundo si se considera la aplicación de esta tecnología para el tratamiento de las aguas residuales urbanas. A pesar de las reconocidas ventajas de los reactores de tipo UASB, algunos problemas han impedido su máximo desempeño operacional. Ignorar la existencia y postergar la solución de esos desafíos puede poner en riesgo los importantes avances alcanzados hasta la fecha, impactando el futuro de la tecnología anaerobia en el país y, en consecuencia, el del sector nacional de saneamiento en aguas residuales. Esta Nota Técnica (NT) tiene por objetivo presentar los principales temas de interés relacionados a la necesidad de perfeccionamiento del diseño, la construcción y la operación de reactores UASB, a partir de un amplio levantamiento junto a especialistas del sector académico y prestadores de servicios de saneamiento de Brasil. Los temas identificados fueron relacionados a los problemas más propensos a ocurrir en los reactores UASB, así como a sus respectivos orígenes. Para cada tema y problemas identificados, se indicaron las principales soluciones que han sido adoptadas, derivadas a partir de las investigaciones más recientes y de las experiencias exitosas en Plantas de Tratamiento de Aguas Residuales (PTARs) de Brasil. Los temas de interés se sintetizan en esta NT y son detallados en el conjunto de NTs que conforman la Colección “Contribución para el perfeccionamiento del diseño, la construcción y la operación de reactores UASB aplicados al tratamiento de aguas residuales urbanas”.

O Brasil detém o maior parque de reatores anaeróbios do mundo, considerando-se a aplicação da tecnologia para o tratamento de esgoto sanitário. Apesar das reconhecidas vantagens dos reatores do tipo UASB, há problemas que têm impedido seu máximo desempenho operacional. Negligenciar a existência e postergar a solução desses desafios pode colocar em risco os importantes avanços conseguidos até o presente, impactando o futuro da tecnologia anaeróbia no país e, consequentemente, o setor de esgotamento sanitário nacional. Esta Nota Técnica (NT) objetiva apresentar os principais tópicos de interesse relacionados à necessidade de aprimoramentos de projeto, construção e operação de reatores UASB, a partir de um amplo levantamento junto a especialistas do setor acadêmico e de prestadores de serviços de saneamento nacionais. Os tópicos identificados foram correlacionados aos problemas passíveis de ocorrerem em reatores UASB, bem como às suas respectivas origens. Para cada tópico e problemas identificados, foram feitas indicações das principais soluções que vêm sendo adotadas, em vista das pesquisas mais recentes e das experiências de sucesso em ETEs no Brasil. Os tópicos de interesse são reportados sinteticamente na presente NT, sendo posteriormente detalhados no conjunto de Notas Técnicas que integram a coletânea “Contribuição para o aprimoramento de projeto, construção e operação de reatores UASB aplicados ao tratamento de esgoto sanitário”.

Objectives: In the diagnosis of nonconvulsive status epilepticus (NCSE), the use of ongoing ictal electroencephalographic (EEG) findings is the gold standard. However, this is difficult without the availability of continuous EEG monitoring facilities. Given this, a small telemetry EEG amplifier (Headset-EEG; AE-120A EEG Headset™) was introduced for use in simple EEG monitoring facilities. In this study, we examined the diagnostic performance of the Headset-EEG for NCSE in a neuroemergency setting.Methods: We retrospectively selected five patients who were diagnosed with NCSE using Headset-EEG by attending physicians between October 2017 and July 2018. Reevaluation with Headset-EEG was performed, and the findings were compared with the initial diagnosis. Results: In Case 1, Headset-EEG clearly revealed repeated ictal discharges associated with acute subdural hematoma. However, in Cases 2 and 3, the initial EEG diagnosis was incorrectly made because of an EEG interpretation error. In Cases 4 and 5, various artifacts, caused by unstable electrode placement, resulted in an initial diagnosis of ongoing seizure activity. Nevertheless, the initial diagnoses and subsequent treatment of Cases 2–5 did not directly affect the patients' outcomes.Conclusion: The present study indicates that Headset-EEG is a possible tool for use in NCSE screening. However, considerable knowledge of EEG interpretation is needed to establish a correct NCSE diagnosis. When NCSE is suspected per Headset-EEG, a subsequent routine EEG with a full montage of 10–20 EEG electrodes should be performed in collaboration with an epileptologist or electroencephalographer. Keywords: Triphasic waves, Metabolic encephalopathy, Artifact

Introduction Inappropriate antidiuretic hormone secretion syndrome can be a serious adverse event of cisplatin‐based chemotherapy. Cisplatin had to be changed to other drugs or chemotherapy completely discontinued in earlier reported cases. Case presentation Three cycles of bleomycin, etoposide, and cisplatin chemotherapy were planned for a 40‐year‐old man with a diagnosis of lymph node recurrence of testicular cancer. On day 9, he suffered from vomiting and mental disturbance. Severe hyponatremia (110 mEq/L) with low plasma osmolality led to a diagnosis of a syndrome of inappropriate antidiuretic hormone secretion, and infusions of hypertonic saline and salt intake were prescribed. Second and third courses of bleomycin, etoposide, and cisplatin chemotherapy could then be given with careful electrolyte management. Conclusion Continuation of cisplatin administration with precise electrolyte adjustment can be a treatment option in regimens where cisplatin is essential for achieving optimal antitumor efficacy.

No Brasil, as atividades de projeto (concepção e dimensionamento) e operação de digestores anaeróbios de lodo acabaram incorporando certas práticas, que acabam por desfavorecer o uso mais racional deste tipo de processo. Enquanto que em países como EUA e Alemanha realizam contínuos esforços para o uso benéfico do biogás, no Brasil, mesmo em ETEs de grande porte, esta prática não se encontra muito difundida. Esta nota técnica destacou elementos de caráter técnico dos digestores anaeróbios de lodo com o intuito de subsidiar os estudos de viabilidade técnico-econômico-ambiental do uso benéfico de biogás. Estas questões de caráter mais técnico checam os fundamentos de tratamento de esgoto e proporcionam um melhor entendimento do tratamento de esgotos em nosso país. Em estudos de viabilidade, além das questões meramente econômicas, como a tarifa de energia elétrica e incentivos fiscais no Brasil, há outros elementos que deveriam ser reavaliados. A falta de preocupação na fase de projeto em relação ao regime de temperatura no interior dos digestores anaeróbios na faixa de 35ºC pode levar à falta de visão de um maior custo operacional devido à maior produção de lodo, bem como em outras questões operacionais relevantes, como recebimento de materiais que interferem negativamente no processo.

Abstract Transplant of human induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) cell-sheet is a promising approach for treating ischemic cardiomyopathy (ICM). However, poor blood supply to the transplanted cell-sheet is a concern related to the effectiveness and durability of the treatment. Herein, we hypothesized that the combined the omentum flap might enhance survival and the therapeutic effects of hiPS-CM cell-sheet transplant for ICM treatment. Treatment by Wnt signaling molecules in hiPS cells produced hiPS-CMs, which were magnetically labeled by superparamagnetic iron oxide (SPIO), followed by culture in the thermoresponsive dishes to generate hiPS-CMs cell-sheets. A porcine ICM model included 4 groups; sham operation, omentum flap only, cell-sheet only, or combination therapy. Ejection fraction (EF) was significantly greater in the cell-sheet only and combination group compared to the other groups during the follow-up period. At 3 months, the EF of the combination group was significantly greater than that of the cell-sheet only group. Consistently, the survival rate of the SPIO-labeled hiPS-CMs, as assessed by MRI, was significantly greater in the combination group than in the cell-sheet only group. This cell delivery system would be useful in optimizing the hiPS-CM cell-sheet transplant for treating severe heart failure.

O uso agrícola de lodo de esgoto é possível através de duas abordagens distintas: como resíduo ou como produto. A abordagem “resíduo” deve seguir as diretrizes do Ministério do Meio Ambiente. Já a abordagem ”produto” deve seguir as diretrizes do Ministério da Agricultura, Pecuária e Abastecimento – MAPA. Este artigo apresenta uma análise crítica dos instrumentos legais do MAPA, que apesar de serem bastante restritivos quanto aos padrões de qualidade do produto derivado contendo lodo de esgoto, apresentam lacunas que, se não forem preenchidas, podem colocar em risco tanto a segurança agrícola quanto a segurança sanitária e ambiental. Como a abordagem de uso agrícola do lodo como um resíduo urbano estabelecido pela Resolução CONAMA – RC nº 375/2006 apresenta uma série de empecilhos de ordem prática, como um número excessivo de análises laboratoriais, monitoramento das áreas de cultivo e outras dificuldades de ordem logística, a abordagem de produto vem ganhando destaque em seu uso, especialmente no Estado de São Paulo. Assim, para viabilizar o uso agrícola via produto, buscou-se complementar os textos do MAPA com os requisitos de higienização e redução da atratividade a vetores dos textos da agência americana de proteção ambiental – EPA, de modo que o lodo tratado seja utilizado como matéria-prima na produção de fertilizante orgânico ou, dependendo de suas características, diretamente como fertilizante, sem comprometer a segurança ambiental e agrícola.

Abstract. Introduction:. Although evidence supports efficacy of treatments that enhance self-management of chronic pain, the efficacy of these treatments has been hypothesized to be influenced by patient readiness for self-management. The Pain Stage of Change Questionnaire (PSOCQ) is a reliable and valid measure of patient readiness to self-manage pain. However, there is not yet a Japanese version of the PSOCQ (PSOCQ-J), which limits our ability to evaluate the role of readiness for pain self-management in function and treatment response in Japanese patients with chronic pain. Objective:. Here, we sought to develop the PSOCQ-J and evaluate its psychometric properties. Methods:. We recruited 201 patients with chronic pain. The study participants were asked to complete the PSOCQ-J and other measures assessing pain severity, pain interference, catastrophizing, self-efficacy, and pain coping strategies. Results:. The results supported a 4-factor structure of the PSOCQ-J. We also found good to excellent internal consistencies and good test–retest reliabilities for the 4 scales. The Precontemplation scale had weak to moderate positive correlations with measures of pain-related dysfunction and maladaptive coping. The Action and Maintenance scales had weak to moderate positive correlations with measures of self-efficacy and adaptive coping. The Contemplation scale had weak positive correlations with measures of pain interference and both adaptive and maladaptive coping. Conclusions:. The PSOCQ-J demonstrated adequate psychometric properties in a sample of Japanese patients with chronic pain. This measure can be used to evaluate the role that readiness to self-manage pain may play in adjustment to chronic pain in Japanese pain populations.

IntroductionOnly a few, large population-based studies, have reported on whiplash-associated disorder (WAD). However, none of them have investigated the influence of crash severity on WAD outcome. In the present study, we aimed to determine whether crash severity predicts outcomes among patients with no-fault government insurance for acute WAD.MethodsWe utilized data from a compulsory, no-fault government automobile liability insurance agency in Japan. Individuals involved in a car accident between April 2001 and June 2015 with residual disabilities reported at the end of the treatment between October 2014 and September 2015 were included. Crash severity was assessed based on property damage costs, size of the other vehicle (large car, medium car, small car, or two-wheeled vehicles), and collision types (rear-end collision, contact with vehicle moving in the same direction, or in the opposite direction). Outcomes included the time to claim closure and the number of treatment visits.ResultsWe analyzed data for a total of 52,251 individuals (28,571 male and 23,680 female) with a median age of 44 years (range: 2-95 years). The median time to claim closure was 220 days (range: 1-4,938 days), and the median number of treatment visits was 102 (range: 1-2,492). There was no significant association between outcomes and property damage costs or size of the other vehicle. Collision types exhibited no consistent association with outcomes. However, older age and affected body parts, in addition to the neck, were independent risk factors for delayed claim closure and a large number of visits, although, all odds ratios were low (often less than 2.0).ConclusionsThere was no obvious association of outcomes with property damage costs, size of the other vehicle, or collision types in acute WAD patients. Further studies should investigate the influence of psychological factors, compensation systems, and cultural conditions.

Induced pluripotent stem cells (iPSCs) from type 1 long QT (LQT1) patients can differentiate into cardiomyocytes (CMs) including ventricular cells to recapitulate the disease phenotype. Although optical recordings using membrane potential dyes to monitor action potentials (APs) were reported, no study has investigated the disease phenotypes of cardiac channelopathy in association with the cardiac subtype at the single-cell level. We induced iPSC-CMs from three control and three LQT1 patients. Single-cell analysis using a fast-responding dye confirmed that ventricular cells were the dominant subtype (control-iPSC-CMs: 98%, 88%, 91%; LQT1-iPSC-CMs: 95%, 79%, 92%). In addition, LQT1-iPSC-ventricular cells displayed an increased frequency of early afterdepolarizations (pvalue=0.031). Cardiomyocyte monolayers constituted mostly of ventricular cells derived from LQT1-iPSCs showed prolonged AP duration (APD) (pvalue=0.000096). High-throughput assays using cardiomyocyte monolayers in 96-well plates demonstrated that IKr inhibitors prolonged APDs in both control- and LQT1-iPSC-CM monolayers. We confirmed that the optical recordings of APs in single cells and monolayers derived from control- and LQT1-iPSC-CMs can be used to assess arrhythmogenicity, supporting the feasibility of membrane potential dye-based high-throughput screening to study ventricular arrhythmias caused by genetic channelopathy or cardiotoxic drugs.

Disseminated intravascular coagulation (DIC) is a systemic life-threatening process that can cause thrombosis and hemorrhage. Chronic DIC has been associated with aortic aneurysm/dissection. Aortic aneurysm/dissection should be included in the differential diagnosis of elderly patients with hemorrhagic diathesis due to DIC of uncertain etiology. Treatment depends on various factors, including the severity of underlying disease, extent of DIC, and patient comorbidities, as well as the ability of the patient to maintain activities of daily living once discharged from the hospital. This report describes the clinical characteristics of four elderly patients with chronic DIC associated with aortic aneurysm/dissection who were treated in our institution. We also offer the recommendations around most appropriate nonsurgical treatment of these patients.

Induced pluripotent stem cells (iPSCs) can serve as a source of cardiomyocytes (CMs) to treat end-stage heart failure; however, transplantation of genetically dissimilar iPSCs even within species (allogeneic) can induce immune rejection. We hypothesized that this might be limited by matching the major histocompatibility complex (MHC) antigens between the donor and the recipient. We therefore transplanted fluorescence-labeled (GFP) iPSC-CMs donated from a macaque with homozygous MHC haplotypes into the subcutaneous tissue and hearts of macaques having heterozygous MHC haplotypes (MHC-matched; group I) or without identical MHC alleles (group II) in conjunction with immune suppression. Group I displayed a higher GFP intensity and less immune-cell infiltration in the graft than group II. However, MHC-matched transplantation with single or no immune-suppressive drugs still induced a substantial host immune response to the graft. Thus, the immunogenicity of allogeneic iPSC-CMs was reduced by MHC-matched transplantation although a requirement for appropriate immune suppression was retained for successful engraftment.

A pesquisa de vazamentos não visíveis por métodos acústicos em sistemas de abastecimento de água é dependente do treinamento, da experiência e da capacidade auditiva dos técnicos. Contudo, os sinais acústicos emitidos pelos vazamentos e transmitidos à superfície dos pavimentos possuem características espectrais que podem ser utilizadas para identificação de vazamentos de água. O desenvolvimento de um sistema baseado no reconhecimento de padrões dos sinais acústicos, que opere de forma independente ou colaborativa ao técnico, pode aumentar a eficiência do diagnóstico, além de reduzir custos com mão de obra e manutenção. Este trabalho apresenta uma Plataforma Digital de Pesquisa de Vazamentos (PDPV) desenvolvida para gravar sinais acústicos de vazamentos, visando à criação de um banco de dados de sinais com informações úteis à identificação de vazamentos de água. A potencialidade dessa plataforma é apresentada na forma de estudos de situações com que os técnicos de pesquisa de vazamento se deparam constantemente.

Background. Spur cell anemia (SCA) is a cause of hemolytic anemia in patients with alcoholic liver cirrhosis. Because dyslipidemia is related to the development of spur cells, SCA was previously treated with plasmapheresis. Case Report. A 52-year-old Japanese man with SCA associated with alcoholic liver cirrhosis (Child–Pugh C) underwent two rounds of plasmapheresis. Clinical features and serum lipid concentrations were compared before and after plasmapheresis. Although indirect hyperbilirubinemia and SCA persisted after plasmapheresis, reticulocyte counts significantly decreased from 22.4% to 4.5%, and Hb levels improved without red cell transfusions. Analysis of lipids showed that total and free cholesterol, HDL cholesterol, phospholipid, and apo-AI concentrations, all of which were reduced before plasmapheresis, had improved after treatment, while LDL cholesterol, lipoprotein (a), and apo-AII concentrations, which were also reduced before plasmapheresis, remained unchanged. Conclusions. Despite plasmapheresis partially ameliorating the degree of hemolysis, the persistence of SCA may have been linked with the lack of improvement in certain types of lipid metabolism.

Muitos autores defendem que as legislações ambientais no Brasil são bastante avançadas quando comparadas às do restante do mundo, incluindo nesse conjunto a Resolução CONAMA nº 357, de 17 de março de 2005, e a Resolução CONAMA nº 430, de 13 de maio de 2011, que dispõem sobre a classificação dos corpos de água e diretrizes ambientais para seu enquadramento, bem como as condições e padrões de lançamento de efluentes de ETEs em corpos receptores. No entanto, há uma série de inconsistências nesses dispositivos legais que levam a distorções em sua aplicação prática, principalmente quando o lançamento do efluente é proveniente de ETEs predominantemente domésticos. O primeiro questionamento refere-se ao caráter mandatório e não diretivo dessas legislações e, em segundo lugar, à falta do reconhecimento de que as tecnologias de tratamento de esgotos possuem limitações técnicas para o atendimento de determinados parâmetros. Por fim, essas inconsistências levam a uma falha sistêmica na questão ambiental relativa ao tratamento de esgotos, deixando em situação fragilizada não só os responsáveis pela operação das ETEs, como também os próprios agentes ambientais envolvidos nas atividades de licenciamento e fiscalização.

We report here two cases of Waldenstrom’s macroglobulinemia (WM), one with central nervous system (CNS) symptoms and severe retinopathy and one with renal failure. In both cases, the serum IgM levels exceeded 3,000 mg/dL and monoclonal IgM-kappa was observed in the blood. At onset, Case 1, a 63-year-old female, developed CNS symptoms—namely, drowsiness and syncope. Case 2, a 58-year-old male, had nausea and dysgeusia on admission associated with renal failure, which is quite rare in patients with WM. Both patients exhibited hyperviscosity-related retinopathy, but it was particularly severe in Case 1: she suddenly lost her vision after admission. However, her vision recovered completely during treatment. Case 2 required hemodialysis immediately after admission. Needle biopsy of his kidney revealed tubulointerstitial nephritis with marked infiltration with CD20-positive lymphoplasmacytic lymphoma cells. After treatment, Case 1 has been in a remission longer than 8 years, but Case 2 died of pneumonia in 6 months. Since the initial symptoms of WM are ambiguous and vary significantly and hyperviscosity-related ophthalmological problems or severe renal dysfunction can arise, it is essential to promptly measure serum IgM levels and to institute appropriate care immediately when WM is confirmed in a patient.

Background: Pain is regarded as one of the most common nonmotor symptoms in Parkinson's disease (PD). In particular, musculoskeletal pain has been reported as the most common type of PD-associated pain. Crowned dens syndrome (CDS), related to microcrystalline deposition in the periodontoid process, is the main cause of acute or chronic cervical pain. Case Presentation: This report describes the case of an 87-year-old woman who had severe bradykinesia, muscle rigidity, gait disturbance and neck pain. Laboratory examination revealed marked elevations of white blood cells (10,100/µl) and C-reactive protein (CRP; 8.63 mg/dl). She was primarily diagnosed with severe and untreated PD, corresponding to Hoehn and Yahr scale score IV, with musculoskeletal pain and urinary tract infection. The patient was treated with antiparkinsonism drugs, antibiotic agents and nonsteroidal anti-inflammatory drugs, but they had only limited effects. Cervical plain computed tomography (CT) scanning detected remarkable crown-like calcification surrounding the odontoid process. Based on CT findings, the patient was diagnosed as having CDS with PD, and was immediately treated with corticosteroid. The severe neck rigidity with pain and the serum CRP level (0.83 mg/dl) of the patient were drastically improved within a week by the additional corticosteroid therapy. Conclusion: Severe neck rigidity and bradykinesia in this patient might have strengthened the chondrocalcinosis around the odontoid process. Cervical plain CT scan is necessary and useful for the definitive diagnosis of CDS. CDS should be considered as a differential diagnosis of a possible etiology for musculoskeletal pain related to rigidity and bradykinesia in PD.

Background: Myelitis is one of the rarest neurological complications of the varicella zoster virus (VZV) infection. Focal muscle weakness with or without sensory disturbance occurs in approximately 5% of the cases after acute VZV infection, with complete recovery in 50-70%. Case Presentation: This report describes two rare cases of elderly patients with VZV myelitis secondary to dermatomal zoster rash. Patient 1 was a 79-year-old woman who developed paraplegia, numbness and decreased sensation in the left arm and below thoracic (Th)-10 after sacral zoster. Spinal cord MRI showed a high-signal-intensity lesion at the cervical spinal nerve 2 on a T2-weighted image. Patient 2 was a 73-year-old man who developed right flaccid leg weakness and urinary retention after right dorsal Th 5-8 zoster. Spinal cord MRI showed a high-signal-intensity lesion at Th 3-4 on a T2-weighted image. In both cases, although the conventional single polymerase chain reaction (PCR) assays all showed negative results, the original nested PCR assay detected VZV DNA in the cerebrospinal fluid (CSF) specimen collected on admission. In addition, the anti-VZV IgG antibody by enzyme immunoassay and antibody index were elevated in the CSF specimens during the clinical courses of both patients. On the basis of these findings, both patients were diagnosed with VZV myelitis and were treated with high-dose acyclovir and corticosteroid. This combined treatment was appropriate and effective for the improvement of their functional outcomes. Conclusion: The detection of VZV DNA in CSF by nested PCR assay and the evaluation of the antibody index to VZV had significant diagnostic value.

Normalmente o critério de vencimento de uma licitação de materiais e equipamentos se baseia no preço do menor lance, bem como no atendimento às especificações técnicas. O que se questiona neste modelo é a não apropriação de impacto de custos operacionais advindos da superação dos requisitos mínimos especificados. Por um lado a determinação dos requisitos mínimos não pode ser tão restritiva que limite a participação de concorrentes e por outro, não se deveria julgar da mesma maneira uma tecnologia com diferencial superior que traria benefícios na redução dos custos operacionais. Situar-se neste meio termo é o desafio proposto num modelo licitatório que leve em conta este diferencial tecnológico, com o objetivo de induzir a introdução de tecnologias inovadoras.

We examined the effects of transforming growth factor β1 (TGFβ1) on cellular functions in human lung cancer cell line A549. Treatment of A549 cells with 1 ng/ml TGFβ1 for more than 3 days altered their morphology from an epithelial cobblestone-like appearance to a fibroblast-like one, reduced the expression of E-cadherin mRNA and protein, and induced the formation of F-actin fibers. These hallmarks indicate that TGF β1 induced the epithelial–mesenchymal transition in A549 cells. Migration of TGF1β1-treated A549 cells, which was quantified by the wound-healing assay, was markedly accelerated by 3 μM ATPγS, a non-hydrolyzable ATP analogue. ATPγS-induced migration of TGFβ1-treated A549 cells was reversed by the P2 antagonist suramin. In contrast, migration of control A549 cells was not altered by ATPγS. TGFβ1-treated A549 cells showed an augmentation of ATP-induced Ca2+ transients, thapsigargin-induced Ca2+ transients, and store-operated Ca2+ entry compared with those in control cells. Basal level of the extracellular ATP concentration was significantly lower in TGFβ1-treated A549 cells than in control cells. We conclude from these results that TGFβ1 augments ATP-induced Ca2+ mobilization, which leads to the acceleration of migration, in A549 cells but, it markedly reduces endogenous ATP release. This implies that the actions of ATP would become a novel therapeutic target for inhibiting cancer cell migration. Keywords:: A549 cell, store-operated calcium entry, P2 receptor, cell migration, epithelial–mesenchymal transition

Purpose: The abdominal procedure of ventriculoperitoneal or lumboperitoneal shunt is difficult because of a deep and narrow operative view, especially for obese patients. We have developed the 'Hoisting method,' which enables us to make abdominal procedures easy and safe. Material and methods: We report our experience with five cases between April 2020 and March 2021. Results: The placement of the shunt was easy and safe in all patients without any complications. Conclusion: The shunt method is very effective and easy without requiring additional devices. [ABSTRACT FROM AUTHOR]

Background: Brain metastasis from undifferentiated pleomorphic sarcoma (UPS) is a rare occurrence, and its clinical course is little known. In this report, we investigate a case of a rapidly growing brain metastasis from gastric UPS. Case Description: An 82-year-old man with a known gastric tumor, pathologically compatible with UPS, underwent partial gastrectomy at an outside facility. 3 months later, a 4-cm brain tumor was detected, which was completely resected. The patient was diagnosed with metastatic tumor from previously treated gastric UPS. Within 2 months of the initial resection, a large recurrent mass was detected in the same location, which was again removed. Although the patient underwent radiotherapy and chemotherapy for other metastatic tumors, he died 5 months after the second craniotomy. Conclusions: Brain metastasis from gastric UPS is rare and difficult to treat. Although aggressive treatment, such as surgical intervention, may improve patient survival in some cases, the timing of treatment is challenging because cerebral metastasis rapidly grows and and patients frequently suffer from synchronous systematic metastasis. Therefore, early detection and close follow-up of rapidly progressing brain metastasis are important to improve treatment outcomes. [ABSTRACT FROM AUTHOR]

Objective: To assess how virtual hepatectomy (VH), conducted using surgical planning software, influences the outcomes of liver surgery. Background: Imaging technology visualizes the territories of the liver vessels, which were previously impossible. However, the clinical impact of VH has not been evaluated. Methods: From 2004 to 2013, we performed 1194 VHs preoperatively. Outcomes of living donor liver transplantation (LDLT) and hepatectomy for hepatocellular carcinoma (HCC)/colorectal liver metastases (CRLM) were compared between patients in whom VH was performed (VH) and those without VH evaluation (non-VH). Results: In LDLT, the rate of right liver graft use was higher in the VH (62.1%) than in the non-VH (46.5%) (P < 0.01), which did not increase morbidity of donor surgery. Duration of recipient surgery in the VH in which middle hepatic vein branch reconstruction was skipped was shorter than that in the VH with venous reconstruction. Among HCC patients with impaired liver function, portal territory-oriented resection was conducted more often in the VH than in the non-VH. The 5-year disease-free survival rate for localized HCC was higher in the VH than in the non-VH (37.2% vs 23.9%; P = 0.04). In CRLM, long-term outcomes were similar in the VH and non-VH despite the larger tumor load in the VH. Conclusions: VH in LDLT allows double equipoise for the recipient and donor by optimizing decision-making on graft selection and venous reconstruction. VH offers a chance for radical hepatectomy even in HCC patients with impaired liver function and CRLM patients with advanced tumors, without compromising survival. [ABSTRACT FROM AUTHOR]

To improve natural killer group 2 member D (NKG2D)-dependent cytotoxicity, the inhibition of cleavage and release of major histocompatibility complex class 1-related chain (MIC) molecules from the tumor surface are required. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is able to induce cell-surface MICA/B on tumor cells. In the present study, the ability of VPA and gemcitabine (GEM) to upregulate MICA/B in pancreatic cancer cells was investigated, resulting in the inhibition of cleavage and release of MIC molecules from the tumor surface. Flow cytometry was used to quantify MICA/B expression in six human pancreatic cancer lines. Functional cytotoxic activity of γδT cells against pancreatic cancer cells treated with VPA and GEM was determined using cytotoxicity assays. At low doses of VPA (0.7 mM) and GEM (0.001 µM), which did not induce tumor growth alterations, the agents individually increased cell-surface MICA/B expression in MICA/B-positive cell lines, but not in the MICA/B-negative cell line. Furthermore, the combination of VPA and GEM synergistically induced cell-surface MICA/B expression. In MICA/B-positive cell lines, the increase in MICA/B expression was dependent on VPA concentration. The combination of low-dose VPA and GEM enhanced the susceptibility of the PANC-1 cell line to γδT cell-mediated tumor cell lysis. It was observed that soluble MIC was released from PANC-1 in the culture supernatant following treatment with GEM. However, the combination of low-dose VPA with low-dose GEM increased MICA/B expression without inducing soluble MIC, resulting in enhanced tumor cell lysis. The results of the present study suggest that the combined administration of low-dose VPA with low-dose GEM has the potential to enhance the therapeutic effects of immunotherapy in pancreatic cancer. Furthermore, it is proposed that the combination acts, in part, by upregulating MICA/B and prevents soluble MIC from being released. [ABSTRACT FROM AUTHOR]

Background: Acquired factor V deficiency (AFVD) caused by Factor V (FV) inhibition is a rare event, characterized by prolonged prothrombin time and activated partial thromboplastin time. To date, various factors were reported as triggers for developing FV inhibitor. Clinical symptoms range from asymptomatic to life-threatening bleeding. Case Report and Conclusions: Here, we report an 84-year-old Japanese male on hemodialysis due to renal failure who developed subcutaneous hemorrhage after administration of cefepime (CFPM) to treat bacteremia. Deficient FV activity (< 1.0%) was identified and AFVD with FV inhibitor titer of 9 BU/mL was diagnosed. Although the patient had multiple risks for developing FV inhibitor, CFPM was thought to be the major culprit in this case. After the diagnosis, oral prednisolone (30 mg/day) was initiated, but the patient died of respiratory/cardiac failure, unrelated to AFVD. [ABSTRACT FROM AUTHOR]

To evaluate the efficacy and safety of mirtazapine in Japanese patients with fibromyalgia (FM), a parallel-group, randomized, double-blind, placebo-controlled phase IIa study was conducted at 57 sites between November 2012 and February 2014. Patients aged 20 to 64 years who met the American College of Rheumatology 1990 diagnostic FM criteria and had stably high pain scores during a placebo run-in period were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to receive mirtazapine orally (15 mg/d for 1 week and then 30 mg/d) or matching placebo for 12 weeks. The primary endpoint was change in mean numerical rating scale (NRS) pain score from baseline to endpoint (week 12 or early discontinuation). Of the 430 patients randomized (n = 215 each group), 422 (n = 211 each group) were analyzed for the primary endpoint. At the study endpoint, mirtazapine caused a significantly greater reduction in the mean NRS pain score compared with placebo (difference, 0.44; 95% confidence interval, -0.72 to -0.17; P = 0.0018). The reduction by mirtazapine remained significantly greater compared with placebo from week 6 onward. More patients treated with mirtazapine had their NRS pain score reduced by ≥30% from baseline (45.5% vs 30.8%). Mirtazapine also improved pain-related quality of life assessed by the Japanese version of the Fibromyalgia Impact Questionnaire and the Short-Form 36 Questionnaire. Adverse events were more common with mirtazapine than placebo (68.8% vs 56.7%), including somnolence (32.1% vs 7.4%), weight gain (17.7% vs 0.9%), and increased appetite (11.6% vs 3.3%). In conclusion, mirtazapine was an effective and safe treatment for Japanese patients with FM. [ABSTRACT FROM AUTHOR]