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Background: No comprehensive analysis of the pulmonary sequelae of coronavirus disease 2019 (COVID-19) in Japan based on respiratory function tests and chest computed tomography (CT) has been reported. We evaluated post-COVID-19 conditions, especially focusing on pulmonary sequelae assessed by pulmonary function tests and chest CT., Methods: For this prospective cohort study, we enrolled 1069 patients who presented pneumonia at the time of admission in 55 hospitals from February 2020 to September 2021. Disease severity was classified as moderateⅠ, moderate II, and severe, defined primarily according to the degree of respiratory failure. The data on post-COVID-19 conditions over 12 months, pulmonary function, and chest CT findings at 3 months were evaluated in this study. Additionally, the impact of COVID-19 severity on pulmonary sequelae, such as impaired diffusion capacity, restrictive pattern, and CT abnormalities, was also evaluated., Results: The most frequently reported post-COVID-19 conditions at 3 months after COVID-19 were muscle weakness, dyspnea, and fatigue (48.4%, 29.0%, and 24.7%, respectively). The frequency of symptoms gradually decreased over subsequent months. In pulmonary function tests at 3 months, the incidence of impaired diffusion capacity and restrictive pattern increased depending on disease severity. There also were differences in the presence of chest CT abnormalities at the 3 months, which was markedly correlated with the severity., Conclusion: We reported a comprehensive analysis of post-COVID-19 condition, pulmonary function, and chest CT abnormalities in Japanese patients with COVID-19. The findings of this study will serve as valuable reference data for future post-COVID-19 condition research in Japan., Competing Interests: Declaration of Competing interest The authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The prevalence of respiratory sarcopenia and its effect on respiratory muscle strength (RMS) in patients with cardiovascular disease (CVD), who are transferred to a convalescent rehabilitation hospital after acute care and require continuous cardiac rehabilitation (CR), is currently unclear. This study aimed to assess changes in RMS, physical function, and activities of daily living (ADL) before and after CR performed in a rehabilitation hospital., Methods: Of 50 consecutive patients transferred to a rehabilitation hospital for ongoing CR, 30 fulfilled the inclusion criteria. Maximal inspiratory and expiratory pressures (MIP and MEP, respectively) were measured at transfer, and patients with decreased RMS were diagnosed with respiratory sarcopenia. RMS, physical function, exercise tolerance, ADL ability, and health-related quality of life (HR-QoL) were measured and compared at transfer and discharge., Results: The prevalence of respiratory sarcopenia at the time of transfer to the rehabilitation hospital was 93.3%. RMS assessments at transfer and discharge demonstrated significant improvements in %MIP (from 46.3±26.1% to 63.6±33.7%) and %MEP (from 44.8±17.3% to 56.6±21.8%). Short physical performance battery, gait speed, handgrip strength, and knee extension muscle strength significantly improved, along with significant prolongation of 6-min walking distance as a measure of exercise tolerance. ADL assessment using the functional independence measure revealed significant improvement, as did HR-QoL assessed according to the five-dimension, five-level, EuroQoL instrument, following CR., Conclusions: Although respiratory sarcopenia was highly prevalent among patients with CVD who required transfer to a rehabilitation hospital after acute care, continuous CR significantly improved RMS, ADL, physical function, and exercise tolerance. These findings support the continued expansion of CR, particularly in dedicated rehabilitation hospitals., Competing Interests: The authors declare no conflict of interest with this manuscript., (Copyright 2024, Matsuo et al.)

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by complex lung pathogenesis affecting approximately three million people worldwide. While the molecular and cellular details of the IPF mechanism is emerging, our current understanding is centered around the lung itself. On the other hand, many human diseases are the products of complex multi-organ interactions. Hence, we postulate that a dysfunctional crosstalk of the lung with other organs plays a causative role in the onset, progression and/or complications of IPF. In this study, we employed a generative computational approach to identify such inter-organ mechanism of IPF. This approach found unexpected molecular relatedness of IPF to neoplasm, diabetes, Alzheimer's disease, obesity, atherosclerosis, and arteriosclerosis. Furthermore, as a potential mechanism underlying this relatedness, we uncovered a putative molecular crosstalk system across the lung and the liver. In this inter-organ system, a secreted protein, kininogen 1, from hepatocytes in the liver interacts with its receptor, bradykinin receptor B1 in the lung. This ligand-receptor interaction across the liver and the lung leads to the activation of calmodulin pathways in the lung, leading to the activation of interleukin 6 and phosphoenolpyruvate carboxykinase 1 pathway across these organs. Importantly, we retrospectively identified several pre-clinical and clinical evidence supporting this inter-organ mechanism of IPF. In conclusion, such feedforward and feedback loop system across the lung and the liver provides a unique opportunity for the development of the treatment and/or diagnosis of IPF. Furthermore, the result illustrates a generative computational framework for machine-mediated synthesis of mechanisms that facilitates and complements the traditional experimental approaches in biomedical sciences., (© 2023. The Author(s).)

Understanding the principles of cell migration necessitates measurements of the forces generated by cells. In traction force microscopy (TFM), fluorescent beads are placed on a substrate's surface and the substrate strain caused by the cell traction force is observed as displacement of the beads. Mathematical analysis can estimate traction force from bead displacement. However, most algorithms estimate substrate stresses independently of cell boundary, which results in poor estimation accuracy in low-density bead environments. To achieve accurate force estimation at low density, we proposed a Bayesian traction force estimation (BTFE) algorithm that incorporates cell-boundary-dependent force as a prior. We evaluated the performance of the proposed algorithm using synthetic data generated with mathematical models of cells and TFM substrates. BTFE outperformed other methods, especially in low-density bead conditions. In addition, the BTFE algorithm provided a reasonable force estimation using TFM images from the experiment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Phase 2 in-patient cardiac rehabilitation (CR) at a rehabilitation hospital is now added the medical service fees in Japan and in light of the recent reimbursement for CR, a study needed to be performed to determine exertional exercise on its effectiveness and benefits to patients. We examined the effects of daily aerobic exercise duration on health-related quality of life (HR-QoL) at 6 months after discharge from phase 2 CR., Methods: Of the 54 consecutive cardiovascular disease patients admitted to a rehabilitation hospital after acute care, 43 were considered acceptable candidates for enrollment according to predetermined inclusion and exclusion criteria. Of these, 40 patients completed study requirements, including return of a questionnaire on HR-QoL survey 6 months after discharge. The primary outcome was HR-QoL as evaluated using the EuroQol five-dimension five-level (EQ-5D-5L). Two multiple regression models were constructed to assess the influences of daily aerobic exercise duration (content of rehabilitation) and other clinicodemographic variables assessed during acute care (model 1) or at transfer from acute care to a rehabilitation hospital (model 2)., Results: Both model 1, which included age, Barthel index of daily function before hospitalization, and daily aerobic exercise duration in the rehabilitation hospital (R 2 = 0.553, P < 0.001), and model 2, which included New York Heart Association functional classification at transfer, Charlson comorbidity index at transfer, and daily aerobic exercise duration (R 2 = 0.336, P = 0.002) identified aerobic exercise duration as a significant independent factor influencing HR-QoL at 6 months post-discharge (model 1: P = 0.041; model 2: P = 0.010)., Conclusions: Enhanced daily aerobic exercise content during phase 2 in-hospital CR can significantly improve longer-term HR-QoL among cardiovascular disease patients independently of other clinicodemographic factors, including age, activities of daily living before treatment, and baseline condition at rehabilitation onset. These findings, that in the small sample size, support the continued expansion of phase 2 CR at a rehabilitation hospital in Japan., Competing Interests: The authors declare that there is no conflict of interest., (Copyright 2023, Matsuo et al.)

Motivation: Human diseases are characterized by multiple features such as their pathophysiological, molecular and genetic changes. The rapid expansion of such multi-modal disease-omics space provides an opportunity to re-classify diverse human diseases and to uncover their latent molecular similarities, which could be exploited to repurpose a therapeutic-target for one disease to another., Results: Herein, we probe this underexplored space by soft-clustering 6955 human diseases by multi-modal generative topic modeling. Focusing on chronic kidney disease and myocardial infarction, two most life-threatening diseases, unveiled are their previously underrecognized molecular similarities to neoplasia and mental/neurological-disorders, and 69 repurposable therapeutic-targets for these diseases. Using an edit-distance-based pathway-classifier, we also find molecular pathways by which these targets could elicit their clinical effects. Importantly, for the 17 targets, the evidence for their therapeutic usefulness is retrospectively found in the pre-clinical and clinical space, illustrating the effectiveness of the method, and suggesting its broader applications across diverse human diseases., Availability and Implementation: The code reported in this article is available at: https://github.com/skozawa170301ktx/MultiModalDiseaseModeling., Supplementary Information: Supplementary data are available at Bioinformatics Advances online., (© The Author(s) 2023. Published by Oxford University Press.)

Aims: To investigate the changes in the proportion of antimicrobial prophylaxis (AP) during the urodynamic study (UDS) and the frequency of posttest genito-urinary tract infections (GUTI) before and after coronavirus disease 2019 (COVID-19) pandemic, and evaluate this associations., Patients and Methods: Patients who underwent UDS between 2015 and 2021 were targeted, and they were allocated to pre-2020 as before the appearance of COVID-19 and post-2020 as after that, and propensity score matching was performed. The impact on AP was assessed by the administration rate, and that on the development of febrile GUTI after UDS was assessed for an equivalence by the GUTI-free rate at 7 days after testing., Results: After matching, 384 cases of 192 cases each were included. The frequency of AP was 58.3% in pre-2020 and 77.1% in post-2020, an increase of about 19%, and the rate increased significantly in post-2020 (p < 0.001). However, the incidence of GUTI after UDS was 4.2% and 4.7%, respectively, with no significant difference. The ratio of GUTI-free rates was within the equivalence margin, confirming an equivalence before and after the appearance of COVID-19., Conclusions: Under the influence of COVID-19 pandemic, even though AP rate during UDS was increased by 19% from that brought by following the guideline-based administration methods, the frequency of GUTI after UDS was similar, so it is thought to be important to use AP during UDS appropriately for high-risk cases as recommended in the guidelines., (© 2022 Wiley Periodicals LLC.)

In patients with chronic obstructive pulmonary disease (COPD), emphysema, airway disease, and extrapulmonary comorbidities may cause various symptoms and impair physical activity. To investigate the relative associations of pulmonary and extrapulmonary manifestations with physical activity in symptomatic patients, this study enrolled 193 patients with COPD who underwent chest inspiratory/expiratory CT and completed COPD assessment test (CAT) and the Life-Space Assessment (LSA) questionnaires to evaluate symptom and physical activity. In symptomatic patients (CAT ≥ 10, n = 100), emphysema on inspiratory CT and air-trapping on expiratory CT were more severe and height-adjusted cross-sectional areas of pectoralis muscles (PM index) and adjacent subcutaneous adipose tissue (SAT index) on inspiratory CT were smaller in those with impaired physical activity (LSA < 60) than those without. In contrast, these findings were not observed in less symptomatic patients (CAT < 10). In multivariable analyses of the symptomatic patients, severe air-trapping and lower PM index and SAT index, but not CT-measured thoracic vertebrae bone density and coronary artery calcification, were associated with impaired physical activity. These suggest that increased air-trapping and decreased skeletal muscle and subcutaneous adipose tissue quantity are independently associated with impaired physical activity in symptomatic patients with COPD., (© 2022. The Author(s).)

The full-iterative model reconstruction generates ultra-high-resolution computed tomography (U-HRCT) images comprising a 1024 × 1024 matrix and 0.25 mm thickness while suppressing image noises, allowing evaluating small airways 1-2 mm in diameter. However, this technique imposes huge computational burdens and requires a long reconstruction time. This study evaluated whether a recently-established deep learning-based reconstruction, Advanced intelligent Clear-IQ Engine (AiCE), allows quantitative morphological analyses of smaller airways with equal or better quality than the full-iterative model reconstruction while shortening the reconstruction time. In phantom tubes mimicking small airways, the measurement error of 0.5-mm-thickness wall was smaller on the AiCE-based than the full-iterative model-based U-HRCT. Moreover, in five patients with chronic obstructive pulmonary disease, the AiCE-based U-HRCT decreased the reconstruction time approximately by 90% with a modest improvement in image noise, contrast, and sharpness compared to the full-iterative model-based U-HRCT. Therefore, the AiCE-based U-HRCT can be readily used clinically for morphologically evaluating peripheral small airways., Competing Interests: Conflict of Interest Yuji Nakamoto and Ryo Sakamoto received a research grant from Canon Medical Systems Corporation. The other authors have no conflicts of interest., (Copyright © 2021 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Purpose: Asthma onset before the age of 40 years is associated with distinct clinical manifestations in chronic obstructive pulmonary disease (COPD) patients, but its morphologic features remain unestablished. This study aimed to explore airway morphology in COPD patients with asthma onset before 40 years of age using ultra-high-resolution computed tomography (U-HRCT), which allows a more accurate quantitation of the lumen and the wall in smaller airways than using conventional CT., Materials and Methods: Clinical data of 500 consecutive patients undergoing full inspiratory U-HRCT (1024×1024 matrix and 0.25 mm slice thickness) were retrospectively analyzed. COPD patients without asthma, COPD patients with asthma onset at age below or 40 years and above, and non-COPD smoker controls (N=137, 29, 34, and 22, respectively) were enrolled. The length, lumen area (LA), wall thickness and area (WA), and wall area percent (WA%) of the segmental (third-generation) to sub-subsegmental (fifth-generation) bronchus and the low attenuation volume percent (LAV%) were measured., Results: LA and WA were smaller in the fourth and fifth generation in COPD patients than in non-COPD controls, regardless of the age of asthma onset. LA was smaller and WA% was larger in the fourth-generation and fifth-generation airways in COPD with asthma onset before 40 years than COPD without asthma, whereas WA did not differ between them. In multivariate analyses, asthma onset before 40 years was associated with smaller LA in COPD patients independent of demographics, use of inhaled corticosteroids and long-acting bronchodilators, airflow limitation, and LAV%., Conclusions: Asthma onset before 40 years of age could be associated with greater lumen narrowing of the airways in COPD., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Dopamine type 1 receptor (D1R) signaling activates protein kinase A (PKA), which then activates mitogen-activated protein kinase (MAPK) through Rap1, in striatal medium spiny neurons (MSNs). MAPK plays a pivotal role in reward-related behavior through the activation of certain transcription factors. How D1R signaling regulates behavior through transcription factors remains largely unknown. CREB-binding protein (CBP) promotes transcription through hundreds of different transcription factors and is also important for reward-related behavior. To identify transcription factors regulated by dopamine signaling in MSNs, we performed a phosphoproteomic analysis using affinity beads coated with CBP. We obtained approximately 40 novel candidate proteins in the striatum of the C57BL/6 mouse brain after cocaine administration. Among them, the megakaryoblastic leukemia-2 (MKL2) protein, a transcriptional coactivator of serum response factor (SRF), was our focus. We found that the interaction between CBP and MKL2 was increased by cocaine administration. Additionally, MKL2, CBP and SRF formed a ternary complex in vivo. The C-terminal domain of MKL2 interacted with CBP-KIX and was phosphorylated by MAPK in COS7 cells. The activation of PKA-MAPK signaling induced the nuclear localization of MKL2 and increased SRF-dependent transcriptional activity in neurons. These results demonstrate that dopamine signaling regulates the interaction of MKL2 with CBP in a phosphorylation-dependent manner and thereby controls SRF-dependent gene expression. Cover Image for this issue: https://doi.org/10.1111/jnc.15067., (© 2021 International Society for Neurochemistry.)

Purpose: Dry eye syndrome is known to develop from several systemic inflammatory diseases. Although dry eye may develop due to extraintestinal complications of ulcerative colitis (UC), the pathogenesis is not well-known. This study aimed to investigate whether there was decrease in the tear secretion volume in a mice model with UC; the difference between the control and dextran sodium sulphate (DSS)-treated group was also determined., Materials and Methods: This study included a mice model with UC induced by the oral administration of 5.0% DSS for 7 days. Following the DSS treatment, the tear volume was measured using the Schirmer's test. The colon and ocular tissues, including the lacrimal gland, were evaluated using histological and protein analyses. Additionally, tumour necrosis factor (TNF)-α and interleukin (IL)-6 in the plasma were determined. Differences between groups (DSS-treated versus control mice) were determined using Student's t -test., Results: The tear volume in DSS-treated mice was decreased compared to that in the control mice. Plasma levels of TNF-α and IL-6 in DSS-treated mice was higher than that of control. Morphological change was observed with the invasion of the inflammatory cell in the lacrimal gland of DSS-treated mice. Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling (TUNEL)-positive cells were increased in the lacrimal glands of DSS-treated mice compared with control group. The distribution of aquaporin-5 expressed in the lacrimal gland of DSS-treated mice was decreased compared to that in the control group., Conclusions: These findings suggest that a decrease in the tear volume in UC was associated with a functional decline in the inflamed lacrimal gland. This result therefore provides useful information that could contribute to the development of treatment approaches for dry eye associated with UC.

Background: Sudden unexpected death in infancy (SUDI) comprises both natural and unnatural causes of death. However, few epidemiological surveys have investigated SUDI in Japan., Objective: This retrospective study was conducted to investigate the latest trends of circumstances and risk factors of SUDI cases in which collapse occurred during sleep., Methods: Forensic pathology sections from eight universities participated in the selection of subjects from 2013 to 2018. Data obtained from the checklist form were analyzed based on information at postmortem., Results: There were 259 SUDI cases consisting of 145 male infants and 114 female infants with a mean birth weight of 2888 ± 553 and 2750 ± 370 g, respectively. Deaths most frequently occurred among infants at 1 month of age (18%). According to population data as the control, the odds ratio (95% confidence interval) of mother's age ≤19 years was 11.1 (6.9-17.7) compared with ages 30-39. The odds ratio for the fourth- and later born infants was 5.2 (3.4-7.9) compared with the frequency of first-born infants. The most frequent time of day for discovery was between 7 and 8 o'clock, and the time difference from the last seen alive was a mean of 4.1 h. Co-sleeping was recorded for 61%, and the prone position was found for 40% of cases at discovery. Mother's smoking habit exhibited an odds ratio of 4.5 (2.9-5.8)., Conclusion: This study confirmed the trends that have been observed for sudden infant death syndrome; particularly, very high odds ratios were evident for teenage mothers and later birth order in comparison with those in other developed countries. Neglect was suspected in some cases of the prolonged time to discovery of unreactive infants. To our knowledge, this is the first report of an extensive survey of SUDI during sleep in Japan., Competing Interests: The authors have declared no competing interests exist.

Background: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is closely associated with emphysema and non-emphysematous gas trapping, termed functional small airway disease (fSAD), on inspiratory and expiratory computed tomography (CT). Because the cranial-caudal emphysema distribution affects pulmonary function and fSAD may precede emphysema on CT, we tested the hypothesis that lobar fSAD distribution would affect lung hyperinflation differently in COPD with minimal and established emphysema., Methods: The volume percentages of fSAD and emphysema (fSAD% and Emph%) over the upper and lower lobes were measured using inspiratory and expiratory CT in 70 subjects with COPD. Subjects were divided into those with minimal and established emphysema (n = 36 and 34) using a threshold of 10% Emph% in the whole lung., Results: In the minimal emphysema group, fSAD% in the upper and lower lobes was positively correlated with functional residual capacity (FRC) and residual volume to total lung capacity ratio (RV/TLC), and the correlation of fSAD% with RV/TLC was greater in the lower lobes. Conversely, in the established emphysema group, fSAD% in the upper and lower lobes was correlated with RV/TLC, but not with FRC. In multivariate analysis, fSAD% in the lower lobes, but not in the upper lobes, was associated with RV/TLC in subjects with minimal emphysema after adjusting for age, smoking status, and bronchodilator use., Conclusion: Non-emphysematous gas trapping in the upper and lower lobes has a distinct physiological effect, especially in COPD with minimal emphysema. This local evaluation might allow sensitive detection of changes in lung hyperinflation in COPD., Competing Interests: Declaration of Competing Interest N.T., S.S., T.O. and T.H. were supported by a grant from FUJIFILM Co., Ltd. K.T. was supported by Canon Medical Systems Corporation. None of these companies had a role in the design or analysis of the study or in the writing of the manuscript. Other authors have no conflict of interest to declare., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Approximately 90% of pre-clinically validated drugs fail in clinical trials owing to unanticipated clinical outcomes, costing over several hundred million US dollars per drug. Despite such critical importance, translating pre-clinical data to clinical outcomes remain a major challenge. Herein, we designed a modality-independent and unbiased approach to predict clinical outcomes of drugs. The approach exploits their multi-organ transcriptome patterns induced in mice and a unique mouse-transcriptome database "humanized" by machine learning algorithms and human clinical outcome datasets. The cross-validation with small-molecule, antibody, and peptide drugs shows effective and efficient identification of the previously known outcomes of 5,519 adverse events and 11,312 therapeutic indications. In addition, the approach is adaptable to deducing potential molecular mechanisms underlying these outcomes. Furthermore, the approach identifies previously unsuspected repositioning targets. These results, together with the fact that it requires no prior structural or mechanistic information of drugs, illustrate its versatile applications to drug development process., Competing Interests: Declaration of Interests T.N.S. is the inventor of the patents filed on hMDB-i and is the scientific founder of and holds shares of Karydo TherapeutiX, Inc., which owns the right to this patent. S.K., S.F., S.E., G.M.D.A., and Y.M. are employees of Karydo TherapeutiX, Inc. Correspondence and requests for materials should be addressed to T.N.S (island1005@gmail.com)., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: In Japan, benign asbestos pleural effusion (BAPE) has been eligible for industrial accident compensation since 2003 as an asbestos-related disease despite the lack of good criteria. We compiled a criteria into a checklist of essential items and for excluding other diseases inducing pleural effusion as a diagnosis process., Method: Thoracentesis was performed in order to confirm the presence of pleural effusion at the initial diagnosis, and 105 suspected BAPE patients were retrospectively examined. We complied a checklist comprising the following diagnostic items: (a) occupational asbestos exposure; (b) confirmation of exudate of pleural effusion; (c) exclusion of pleural effusion with malignant tumors based on negative results of CEA and hyaluronic acid, and cytology of pleural effusion; (d) exclusion of rheumatic, bacterial, and tuberculous pleuritis; (d) radiological findings for exclusion of malignancies; and (e) histopathological findings based on thoracoscopy that exclude malignancies (when thoracoscopy was not performed, there was confirmation that no malignancies were present during 3-month follow-up observation). Cases that satisfied all items were defined as BAPE., Results: Among the 105 suspected cases, there were five cases that had no occupational asbestos exposure; six cases in which transudate of on pleural effusion; one case each of rheumatoid pleuritis and tuberculous pleuritis; and five cases of pleural mesothelioma based on chest radiography and histopathological findings within 3 months after initial diagnosis. Therefore, we excluded 18 cases from the 105 candidates and determined 87 cases of BAPE., Conclusion: We consider that six items described above are suitable for diagnosing BAPE., (© 2020 Japan Organization of Occupational Health and Safety. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Dopamine (DA) activates mitogen-activated protein kinase (MAPK) via protein kinase A (PKA)/Rap1 in medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R) in the nucleus accumbens (NAc), thereby regulating reward-related behavior. However, how MAPK regulates reward-related learning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we perform proteomic analysis using affinity beads coated with cyclic AMP response element binding protein (CREB)-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identify more than 400 CBP-interacting proteins, including Neuronal Per Arnt Sim domain protein 4 (Npas4). We find that MAPK phosphorylates Npas4 downstream of PKA, increasing the Npas4-CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. The deletion of Npas4 in D1R-expressing MSNs impairs cocaine-induced place preference, which is rescued by Npas4-wild-type (WT), but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases transcriptional activity to enhance reward-related learning and memory., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Disease in small airways <2 mm in diameter is a major pathology of chronic obstructive pulmonary disease (COPD). However, compared to airways <1 mm in diameter, the pathophysiological role of airways 1-2 mm in diameter remains unclear. This study analysed phantom and human COPD data to test the hypothesis that ultra-high-resolution computed tomography (U-HRCT) can accurately measure peripheral airways that are difficult to measure with conventional CT., Method: The lower limit of lumen sizes measurable on U-HRCT was determined using phantom tubes. In the cross-sectional data of 110 males with COPD who underwent U-HRCT (1024 × 1024 matrix, 0.25 mm slice thickness) and spirometry, all 3 rd (segmental) to 6 th generation airways of the right apical and basal posterior bronchus (RB1 and RB10) were analysed., Results: The errors in measuring the lumen area (LA) of phantom tubes ≥1.3 and 1.0 mm in diameter were within ±10 and -24%, respectively. The internal diameters for 70 and 62% of the 6 th generation RB1 and RB10 airways were <2 mm. The numbers of 6 th generation RB1 and RB10 airways decreased as the airflow limitation severity increased. Among the mean LA and sum of LA(sum-LA) of the 3 rd to 6 th generation airways, the sum-LA of the 6 th generation had the largest impact on airflow limitation., Conclusions: U-HRCT enables accurate and direct evaluation of peripheral airways 1-2 mm in diameter. The 6 th generation airways are commonly <2 mm in diameter, and the sum-LA can be a useful CT biomarker that reflects airflow limitation in COPD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Poly(acrylic acid) (PAA) gels synthesized via free-radical polymerization of acrylic acid, N,N'-methylenebisacrylamide and high molarities of salts in water exhibit properties markedly different from PAA gels synthesized without salt, even when the latter are incubated in high-molarity salt solutions after gelation. Particularly noteworthy is unusual mechanical behaviour that includes substantially increased elongation, increased modulus, and rapid recovery after strain. The greatest enhancement in viscoelastic behaviour is evident in 2 M LiCl and ZnCl 2 samples, with LiCl samples having a modulus of 39 kPa and reaching an extension ratio of 10 and a fracture stress of 135 kPa, and ZnCl 2 samples having a modulus of 43 kPa and reaching an extension ratio of 8.5 and a fracture stress of 175 kPa. This enhanced elasticity is thought to be brought about by a combination of coiled but only weakly-entangled PAA chains with phase-separated regions of salt acting as a plasticizer and modulating intermolecular interactions among AA units.

Purpose: We compared image quality and volume of a moving simulated tumour and of lung tumours in patients who were treated with stereotactic body radiotherapy (SBRT) in a 16-row multi-detector CT (MDCT) versus a 320-row area-detector CT (ADCT). Tumour volumes in each respiratory phase were also evaluated., Materials and Methods: We acquired static and four-dimensional CT (4DCT) images of a moving phantom with 10- and 30-mm amplitudes with three periods of patterns (2, 4, and 6 s). Breath-hold and 4DCT images were acquired for 12 lung tumour patients who underwent SBRT. Image data were acquired via MDCT and ADCT. The tumours were delineated in each respiratory phase and their volumes in end-expiratory/end-inspiratory phase and mid-respiratory phase were compared., Results: In the phantom study, tumour volumes were smaller and closer to the static image when evaluated by ADCT than by MDCT. In the clinical study, average tumour volumes ± standard deviations were 9.58 ± 1.07 cm 3 with MDCT (2.5-mm slice), and 7.12 ± 0.23 cm 3 with ADCT (p < 0.01). Tumour volumes were closer to that of the breath hold CT in all patients evaluated by ADCT than by MDCT. Unlike MDCT, tumour volumes acquired by ADCT were smaller in end-expiratory or end-inspiratory phase than in the mid-respiratory phase., Conclusions: Tumour volumes in each of the respiratory phases in ADCT were significantly smaller and closer to the static image than the corresponding volumes in MDCT. This suggests that treated volume can be reduced if ADCT is used in treatment planning., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An autopsy case of sudden death due to pulmonary arterial hypertension (PAH) in a 5-year-old boy whose cause of death was not determined during autopsy, but was later determined by postmortem examination, is presented. The boy developed convulsions that subsequently stopped, but remained unconscious. He was transported to hospital by ambulance, but died soon after. The boy had been found to have right ventricular overload on ECG 2 weeks earlier. A plan had been made to consult a doctor for a specialist visit 2 months later. During autopsy, significant abnormalities or injuries were not observed on the body's external surface. Internal examination showed congested organs, and the blood remaining in the body was dark red with fluidity. The heart was significantly enlarged (146 g), with nearly equivalent thickness of the left and right ventricles, showing right ventricular hypertrophy. Obvious macroscopic abnormalities were not observed at the origin and main trunk of the pulmonary artery. The lungs were slightly swollen (right lung 100 g, left lung 95 g), severely congested, and edematous. A postmortem CT scan displayed some patchy shadows in both lungs; however, no significant abnormalities were detected. Histopathological examination suggested a diagnosis of PAH. Three genes (BMPR2, ALK1, and ENG) were tested, revealing a heterozygous insertion of five nucleotides, TTTCC, between nucleotides 2677 and 2678 within exon 12 of the BMPR2 gene. Therefore, the subject was considered to have had heritable PAH due to a BMPR2 gene mutation., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Depression in dementia patients is associated with complications such as decreased activities of daily living and decreased quality of life. Because pharmacotherapeutic treatments for depression in dementia patients may have a poor risk-benefit ratio, effective non-pharmacotherapeutic interventions are favourable. However, the development of effective treatments requires the identification of depression-associated factors that can be modified by non-pharmacotherapeutic means in dementia patients. This systematic literature review aimed to identify modifiable factors related to depression and confirm that these factors can be improved by non-pharmacotherapeutic interventions. We searched PubMed, SpringerLink, the Web of Science, and the Cochrane Library for articles published between June 2007 and June 2017. We included studies that investigated causes of depression in dementia patients and excluded studies with unclear dementia diagnostic criteria or operational definitions. Of 9004 records screened, 6 studies were included. The participants included community-dwelling individuals and long-term care facility residents. The severity of dementia varied from mild to severe. After reviewing the studies, we identified five modifiable relevant factors in community-dwelling individuals: (i) pain; (ii) neuropsychiatric symptoms; (iii) cognitive decline; (iv) social isolation; and (v) quality of life. In long-term care facility residents, we identified neuropsychiatric symptoms and quality of life as relevant factors. Our results indicated that non-pharmacological interventions that improve these factors may improve symptoms of depression. A longitudinal study is recommended to clarify the mechanisms underlying depression symptoms and treatment in dementia patients. In addition, further investigation is needed to elucidate the ways in which differing dementia types and severity affect symptoms of depression., (© 2018 Japanese Psychogeriatric Society.)

Background: Quantitative measurement of airway dimensions using computed tomography (CT) is performed in relatively larger airways due to the limited resolution of CT scans. Nevertheless, the small airway is an important pathological lesion in lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Ultra-high resolution scanning may resolve the smaller airway, but its accuracy and limitations are unclear., Methods: Phantom tubes were imaged using conventional (512 × 512) and ultra-high resolution (1024 × 1024 and 2048 × 2048) scans. Reconstructions were performed using the forward-projected model-based iterative reconstruction solution (FIRST) algorithm in 512 × 512 and 1024 × 1024 matrix scans and the adaptive iterative dose reduction 3D (AIDR-3D) algorithm for all scans. In seven subjects with COPD, the airway dimensions were measured using the 1024 × 1024 and 512 × 512 matrix scans., Results: Compared to the conventional 512 × 512 scan, variations in the CT values for air were increased in the ultra-high resolution scans, except in the 1024×1024 scan reconstructed through FIRST. The measurement error of the lumen area of the tube with 2-mm diameter and 0.5-mm wall thickness (WT) was minimal in the ultra-high resolution scans, but not in the conventional 512 × 512 scan. In contrast to the conventional scans, the ultra-high resolution scans resolved the phantom tube with ≥ 0.6-mm WT at an error rate of < 11%. In seven subjects with COPD, the WT showed a lower value with the 1024 × 1024 scans versus the 512 × 512 scans., Conclusions: The ultra-high resolution scan may allow more accurate measurement of the bronchioles with smaller dimensions compared with the conventional scan., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Virtually all diseases affect multiple organs. However, our knowledge of the body-wide effects remains limited. Here, we report the body-wide transcriptome landscape across 13-23 organs of mouse models of myocardial infarction, diabetes, kidney diseases, cancer, and pre-mature aging. Using such datasets, we find (1) differential gene expression in diverse organs across all models; (2) skin as a disease-sensor organ represented by disease-specific activities of putative gene-expression network; (3) a bone-skin cross talk mediated by a bone-derived hormone, FGF23, in response to dysregulated phosphate homeostasis, a known risk-factor for kidney diseases; (4) candidates for the signature activities of many more putative inter-organ cross talk for diseases; and (5) a cross-species map illustrating organ-to-organ and model-to-disease relationships between human and mouse. These findings demonstrate the usefulness and the potential of such body-wide datasets encompassing mouse models of diverse disease types as a resource in biological and medical sciences. Furthermore, the findings described herein could be exploited for designing disease diagnosis and treatment., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The cardiovascular system facilitates body-wide distribution of oxygen, a vital process for the development and survival of virtually all vertebrates. However, the zebrafish, a vertebrate model organism, appears to form organs and survive mid-larval periods without a functional cardiovascular system. Despite such dispensability, it is the first organ to develop. Such enigma prompted us to hypothesize other cardiovascular functions that are important for developmental and/or physiological processes. Hence, systematic cellular ablations and functional perturbations were performed on the zebrafish cardiovascular system to gain comprehensive and body-wide understanding of such functions and to elucidate the underlying mechanisms. This approach identifies a set of organ-specific genes, each implicated for important functions. The study also unveils distinct cardiovascular mechanisms, each differentially regulating their expressions in organ-specific and oxygen-independent manners. Such mechanisms are mediated by organ-vessel interactions, circulation-dependent signals, and circulation-independent beating-heart-derived signals. A comprehensive and body-wide functional landscape of the cardiovascular system reported herein may provide clues as to why it is the first organ to develop. Furthermore, these data could serve as a resource for the study of organ development and function., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

The purpose of this study is to clarify the degree of impregnation resulting from treatment of internal waterlogged wood samples using MRI. On a 1.5T MR scanner, T 1 and T 2 measurements were performed using inversion recovery and spin-echo sequences, respectively. The samples were cut waterlogged pieces of wood treated with various impregnation techniques which were divided into different concentrations of trehalose (C 12 H 22 O 11 ) and polyethylene glycol (PEG; HO-(C 2 H 4 O) n -H) solutions. Then these samples underwent impregnation treatment every two weeks. From the results, we found that the slope of the T 1 -concentration curve using linear fitting showed the value of the internal area for PEG to be higher than the external area; internal, -2.73ms/wt% (R 2 =0.880); external, -1.50ms/wt% (R 2 =0.887). Furthermore, the slope of the T 1 -concentration curve using linear fitting showed the values for trehalose to have almost no difference when comparing the internal and the external areas; internal, -2.79ms/wt% (R 2 =0.759); external, -3.02ms/wt% (R 2 =0.795). However, the slope of the T 2 -concentration curve using linear fitting for PEG showed that there was only a slight change between the internal and the external areas; internal, 0.26ms/wt% (R 2 =0.642); external, 0.18ms/wt% (R 2 =0.920). The slope of the T 2 -concentration curve did not show a change in linear relationship between the internal and the external areas; internal, 0.06ms/wt% (R 2 =0.175); external, -0.14ms/wt% (R 2 =0.043). In conclusion, using visualization of relaxation time T 1 , it is possible to obtain more detail information noninvasively concerning the state of impregnation treatment of internal waterlogged wood., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Non-invasive fractional flow reserve measured by coronary computed tomography angiography (FFR CT ) has demonstrated a high diagnostic accuracy for detecting coronary artery disease (CAD) in selected patients in prior clinical trials. However, feasibility of FFR CT in unselected population have not been fully evaluated. Among 60 consecutive patients who had suspected significant CAD by coronary computed tomography angiography (CCTA) and were planned to undergo invasive coronary angiography, 48 patients were enrolled in this study comparing FFR CT with invasive fractional flow reserve (FFR) without any exclusion criteria for the quality of CCTA image. FFR CT was measured in a blinded fashion by an independent core laboratory. FFR CT value was evaluable in 43 out of 48 (89.6 %) patients with high prevalence of severe calcification in CCTA images [calcium score (CS) >400: 40 %, and CS > 1000: 19 %). Per-vessel FFR CT value showed good correlation with invasive FFR value (Spearman's rank correlation = 0.69, P < 0.001). The area under the receiver operator characteristics curve (AUC) of FFR CT was 0.87. Per-vessel accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 68.6, 92.9, 52.4, 56.5, and 91.7 %, respectively. Even in eight patients (13 vessels) with extremely severely calcified lesions (CS > 1000), per-vessel FFR CT value showed a diagnostic performance similar to that in patients with CS ≤ 1000 (Spearman's rank correlation = 0.81, P < 0.001). FFR CT could be measured in the majority of consecutive patients who had suspected significant CAD by CCTA in real clinical practice and demonstrated good diagnostic performance for detecting hemodynamically significant CAD even in patients with extremely severe calcified vessels.

Combination of live-imaging and live-manipulation of developing embryos in vivo provides a useful tool to study developmental processes. Identification and selection of target cells for an in vivo live-manipulation are generally performed by experience- and knowledge-based decision-making of the observer. Computer-assisted live-prediction method would be an additional approach to facilitate the identification and selection of the appropriate target cells. Herein we report such a method using developing zebrafish embryos. We choose V2 neural progenitor cells in developing zebrafish embryo as their successive shape changes can be visualized in real-time in vivo. We developed a relatively simple mathematical method of describing cellular geometry of V2 cells to predict cell division-timing based on their successively changing shapes in vivo. Using quantitatively measured 4D live-imaging data, features of V2 cell-shape at each time point prior to division were extracted and a statistical model capturing the successive changes of the V2 cell-shape was developed. By applying sequential Bayesian inference method to the model, we successfully predicted division-timing of randomly selected individual V2 cells while the cell behavior was being live-imaged. This system could assist pre-selecting target cells desirable for real-time manipulation-thus, presenting a new opportunity for in vivo experimental systems.

Acute gastric volvulus resulting in abdominal compartment syndrome was determined to be the cause of death in a 4-year-old girl who presented with abdominal distension. At about 1AM on the day of her death, she was brought to our emergency medical center. Physical examination and plain abdominal X-ray revealed pronounced gastric dilatation. A decompression procedure was performed, followed by observation. She went into cardiopulmonary arrest around 1PM on the same day and died. Postmortem investigation, including an autopsy and computed tomography (CT), was performed to determine the cause of death. The findings included that the stomach was severely distended. Evidence was seen of mucosal hemorrhage in the gastric mucosa on the greater curvature side, which was thinned in places but without perforation. No necrosis of the gastric mucosa was observed; reversible changes were evident on histopathological examination. The postmortem CT images suggested that the pyloric region was positioned cranioventrally to the cardiac region. None of the findings indicated sudden blockage, and the cause of death was determined to be acute gastric volvulus resulting in abdominal compartment syndrome. The abnormal placement of the organs was difficult to determine based on physical examination alone; postmortem CT and careful examination were helpful in conducting the autopsy in this case., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Motile cells transduce environmental chemical signals into mechanical forces to achieve properly controlled migration. This signal-force transduction is thought to require regulated mechanical coupling between actin filaments (F-actins), which undergo retrograde flow at the cellular leading edge, and cell adhesions via linker "clutch" molecules. However, the molecular machinery mediating this regulatory coupling remains unclear. Here we show that the F-actin binding molecule cortactin directly interacts with a clutch molecule, shootin1, in axonal growth cones, thereby mediating the linkage between F-actin retrograde flow and cell adhesions through L1-CAM. Shootin1-cortactin interaction was enhanced by shootin1 phosphorylation by Pak1, which is activated by the axonal chemoattractant netrin-1. We provide evidence that shootin1-cortactin interaction participates in netrin-1-induced F-actin adhesion coupling and in the promotion of traction forces for axon outgrowth. Under cell signaling, this regulatory F-actin adhesion coupling in growth cones cooperates with actin polymerization for efficient cellular motility., (© 2015 Kubo et al.)

Objectives: The management of acute type A aortic dissection complicated by coma remains controversial. We previously reported an excellent rate of recovery of consciousness provided aortic repair was performed within 5 hours of the onset of symptoms. This study evaluates the early and long-term outcomes using this approach., Methods: Between August 2003 and July 2013, of the 241 patients with acute type A aortic dissection brought to the Japanese Red Cross Kobe Hospital and Hyogo Emergency Medical Center, 30 (12.4%) presented with coma; Glasgow Coma Scale was less than 11 on arrival. Surgery was performed in 186 patients, including 27 (14.5%) who were comatose. Twenty-four comatose patients underwent successful aortic repair immediately (immediate group). Their mean age was 71.0 ± 11.1 years, Glasgow Coma Scale was 6.5 ± 2.4, and prevalence of carotid dissection was 79%. For brain protection, deep hypothermia with antegrade cerebral perfusion was used, and postoperative induced hypothermia was performed. Neurologic evaluations were performed using the Glasgow Coma Scale, National Institutes of Health Stroke Scale, and modified Rankin Scale., Results: In the immediate group, the time from the onset of symptoms to arrival in the operating theater was 222 ± 86 minutes. Hospital mortality was 12.5%. Full recovery of consciousness was achieved in 79% of patients in up to 30 days. Postoperative Glasgow Coma Scale and National Institutes of Health Stroke Scale improved significantly when compared with the preoperative score (P < .05), and postoperative activities of daily living independence (modified Rankin Scale <3) was achieved in 50% of patients. The mean follow-up period was 56.5 months, and the cumulative survival was 48.2% after 10 years. Cox proportional hazards regression analysis indicated that immediate repair (hazard ratio, 4.3; P = .007) was the only significant predictor of postoperative survival over a 5-year period., Conclusions: The early and long-term outcomes as a result of immediate aortic repair for acute type A aortic dissection complicated by coma were satisfactory., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The polarization of neurons, which mainly includes the differentiation of axons and dendrites, is regulated by cell-autonomous and non-cell-autonomous factors. In the developing central nervous system, neuronal development occurs in a heterogeneous environment that also comprises extracellular matrices, radial glial cells, and neurons. Although many cell-autonomous factors that affect neuronal polarization have been identified, the microenvironmental cues involved in neuronal polarization remain largely unknown. Here, we show that neuronal polarization occurs in a microenvironment in the lower intermediate zone, where the cell adhesion molecule transient axonal glycoprotein-1 (TAG-1) is expressed in cortical efferent axons. The immature neurites of multipolar cells closely contact TAG-1-positive axons and generate axons. Inhibition of TAG-1-mediated cell-to-cell interaction or its downstream kinase Lyn impairs neuronal polarization. These results show that the TAG-1-mediated cell-to-cell interaction between the unpolarized multipolar cells and the pioneering axons regulates the polarization of multipolar cells partly through Lyn kinase and Rac1., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Advanced airway management in the prehospital setting is a serious issue in Japan because emergency medical technicians are not authorized to perform such management, whereas physicians-who are authorized to perform advanced airway management-do not usually engage in prehospital emergency medical activity. The purpose of this investigation was to investigate the success rate for endotracheal intubation (ETI) procedures and other methods of airway management employed by physicians in the prehospital setting in a single institution, as well as to examine the risk factors associated with difficult or failed endotracheal intubation (D/F ETI)., Methods: We performed a retrospective survey of patients treated in the prehospital setting by emergency physicians of the Hyogo Emergency Medical Center from 2004 to 2011. Patients were divided into two groups: a cardiopulmonary arrest (CPA) group and a non-CPA group. Data on cases of D/F ETI were obtained, and risk factors for these two groups were identified using univariate and statistical analysis., Results: During the investigation period, ETI was attempted in the prehospital setting on 742 eligible patients; in 30 (4.04 %) of these cases, the attempts at ETI proved difficult or failed. Of those 30 patients, 13 patients received a surgical airway (attempts to provide a surgical airway failed in two patients), a blind ETI was performed in four, a video-assisted airway device was used in another four, and esophageal intubation was performed in four patients. Bag-valve ventilation alone was performed in one patient. The incidence of D/F ETI was higher in the non-CPA group than in the CPA group (6.27 vs. 2.63 %: p < 0.05). Facial or neck injury was a risk factor for D/F ETI in the prehospital setting in the CPA group (odds ratio 7.855; 95 % CI 1.754-36.293: p = 0.042). On the other hand, no risk factors for D/F ETI in the prehospital setting in the non-CPA group were identified., Conclusion: The success rate for ETI performed by physicians in the prehospital setting at a single emergency medical center was high, and the incidence of D/F ETI was 4.31 %. The success rate for ETI in the CPA group was greater than that in the non-CPA group.

Soluble guidance cues can direct cellular protrusion and migration by modulating adhesion and cytoskeletal dynamics. Actin filaments (F-actins) polymerize at the leading edge of motile cells and depolymerize proximally [1, 2]; this, together with myosin II activity, induces retrograde flow of F-actins [3-5]. It has been proposed that the traction forces underlying cellular motility may be regulated by the modulation of coupling efficiency between F-actin flow and the extracellular substrate via "clutch" molecules [6-10]. However, how cell signaling controls the coupling efficiency remains unknown. Shootin1 functions as a linker molecule that couples F-actin retrograde flow and the substrate at neuronal growth cones to promote axon outgrowth [11]. Here we show that shootin1 is located at a critical interface, transducing a chemical signal into traction forces for axon outgrowth. We found that a chemoattractant, netrin-1, positively regulates traction forces at axonal growth cones via Pak1-mediated shootin1 phosphorylation. This phosphorylation enhanced the interaction between shootin1 and F-actin retrograde flow, thereby promoting F-actin-substrate coupling, force generation, and concomitant filopodium extension and axon outgrowth. These results suggest that dynamic actin-substrate coupling can transduce chemical signals into mechanical forces to control cellular motility and provide a molecular-level description of how this transduction may occur., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We developed a novel tool for concluding drowning as a cause of death. We designed nine primer pairs to detect representative freshwater or marine bacterioplankton (aquatic bacteria) and then used real-time PCR with TaqMan probes to rapidly and specifically detect them. We previously cultured the genus Aeromonas, which is a representative freshwater bacterial species, in blood samples from 94% of victims who drowned in freshwater and the genera Vibrio and/or Photobacterium that are representative marine bacteria in 88% of victims who drowned in seawater. Based on these results, we simultaneously detected eight species of bacterioplankton (Aeromonas hydrophila, A. salmonicida; Vibrio fischeri, V. harveyi, V. parahaemolyticus; Photobacterium damselae, P. leiognathi, P. phosphoreum) using three sets of triplex real-time PCR assays and TaqMan probes labelled with fluorophores (FAM, NED, Cy5). We assayed 266 specimens (109 blood, 157 tissues) from 43 victims, including 32 who had drowned in rivers, ditches, wells, sea or around estuaries. All lung samples of these 32 victims were TaqMan PCR-positive including the lung periphery into which water does not readily enter postmortem. On the other hand, findings in blood and/or closed organs (kidney or liver) were PCR-positive in 84% of the drowned victims (except for those who drowned in baths) although the conventional test detected diatoms in closed organs in only 44% of the victims. Thus, the results of the PCR assay reinforced those of diatom tests when only a few diatoms were detectable in organs due to the low density of diatoms in the water where they were found. Multiplex TaqMan PCR assays for bacterioplankton were rapid, less laborious and high-throughput as well as sensitive and specific. Therefore, these assays would be useful for routine forensic screening tests to estimate the amount and type of aspirated water., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Current 454-pyrosequencing technology enables massive parallel sequencing. We used this technology to investigate the diversity of aquatic microbes in 14 specimens (blood and organs) of two drowning victims and in two water samples taken from the discovery sites. The 16S ribosomal RNA (rRNA) genes of microbes, which are often used to identify species (or genera), have nine highly variable regions (V1-V9), each of which is surrounded by conserved regions. Some parts within the conserved regions are common over domains of microbes, such as between bacteria and algae (16S rRNA genes on algal chloroplast genomes). We therefore simultaneously amplified the target regions (V7 and V8) of various microbes in the blood and organs of drowning victims using PCR with custom-designed primers that were based on the conserved regions. We then exhaustively analyzed the PCR products by pyrosequencing using the Genome Sequencer FLX Titanium system (Roche-454 Life Sciences). This approach identified a wide array of bacteria including cyanobacteria and algae including Bacillariophyceae (diatom), Cryptophyceae, Dictyochophyceae, Chrysophyceae and Trebouxiophyceae in the blood and organs of the victims and water at discovery sites. Our data further indicated that when conventional diatom testing of lungs yielded insufficient evidence of water aspiration, the detection of various exogenous microbes by 454-pyrosequencing is very useful to support a conclusion of death by drowning. To the best of our knowledge, this is the first attempt to use a new generation sequencer to investigate diverse aquatic microbes in the blood and closed organs of drowning victims., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Peroxisomes catalyze a range of essential metabolic functions, mainly related to lipid metabolism. However, their roles in obesity have yet to be clarified. The aim of this study was to investigate the correlation between obesity and peroxisomal lipid metabolism, particularly very long-chain fatty acid (VLCFA) metabolism, gene expression of peroxisomal β-oxidation enzymes, peroxisomal ATP-binding cassette (ABC) transporter adrenoleukodystrophy (ABCD1) gene and its related gene, ABCD2, the elongation of the VLCFA (ELOVL) gene family and the transcriptional factors involved in the regulation of these genes, including peroxisome proliferator-activated receptor α (PPARα) and sterol regulatory element-binding protein. These factors were analyzed in livers from mice fed a high-fat diet (HFD) or a regular diet (RD) for 20 weeks. Furthermore, the amounts of plasma saturated and unsaturated fatty acids, including VLCFAs, were measured. A HFD induced hepatic gene expression of not only hydroxysteroid 17-β dehydrogenase 4 (HSD17b4) and sterol carrier protein 2 (SCP2) in peroxisomal β-oxidation enzymes but also of ELOVL1, 2, 5 and 6, which are involved in the elongation of saturated and unsaturated VLCFAs. Furthermore, ABCD2 mRNA prominently increased in the HFD mice. The transcriptional regulator of these genes, PPARα, was also up-regulated in the HFD mice. VLCFA ratios including C24:0/C22:0, C25:0/C22:0 and C26:0/C22:0 are the most significant diagnostic markers of inherited peroxisomal diseases. These ratios were found to be low in the plasma of the HFD mice compared with the RD mice. The results suggest that HFD activates hepatic peroxisomal VLCFA metabolism, and may provide useful fundamental information to explain the role of peroxisomal function in obesity and lifestyle-related diseases.

Background: Management of acute type A aortic dissection (AADA) complicated by coma remains controversial. We analyzed our experience in managing AADA complicated by coma to determine the relationship of duration of preoperative coma to postoperative neurological recovery., Methods and Results: Between September 2003 and October 2010, 181 patients with AADA were treated, including 27 presenting with coma (Glasgow Coma Scale <11) on arrival. Twenty-one patients were repaired immediately (immediate group); time from onset of symptoms to operating room was <5 hours. For brain protection, deep hypothermia with antegrade cerebral perfusion was used, and postoperative therapeutic hypothermia with magnesium treatment was performed. Six patients initially were managed medically, and 3 of them were followed by eventual repair because time from onset was >5 hours (delayed group). The preoperative National Institutes of Health Stroke Scale score was 31.4 ± 6.6 in the immediate group and 28.3 ± 9.5 in the delayed group. Hospital mortality was 14% in the immediate group and 67% in the delayed group. Full recovery of consciousness was achieved in 86% of patients in the immediate group and in 17% in the delayed group. In immediate group, the postoperative National Institutes of Health Stroke Scale score significantly improved to 6.4 ± 8.4, cumulative survival rate was 71.8% in 3 years, and independence in daily activities was achieved in 52% (11/21)., Conclusions: Aortic repair, if performed immediately from the onset of symptoms, showed satisfactory recovery of consciousness and neurological function in patients with AADA complicated by coma. In this patient population, immediate aortic repair is warranted.