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Long-term measurements of the mass concentration of black carbon (BC) in the atmosphere (MBC) with well-constrained accuracy are indispensable to quantify its emission, transport, and deposition. The aerosol light absorption coefficient (babs), usually measured by a filter-based absorption photometer, including an Aethalometer (AE), is often used to estimate MBC. The measured babs is converted to MBC by assuming a value for the mass absorption cross section (MAC). Previously, we derived the MAC for AE (MAC (AE)) from measured babs and independently measured MBC values at two sites in the Arctic. MBC was measured with a filter-based absorption photometer with a heated inlet (COSMOS). The accuracy of the COSMOS-derived MBC (MBC (COSMOS)) was within about 15%. Here, we obtained additional MAC (AE) measurements to improve understanding of its variability and uncertainty. We measured babs (AE) and MBC (COSMOS) at Alert (2018–2020), Barrow (2012–2022), Ny-Ålesund (2012–2019), and Pallas (2019–2022). At Pallas, we also obtained four-wavelength photoacoustic aerosol absorption spectrometer (PAAS-4λ) measurements of babs. babs (AE) and MBC (COSMOS) were tightly correlated; the average MAC (AE) at the four sites was 11.4 ± 1.2 m2 g−1 (mean ± 1σ) at 590 nm and 7.76 ± 0.73 m2 g−1 at 880 nm. The spatial variability of MAC (AE) was about 11% (1σ), and its year-to-year variability was about 18%. We compared MAC (AE) in the Arctic with values at mid-latitudes, measured by previous studies, and with values obtained by using other types of filter-based absorption photometer, and PAAS-4λ. Copyright © 2024 American Association for Aerosol Research [ABSTRACT FROM AUTHOR]

Background: The efficacy of therapeutic drug monitoring (TDM)-based antimicrobial dosing optimization strategies on pharmacokinetics/pharmacodynamics and specific drug properties for critically ill patients is unclear. Here, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the effectiveness of TDM-based regimen in these patients. Methods: Articles from three databases were systematically retrieved to identify relevant randomized control studies. Version two of the Cochrane tool for assessing risk of bias in randomized trials was used to assess the risk of bias in studies included in the analysis, and quality assessment of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. Primary outcome was the 28-day mortality and secondary outcome were in-hospital mortality, clinical cure, length of stay in the intensive care unit (ICU) and target attainment at day 1 and 3. Results: In total, 5 studies involving 1011 patients were included for meta-analysis of the primary outcome, of which no significant difference was observed between TDM-based regimen and control groups (risk ratio [RR] 0.94, 95% confidence interval [CI]: 0.77–1.14; I2 = 0%). In-hospital mortality (RR 0.96, 95% CI: 0.76–1.20), clinical cure (RR 1.23, 95% CI: 0.91–1.67), length of stay in the ICU (mean difference 0, 95% CI: − 2.18–2.19), and target attainment at day 1 (RR 1.14, 95% CI: 0.88–1.48) and day 3 (RR 1.35, 95% CI: 0.90–2.03) were not significantly different between the two groups, and all evidence for the secondary outcomes had a low or very low level of certainty because the included studies had serious risk of bias, variation of definition for outcomes, and small sample sizes. Conclusion: TDM-based regimens had no significant efficacy for clinical or pharmacological outcomes. Further studies with other achievable targets and well-defined outcomes are required. Trial registration: Clinical trial registration; PROSPERO (https://www.crd.york.ac.uk/prospero/), registry number: CRD 42022371959. Registered 24 November 2022. [ABSTRACT FROM AUTHOR]

Background: Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) is one effective treatment for COVID-19 pneumonia, but controversy regarding VV-ECMO management in obese patients still exists. In this report, we described a case in which two oxygenators were used in parallel in a severely obese patient (Body mass index: 60 kg/m2, body surface area: 2.8 m2). Case: The case was of a 27-year-old man diagnosed with COVID-19 pneumonia and admitted to our hospital. VV-ECMO was required on the fifth day after admission due to gradually worsening respiratory conditions and partial pressure of arterial oxygen (PaO2)/FiO2 ratio of 77. Immediately after the initiation of VV-ECMO, post-oxygenator in circuit, PaO2 was low at 134 mmHg. Even though the VV-ECMO circuit was replaced on the same day, the PaO2 still was low at 261 mmHg. Thus, we decided to use two oxygenators in parallel, after which the PaO2 stabilized at 400–500 mmHg. Conclusions: In this case, VV-ECMO oxygenation could be stabilized by utilizing two oxygenators in parallel. Using two membrane oxygenators may be a treatment option in severely obese patients with respiratory failure. [ABSTRACT FROM AUTHOR]

Sepsis-associated muscle wasting (SAMW) is characterized by decreased muscle mass, reduced muscle fiber size, and decreased muscle strength, resulting in persistent physical disability accompanied by sepsis. Systemic inflammatory cytokines are the main cause of SAMW, which occurs in 40–70% of patients with sepsis. The pathways associated with the ubiquitin–proteasome and autophagy systems are particularly activated in the muscle tissues during sepsis and may lead to muscle wasting. Additionally, expression of muscle atrophy-related genes Atrogin-1 and MuRF-1 are seemingly increased via the ubiquitin–proteasome pathway. In clinical settings, electrical muscular stimulation, physiotherapy, early mobilization, and nutritional support are used for patients with sepsis to prevent or treat SAMW. However, there are no pharmacological treatments for SAMW, and the underlying mechanisms are still unknown. Therefore, research is urgently required in this field. [ABSTRACT FROM AUTHOR]

Here, we used a modified single-particle soot photometer (SP2) coupled with a concentric pneumatic nebulizer to measure the size-resolved number and mass concentrations of light-absorbing iron oxide aerosols (FeOx) in liquid water (CNFeOx and CMFeOx, respectively). The SP2 could selectively detect individual FeOx particles in mixed wüstite–fullerene soot laboratory samples and melted Arctic snow samples. The nebulizer efficiency for FeOx particles was about 50% within the 70–650 nm diameter range, as derived from the ratio of the volume of ammonium sulfate before and after extraction by the nebulizer and the size-resolved transmission efficiency in the nebulizer–SP2 sampling line. Uncertainty from the boundary lines empirically drawn to discriminate the scatterplots of FeOx and black carbon in the mixed wüstite–fullerene soot suspensions and snow samples was approximately 3.0% and 10%, respectively. Overall uncertainty in total CNFeOx and CMFeOx (220–1400 nm) was approximately 19% and 18%, respectively. After storage at 4 °C for 16 months, the FeOx particle size distributions in melted Arctic snow had remained stable, and CNFeOx and CMFeOx had changed by less than 19% and 1.0%, on average, respectively. Most of the FeOx on dust particles measured by this system was estimated to be in the diameter range smaller than 1000 nm, considering the nebulizer efficiency for dust particles. The high accuracy of the CNFeOx and CMFeOx measurements will help to improve our quantitative understanding of the wet deposition of FeOx and provide more accurate estimates of the effects of FeOx on snow surface albedo. [ABSTRACT FROM AUTHOR]

The 2016 International Guidelines for the Management of Sepsis and Septic Shock recommend antibiotic therapy for 7–10 days for most patients with sepsis. However, evidence on critically ill patients is limited. Thus, we conducted the first systematic review and meta-analysis comparing the effectiveness and adverse events of shorter- (≤1 week) with longer-course antibiotics in adults with critical infections including sepsis. We searched the MEDLINE, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases for randomised controlled trials (RCTs) and observational studies (OSs) from inception to 31 March 2021. We included 6 of 3,766 identified articles, incorporating data from 4 RCTs and 2 OSs (1,721 patients) in meta-analyses. Three RCTs and one OS focussed on ventilator-associated pneumonia, and one RCT and one OS investigated intra-abdominal infections. The severity score levels were similar to that of sepsis, but no study comprehensively focussing on sepsis was found. There were no significant differences in mortality at a maximum follow-up of 30 days (RR 1.08, 95%CI 0.80–1.46); 28-day mortality, clinical cure, the occurrence of new events, and the emergence of resistant organisms between the groups in the RCTs. The OSs findings were consistent. The quality of evidence was assessed as very low to moderate using the GRADE approach, with no uniform description of severity scores, sepsis, or adverse events. Shorter, fixed-duration antibiotic therapy for clinically heterogeneous sepsis or severe infections was not associated with poorer outcomes, but the overall quality of evidence was poor. [ABSTRACT FROM AUTHOR]

In this study, we aimed to develop and validate a machine learning-based mortality prediction model for hospitalized heat-related illness patients. After 2393 hospitalized patients were extracted from a multicentered heat-related illness registry in Japan, subjects were divided into the training set for development (n = 1516, data from 2014, 2017–2019) and the test set (n = 877, data from 2020) for validation. Twenty-four variables including characteristics of patients, vital signs, and laboratory test data at hospital arrival were trained as predictor features for machine learning. The outcome was death during hospital stay. In validation, the developed machine learning models (logistic regression, support vector machine, random forest, XGBoost) demonstrated favorable performance for outcome prediction with significantly increased values of the area under the precision-recall curve (AUPR) of 0.415 [95% confidence interval (CI) 0.336–0.494], 0.395 [CI 0.318–0.472], 0.426 [CI 0.346–0.506], and 0.528 [CI 0.442–0.614], respectively, compared to that of the conventional acute physiology and chronic health evaluation (APACHE)-II score of 0.287 [CI 0.222–0.351] as a reference standard. The area under the receiver operating characteristic curve (AUROC) values were also high over 0.92 in all models, although there were no statistical differences compared to APACHE-II. This is the first demonstration of the potential of machine learning-based mortality prediction models for heat-related illnesses. [ABSTRACT FROM AUTHOR]

Aim: Early outcome prediction for out-of-hospital cardiac arrest with initial shockable rhythm is useful in selecting the choice of resuscitative treatment by clinicians. This study aimed to develop and validate a machine learning-based outcome prediction model for out-of-hospital cardiac arrest with initial shockable rhythm, which can be used on patient's arrival at the hospital.Methods: Data were obtained from a nationwide out-of-hospital cardiac arrest registry in Japan. Of 43,350 out-of-hospital cardiac arrest patients with initial shockable rhythm registered between 2013 and 2017, patients aged <18 years and those with cardiac arrest caused by external factors were excluded. Subjects were classified into training (n = 23,668, 2013-2016 data) and test (n = 6381, data from 2017) sets for validation. Only 19 prehospital variables were used for the outcome prediction. The primary outcome was death at 1 month or survival with poor neurological function (cerebral performance category 3-5; "poor" outcome). Several machine learning models, including those based on logistic regression, support vector machine, random forest, and multilayer perceptron classifiers were compared.Results: In validation analyses, all machine learning models performed satisfactorily with area under the receiver operating characteristic curve values of 0.882 [95% confidence interval [CI]: 0.869-0.894] for logistic regression, 0.866 [95% CI: 0.853-0.879] for support vector machine, 0.877 [95% CI: 0.865-0.890] for random forest, and 0.888 [95% CI: 0.876-0.900] for multilayer perceptron classifiers.Conclusions: A favourable machine learning-based prognostic model available to use on patient arrival at the hospital was developed for out-of-hospital cardiac arrest with initial shockable rhythm. [ABSTRACT FROM AUTHOR]

Background: Intracranial pressure control has long been recognized as an important requirement for patients with severe traumatic brain injury. Hypertonic saline has drawn attention as an alternative to mannitol in this setting. The aim of this study was to assess the effects of hypertonic saline versus mannitol on clinical outcomes in patients with traumatic brain injury in prehospital, emergency department, and intensive care unit settings by systematically reviewing the literature and synthesizing the evidence from randomized controlled trials. Methods: We searched the MEDLINE database, the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi (ICHUSHI) Web database with no date restrictions. We selected randomized controlled trials in which the clinical outcomes of adult patients with traumatic brain injury were compared between hypertonic saline and mannitol strategies. Two investigators independently screened the search results and conducted the data extraction. The primary outcome was all-cause mortality. The secondary outcomes were 90-day and 180-day mortality, good neurological outcomes, reduction in intracranial pressure, and serum sodium level. Random effects estimators with weights calculated by the inverse variance method were used to determine the pooled risk ratios. Results: A total of 125 patients from four randomized trials were included, and all the studies were conducted in the intensive care unit. Among 105 patients from three trials that evaluated the primary outcome, 50 patients were assigned to the hypertonic saline group and 55 patients were assigned to the mannitol group. During the observation period, death was observed for 16 patients in the hypertonic saline group (32.0%) and 21 patients in the mannitol group (38.2%). The risks were not significant between the two infusion strategies (pooled risk ratio, 0.82; 95% confidence interval, 0.49–1.37). There were also no significant differences between the two groups in the other secondary outcomes. However, the certainty of the evidence was rated very low for all outcomes. Conclusions: Our findings revealed no significant difference in the all-cause mortality rates between patients receiving hypertonic saline or mannitol to control intracranial pressure. Further investigation is warranted because we only included a limited number of studies [ABSTRACT FROM AUTHOR]

Purpose: Aside from severe traumatic brain injury, uncontrolled bleeding and corresponding haemorrhage shock are the leading causes of traumatic deaths. No established recommendations exist about venous access placement for severely injured, bleeding children at a pre-hospital scene. This study sought to evaluate the association between pre-hospital venous access placement and mortality in a paediatric trauma population by analysing the Japan Trauma Data Bank (JTDB). Methods: This epidemiologic study compared the outcomes of severe traumatic paediatric patients with or without venous access placement at a pre-hospital scene. Data were obtained from JTDB from 2004 to 2015. Results: Of 4,109 patients who met our inclusion criteria, 144 patients received venous access placement and 3,965 patients did not. The probability of survival was lower in the venous access group than in the no access group (0.90 [0.67–0.97] vs. 0.97 [0.90–0.99], p < 0.01). After multivariable logistic analysis, venous access placement did not improve survival to hospital discharge (odds ratio = 1.40, confidence interval = 0.32–6.15, p = 0.653). Conclusions: The probability of survival was lower in the venous access group than in the no access group. Survival outcome at discharge was not affected by venous access placement at a pre-hospital scene. [ABSTRACT FROM AUTHOR]

Long-term measurements of black carbon (BC) aerosols by filter-based absorption photometers with a heated inlet (COSMOS) in different regions have been useful in elucidating spatial variations and radiative impacts of BC. Evaluations of mass concentrations of BC (MBC) measured by the COSMOS have been made by our previous studies through comparisons with other measurement techniques. However, how variations in the microphysical properties of BC and the co-existing light scattering aerosols affect the COSMOS measurements should be evaluated in more detail. In this study, we assessed these potential effects under various field environments in the Arctic and in the East Asia. From the slopes of the correlation plots between the MBC values measured by the COSMOS and a single-particle soot photometer, the average accuracy of the COSMOS was estimated as ∼10% in the MBC range 1–3000 ng m−3. On an hourly basis, the estimated sensitivity of the COSMOS MBC values to the changes in the BC size distributions was less than 10%, within the typical variabilities of BC size at individual observation sites. The COSMOS measurements depended little on the mixing states of BC and the concentrations of co-existing light scattering aerosols, except in the maritime air masses of East Asia, where the relative abundance of sea salt to BC was very high. The MBC measured by COSMOS also well agreed with elemental carbon measurements. Our results demonstrate the high reliability of COSMOS measurements under various environments. Copyright © 2019 American Association for Aerosol Research [ABSTRACT FROM AUTHOR]

Key Clinical Message: In our case reports, we mentioned about the utility of NPPV therapy in addition to standard pharmacologic therapy for acute asthma exacerbations in pregnant women with dyspnea and hypoxemia compared with that of oxygen therapy alone. Careful patient selection and clinicians' NPPV experience are crucial in optimizing patient outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Prognosis of cardiopulmonary arrest occurring in patients with blunt trauma is very poor; patients rarely recover from this condition. We either do not attempt cardiopulmonary resuscitation or terminate it after some time in blunt trauma–cardiopulmonary arrest cases. We presented a rare case of successful resuscitation of a patient with blunt trauma–cardiopulmonary arrest. Case presentation: A 54-year-old man was admitted to our emergency department after being injured in a traffic accident. The patient suffered from ventricular fibrillation, and spontaneous circulation was restored by a defibrillator. The estimated arrest time was 20 min. Discussion: On arrival of our emergency department, the patient showed intra-abdominal hemorrhage and we performed emergency surgery; 10 days after admission, the patient suffered from pulseless ventricular tachycardia—coronary angiography was performed, which revealed that the patient had coronary artery stenosis. Conclusion: We experienced trauma patients concealed with coronary artery stenosis. In traumatic arrest with ventricular fibrillation, it may be due to a medical reason, and more prolonged and intensive resuscitation may be considered. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that several factors such as hemodynamic instability at admission are risk factors for rebleeding of peptic ulcer bleeding. However, whether steroid use increases the risk of rebleeding remains elusive.Aims: This study aimed to clarify the risk factors for rebleeding after endoscopic hemostasis for peptic ulcer bleeding.Methods: A total of 185 patients who underwent endoscopic hemostasis for peptic ulcer bleeding at our institution between 2005 and 2017 were retrospectively analyzed. We evaluated factors, including comorbid conditions, in-hospital onset, and steroid use, associated with rebleeding by logistic regression analysis. In addition, we investigated the association between the dose of steroids and rebleeding.Results: The rebleeding rate after endoscopic hemostasis for peptic ulcer bleeding was 14.6%. In the multivariate analysis, the independent risk factors for rebleeding were steroid use (odds ratio 4.56, p = 0.015), multiple ulcers (4.43, p = 0.005), number of comorbidities ≥ 3 3.18, p = 0.026), hemodynamic instability (3.06, p = 0.039), and number of comorbidities ≥ 3 (2.93, p = 0.047). Furthermore, the use of higher dose steroids (≥ 20 mg per day in prednisolone; 10.55, p = 0.002), but not lower dose (< 20 mg per day in prednisolone), was an independent risk factor for rebleeding in the multivariate analysis. The relationship between steroid use and rebleeding was observed in a dose-dependent manner (p for trend = 0.002).Conclusions: This study first revealed that using higher dose steroids was an independent risk factor for rebleeding after endoscopic hemostasis for peptic ulcer bleeding, with a dose-response relation. [ABSTRACT FROM AUTHOR]

Background: We sought to develop a novel risk assessment tool to predict the clinical outcomes after heat-related illness. Methods: Prospective, multicenter observational study. Patients who transferred to emergency hospitals in Japan with heat-related illness were registered. The sample was divided into two parts: 60% to construct the score and 40% to validate it. A binary logistic regression model was used to predict hospital admission as a primary outcome. The resulting model was transformed into a scoring system. Results: A total of 3,001 eligible patients were analyzed. There was no difference in variables between development and validation cohorts. Based on the result of a logistic regression model in the development phase (n = 1,805), the J-ERATO score was defined as the sum of the six binary components in the prehospital setting (respiratory rate≥22 /min, Glasgow coma scale<15, systolic blood pressure≤100 mmHg, heart rate≥100 bpm, body temperature≥38°C, and age≥65 y), for a total score ranging from 0 to 6. In the validation phase (n = 1,196), the score had excellent discrimination (C-statistic 0.84; 95% CI 0.79–0.89, p<0.0001) and calibration (P>0.2 by Hosmer-Lemeshow test). The observed proportion of hospital admission increased with increasing J-ERATO score (score = 0, 5.0%; score = 1, 15.0%; score = 2, 24.6%; score = 3, 38.6%; score = 4, 68.0%; score = 5, 85.2%; score = 6, 96.4%). Multivariate analyses showed that the J-ERATO score was an independent positive predictor of hospital admission (adjusted OR, 2.43; 95% CI, 2.06–2.87; P<0.001), intensive care unit (ICU) admission (3.73; 2.95–4.72; P<0.001) and in-hospital mortality (1.65; 1.18–2.32; P = 0.004). Conclusions: The J-ERATO score is simply assessed and can facilitate the identification of patients with higher risk of heat-related hospitalization. This scoring system is also significantly associated with the higher likelihood of ICU admission and in-hospital mortality after heat-related hospitalization. [ABSTRACT FROM AUTHOR]

Background: This meta-analysis compared the effects of non-invasive ventilation (NIV) with invasive mechanical ventilation (InMV) and standard oxygen (O) therapy on mortality and rate of tracheal intubation in patients presenting acute respiratory failure (ARF). Methods: We searched the MEDLINE, EMBASE and Cochrane Central Register of clinical trials databases between 1949 and May 2015 to identify randomized trials of NIV for ARF. We excluded the ARF caused by extubation, cardiogenic pulmonary edema, and COPD. Results: The meta-analysis included 21 studies and 1691 patients, of whom 846 were assigned to NIV and 845 to control (InMV or standard O therapy). One hundred ninety-one patients (22.6%) in the NIV group and 261 patients (30.9%) in the control group died before discharge from hospital. The pooled odds ratio (OR) for short-term mortality (in-hospital mortality) was 0.56 (95% CI 0.40-0.78). When comparing NIV with standard O therapy, the short-term mortality was 155 (27.4%) versus 204 (36.0%), respectively. For this comparison, the pooled OR of short-term mortality was 0.56 (95% CI 0.36-0.85). When comparing NIV with InMV, the short-term mortality was 36 (12.9%) versus 57 (20.5%) patients, respectively. For this comparison, the pooled OR of short-term mortality was 0.56 (95% CI 0.34-0.90). Tracheal intubation was performed in 106 patients (22.7%) in the NIV and in 183 patients (39.4%) in the standard O group, representing a pooled OR of 0.37 (95% CI 0.25-0.55). There were publication biases and the quality of the evidence was graded as low. Conclusion: Compared with standard O therapy or InMV, NIV lowered both the short-term mortality and the rate of tracheal intubation in patients presenting with ARF. [ABSTRACT FROM AUTHOR]

While representations of 3D shapes are used in the teaching of geometry in lower secondary school, it is known that such representations can provide difficulties for students. In order to assess students’ thinking about 3D shapes, we constructed an assessment framework based on existing research studies and data from G7-9 students (aged 12–15). We then applied our framework to assess students’ geometric thinking in lessons. We report two cases of qualitative findings from a classroom experiment in which Grade 7 students (aged 12–13) tackled a problem in 3D geometry that was, for them, quite challenging. We found that students who failed to answer given problems did not mentally manipulate representations effectively, while others could mentally manipulate representations and reason about them in order to reach correct solutions. We conclude with the proposition that this finding shows the framework can be used by teachers in instruction to assess their students’ 3D geometric thinking. [ABSTRACT FROM AUTHOR]

Objective: Sepsis remains an unresolved clinical problem. Therapeutic strategies focusing on inhibition of neutrophils (polymorphonuclear neutrophils) have failed, which indicates that a more detailed understanding of the underlying pathophysiology of sepsis is required. Polymorphonuclear neutrophil activation and chemotaxis require cellular adenosine triphosphate release via pannexin-1 channels that fuel autocrine feedback via purinergic receptors. In the current study, we examined the roles of endogenous and systemic adenosine triphosphate on polymorphonuclear neutrophil activation and host defense in sepsis.Design: Prospective randomized animal investigation and in vitro studies.Setting: Preclinical academic research laboratory.Subjects: Wild-type C57BL/6 mice, pannexin-1 knockout mice, and healthy human subjects used to obtain polymorphonuclear neutrophils for in vitro studies.Interventions: Wild-type and pannexin-1 knockout mice were treated with suramin or apyrase to block the endogenous or systemic effects of adenosine triphosphate. Mice were subjected to cecal ligation and puncture and polymorphonuclear neutrophil activation (CD11b integrin expression), organ (liver) injury (plasma aspartate aminotransferase), bacterial spread, and survival were monitored. Human polymorphonuclear neutrophils were used to study the effect of systemic adenosine triphosphate and apyrase on chemotaxis.Measurements and Main Results: Inhibiting endogenous adenosine triphosphate reduced polymorphonuclear neutrophil activation and organ injury, but increased the spread of bacteria and mortality in sepsis. By contrast, removal of systemic adenosine triphosphate improved bacterial clearance and survival in sepsis by improving polymorphonuclear neutrophil chemotaxis.Conclusions: Systemic adenosine triphosphate impairs polymorphonuclear neutrophil functions by disrupting the endogenous purinergic signaling mechanisms that regulate cell activation and chemotaxis. Removal of systemic adenosine triphosphate improves polymorphonuclear neutrophil function and host defenses, making this a promising new treatment strategy for sepsis. [ABSTRACT FROM AUTHOR]

Recent studies provide compelling evidence that epigenetic dysregulation is involved in almost every step of tumor development and progression. Differences in tumor behavior, which ultimately reflects clinical outcome, can be explained by variations in gene expression patterns generated by epigenetic mechanisms, such as DNA methylation. Therefore, epigenetic abnormalities are considered potential biomarkers and therapeutic targets. DNA methylation is stable at certain specific loci in cancer cells and predominantly reflects the characteristic clinicopathological features. Thus, it is an ideal biomarker for cancer screening, classification and prognostic purposes. Epigenetic treatment for cancers is based on the pharmacologic targeting of various core transcriptional programs that sustains cancer cell identity. Therefore, targeting aberrant epigenetic modifiers may be effective for multiple processes compared with using a selective inhibitor of aberrant single signaling pathway. This review provides an overview of the epigenetic alterations in human cancers and discusses about novel therapeutic strategies targeting epigenetic alterations. [ABSTRACT FROM AUTHOR]

It is widely accepted that epigenetic alterations are associated with different stages of tumour formation and progression in many cancers. Therefore, epigenetic abnormalities in cancers are emerging as important biomarkers and may have therapeutic potential. The polycomb repressive complex 2 (PRC2) is a key epigenetic regulator that catalyses trimethylation of lysine 27 on histone H3 (H3K27me3) via the histone methyltransferase, EZH2, which confers stemness and regulates differentiation during embryonic development. Given these roles of EZH2 and H3K27me3, plastic and dynamic features of cancer cells, especially cancer stem cells (CSCs), may be closely associated with this epigenetic mechanism. In addition, recent sequencing technology revealed that there are many recurrent mutations in polycomb-related genes, including EZH2, in different types of cancers. Therefore, researchers focused on targeting EZH2 as a novel cancer treatment and identified small compounds that inhibit EZH2 activity. Some of them are now under clinical trial in B-cell lymphoma. However, the underlying mechanisms by which PRC2 precisely regulate epigenetic alterations at certain genomic loci under different cellular conditions remain unclear. In this review, I focus on the recent advancements in EZH2 research, especially its dynamic regulation of epigenetic alterations in tumour cells, including the CSC population, and discuss perspectives and challenges for cancer treatment in the near future. [ABSTRACT FROM AUTHOR]

Abstract: It has been reported that tumor necrosis factor α (TNFα) activated the p38 MAP kinase pathway, followed by phosphorylation of epidermal growth factor receptor (EGFR) at serine 1047 (Ser1047). Although the phosphorylation of Ser1047 reportedly induced an internalization of EGFR, a protein kinase responsible for the phosphorylation has not been elucidated. In the present study, we found that treatment with flagellin of A549 cells, an alveolar epithelial cell line, induced the activation of p38 MAP kinase, followed by phosphorylation of EGFR at Ser1047. The phosphorylation was strongly inhibited by SB203580, an inhibitor of p38 MAP kinase. The flagellin treatment activated MAP kinase-activated protein kinase-2 (MAPKAPK-2), a protein kinase downstream of p38 MAP kinase, and MK2a inhibitor, an inhibitor of MAPKAPK-2, inhibited the flagellin-induced phosphorylation of EGFR at Ser1047. Unlike the flagellin treatment, the TNFα treatment induced the phosphorylation of EGFR at both Ser1047 and Tyr1173. SB203580 and MK2a inhibitor strongly inhibited the phosphorylation of Ser1047 but not Tyr1173 in EGFR. Finally, bacterially expressed and activated MAPKAPK-2 phosphorylated EGFR at Ser1047 in vitro. These results suggest that flagellin regulates the residence time of EGFR on the plasma membrane and thus the signaling of EGFR through phosphorylation of Ser1047 by MAPKAPK-2. [Copyright &y& Elsevier]

We used a single-particle soot photometer (SP2) to measure the mass of individual black carbon (BC) particles down to ∼ 0.5 fg by means of laser-induced incandescence with an intra-cavity, continuous-wave laser. The incandescence of nine different types of BC samples was investigated to provide a physical basis for choosing appropriate BC materials for SP2 calibration. We estimated the vaporization temperatures of these BC samples from the spectral dependence of incandescence at the limit of the small size parameter x, for which spectral dependence of emissivity is known a priori. The vaporization temperatures differed by less than 2.2% among the samples. For the x < 1 regime of particle size, the peak amplitude of the incandescence signal measured by the SP2 was linearly proportional to the particle mass. The slopes of such linear proportionality were positively correlated with | (m2-1)/(m2+2)|, where the m is the complex refractive index of the BC particle. For particles in which x > 1, the rate of increase in the peak amplitude of the incandescence signal with increasing particle mass was negatively correlated with the compactness of particle shape, consistent with the theoretical prediction of emissivity, which accounts for particle shape. The incandescence-BC mass relationships were similar between fullerene soot and ambient soot sampled in Tokyo, thus suggesting that fullerene soot is a suitable calibration standard for SP2 measurements of ambient soot. [ABSTRACT FROM AUTHOR]

Abstract: We demonstrate a new method to measure refractive indices m of small nonspherical particles by simultaneous measurement of particle volume and light-scattering cross section. In contrast to traditional methods, this method can suppress uncertainties due to unknown particle shape. As demonstration of the method, laboratory experiments using an aerosol particle mass analyzer (APM) and single-particle soot photometer (SP2) have been conducted to determine the refractive indices of seven types of commercial black carbon particles and ambient soot at 1064nm wavelength. Difference in measured |(m 2−1)/(m 2+2)| values among the seven commercial black carbon samples is consistent with the difference in their crystalline structures identified by a transmission electron microscope. The complex refractive index m=(n, k) of ambient soot particles in Tokyo urban area was determined to be m=(2.26±0.13, 1.26±0.13). [Copyright &y& Elsevier]

Abstract: We present new physical models to interpret the response characteristics of filter-based measurements of aerosol light absorption. They were motivated by a recently found particle size dependence of a systematic bias in absorption measurements that cannot be interpreted by any models reported thus far. A theory of particle filtration by fibrous filter is applied to reproduce the penetration depth of particles into a filter matrix, and the light transmissivity of the matrix is calculated by the use of radiative transfer theory for plane-parallel layers. Optical properties of individual layers are calculated from microphysical properties and the number density of filter fibers and deposited particles. The size-dependent systematic bias in absorption measurement is successfully explained by the particle size dependence of penetration depth into a filter matrix. In practice the physical models developed here are useful for selecting operating conditions and filter matrices for instruments with fewer systematic biases. [Copyright &y& Elsevier]

Abstract: The directional intensity distribution of thermal emission from nonspherical particles can be predicted in the geometric optics limit using the Kirchhoff''s law, or, in general case, using the Rytov''s theory based on the fluctuation–dissipation theorem. This study demonstrates the first experimental evidence of the directional variation of thermal emission from nonspherical particles of a size smaller than the geometric optics limit. We used a method of laser-induced incandescence with multi-angle detectors to observe the directional dependences of thermal emission from individual carbon particles. For laboratory carbon particles with various shapes, the measured directional dependences of thermal emission were consistent with theoretical calculations for model nonspherical particles. This study provides a new physical principle for measuring the shape of aerosols according to the directional dependence of their thermal emission and is especially useful for online, in situ shape classification of carbon particles. [Copyright &y& Elsevier]

Hundreds of genes show aberrant DNA hypermethylation in cancer, yet little is known about the causes of this hypermethylation. We identified RIL as a frequent methylation target in cancer. In search for factors that influence RIL hypermethylation, we found a 12-bp polymorphic sequence around its transcription start site that creates a long allele. Pyrosequencing of homozygous tumors revealed a 2.1-fold higher methylation for the short alleles (P,0.001). Bisulfite sequencing of cancers heterozygous for RIL showed that the short alleles are 3.1-fold more methylated than the long (P<0.001). The comparison of expression levels between unmethylated long and short EBV-transformed cell lines showed no difference in expression in vivo. Electrophorectic mobility shift assay showed that the inserted region of the long allele binds Sp1 and Sp3 transcription factors, a binding that is absent in the short allele. Transient transfection of RIL allelespecific transgenes showed no effects of the additional Sp1 site on transcription early on. However, stable transfection of methylation-seeded constructs showed gradually decreasing transcription levels from the short allele with eventual spreading of de novo methylation. In contrast, the long allele showed stable levels of expression over time as measured by luciferase and ~2-3-fold lower levels of methylation by bisulfite sequencing (P,0.001), suggesting that the polymorphic Sp1 site protects against time-dependent silencing. Our finding demonstrates that, in some genes, hypermethylation in cancer is dictated by protein-DNA interactions at the promoters and provides a novel mechanism by which genetic polymorphisms can influence an epigenetic state. [ABSTRACT FROM AUTHOR]

Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation. [ABSTRACT FROM AUTHOR]

Background: Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications. However, the functional roles of the histone methyltransferases (HMT) in cancer remain unclear. Methodology/Principal Findings: We studied RNAi-based inhibition (knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the 2 HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. G9a KD cells showed increased DNA content (1.7-fold in 2 independent clones) compared with FACS analyses to control. Karyotype analyses showed that this was due to an increased number of chromosomes (from 61 to 102) in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in about 25% of the G9a KD cells, while centrosomes were morphologically normal in control cells. Microarray analyses after KD of SUV39H1 or G9a showed very few genes up-regulated among the 39,000 genes. The silenced tumor-suppressor genes p16 and RASSF1A were not activated in KD cells. Conclusions/Significance: These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers. [ABSTRACT FROM AUTHOR]

Abstract: We develop a new method of measuring the time-dependent solid angle scattering cross section for detection of individual particles flowing across a Gaussian laser beam. This method is based on the principle that the normalized derivative of the scattering signal measured by an instrument can be decomposed into the normalized derivative of the incident irradiance and that of the scattering cross section . For evaporative particles, holds true until evaporation starts at a certain position in the laser beam. The for individual particles is determined from , which is extracted from . is derived from and . We apply the method to particles with and without evaporation using a single-particle soot photometer. The robustness of the method is confirmed through results for non-evaporative particles. For evaporative particles, derived values before the onset of evaporation are compared to Mie theory. [Copyright &y& Elsevier]

Aim: The aim of the present study was to examine DNA methylation and histone modification changes in hepatocellular carcinomas (HCC). Methods: DNA methylation in the P16, RASSF1a, progesterone receptor ( PGR) and estrogen receptor α ( ERα) promoters was determined by quantitative bisulfite-pyrosequencing technique in HCC patients. Histone H3-lysine (K) 4, H3-K9 and H3-K27 modifications in all these four genes were examined by chromatin immunoprecipitation (ChIP) assay in HCC cell lines. Expression of two DNA methyltransferases (DNMT1 and DNMT3b) and three histone methyltransferases (SUV39H1, G9a and EZH2) in HCC patients was measured by real-time polymerase chain reaction. Results: Aberrant DNA methylation was detected in all the HCC. Patients with DNA methylation in the RASSF1a, PGR and ERα promoters in cancers also had substantial DNA methylation in their non-cancerous liver tissues, whereas DNA methylation in the P16 promoter was cancer specific. Epigenetic states in HCC cell lines showed that silencing of P16 and RASSF1a depended on DNA methylation and histone H3-K9 methylation. However, silencing of the PGR and ERα genes was more closely related to H3-K27 methylation rather than DNA methylation. Consistent with the alteration of histone status, higher expression of G9a and EZH2 was found in HCC than in non-cancerous liver tissues ( P < 0.01). Conclusion: These data suggest that multiple epigenetic silencing mechanisms are inappropriately active in HCC cells. [ABSTRACT FROM AUTHOR]

The role of CpG island methylation in normal development and cell differentiation is of keen interest, but remains poorly understood. We performed comprehensive DNA methylation profiling of promoter regions in normal peripheral blood by methylated CpG island amplification in combination with microarrays. This technique s allowed us to simultaneously determine the methylation status of 6,177 genes, 92% of which include dense CpG islands. Among these 5,549 autosomal genes with dense CpG island promoters, we have identified 4.0% genes that are nearly completely methylated in normal blood, providing another exception to the general rule that CpG island methylation in normal tissue is limited to X inactivation and imprinted genes. We examined seven genes in detail, including ANKRD30A, FLJ40201, INSL6, SOHLH2, FTMT, C12orf12, and DPPA5. Dense promoter CpG island methylation and gene silencing were found in normal tissues studied except testis and sperm. In both tissues, bisulfite cloning and sequencing identified cells carrying unmethylated alleles. Interestingly, hypomethylation of several genes was associated with gene activation in cancer. Furthermore, reactivation of silenced genes could be induced after treatment with a DNA demethylating agent or in a cell line lacking DNMT1 and/or DNMT3b. Sequence analysis identified five motifs significantly enriched in this class of genes, suggesting that cis-regulatory elements may facilitate preferential methylation at these promoter CpG islands. We have identified a group of non-X-linked bona fide promoter CpG islands that are densely methylated in normal somatic tissues, escape methylation in germline cells, and for which DNA methylation is a primary mechanism of tissue-specific gene silencing. [ABSTRACT FROM AUTHOR]

Laboratory experiments and theoretical calculations were made to characterize the performance of a Single Particle Soot Photometer (SP2) manufactured by Droplet Measurement Technologies (DMT), which was designed to measure the mass and the mixing state of individual black carbon (BC) or elemental carbon (EC) particles, based on the laser-induced incandescence (LII) technique. In this study, graphite was used as a surrogate of EC. Graphite particles with mass equivalent diameters of 110-200 nm were layered with organic liquids (glycerol and oleic acid) to produce coated graphite with diameters up to 650-800 nm. These were sampled by the SP2 to measure the waveforms (i.e., time development) of the LII and scattering signals. The peak temperature and the peak LII signal of graphite particles were independent of the coating thickness or the coating material to within experimental errors. These results indicate that the mass of EC can be measured by using peak LII signal without interference by the coating conditions. It was also shown that the difference between the times of the scattering and LII peaks can be used as an indicator of coating on EC with thicknesses larger than about 100-200 nm. LII and scattering waveforms were calculated using a newly developed theoretical model that takes into account the physical processes controlling the temperature and evaporation rate of the coated graphite particle in the laser beam. The calculations reproduced the general features of observed waveforms of LII and scattering signals, providing a firm theoretical basis for the interpretation of the SP2 data. [ABSTRACT FROM AUTHOR]

Background: Sporadic colorectal cancers often arise from a region of cells characterized by a ‘field defect’ that has not been well defined molecularly. DNA methylation has been proposed as a candidate mediator of this field defect. The DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa. Methods: We studied MGMT promoter methylation by three different bisulfite-based techniques in tumor, adjacent mucosa, and nonadjacent mucosa from 95 colorectal cancer patients and in colon mucosa from 33 subjects with no evidence of cancer. Statistical tests were two-sided. Results: MGMT promoter methylation was present in 46% of the tumors. Patients whose cancer had MGMT promoter methylation also had substantial MGMT promoter methylation in apparently normal adjacent mucosa. This methylation was seen with a quantitative assay in 50% (22/44; 95% confidence interval [CI] = 34% to 65%) of normal samples with MGMT promoter methylation in the adjacent tumors, 6% (3/51; 95% CI = 1% to 16%) of samples without MGMT methylation in adjacent tumors, and 12% (4/33; 95% CI = 3% to 28%) of control samples (P«.001 for comparison between each of the latter two groups and the first group). MGMT methylation was detected with a more sensitive assay in 94%, 34%, and 27% of these samples, respectively (P«.001 ). In grossly normal colonic mucosa of colon cancer patients, methylation was detected 10 cm away from the tumor in 10 of 13 cases. Tumors with MGMT promoter methylation had a higher rate of G-to-A mutation in the KRAS oncogene than tumors without MGMT promoter methylation (10/42 versus 3/46, P = .03). Using a sensitive mutant allele-specific amplification assay for KRAS mutations, we also found KRAS mutations in 12% (3/25; 95% CI = 2.5% to 31%) of colorectal mucosas with detectable MGMT methylation and 3% (2/64; 95% CI = 0.4% to 11%) of colorectal mucosas without MGMT methylation (P = .13). Conclusion: Some colorectal cancers arise from a field defect defined by epigeneric inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer. [ABSTRACT FROM AUTHOR]

Switching from acetylation to methylation at histone H3 lysine 9 (K9) has recently been shown to contribute to euchromatin gene silencing. To identify genes silenced by K9 modifications, we probed a human CpG island microarray with DNA obtained by chromatin immunoprecipitation (ChIP) in a cancer cell line using an anti-H3-K9 methylated antibody or an anti-H3-K9 acetylated anti- body. Of the 27 clones with the highest signal ratio of K9 methylation over acetylation (Me/Ac), 13 contained repetitive sequences. Among 14 nonrepetitive clones, we identified 11 genes (seven known and four previously undescribed), one EST, and two unknown fragments. Using ChlP-PCR, all 18 examined clones showed higher ratios of H3-K9 Me/Ac than the active gene control, P21, thus confirming the microarray data. In addition, we found a strong correlation between the K9 Me/Ac ratio and CpG island DNA methylation (R = 0.92, P < 0.01), and five of seven genes examined (megalin, thrombospondin-4, KR18, latrophilin-3, and phosphatidylinositol-3-OH kinase P101 subunit) showed lack of expression by RT-PCR and reactivation by DNA methylation and/or histone deacetylase inhibition, suggesting that these genes are true targets of silencing through histone modifications. All five genes also showed significant DNA methylation in a cell line panel and in primary colon cancers. Our data suggest that CpG island microarray coupled with ChlP can identify novel targets of gene silencing in cancer. This unbiased approach confirms the tight coupling between DNA methylation and histone modifications in cancer and could be used to probe gene silencing in nonneoplastic conditions as well. [ABSTRACT FROM AUTHOR]

The aim of the present study was to determine whether evaluating the status of loss of heterozygosity (LOH) before interferon (IFN) therapy is predictive for development of hepatocellular carcinoma (HCC) in chronic hepatitis and liver cirrhosis patients. Eighteen patients with hepatitis C virus were studied, nine of whom developed HCC (HCC group) after IFN therapy and nine whom did not (non-HCC group). Samples before IFN therapy from both groups (pre-IFN-N and pre-IFN-H samples from the non-HCC and HCC groups, respectively) were analyzed for LOH using 12 microsatellite markers. To evaluate the LOH incidence in different steps in HCC patients, paired samples of cancerous tissue (CT) and adjacent non-CT (ANCT) obtained from the HCC group were also analyzed. Frequency of LOH in the pre-IFN-H samples was significantly higher than that in the pre-IFN-N samples regardless of the response to IFN therapy. Interestingly, in the HCC group, there is no significant difference in the frequency of LOH among the pre-IFN-H, ANCT and CT samples. The present results suggest the theory that genetic instability, such as LOH, had already accumulated at stages before the development of HCC. The authors propose that the status of LOH in chronic hepatitis and liver cirrhosis patients before IFN therapy could be a potential predictor for the development of HCC. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify in human cells common targets of histone H3 lysine 9 (H3-Lys[sup 9]) methylation, a modification that is generally associated with gene silencing. After chromatin immunoprecipitation using an H3-Lys[sup 9] methylated antibody, we cloned the recovered DNA and sequenced 47 independent clones. Of these, 38 clones (81%) contained repetitive elements, either short interspersed transposable element (SINE or Alu elements), long terminal repeat (LTR), long interspersed transposable element (LINE), or satellite region (ALR/Alpha) DNA, and three additional clones were near Alu elements. Further characterization of these repetitive elements revealed that 32 clones (68%) were Alu repeats, corresponding to both old Alu (23 clones) and young Alu (9 clones) subfamilies. Association of H3Lys[sup 9] methylation was confirmed by chromatin immunoprecipitation-PCR using conserved Alu primers. In addition, we randomly selected 5 Alu repeats from the recovered clones and confirmed association with H3Lys[sup 9] by PCR using primer sets flanking the Alu elements. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine rapidly decreased the level of H3-Lys[sup 9] methylation in the Alu elements, suggesting that H3-Lys[sup 9] methylation may be related to the suppression of Alu elements through DNA methylation. Thus H3-Lys[sup 9] methylation is enriched at human repetitive elements, particularly Alu elements, and may play a role in the suppression of recombination by these elements. [ABSTRACT FROM AUTHOR]

The mechanism of DNA hypermethylation-associated tumor suppressor gene silencing in cancer remains incompletely understood. Here, we show by chromatin immunoprecipitation that for three genes (P16, MLH1, and the O[sup 6]-methylguanine-DNA methyltransferase gene, MGMT), histone H3 Lys-9 methylation directly correlates and histone H3 Lys-9 acetylation inversely correlates with DNA methylation in three neoplastic cell lines. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) resulted in moderately increased Lys-9 acetylation at silenced loci with no effect on Lys-9 methylation and minimal effects on gene expression. By contrast, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza-dC) rapidly reduced Lys-9 methylation at silenced loci and resulted in reactivation for all three genes. Combined treatment with 5Aza-dC and TSA was synergistic in reactivating gene expression through simultaneous effects on Lys-9 methylation and acetylation, which resulted in a robust increase in the ratio of Lys-9 acetylated and methylated histones at loci showing dense DNA methylation. By contrast to Lys-9, histone H3 Lys-4 methylation inversely correlated with promoter DNA methylation, was not affected by TSA, and was increased moderately at silenced loci by 5Aza-dC. Our results suggest that reduced H3 Lys-4 methylation and increased H3 Lys-9 methylation play a critical role in the maintenance of promoter DNA methylation-associated gene silencing in colorectal cancer. [ABSTRACT FROM AUTHOR]

Despite the increasing threat of heatstroke with global warming, pathophysiologic injury continues to be defined. In addition, morphological changes of the peripheral blood cells in heatstroke have not been well characterized. We evaluated pathophysiologic changes in bone marrow and blood cells in a rat heatstroke model using a 39.5 °C climate chamber. After three hours of incubation, blood and bone marrow samples were collected for morphology, and the direct effects of heat on leukocytes in vitro were evaluated using time-lapse observation. The blood cell count and peripheral/bone marrow smear were examined either in a lethal model (core body temperature exceeded 42.5 °C) or in a sublethal model (<41.5 °C). Significant decreases in platelet and white blood counts occurred in the lethal model (>35% and >20% decreases, respectively) and changes were less in the sublethal model. Platelet clumping with the appearance of large platelets was observed. The neutrophils often demonstrated hyper-segmented nuclei, and lymphocytes showed reactive or blast-like changes. Further, the direct effect of heat on leukocytes noted apoptotic cell death at 41.5 °C, but subsequent necrosis at 43 °C. In summary, our rodent model showed that heatstroke causes platelet aggregation, leukocyte injury, and aponecrotic cell death. Such changes were milder and reversible in sublethal heatstroke. The appearance of immature cells may result from damage to the bone marrow microenvironment. These findings may provide useful information for potential diagnostic and therapeutic considerations. [ABSTRACT FROM AUTHOR]

Geriatric trauma is a major socio-economic problem, especially among the aging Japanese society. Geriatric people are more vulnerable to trauma than younger people; thus, their outcomes are often severe. This study evaluates the characteristics of geriatric trauma divided by age in the Japanese population. We evaluated trauma characteristics in patients (n = 131,088) aged ≥ 65 years by segregating them into 2 age-based cohorts: age 65–79 years (65–79 age group; n = 70,707) and age ≥ 80 years (≥ 80 age group; n = 60,381). Clinical characteristics such as patient background, injury mechanism, injury site and severity, treatment, and outcome were examined. Injuries among men were more frequent in the 65–79 age group (58.6%) than in the ≥ 80 age group (36.3%). Falls were the leading cause of trauma among the 65–79 age group (56.7%) and the ≥ 80 age group (78.9%). In-hospital mortality was 7.7% in the 65–79 age group and 6.6% in the ≥ 80 age group. High fall in the ≥ 80 age group showed 30.5% mortality. The overall in-hospital mortality was 11.8% (the 65–79 age group, 12.3%; the ≥ 80 age group, 11.2%). Most hospitalized patients were transferred to another hospital (the 65–79 age group, 52.5%; the ≥ 80 age group, 66.2%). We demonstrated the epidemiological characteristics of Japanese geriatric trauma patients. The overall in-hospital mortality was 11.8%, and fall injury in the ≥ 80 age group required caution of trauma care. [ABSTRACT FROM AUTHOR]

Background: The prolonged β-lactam infusion strategy has emerged as the standard treatment for sepsis or septic shock despite its unknown efficacy. This study aimed to assess the efficacy of prolonged versus intermittent β-lactam antibiotics infusion on outcomes in sepsis or septic shock patients by conducting a systematic review and meta-analysis. Methods: A thorough search was conducted on MEDLINE, the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi databases. Randomized controlled trials (RCTs) comparing mortality between prolonged and intermittent infusion in adult patients with sepsis or septic shock were included. The primary outcome was hospital mortality. The secondary outcomes were the attainment of the target plasma concentration, clinical cure, adverse events, and occurrence of antibiotic-resistant bacteria. We performed a subgroup analysis stratified according to the year of publication before or after 2015 and a trial sequential analysis (TSA). The Der Simonian–Laird random-effects models were subsequently used to report the pooled risk ratios (RR) with confidence intervals (CI). Results: We identified 2869 studies from the 3 databases, and 13 studies were included in the meta-analysis. Hospital mortality did not decrease (RR 0.69 [95%CI 0.47–1.02]) in the prolonged infusion group. The attainment of the target plasma concentration and clinical cure significantly improved (RR 0.40 [95%CI 0.21–0.75] and RR 0.84 [95%CI 0.73–0.97], respectively) in the prolonged infusion group. There were, however, no significant differences in the adverse events and the occurrence of antibiotic-resistant bacteria between the groups (RR 1.01 (95%CI 0.95–1.06) and RR 0.53 [95%CI 0.10–2.83], respectively). For the subgroup analysis, a significant improvement in hospital mortality or clinical cure was reported in studies published in or after 2015 (RR 0.66 [95%CI 0.44–0.98] and RR 0.67 [95%CI 0.50–0.90], respectively). The results of the TSA indicated an insufficient number of studies for a definitive analysis. Conclusions: The prolonged infusion of β-lactam antibiotics significantly improved upon attaining the target plasma concentration and clinical cure without increasing the adverse event or the occurrence of antibiotic-resistant bacteria. Prolonged infusion could not improve hospital mortality although an improvement was shown for studies published in or after 2015. Further studies are warranted as suggested by our TSA results. [ABSTRACT FROM AUTHOR]

Decompression illness ( DCI) develops during or after diving. Pulmonary decompression illness (' Chokes') is rarely seen because the affected individual usually dies in the water. We encountered a rare and interesting case. A 60-year-old man complained of leg pain after diving. Despite rapid transfer to a nearby hospital, advanced respiratory failure and shock had set in. He was then transferred to our hospital for hyperbaric oxygen therapy ( HBOT). On account of his poor general condition, we initially treated him in the intensive care unit without HBOT, where he showed extreme hyperpermeability and a high level of serum procalcitonin ( PCT; 20.24 ng/mL). Despite large-volume fluid therapy, severe intravascular dehydration and shock status remained. We assume that the injured endothelial cells induced vascular hyperpermeability and increased levels of inflammatory cytokines leading to the high serum PCT level. PCT might be a useful stress marker of endothelial damage and severity in DCI, including Chokes. [ABSTRACT FROM AUTHOR]

Surgical treatment for internal fistula is rarely indicated for terminally ill patients with cancer because of their poor prognoses. Reports of surgical or pharmacologic treatment of vesicoenteric fistula in terminally ill patients with cancer are rare. A 73-year-old woman with rectal cancer that had directly invaded the bladder and metastasized to the liver was admitted to our hospital with high fever and severe perineal pain. Retrograde urography indicated an enterovesical fistula. Although the urinary tract infection was treatable with antibiotics, frequent episodic pain, due to urethritis secondary to the fistula, was not alleviated with opioid and topical treatment. Three days after starting octreotide 0.3 mg/d, the severe pain was alleviated, and follow-up retrograde urography revealed closure of the fistula. This suggests that treatement with octreotide may have enabled closure of the fistula. Thus, octreotide should be considered a viable therapeutic option in terminally ill patients with inoperable internal fistula. [ABSTRACT FROM AUTHOR]

OBJECTIVES To assess the treatment outcome and benefits after varicocelectomy in men with unobstructive azoospermia (UOA) and severe oligospermia (SO). PATIENTS AND METHODS The records were retrospectively evaluated for six patients with UOA and 54 with SO who had microsurgical inguinal varicocele ligation (mean age 33.3 years,sd 5.3). Fifty-one (85%) had a unilateral left-sided procedure (five of six with UOA, 46 of 54 with SO), and nine (15%) had a bilateral procedure. RESULTS After ligation, spermatogenesis was induced in two of the six men with UOA; the mean (sd) sperm concentration increased from 2.3 (1.6) to 9.2 (12.6) million/mL ( P < 0.001), but the sperm motility did not change significantly. Four (7%) of the 54 men with SO achieved paternity, with unassisted pregnancies. CONCLUSIONS Varicocelectomy resulted in the induction or enhancement of spermatogenesis for several men with UOA or SO; it seems to be a reasonable option in selected patients with UOA or SO. [ABSTRACT FROM AUTHOR]

Background: Abdominal aortic injury (AAI) is a life-threatening condition that occurs in only 0.1% of all trauma admissions. Because of its rarity, the clinical features of AAI remain unclear. We investigated the characteristics, treatments, and clinical outcomes among patients with AAI. Methods: This retrospective cohort study was performed using the Japanese Diagnosis Procedure Combination database. We identified patients with a confirmed diagnosis of AAI with emergency admission from 1 July 2010 to 31 March 2017. Eligible patients were divided into three groups: those who were treated with no surgery or endovascular treatment (non-repair group), those who underwent surgery without endovascular treatment (open repair group), and those who received endovascular treatment without surgery (endovascular repair group). Results: A total of 238 patients met the inclusion criteria during the study period. Of these, 191 (80.3%) were allocated to the non-repair group, 20 (8.4%) were allocated to the open repair group, and 27 (11.3%) were allocated to the endovascular repair group. The proportions of patients in the non-repair group from July 2010 to March 2012, April 2012 to March 2014, April 2014 to March 2016, and April 2016 to March 2017 were 93.5%, 75.9%, 80.6%, and 73.2%, respectively. The crude in-hospital mortality rate was 26.2%, 35.0%, and 18.5% in the non-repair, open repair, and endovascular repair group, respectively. Conclusions: In this cohort, the proportion of non-repair for AAI decreased from 2010 to 2017, whereas the proportion of endovascular repair increased. Younger patients were more likely to undergo open repair, whereas older patients were more likely to undergo endovascular repair. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions We previously identified that ever‐smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol‐related genetic polymorphism with SGCs and also stratify their risk.This multi‐center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study.Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0–3 risk factors in the combined evaluation of three risk factors (ever‐smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001).Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk. [ABSTRACT FROM AUTHOR]

Long-term measurements of atmospheric mass concentrations of black carbon (BC) are needed to investigate changes in its emission, transport, and deposition. However, depending on instrumentation, parameters related to BC such as aerosol absorption coefficient (babs) have been measured instead. Most ground-based measurements of babs in the Arctic have been made by filter-based absorption photometers, including particle soot absorption photometers (PSAPs), continuous light absorption photometers (CLAPs), Aethalometers, and multi-angle absorption photometers (MAAPs). The measured babs can be converted to mass concentrations of BC (MBC) by assuming the value of the mass absorption cross section (MAC; MBC= babs/ MAC). However, the accuracy of conversion of babs to MBC has not been adequately assessed. Here, we introduce a systematic method for deriving MAC values from babs measured by these instruments and independently measured MBC. In this method, MBC was measured with a filter-based absorption photometer with a heated inlet (COSMOS). COSMOS-derived MBC (MBC (COSMOS)) is traceable to a rigorously calibrated single particle soot photometer (SP2), and the absolute accuracy of MBC (COSMOS) has been demonstrated previously to be about 15 % in Asia and the Arctic. The necessary conditions for application of this method are a high correlation of the measured babs with independently measured MBC and long-term stability of the regression slope, which is denoted as MAC cor (MAC derived from the correlation). In general, babs – MBC (COSMOS) correlations were high (r2= 0.76–0.95 for hourly data) at Alert in Canada, Ny-Ålesund in Svalbard, Barrow (NOAA Barrow Observatory) in Alaska, Pallastunturi in Finland, and Fukue in Japan and stable for up to 10 years. We successfully estimated MAC cor values (10.8–15.1 m 2 g -1 at a wavelength of 550 nm for hourly data) for these instruments, and these MAC cor values can be used to obtain error-constrained estimates of MBC from babs measured at these sites even in the past, when COSMOS measurements were not made. Because the absolute values of MBC at these Arctic sites estimated by this method are consistent with each other, they are applicable to the study of spatial and temporal variation in MBC in the Arctic and to evaluation of the performance of numerical model calculations. [ABSTRACT FROM AUTHOR]

Long-term measurements of atmospheric mass concentrations of black carbon (BC) are needed to investigate changes in its emission, transport, and deposition. However, depending on instrumentation, parameters related to BC such as aerosol absorption coefficient (babs) have been measured instead. Most ground-based measurements of babs in the Arctic have been made by filter-based absorption photometers, including particle soot absorption photometers (PSAP), continuous light absorption photometer (CLAP), Aethalometers, and multi-angle absorption photometers (MAAP). The measured babs can be converted to mass concentrations of BC (MBC) by assuming the value of the mass absorption cross section (MAC; MBC = babs/MAC). However, the accuracy of conversion of babs to MBC has not been adequately assessed. Here, we introduce a systematic method for deriving MAC values from babs measured by these instruments and independently measured MBC. In this method, MBC was measured with a filter-based absorption photometer with a heated inlet (COSMOS). COSMOS-derived MBC (MBC (COSMOS)) is traceable to a rigorously calibrated single particle soot photometer (SP2) and the absolute accuracy of MBC (COSMOS) has been demonstrated previously to be about 15 % in Asia and the Arctic. The necessary conditions for application of this method are a high correlation of the measured babs with independently measured MBC, and long-term stability of the regression slope, which is denoted as MACcor (MAC derived from the correlation). In general, babs-MBC (COSMOS) correlations were high (r2 = 0.76-0.95 for hourly data) at Alert in Canada, Ny-Ålesund in Svalbard, Barrow in Alaska, Pallastunturi in Finland, and Fukue in Japan, and stable for up to 10 years. We successfully estimated MACcor values (10.6-15.2 m2 g-1 at a wavelength of 550 nm) for these instruments and these MACcor values can be used to obtain error-constrained estimates of MBC from babs measured at these sites even in the past, when COSMOS measurements were not made. Because the absolute values of MBC in these Arctic sites estimated by this method are consistent with each other, they are applicable to the study of spatial and temporal variation of MBC in the Arctic and to evaluation of the performance of numerical model calculations. [ABSTRACT FROM AUTHOR]

Background: Early and accurate diagnosis of sepsis is challenging. Although procalcitonin and presepsin have been identified as potential biomarkers to differentiate between sepsis and other non-infectious causes of systemic inflammation, the diagnostic accuracy of these biomarkers remains controversial. Herein, we performed a comprehensive meta-analysis to assess the overall diagnostic value of procalcitonin and presepsin for the diagnosis of sepsis. Methods: We searched three electronic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) for relevant studies. Two authors independently screened articles on the basis of inclusion and exclusion criteria. The pooled sensitivity, specificity, and summary receiver operating characteristic curves were estimated. The quality of evidence for diagnostic accuracy in absolute effects, i.e., the number of true or false positives and true or false negatives, gave a particular pre-test probability. Results: We included 19 studies (19 observational studies and no randomized controlled trials) that had enrolled 3012 patients. Analyses of summary receiver operating characteristic curves revealed areas under the receiver operating characteristic curves of 0.84 for procalcitonin and 0.87 for presepsin. The pooled sensitivities and specificities were 0.80 (95% confidence interval 0.75 to 0.84) and 0.75 (95% confidence interval 0.67 to 0.81) for procalcitonin. For presepsin, these values were 0.84 (95% confidence interval 0.80 to 0.88) and 0.73 (95% confidence interval 0.61 to 0.82), respectively. There were no statistically significant differences in both pooled sensitivities (p = 0.48) and specificities (p = 0.57) between procalcitonin and presepsin. Conclusion: Our meta-analysis provided evidence that the diagnostic accuracy of procalcitonin and presepsin in detecting infection was similar and that both are useful for early diagnosis of sepsis and subsequent reduction of mortality in critically ill adult patients. Systematic review registration: The study was registered in PROSPERO under the registration number CRD42016035784. [ABSTRACT FROM AUTHOR]

Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the "Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit" to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions. [ABSTRACT FROM AUTHOR]