Extracorporeal cardiopulmonary resuscitation with temperature management could improve the neurological outcomes of out-of-hospital cardiac arrest: a retrospective analysis of a nationwide multicenter observational study in Japan.

BACKGROUND: Target temperature management (TTM) is an effective component of treating out-of-hospital cardiac arrest (OHCA) after return of spontaneous circulation in conventional cardiopulmonary resuscitation. However, therapeutic hypothermia (32-34 °C TTM) is not recommended based on the results of recent studies. Extracorporeal cardiopulmonary resuscitation (ECPR) with veno-arterial extracorporeal membrane oxygenation is another promising therapy for OHCA, but few studies have examined the effectiveness of ECPR with TTM. Therefore, we hypothesized that ECPR with TTM could have the effectiveness to improve the neurological outcomes for adults following witnessed OHCA, in comparison to ECPR without TTM. METHODS: We performed retrospective subanalyses of the Japanese Association for Acute Medicine OHCA registry. We focused on adults who underwent ECPR for witnessed OHCA. We performed univariate (the Mann-Whitney U test and Fisher's exact test), multivariable (logistic regression analyses), and propensity score analyses (the inverse probability of the treatment-weighting method) with to compare the neurological outcomes between patients with or without TTM, among all eligible patients, patients with a cardiogenic cause, and patients divided into subgroups according to the interval from collapse to pump start (ICPS) (> 30, > 45, or > 60 min). RESULTS: We analyzed data for 977 patients. Among 471 patients treated with TTM, the target temperature was therapeutic hypothermia in 70%, and the median interval from collapse to target temperature was 249 min. Propensity score analysis showed a positive association between TTM and favorable neurological outcomes in all patients (odds ratio 1.546 [95% confidence interval 1.046-2.286], P = 0.029), and in patients with ICPS of > 30 or > 45 min, but not in those with ICPS of > 60 min. The propensity score analysis also showed a positive association between TTM and favorable neurological outcomes in patients with a cardiogenic cause (odds ratio 1.655 [95% confidence interval 1.096-2.500], P = 0.017), including in all ICPS subgroups (> 30, > 45, and > 60 min). CONCLUSION: Within patients who underwent ECPR following OHCA, ECPR with TTM could show the potential of improvement in the neurological outcomes, compared to ECPR without TTM.

Shorter Interval from Witnessed Out-Of-Hospital Cardiac Arrest to Reaching the Target Temperature Could Improve Neurological Outcomes After Extracorporeal Cardiopulmonary Resuscitation with Target Temperature Management: A Retrospective Analysis of a Japanese Nationwide Multicenter Observational Registry.

Extracorporeal cardiopulmonary resuscitation (ECPR) with extracorporeal membrane oxygenation is a more promising treatment for out-of-hospital cardiac arrest (OHCA) than conventional cardiopulmonary resuscitation (CCPR). However, previous studies that compared ECPR and CCPR included mixed groups of patients with or without target temperature management (TTM). In this study, we compared the neurological outcomes of OHCA between ECPR and CCPR with TTM in all patients. We performed retrospective subanalyses of the Japanese Association for Acute Medicine OHCA registry. Witnessed adult cases of cardiogenic OHCA treated with TTM were eligible for this study. We used univariate and multivariable analyses in all eligible patients to compare the neurological outcomes after ECPR or CCPR. We also conducted propensity score analyses of all patients and according to the interval from witnessed OHCA to reaching the target temperature (IWT) of ≤600, ≤480, ≤360, ≤240, and ≤120 minutes. We analyzed 1146 cases. The propensity score analysis did not show a significant difference in favorable neurological outcomes (defined as a Glasgow-Pittsburgh Cerebral Performance Category of 1-2 at 1 month after collapse) between EPCR and CCPR (odds ratio: OR 4.683 [95% confidence interval: CI 0.859-25.535], p = 0.747). However, ECPR was associated with more favorable neurological outcomes in patients with IWT of ≤600 minutes (OR 7.089 [95% CI 1.091-46.061], p = 0.406), ≤480 minutes (OR 10.492 [95% CI 1.534-71.773], p = 0.0168), ≤360 minutes (OR 17.573 [95% CI 2.486-124.233], p = 0.0042), ≤240 minutes (OR 38.908 [95% CI 5.045-300.089], p = 0.0005), and ≤120 minutes (OR 200.390 [95% CI 23.730-1692.211], p < 0.001). This study revealed significant differences in the neurological outcomes between ECPR and CCPR in patients with TTM whose IWT was ≤600 minutes.

Extracorporeal cardiopulmonary resuscitation without target temperature management for out-of-hospital cardiac arrest patients prolongs the therapeutic time window: a retrospective analysis of a nationwide multicentre observational study in Japan.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) with extracorporeal membrane oxygenation (ECMO) is a promising therapy for out-of-hospital cardiac arrest (OHCA) compared with conventional cardiopulmonary resuscitation (CCPR). The no and low-flow time (NLT), the interval from collapse to reperfusion to starting ECMO or to the return of spontaneous circulation (ROSC) in CCPR, is associated with the neurological outcome of OHCA. Because the effects of target temperature management (TTM) on the outcomes of ECPR are unclear, we compared the neurological outcomes of OHCA between ECPR and CCPR without TTM. METHODS: We performed retrospective subanalyses of the Japanese Association for Acute Medicine OHCA registry. Witnessed cases of adult cardiogenic OHCA without TTM were selected. We performed univariate, multivariable and propensity score analyses to compare the neurological outcomes after ECPR or CCPR in all eligible patients and in patients with NLT of > 30 min or > 45 min. RESULTS: We analysed 2585 cases. Propensity score analysis showed negative result in all patients (odds ratio 0.328 [95% confidence interval 0.141-0.761], P = 0.010). However, significant associated with better neurological outcome was shown in patients with NLT of > 30 min or > 45 min (odds ratio 2.977 [95% confidence interval 1.056-8.388], P = 0.039, odds ratio 5.099 [95% confidence interval 1.259-20.657], P = 0.023, respectively). CONCLUSION: This study revealed significant differences in the neurological outcomes between ECPR and CCPR without TTM, in patients with NLT of > 30 min.

Predictors of short-term repetition of self-harm among patients admitted to an emergency room following self-harm: A retrospective one-year cohort study.

We conducted a retrospective chart-review study, examining predictors of the repetition of short-term self-harm (<1 month and <6 months) among the patients who were admitted to an emergency department in Japan following self-harm. A total of 405 patients were enrolled and were followed-up for a subsequent one year. The incidence of repeated self-harm within one- and six- months were 6.4% and 13.1%, respectively. Cox's proportional hazards model analyses demonstrated that history of self-harm and comorbid physical illness were associated with repeated self-harm within one month. The patients who lived alone and who were directly discharged from the emergency room after referral to a psychiatrist were at higher risk for repeated self-harm within both one and six months. Living on public assistance and having been discharged from psychiatric wards within the past 12 months were associated with repetition within six months. These risk factors should be incorporated into routine assessment at an emergency room, and elaborate follow-up plan should be provided to the patients with these risk factors upon discharge from the emergency room. Further prospective studies are warranted, addressing more comprehensive factors that are associated with short-term risk for self-harm and suicide.

Determination method for p-Phenylazoaniline and 2-methyl-4-(2-tolylazo)aniline in workplace air by high-performance liquid chromatography.

OBJECTIVES: The purpose of this research was to develop a method for the simultaneous determination of p-Phenylazoaniline (also called 4-aminoazobenzene, AAB) and 2-methyl-4-(2-tolylazo)aniline (also called o-aminoazotoluene, AAT) in workplace air for risk assessment. METHODS: The characteristics of the proposed method, such as recovery, limit of quantitation, reproducibility and storage stability of the samples were examined. RESULTS: An air sampling cassette containing two sulfuric acid-treated glass fiber filters was chosen as the sampler. The AAB and AAT were extracted from the sampler filters by methanol and then analyzed by a high-performance liquid chromatograph equipped with a photo-diode array detector. The overall recoveries from spiked samplers were 77-98 and 85-98% for AAB and AAT, respectively. The recovery after 5 days of storage in a refrigerator exceeded 96%. The overall limits of quantitation were 5.00 and 2.50 µg/sample for AAB and AAT, respectively. The relative standard deviations, which represent the overall reproducibility defined as precision, were 0.6-1.8 and 0.5-2.2% for AAB and AAT, respectively. CONCLUSIONS: The proposed method enables 4-h personal exposure monitoring of AAB and AAT at concentrations of 21 to 2,000 µg/m3 for AAB and 10 to 2,000 µg/m3 for AAT, respectively. The proposed method is useful for estimating worker exposure to AAB and AAT.

Determination method for mono- and diethanolamine in workplace air by high-performance liquid chromatography.

OBJECTIVES: The purpose of this research was to develop a simultaneous determination method for monoethanol-amine (MEA) and diethanolamine (DEA) in workplace air for risk assessment. METHODS: The characteristics of the proposed method, such as recovery, quantitation limit, reproducibility and storage stability of the samples, were examined. RESULTS: An air sampling cassette containing two sulfuric acid-treated glass fiber filters was chosen as the sampler. The MEA and DEA were extracted from the sampler filters, derivatized with 9-fluorenylmethyloxycarbonyl chloride and then analyzed by a high-performance liquid Chromatograph equipped with a fluorescence detector or photo-diode array detector. The overall recoveries from spiked samplers were 86-99 and 88-99% for MEA and DEA, respectively. The recovery after 5 days of storage in a refrigerator exceeded 95%. The overall limits of quantitation were 0.750 and 0.100 jug/sample for MEA and DEA, respectively. The relative standard deviations, which represent the overall reproducibility defined as precision, were 0.3-1.6 and 0.4-5.7% for MEA and DEA, respectively. CONCLUSIONS: The proposed method enables 4-h personal exposure monitoring of MEA and DEA at concentrations equaling 1/3,000-2 times the threshold limit value-time-weighted average (TLV-TWA: 3 ppmfor MEA, 1 mg/m(3) for DEA) adopted by the American Conference of Governmental Industrial Hygienists and also by the Japan Society for Occupational Health. The method is useful for estimating worker exposure to MEA and DEA.

Determination method for xylidines in workplace air.

OBJECTIVES: The purpose of this research was to develop a determination method for xylidines (XLDs) in workplace air for risk assessment. METHODS: The characteristics of the proposed method, such as recovery, detection limit, reproducibility, and storage stability of the samples were examined. RESULTS: An air sampler cassette containing two sulfuric acid-treated glass fiber filters was chosen as the sampler. The XLDs were extracted from the sampler filters, derivatized with heptafluorobutyric anhydride, and then analyzed by a gas chromatograph equipped with a mass spectrometer. The average recoveries of XLDs from the spiked sampler were 83-101% for personal exposure monitoring. The recovery after 5 days of storage in a refrigerator exceeded 90%. The overall limit of quantitation (LOQ) was 0.600 g/sample. The relative standard deviation, which represents the overall reproducibility defined as precision, was 0.8-10.3%. CONCLUSIONS: The proposed method enables 4-hour personal exposure monitoring of XLDs at concentrations equaling 0.001-2 times the threshold limit value-time-weighted average (TLV-TWA: 0.5 ppm) adopted by the American Conference of Governmental Industrial Hygienists, and is useful for estimating worker exposure to XLDs.

Determination method for nitromethane in workplace air.

OBJECTIVES: The purpose of this research was to develop a determination method for nitromethane (NM) in workplace air for risk assessment. METHODS: A suitable sampler and appropriate desorption condition were selected by a recovery test in which a spiked sampler was used. The characteristics of the proposed method, such as recovery, detection limit, and reproducibility, and the storage stability of the sample were examined. RESULTS: A sampling tube containing bead-shaped activated carbon was chosen as the sampler. NM in the sampler was desorbed with acetone and analyzed by a gas chromatograph equipped with a flame ionization detector. The recoveries of NM from the spiked sampler were 81-97% and 80-98% for personal exposure monitoring and working environment measurement, respectively. On the first day of storage in a refrigerator, the recovery from the spiked samplers exceeded 90%; however, it decreased dramatically with increasing storage time. In particular, the decrease was more remarkable for the smaller spiked amounts. The overall LOQ was 2 microg/sample. The relative standard deviation, which represents the overall reproducibility, was 1.1-4.0%. CONCLUSIONS: The proposed method enables 4-hour personal exposure monitoring of NM at concentrations equaling 0.001-2 times the threshold limit value-time-weighted average (TLV-TWA: 20 ppm) proposed by the American Conference of Governmental Industrial Hygienists, as well as 10-minute working environment measurement at concentrations equaling 0.02-2 times TLV-TWA. Thus, the proposed method will be useful for estimating worker exposure to NM.

Treatment of Parkinson's disease model mice with allogeneic embryonic stem cells: necessity of immunosuppressive treatment for sustained improvement.

OBJECTIVE: The purpose of the present study was to examine the efficacy of transplantation of mouse embryonic stem (ES) into Parkinson's disease (PD) model mice as well as the necessity of immunosuppression in allogeneic donor-host combinations. MATERIALS AND METHODS: ES cells, derived from SvJ129 strain mice, were differentiated into tyrosine hydroxylase (TH)-positive neurons in vitro by an embryoid body (EB)-based multistep differentiation method and used as graft cells for PD mice, which were prepared by injection of 6-hydroxydopamine (OHDA) into C57BL/6, BALB/c and C3H/HeN strains. Mice from each strain were divided into Groups 1-3. Four weeks after the 6-OHDA injection, Group 1 received phosphate-buffered saline in the striatum wounds, while Group 2 received 2 x 10(4) graft cells, and Group 3 mice received 2 x 10(4) graft cells and were also treated with cyclosporine A. RESULTS: Apomorphine-induced rotational behavior was improved in Groups 2 and 3, but not in Group 1. However, the behavioral improvement ceased later in Group 2, whereas sustained improvement was observed in Group 3 throughout the 8 week observation period after transplantation. ES-derived TH(+) cells were found at the grafted sites at the end of the experiment in Groups 2 and 3, and tended to be more abundant in Group 3. CONCLUSION: Intra-striatum transplantation of ES-derived dopaminergic neurons was effective in treating PD mice, even in allogeneic donor-host combinations. Immunosuppressive treatment did not have an effect on initial behavioral restoration after transplantation; however, it was necessary for sustained improvement over a prolonged period.

Meltrin beta expressed in cardiac neural crest cells is required for ventricular septum formation of the heart.

The heart is divided into four chambers by membranous septa and valves. Although evidence suggests that formation of the membranous septa requires migration of neural crest cells into the developing heart, the functional significance of these neural crest cells in the development of the endocardial cushion, an embryonic tissue that gives rise to the membranous appendages, is largely unknown. Mice defective in the protease region of Meltrin beta/ADAM19 show ventricular septal defects and defects in valve formation. In this study, by expressing Meltrin beta in either endothelial or neural crest cell lineages, we showed that Meltrin beta expressed in neural crest cells but not in endothelial cells was required for formation of the ventricular septum and valves. Although Meltrin beta-deficient neural crest cells migrated into the heart normally, they could not properly fuse the right and left ridges of the cushion tissues in the proximal outflow tract (OT), and this led to defects in the assembly of the OT and AV cushions forming the ventricular septum. These results genetically demonstrated a critical role of cardiac neural crest cells expressing Meltrin beta in triggering fusion of the proximal OT cushions and in formation of the ventricular septum.

Impaired fatty acid utilization in thioredoxin binding protein-2 (TBP-2)-deficient mice: a unique animal model of Reye syndrome.

Thioredoxin binding protein-2 (TBP-2) is a negative regulator of thioredoxin and has multiple regulatory functions in cellular redox, growth, differentiation, apoptosis, and aging. To investigate the function of TBP-2 in vivo, we generated mice with targeted inactivation of TBP-2 (TBP-2-/- mice). Here, we show that TBP-2 expression is markedly up-regulated during fasting in wild-type mice, while TBP-2-/- mice were predisposed to death with bleeding tendency, as well as hepatic and renal dysfunction as a result of 48 h of fasting. The fasting-induced death was rescued by supplementation of glucose but not by that of oleic acid, suggesting that inability of fatty acid utilization plays an important role in the anomaly of TBP-2-/- mice. In these mice, plasma free fatty acids levels are higher, whereas glucose levels are lower than those of wild-type mice. Compared with wild-type mice, TBP-2-/- mice showed increased levels of plasma ketone bodies, pyruvate and lactate, indicating that Krebs cycle-mediated fatty acid utilization is impaired. Because the fatal impairment of fatty acid utilization is a characteristically metabolic feature of Reye (-like) syndrome, TBP-2-/- mouse may represent a novel model for investigating the pathophysiology of these disorders.

Partial correction of abnormal cardiac development in caspase-8-deficient mice by cardiomyocyte expression of p 35.

Baculovirus p 35 protein protects cells from apoptotic cell death by inhibiting caspase activation. We have established transgenic mouse lines specifically expressing p 35 in cardiomyocytes, and primary cardiomyocytes isolated from these mice exhibit resistance to staurosporine-induced apoptosis. In a previous study, we observed defects in heart formation associated with abdominal hemorrhage and cardiomyocyte cell death in caspase-8-deficient animals. In order to better understand the etiology of the cardiac defects and embryonic lethality in caspase-8-deficient mice, we crossed these mice with the p 35 transgenic animals. Although the newly generated mice still died in utero and exhibited some cardiac defects, cardiomyocyte apoptosis was suppressed and ventricular trabeculation was restored. Thus, cardiomyocyte expression of p 35 prevented cell death induced by staurosporine or caspase-8 deficiency. Additionally, our data suggest that caspase-8 plays multiple roles in cardiac development.

HSF4 is required for normal cell growth and differentiation during mouse lens development.

The heat shock transcription factor (HSF) family consists of three members in mammals and regulates expression of heat shock genes via a heat shock element. HSF1 and HSF2 are required for some developmental processes, but it is unclear how they regulate these processes. To elucidate the mechanisms of developmental regulation by HSFs, we generated mice in which the HSF4 gene is mutated. HSF4-null mice had cataract with abnormal lens fiber cells containing inclusion-like structures, probably due to decreased expression of gamma-crystallin, which maintains protein stability. Furthermore, we found increased proliferation and premature differentiation of the mutant lens epithelial cells, which is associated with increased expression of growth factors, FGF-1, FGF-4, and FGF-7. Unexpectedly, HSF1 competed with HSF4 for the expression of FGFs not only in the lens but also in other tissues. These findings reveal the lens-specific role of HSF4, which activates gamma-crystallin genes, and also indicate that HSF1 and HSF4 are involved in regulating expression of growth factor genes, which are essential for cell growth and differentiation.

Activation of heat shock genes is not necessary for protection by heat shock transcription factor 1 against cell death due to a single exposure to high temperatures.

Heat shock response, which is characterized by the induction of a set of heat shock proteins, is essential for induced thermotolerance and is regulated by heat shock transcription factors (HSFs). Curiously, HSF1 is essential for heat shock response in mammals, whereas in avian HSF3, an avian-specific factor is required for the burst activation of heat shock genes. Amino acid sequences of chicken HSF1 are highly conserved with human HSF1, but those of HSF3 diverge significantly. Here, we demonstrated that chicken HSF1 lost the ability to activate heat shock genes through the amino-terminal domain containing an alanine-rich sequence and a DNA-binding domain. Surprisingly, chicken and human HSF1 but not HSF3 possess a novel function that protects against a single exposure to mild heat shock, which is not mediated through the activation of heat shock genes. Overexpression of HSF1 mutants that could not bind to DNA did not restore the susceptibility to cell death in HSF1-null cells, suggesting that the new protective role of HSF1 is mediated through regulation of unknown target genes other than heat shock genes. These results uncover a novel role of vertebrate HSF1, which has been masked under the roles of heat shock proteins.