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Propofol has addictive properties, even with a single administration, and facilitates dopamine secretion in the nucleus accumbens (NAc). Activation of the dopaminergic circuits of the midbrain reward system, including the ventral tegmental area (VTA) and NAc, plays a crucial role in addiction. However, the effects of propofol on synaptic transmission and biochemical changes in the VTA-NAc circuit remain unclear.We investigated the effects of subanesthetic doses of propofol on rat VTA neurons and excitatory synaptic transmission in the NAc using slice patch-clamp experiments. Using immunohistochemistry and western blot analyses, we evaluated the effects of intraperitoneal propofol administration on the expression of addiction-associated transcription factor ΔFosB (truncated form of the FBJ murine osteosarcoma viral oncogene homolog B protein) in the NAcs in 5-week-old rats.In the current-clamp mode, a subanesthetic dose (0.5-5 µmol/L) of propofol increased the action potential frequency in about half the VTA neurons (excited neurons: control: 9.4 ± 3.0 Hz, propofol 0.5 µmol/L: 21.5 ± 6.0 Hz, propofol 5 µmol/L: 14.6 ± 5.3 Hz, wash: 2.0 ± 0.7 Hz, n = 14/27 cells; unchanged/suppressed neurons: control: 1.68 ± 0.94 Hz, propofol 0.5 µmol/L: 1.0 ± 0.67 Hz, propofol 5 µmol/L: 0.89 ± 0.87 Hz, wash: 0.16 ± 0.11 Hz, n = 13/27 cells). In the voltage-clamp mode, about half the VTA principal neurons showed inward currents with 5 µmol/L of propofol (inward current neurons: control: -20.5 ± 10.0 pA, propofol 0.5 µmol/L: -62.6 ± 14.4 pA, propofol 5 µmol/L: -85.2 ± 18.3 pA, propofol 50 µmol/L: -17.1 ± 39.2 pA, washout: +30.5 ± 33.9 pA, n = 6/11 cells; outward current neurons: control: -33.9 ± 14.6 pA, propofol 0.5 µmol/L: -29.5 ± 16.0 pA, propofol 5 µmol/L: -0.5 ± 20.9 pA, propofol 50 µmol/L: +38.9 ± 18.5 pA, washout: +40.8 ± 32.1 pA, n = 5/11 cells). Moreover, 0.5 µmol/L propofol increased the amplitudes of evoked excitatory synaptic currents in the NAc, whereas5 µmol/L propofol decreased them (control: 100.0 ± 2.0%, propofol 0.5 µmol/L: 118.4 ± 4.3%, propofol 5 µmol/L: 98.3 ± 3.3%, wash [within 10 min]: 70.7 ± 3.3%, wash [30 minutes later]: 89.9 ± 2.5%, n = 13 cells, P.001, Dunnett's test comparing control and propofol 0.5 µmol/L). Intraperitoneally administered subanesthetic dose of propofol increased ΔFosB expression in the NAc, but not in VTA, 2 and 24 hours after administration, compared with the Intralipid control group (propofol 2 hours: 0.94 ± 0.15, 24 hours: 0.68 ± 0.07; Intralipid 2 hours: 0.40 ± 0.03, 24 hours: 0.37 ± 0.06, P = .0002 for drug in the 2-way analysis of variance).Even a single administration of a subanesthetic dose of propofol may cause rewarding change in the central nervous system. Thus, there is a potential propofol rewarding effect among patients receiving anesthesia or sedation with propofol, as well as among health care providers exposed to propofol.

Objectives:We aimed to investigate whether whole-body CT for children with trauma is associated with a different mortality than only selective CT.Design:A multicenter, retrospective cohort study.Setting:Nationwide trauma registry from 183 tertiary emergency medical centers in Japan.Patients:We enrol

We investigated the clinical course of individuals with 2019 novel coronavirus disease (COVID-19) who were transferred from the Diamond Princess cruise ship to 12 local hospitals. The conditions and clinical courses of patients with pneumonia were compared with those of patients without pneumonia. Among 70 patients (median age: 67 years) analyzed, the major symptoms were fever (64.3%), cough (54.3%), and general fatigue (24.3%). Forty-three patients (61.4%) had pneumonia. Higher body temperature, heart rate, and respiratory rate as well as higher of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and C-reactive protein (CRP) levels and lower serum albumin level and lymphocyte count were associated with the presence of pneumonia. Ground-glass opacity was found in 97.7% of the patients with pneumonia. Patients were administered neuraminidase inhibitors (20%), lopinavir/ritonavir (32.9%), and ciclesonide inhalation (11.4%). Mechanical ventilation and veno-venous extracorporeal membrane oxygenation was performed on 14 (20%) and 2 (2.9%) patients, respectively; two patients died. The median duration of intubation was 12 days. The patients with COVID-19 transferred to local hospitals during the outbreak had severe conditions and needed close monitoring. The severity of COVID-19 depends on the presence of pneumonia. High serum LDH, AST and CRP levels and low serum albumin level and lymphocyte count were found to be predictors of pneumonia. It was challenging for local hospitals to admit and treat these patients during the outbreak of COVID-19. Assessment of severity was crucial to manage a large number of patients.

We aimed to determine the association between the intensive care unit (ICU) model and in-hospital mortality of patients with severe sepsis and septic shock. This was a secondary analysis of a multicenter prospective observational study conducted in 59 ICUs in Japan from January 2016 to March 2017. We included adult patients (aged ≥16 years) with severe sepsis and septic shock based on the sepsis-2 criteria who were admitted to an ICU with a 1:2 nurse-to-patient ratio per shift. Patients were categorized into open or closed ICU groups, according to the ICU model. The primary outcome was in-hospital mortality. A total of 1018 patients from 45 ICUs were included in this study. Patients in the closed ICU group had a higher severity score and higher organ failure incidence than those in the open ICU group. The compliance rate for the sepsis care 3-h bundle was higher in the closed ICU group than in the open ICU group. In-hospital mortality was not significantly different between the closed and open ICU groups in a multilevel logistic regression analysis (odds ratio = 0.83, 95% confidence interval; 0.52–1.32, P = .43) and propensity score matching analysis (closed ICU, 21.2%; open ICU, 25.7%, P = .22). In-hospital mortality between the closed and open ICU groups was not significantly different after adjusting for ICU structure and compliance with the sepsis care bundle.

This multicentre, retrospective observational study was conducted from January 2010 to December 2010 to determine the optimal time for discontinuing continuous renal replacement therapy (CRRT) by evaluating factors predictive of successful discontinuation in patients with acute kidney injury. Analysis was performed for patients after CRRT was discontinued because of renal function recovery. Patients were divided into two groups according to the success or failure of CRRT discontinuation. In multivariate logistic regression analysis, urine output at discontinuation, creatinine level and CRRT duration were found to be significant variables (area under the receiver operating characteristic curve for urine output, 0.814). In conclusion, we found that higher urine output, lower creatinine and shorter CRRT duration were significant factors to predict successful discontinuation of CRRT.

Background Information on epidemiology of prolonged mechanical ventilation (PMV) patients in the acute care setting in Japan is totally lacking. We aimed to investigate clinical features, impact, and long-term outcomes of PMV patients. Methods This was a retrospective observational study conducted in a tertiary care hospital. Adult patients who were admitted to our intensive care unit (ICU) from April 2009 to March 2014 and required mechanical ventilation (MV) for ≥ 2 days were included. PMV was defined as having MV for ≥ 21 consecutive days. Results Among 1282 MV patients, 93 (7.3%) required PMV, and median duration of MV was 37.0 days. Compared with the non-PMV patients, PMV patients had longer total ICU and high care unit (HCU) stay (34.0 vs. 7.0 days, p p p Conclusion In this investigation, 7.3% of the patients with MV required PMV. Most PMV patients were liberated from MV during hospitalization, while occupying critical care beds for an extended period. A nationwide survey is required to further elucidate the overall picture of PMV patients and to discuss whether specialized weaning centers to treat PMV patients are required in Japan.

Background Accurate and early identification of infection sites might help to drive crucial decisions regarding the treatment of sepsis. We aimed to determine the clinical and etiological features of infection according to sites among patients with severe sepsis in Japan. Methods This secondary analysis of a multicenter, prospective cohort study included 59 intensive care units (ICU) and proceeded between January 2016 and March 2017. The study cohort comprised 1184 adults (≥ 16 years) who were admitted to an ICU with severe sepsis and septic shock diagnosed according to the sepsis-2 criteria. Sites of infection diagnosed by physicians in charge at the time of arrival comprised the lung, abdomen, urinary tract, soft tissue, bloodstream, central nervous system (CNS), and undifferentiated infections. The primary outcome was in-hospital mortality. Results The most common sites of infection were the lungs (31.0%), followed by intra-abdominal sites (26.3%), the urinary tract (18.4%), and soft tissue (10.9%). The characteristics of the patients with severe sepsis across seven major suspected infection sites were heterogeneous. Septic shock was more frequent among patients with intra-abdominal (72.2%) and urinary tract (70.2%) infections than other sites. The in-hospital mortality rate due to severe sepsis and septic shock of a pooled sample was 23.4% (range, 11.9% [urinary tract infection] to 47.6% [CNS infection]). After adjusting for clinical background, sepsis severity, and stratification according to the presence or absence of shock, variations in hospital mortality across seven major sites of infection remained essentially unchanged from those for crude in-hospital mortality; adjusted in-hospital mortality rates ranged from 7.7% (95%CI, − 0.3 to 15.8) for urinary tract infection without shock to 58.3% (95%CI, 21.0–95.7) for CNS infection with shock in a generalized estimating equation model. Intra-abdominal and urinary tract infections were statistically associated with less in-hospital mortality than pneumonia. Infections of the CNS were statistically associated with higher in-hospital mortality rates than pneumonia in a logistic regression model, but not in the generalized estimating equation model. Conclusions In-hospital mortality and clinical features of patients with severe sepsis and septic shock were heterogeneous according to sites of infection. Electronic supplementary material The online version of this article (10.1186/s40560-019-0383-3) contains supplementary material, which is available to authorized users.

OBJECTIVE To study the hospital mortality of patients with severe acute kidney injury treated with low-intensity continuous renal replacement therapy. DESIGN Multicenter retrospective observational study (Japanese Society for Physicians and Trainees in Intensive Care), combined with previously conducted multinational prospective observational study (Beginning and Ending Supportive Therapy). SETTING Fourteen Japanese ICUs in 12 tertiary hospitals (Japanese Society for Physicians and Trainees in Intensive Care) and 54 ICUs in 23 countries (Beginning and Ending Supportive Therapy). PATIENTS Consecutive adult patients with severe acute kidney injury requiring continuous renal replacement therapy admitted to the participating ICUs in 2010 (Japanese Society for Physicians and Trainees in Intensive Care, n = 343) and 2001 (Beginning and Ending Supportive Therapy Beginning and Ending Supportive Therapy, n = 1,006). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patient characteristics, variables at continuous renal replacement therapy initiation, continuous renal replacement therapy settings, and outcomes (ICU and hospital mortality and renal replacement therapy requirement at hospital discharge) were collected. Continuous renal replacement therapy intensity was arbitrarily classified into seven subclasses: less than 10, 10-15, 15-20, 20-25, 25-30, 30-35, and more than 35 mL/kg/hr. Multivariable logistic regression analysis was conducted to investigate risk factors for hospital mortality. The continuous renal replacement therapy dose in the Japanese Society for Physicians and Trainees in Intensive Care database was less than half of the Beginning and Ending Supportive Therapy database (800 mL/hr vs 2,000 mL/hr, p < 0.001). Even after adjusting for the body weight and dilution factor, continuous renal replacement therapy intensity was statistically different (14.3 mL/kg/hr vs 20.4 mL/kg/hr, p < 0.001). Patients in the Japanese Society for Physicians and Trainees in Intensive Care database had a lower ICU mortality (46.1% vs 55.3%, p = 0.003) and hospital mortality (58.6% vs 64.2%, p = 0.070) compared with patients in the Beginning and Ending Supportive Therapy database. In multivariable regression analysis after combining the two databases, no continuous renal replacement therapy intensity subclasses were found to be statistically different from the reference intensity (20-25 mL/kg/hr). Several sensitivity analyses (patients with sepsis, patients from Western countries in the Beginning and Ending Supportive Therapy database) confirmed no intensity-outcome relationship. CONCLUSIONS Continuous renal replacement therapy at a mean intensity of 14.3 mL/kg/hr did not have worse outcome compared with 20-25 mL/kg/hr of continuous renal replacement therapy, currently considered the standard intensity. However, our study is insufficient to support the use of low-intensity continuous renal replacement therapy, and more studies are needed to confirm our findings.

The fibrotic scar formed after central nervous system injury has been considered an obstacle to axonal regeneration. The present study was designed to examine whether cell transplantation into a damaged central nervous system can reduce fibrotic scar formation and promote axonal regeneration. Nigrostriatal dopaminergic axons were unilaterally transected in rats and cultures of olfactory-ensheathing cells (OECs), and olfactory nerve fibroblasts were transplanted into the lesion site. In the absence of transplants, few tyrosine hydroxylase-immunoreactive axons extended across the lesion 2 weeks after the transection. Reactive astrocytes increased around the lesion, and a fibrotic scar containing type IV collagen deposits developed in the lesion center. The immunoreactivity of chondroitin sulfate side chains and core protein of NG2 proteoglycan increased in and around the lesion. One and 2 weeks after transection and simultaneous transplantation, dopaminergic axons regenerated across the transplanted tissues, which consisted of p75-immunoreactive OECs and fibronectin-immunoreactive fibroblasts. Reactive astrocytes and chondroitin sulfate immunoreactivity increased around the transplants, whereas the deposition of type IV collagen and fibrotic scar formation were completely prevented at the lesion site. Transplantation of meningeal fibroblasts similarly prevented the formation of the fibrotic scar, although its effect on regeneration was less potent than transplantation of OECs and olfactory nerve fibroblasts. The present results suggest that elimination of the inhibitory fibrotic scar is important for neural regeneration.

The authors previously demonstrated that isoflurane, a widely used volatile anesthetic, induced depolarization and increased the frequency of spontaneous action potentials in principal dopamine neurons in rat substantia nigra pars compacta. We studied the effects of isoflurane on voltage-dependent K channels to clarify the mechanisms of the increase in excitability in these neurons. Voltage-clamp whole-cell recordings were made in rat midbrain slices. We recorded the outward membrane currents in response to depolarizing voltage steps from -120 mV and -25 mV and isolated the transient outward current mediated through A-type K channels by subtraction. Isoflurane at clinically relevant concentrations accelerated the decay of the A-type K current and delayed the recovery from inactivation without changing the steady-state inactivation curves. Isoflurane did not affect the non-inactivating outward current. Addition of 4-aminopyridine partially occluded the excitatory effects of isoflurane in current-clamp recordings. These results demonstrate that isoflurane accelerated the inactivation and delayed the recovery from inactivation of A-type K channels in principal neurons in rat substantia nigra pars compacta without affecting delayed rectifier K channels. These effects may contribute in part to excitation of these neurons and the isoflurane-induced increases in dopamine release reported in vitro and in vivo.

Background/Aims: Acute kidney injury (AKI) is associated with high mortality. Multiple AKI severity scores have been derived to predict patient outcome. We externally validated new AKI severity scores using the Japanese Society for Physicians and Trainees in Intensive Care (JSEPTIC) database. Methods: New AKI severity scores published in the 21st century (Mehta, Stuivenberg Hospital Acute Renal Failure (SHARF) II, Program to Improve Care in Acute Renal Disease (PICARD), Vellore and Demirjian), Liano, Simplified Acute Physiology Score (SAPS) II and lactate were compared using the JSEPTIC database that collected retrospectively 343 patients with AKI who required continuous renal replacement therapy (CRRT) in 14 intensive care units. Accuracy of the severity scores was assessed by the area under the receiver-operator characteristic curve (AUROC, discrimination) and Hosmer-Lemeshow test (H-L test, calibration). Results: The median age was 69 years and 65.8% were male. The median SAPS II score was 53 and the hospital mortality was 58.6%. The AUROC curves revealed low discrimination ability of the new AKI severity scores (Mehta 0.65, SHARF II 0.64, PICARD 0.64, Vellore 0.64, Demirjian 0.69), similar to Liano 0.67, SAPS II 0.67 and lactate 0.64. The H-L test also demonstrated that all assessed scores except for Liano had significantly low calibration ability. Conclusions: Using a multicenter database of AKI patients requiring CRRT, this study externally validated new AKI severity scores. While the Demirjian's score and Liano's score showed a better performance, further research will be required to confirm these findings.

To identify structures that determine the 90° orientation of thin espalier dendritic trees of Purkinje cells with respect to parallel fibers (axonal neurite bundles of granule cells) in the cerebellar cortex, we designed five types of two-dimensional and three-dimensional cell and tissue cultures of cerebella from postnatal mice and analyzed the orientation of Purkinje cell dendrites with respect to neurite bundles and astrocyte fibers by immunofluorescence double or triple staining. We cultured dissociated cerebellar cells on micropatterned substrates and preformed neurite bundles of a microexplant culture two-dimensionally and in matrix gels three-dimensionally. Dendrites, but not axons, of Purkinje cells extended toward the neurites of granule cells and oriented at right angles two-dimensionally to aligned neurite bundles in the three cultures. In a more organized explant proper of the microexplant culture, Purkinje cell dendrites extended toward thin aligned neurite bundles not only consistently at right angles but also two-dimensionally. However, in the “organotypic microexplant culture,” in which three-dimensionally aligned thick neurite bundles mimicking parallel fibers were produced, Purkinje cell dendrites often oriented perpendicular to the thick bundles three-dimensionally. Astrocytes were abundant in all cultures, and there was no definite correlation between the presence of and orientation to Purkinje cell dendrites, although their fibers were frequently associated in parallel with dendrites in the organotypic microexplant culture. Therefore, Purkinje cells may grow their dendrites to the newly produced neurite bundles of parallel fibers in the cerebellar cortex and be oriented at right angles three-dimensionally mainly via “perpendicular contact guidance.” J. Comp. Neurol. 499:274–289, 2006. © 2006 Wiley-Liss, Inc.

Thyroid hormones (THs) are important for brain development, and polychlorinated biphenyl (PCB) accumulation in humans is a serious problem because PCBs may affect TH functions. To determine the effects of hydroxylated metabolites of PCBs (OH-PCBs) on brain development, we performed mouse cerebellar culture assays. 4-OH-2',3,3',4',5'-pentachlorobiphenyl and 4-OH-2',3,3',4',5,5'-hexachlorobiphenyl significantly inhibited the TH-dependent extension of Purkinje cell dendrites even at 5 x 10(-11) M and 5 x 10(-12) M, respectively. OH-PCBs may disturb TH-dependent brain development.

ObjectivesTrauma is one of the main causes of death in Japan, and treatments and prognoses of these injuries are constantly changing. We therefore aimed to investigate a 10-year trend (2004–2013) in inhospital mortality among patients with trauma in Japan.DesignMulticentre observational study.SettingJapanese nationwide trauma registry (the Japan Trauma Data Bank) data.ParticipantsAll patients with trauma whose Injury Severity Score (ISS) were 3 and above, who were aged 15 years or older, and whose mechanisms of injury (MOI) were blunt and penetrating between 2004 and 2013 (n=90 833).Outcome measuresA 10-year trend in inhospital mortality.ResultsInhospital mortality for all patients with trauma significantly decreased over the study decade in our Cochran-Armitage test (PConclusionInhospitalmortality for patients with trauma in Japan significantly decreased during the study decade after adjusting for patient characteristics, injury severity and the response environment after injury.

Using a well-defined medium with insulin, transferrin and selenium but without serum and albumin, we quantitatively determined the effect of thyroid hormones on the development of Purkinje cells in mouse cerebellar monolayer cultures. Addition of a thyroid hormone, T3 or T4, to the serum-free medium resulted in a highly elaborate dendritic development of Purkinje cells. The cultured Purkinje cells in the presence of T4 even showed similarities in shape and in synapse formation to normal Purkinje cells in vivo. Such effect of T4 on the dendritic arborization of Purkinje cells was dose dependent and significantly sensitive to a low dose of T4 even at 50 pM. The effect of T4 was confirmed by an inhibition experiment using amiodarone, which was reported to induce thyroid dysfunction. Furthermore, T4 affected not only Purkinje cell development but also the shape of other neural cells such as small interneurons (mainly granule cells) and astrocytes in cerebellar cultures. T4 induced development of both interneurons and astrocytes having long processes. These results indicate that thyroid hormones play a pivotal role in the development of mouse Purkinje cell dendrites acting on Purkinje cells directly and/or indirectly via the close interaction with interneurons and astrocytes.

The carboxy-terminal globular domain (G-domain) of the laminin alpha1 chain has been shown to promote heparin binding, cell adhesion, and neurite outgrowth. In this study, we defined the potential sequences originating from the G-domain of laminin alpha1 chain which possess these functional activities. A series of peptides were synthesized from the G-domain, termed LG peptides (LG-1 to LG-6) and were tested for their various biological activities. In the direct [3H] heparin binding assays, LG-6 (residues 2,335-2,348: KDFLSIELVRGRVK) mediated high levels of [3H]heparin binding, and this peptide also directly promoted cell adhesion and spreading, including B16F10, M2, HT1080, and PC12 cells. The peptide LG-6 also promoted the neurite outgrowth of PC12 cells, mouse granule cells, and chick telencephalic cells. An anti-peptide LG-6 antibody inhibited laminin-1 and peptide LG-6-mediated cell adhesion and neurite outgrowth. Furthermore, an anti-integrin alpha2 antibody also inhibited the cell adhesion activity. These results suggest that peptide LG-6 plays a functional role as a heparin binding site in the G-domain of the laminin alpha1 chain, and this sequence was thus concluded to play a crucial role in regulating cell adhesion and spreading and neurite out-growth which is related to integrin alpha2.

To elucidate the molecular mechanisms that regulate the maturation of action potential, we began by examining voltage-dependent K+ currents, known to contribute to the maturation of action potential, of developing granule cells in mouse cerebellar microexplant cultures. The migration of developing granule cells in this culture is reported to mimic the in vivo process, but their specific identification is still incomplete. In this study, we identified and characterized granule cells in this culture. Immunocytochemical analysis found that granule cells migrated radially out from explants and subsequently formed small clusters and also that their morphology changed from a bipolar to a T shape during migration. Moreover, in the electrophysiological study, the GABA response of granule cells in this culture clarified that the electrophysiological properties of granule cells were normally maintained. We therefore have concluded, that this culture system is a powerful tool for investigating the differentiation of cerebellar granule cells. Based on these findings, we recorded voltage-dependent K+ currents of developing granule cells in this culture, while concurrently observing their morphology. Our results show that voltage-dependent K+ currents of developing granule cells change from delayed rectifier to A current in parallel with their morphological changes from bipolar to T-shaped cells.

This study aimed to identify factors that may predict early kidney recovery (less than 48 hours) or early death (within 48 hours) after initiating continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) patients. This is a multicenter retrospective observational study of 14 Japanese Intensive care units (ICUs) in 12 tertiary hospitals. Consecutive adult patients with severe AKI requiring CRRT admitted to the participating ICUs in 2010 (n=343) were included. Patient characteristics, variables at CRRT initiation, settings, and outcomes were collected. Patients were grouped into early kidney recovery group (CRRT discontinuation within 48 hours after initiation, n=52), early death group (death within 48 hours after CRRT initiation, n=52), and the rest as the control group (n=239). The mean duration of CRRT in the early kidney recovery group and early death group was 1.3 and 0.9 days, respectively. In multivariable regression analysis, in comparison with the control group, urine output (mL/h) (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.03), duration between ICU admission to CRRT initiation (days) (OR: 0.65, 95% CI: 0.43-0.87), and the sepsis-related organ failure assessment score (OR: 0.87, 95% CI; 0.78-0.96) were related to early kidney recovery. Serum lactate (mmol/L) (OR: 1.19, 95% CI: 1.11-1.28), albumin (g/dL) (OR: 0.52, 95% CI: 0.28-0.92), vasopressor use (OR: 3.68, 95% CI: 1.37-12.16), and neurological disease (OR: 9.64, 96% CI: 1.22-92.95) were related to early death. Identifying AKI patients who do not benefit from CRRT and differentiating such patients from the study cohort may allow previous and future studies to effectively evaluate the indication and role of CRRT.

This study aimed to identify factors that may predict early kidney recovery (less than 48 hours) or early death (within 48 hours) after initiating continuous renal replacement therapy (CRRT) in acute kidney injury (AKI) patients. This is a multicenter retrospective observational study of 14 Japanese Intensive care units (ICUs) in 12 tertiary hospitals. Consecutive adult patients with severe AKI requiring CRRT admitted to the participating ICUs in 2010 (n=343) were included. Patient characteristics, variables at CRRT initiation, settings, and outcomes were collected. Patients were grouped into early kidney recovery group (CRRT discontinuation within 48 hours after initiation, n=52), early death group (death within 48 hours after CRRT initiation, n=52), and the rest as the control group (n=239). The mean duration of CRRT in the early kidney recovery group and early death group was 1.3 and 0.9 days, respectively. In multivariable regression analysis, in comparison with the control group, urine output (mL/h) (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.03), duration between ICU admission to CRRT initiation (days) (OR: 0.65, 95% CI: 0.43-0.87), and the sepsis-related organ failure assessment score (OR: 0.87, 95% CI; 0.78-0.96) were related to early kidney recovery. Serum lactate (mmol/L) (OR: 1.19, 95% CI: 1.11-1.28), albumin (g/dL) (OR: 0.52, 95% CI: 0.28-0.92), vasopressor use (OR: 3.68, 95% CI: 1.37-12.16), and neurological disease (OR: 9.64, 96% CI: 1.22-92.95) were related to early death. Identifying AKI patients who do not benefit from CRRT and differentiating such patients from the study cohort may allow previous and future studies to effectively evaluate the indication and role of CRRT.

Background Measures of aortic occlusion (AO) for resuscitation in patients with severe torso trauma remain controversial. Our aim was to characterize the current use of resuscitative endovascular balloon occlusion of the aorta (REBOA) and resuscitative open aortic cross-clamping (ACC), and to evaluate whether REBOA should be an alternative method to resuscitative open ACC. Methods This study was a retrospective cohort study between 2004 and 2013 from a nationwide trauma registry in Japan. Participants were selected who underwent either REBOA or ACC. Their characteristics, interventions, and outcomes were analyzed to compare REBOA and ACC directly. The primary outcome was in-hospital mortality and the secondary outcome was mortality in the emergency department. Logistic regression analysis was performed to compare the outcomes between REBOA and ACC with adjustment for severity; 1:1 propensity score matching was also performed. Results Of the 159,157 trauma patients, 903 were eligible based on the selection criteria. Overall, 405/607 patients (67%) who had REBOA died compared to 210/233 patients (90%) who had ACC. Patients with REBOA had higher revised trauma score (RTS) (mean ± SD, 5.2 ± 2.0 vs. 4.2 ± 2.2; P

The Ministry of Health, Labour and Welfare and the Heatstroke STUDY 20082010 regarding the characteristics of laborers who suffered and died from heatstroke demonstrated the involvement of more laborers who worked in construction, from July to August and at around 3 p.m. Also, more laborers who worked at around 11 a.m. got heatstroke, and there were more laborers who died from it within 1 week from starting to work. The results showed that the heat environment and the time and period when laborers started to be exposed to a hot environment adversely effect the development of heatstroke and subsequent heatstroke-related death. It is important to estimate and take measures against a hot environment and to make time to be acclimated to a hot environment.

Granule cells were dissociated from early postnatal mouse cerebella and labeled with a fluorescent dye probe PKH26. Small number of the labeled cells were mixed with cerebellar cortical microexplant cultures or transplanted into cerebellar cortical organotypic explants, and their time-dependent morphological changes during cultures were examined with fluorescence microscopy. Granule cell neurons first extended asymmetrical short bipolar processes in both cultures, and migrated actively in microexplant cultures. After elongation of symmetrically bipolar long and thin neurites, they sprouted short thick processes from cell bodies and migrated perpendicular to neurite bundles that were devoid of glia in microexplant cultures, or migrated vertically inward into the internal granular layer in the organotypic explant. During such migrations, they extended short thick processes in front and thin processes behind the cell body. The latter processes were connected to thin long neurites with T- or Y-shaped junctions in both cultures. Finally, they extended many short thick processes from cell bodies in both cultures. Such behaviors of granule cell neurons in microexplant cultures were, thus, similar to those in organotypic explant cultures despite of the absence of Bergmann glial cells. These migration patterns may be closely related to migration of granule cells in histogenesis of the cerebellar cortex.

We examined the fine structure of migrating granule cell neurons in cerebellar microexplant cultures. Radially migrating bipolar cells extended microspikes or small filopodia from their soma and processes and frequently made contact with neighboring cells. These microspikes contained microfilaments but no microtubules. At the later phase of the migration, in which they had symmetrical bipolar long processes, filopodia extending from perikarial region of cells contained microtubules, suggesting that they are precursors of the future thick perpendicular processes. When cell bodies changed orientation from radial to perpendicular, microtubules that were nucleated from perinuclear centrioles frequently extended into both thick radial and perpendicular processes from the perikarial region. Bundles of 10nm intermediate filaments also appeared in these processes. During migration by the perpendicular contact guidance, many filopodia extending from both the thick leading processes and thin trailing processes made close contacts with the radial parallel neurite. These findings suggest that; 1) The direct contact of the filopodia from both the growth cones and their processes of the granule cells to the neurite bundle plays roles in both the parallel and perpendicular contact guidances. 2) The spacial and temporal changes of cytoskeletons and the association of microtubules with perinuclear centrioles are important for the formation of perpendicular processes and initiation of the perpendicular contact guidance.

In order to study roles of the extracellular matrix (ECM) in the cerebellar granule cell migration, cerebellar microexplants of neonatal to postnatal 11-day-old mice were cultured on 3 kinds of substrata, poly- l -lysine (PL), PL/fibronectin and PL/laminin. A prominent outgrowth of small granule cells, which did not uptake GABA, was observed only on the PL/laminin substratum. The granule cells showed the following sequence of events: (1) Many polygonal undifferentiated cells migrated out from the microexplants. These blast cells differentiated into small bipolar neurons with long fine neurites which extended radially from the explants. (2) These cells then changed their orientation perpendicular to their radial neurites, by protruding a short process from the cell body at right angles. (3) Finally, cell bodies of these granule cells adhered to each other to form cell aggregates. Quantitative labelings by bromodeoxyuridine revealed that there were less mitotic cells in explants from the later postnatal cerebella compared to the earlier postnatal ones. Anti-MAP2 immunoreactivity was localized in short perpendicular processes of the aggregated granule cells. Thus, this unique cell behavior exhibited on the PL/laminin substratum provides the first defined experimental system for studying the granule cell differentiation in vitro.

Polychlorinated biphenyls (PCBs) and hydroxy-PCB (OH-PCB) metabolites are widely distributed bioaccumulative environmental chemicals and have similar chemical structures to those of thyroid hormones (THs). Previously, we reported that THs are essential for neuronal development and the low doses of two OH-PCBs, namely, 4-OH-2',3,3',4',5'-pentachlorobiphenyl (4'-OH-PeCB-106) and 4-OH-2',3,3',4',5,5'-hexachlorobiphenyl (4'-OH-HxCB-159), inhibited the TH-dependent dendritic development of Purkinje cells in mouse cerebellar cultures using serum-free defined medium. To determine which type of OH-PCBs affect neuronal development, we further examined several OH-PCBs and other estrogenic chemicals using this simple and sensitive assay system. Two-way ANOVA was used to assess the effects of OH-PCBs and other chemicals on both factors of their concentrations and with/without T4 in the assay of TH-dependent dendritic development of Purkinje cells. Aside from the two OH-PCBs, 4-OH-2',3,4',5,6'-pentachlorobiphenyl (4'-OH-PeCB-121) and bisphenol A significantly inhibited the TH-dependent dendritic development of Purkinje cells, whereas 4-OH-2',3,3',5',6'-pentachlorobiphenyl (4'-OH-PeCB-112), 4-OH-2',3,3',5,5',6'-hexachlorobiphenyl (4'-OH-HxCB-165), 4-OH-2,2',3,4',5,5',6-heptachlorobiphenyl (4-OH-HpCB-187), progesterone and nonylphenol did not induce any inhibition, but significantly promoted the dendritic extension of Purkinje cells in the absence of THs. Other estrogenic chemicals, including beta-estradiol, diethyl stilbestrol and p-octylphenol did not show significant inhibitory or promoting effects. From these results, it is suggested that exposure to OH-PCBs and other environmental chemicals may disrupt normal neuronal development and cause some developmental brain disorders, such as LD, ADHD, and autism.

Chondroitin sulfate is a long sulfated polysaccharide with enormous structural heterogeneity that binds with various proteins, such as growth factors, in a structure-dependent manner. In this study, we analyzed the expression of chondroitin sulfate in the postnatally developing cerebellar cortex by using three monoclonal antibodies against chondroitin sulfate, MO-225, 2H6, and CS-56, which recognize different structural domains in this polysaccharide. During the first postnatal week, the patterns of immunohistochemical staining made by these antibodies were quite similar, and the molecular layer, the granule cell layer, and Bergmann glial fibers in the external granular layer were densely stained. After postnatal day 12 (P12), the expression of 2H6 epitopes was down-regulated in the molecular layer, and the expression of CS-56 epitopes in this layer was also reduced after P16. On the other hand, the strong expression of MO-225 epitopes, GlcA(2S)β1–3GalNAc(6S) (D unit)-containing structures, remained until adulthood. These chondroitin sulfate epitopes were observed around Purkinje cells, including cell soma and dendrites. Detailed immunohistochemical analysis suggested that chondroitin sulfate was deposited between Purkinje cell surfaces and the processes of Bergmann glia. Furthermore, the amount of pleiotrophin, a heparin-binding growth factor, in the cultured cerebellar slices was remarkably diminished after treatment with chondroitinase ABC or D unit-rich chondroitin sulfate. With the previous findings that pleiotrophin binds to D unit-rich chondroitin sulfate, we suggest that the D-type structure is important for the signaling of pleiotrophin, which plays roles in Purkinje cell–Bergmann glia interaction, and that the structural changes of chondroitin sulfate regulate this signaling pathway. © 2005 Wiley-Liss, Inc.

We studied the expression of ganglioside antigens in primary cultures of rat cerebellum using an immunocytochemical technique with mouse monoclonal antibodies (MAbs) specific for various gangliosides. Twelve MAbs that specifically recognize each ganglioside were used. Our study revealed that there is a cell type-specific expression of ganglioside antigens in the primary cultures. A number of b-series gangliosides were detected in the granule cells, whereas a-series gangliosides were not intensely expressed. GD1b was detected in the granule cells. GD2 appeared to be present in a subset of the granule cells or a type of small neurons. GD3 was associated not only with the granule cells, but also with both astrocytes and oligodendrocytes. An O-Ac-disialoganglioside, which was suggested to be O-Ac-LD1, was restrictedly detected in Purkinje cells. The other gangliosides were not detected clearly in these cells. These results suggest that several gangliosides may be useful markers for identifying cells in primary cultures of the rat cerebellum; particularly b-series gangliosides such as GD2 and GD1b for the granule cells and O-Ac-LD1 for Purkinje cells.

The behaviors of neuroblasts of granule cell neurons and their precursor cells on a poly-L-lysine/laminin substratum were examined in cerebellar microexplant cultures from early postnatal reeler mutant and normal mice. The total numbers of migrating neuroblasts and their precursor cells or blast cells derived from the mutant cerebellum were markedly reduced in comparison with their normal counterparts. However, no difference was shown between these two strains in either the numbers of blast cells or neuroblasts that migrated from single explants. In addition, all behaviors examined, such as migration of neuroblasts and the proliferation of blast cells in culture were identical between both genotypes. Thus, behaviors of both granule cells and their precursors in the cerebellar cortex of reeler mutant mouse may be qualitatively identical to those of normal counterparts, but precursors of granule cells in the external germinal layer of the cerebellar cortex may be reduced in the reeler mouse.

Rodent CNS neuroblasts show parallel and perpendic-ular contact guidance behaviors on aligned neurite bun-dles in microexplant cultures (Nakatsuji, N. and Nagata, I. (1989) Development, 106, 441-447; N. I. and N. N. (1991) ibid., 112, 581-590). To test the hypothesis that the physical surface structure of the neurite bundle causes the perpendicular contact guidance, we cultured dissociated neuroblasts on quartz plates on which grat-ing-like microstructures were fabricated by lithographic techniques. Various types of CNS neuroblasts, but not PNS neurons, oriented their processes and migrated both perpendicular and parallel to the axis of the microstructure. Perpendicular orientation was fre-quently observed when the microstructured grooves had depths between 0.3 m and 0.8 m and a width of 1 m, which roughly mimics a tightly aligned neurite bundle. Thus, CNS neuroblasts have the ability to extend their processes and migrate perpendicular to aligned surface microstructures.

Mouse cerebellar granule cells showed two types of migration behavior in microexplant cultures. They first migrated along their neurites, showing the typical contact guidance, and then oriented themselves at right angles to the parallel neurites, thus exhibiting the ‘perpendicular contact guidance’ (Nakatsuji, N. and Nagata, I. 1989 Development, 106, 441–447). To study whether other neurons have the capacity to show similar ‘perpendicular contact guidance’, we cultured dissociated neuroblasts from various parts of CNS or PNS on parallel neurite bundles. The PNS neuroblasts always extended their processes parallel to the neurite bundle. In contrast, almost all kinds of CNS neuroblasts tested oriented their processes both perpendicular and parallel to the neurite bundles that were all free of glia. Time-lapse video recording revealed that neuroblasts migrated in both directions. Thus, CNS neuroblasts possess the capacity to migrate and extend their processes at right angles to the substratum of heterotypic neurite bundles, which may play an important role in histogenesis of the CNS during development.