Predicting mortality in pediatric sepsis: A nationwide data analysis using a pediatric sepsis surveillance method.

INTRODUCTION: A sepsis surveillance method using electronic health records is increasingly used to describe the epidemiology of adult sepsis. However, its application in pediatric populations has been limited, and real-world epidemiology of pediatric sepsis remains unknown. We aimed to determine whether this surveillance method could identify children with sepsis at high-risk of mortality. PATIENTS AND METHODS: From a nationwide inpatient database in Japan, we included children who underwent blood culture and received antimicrobials for ≥ 4 days between 2014 and 2021. We stratified these children into those with sepsis or without sepsis by the presence of organ dysfunction. We evaluated the discrimination for in-hospital mortality by the sepsis diagnosis and the number of organ dysfunction. RESULTS: Among 6553 eligible children, in-hospital mortality was 7.2 % in 875 children with sepsis and 0.2 % in 5678 children without sepsis. Sepsis diagnosis discriminated in-hospital mortality with a sensitivity of 0.84 and a specificity of 0.87. The area under the curve for mortality based on the number of organ dysfunction was 0.88 (95 % confidence interval:0.84 to 0.93). In-hospital mortality incrementally increased with the number of organ dysfunction; zero, 0.2 %; one, 3.4 %; two, 12.7 %; three, 20.9 %; four, 33.3 %; and five, 50.0 %. CONCLUSIONS: The surveillance method effectively identified children with sepsis with high-risk of mortality and demonstrated strong discrimination of mortality.

Regional variation of pediatric interhospital critical care transport in Japan.

BACKGROUND: An in-depth understanding of the epidemiology of ill or injured children transported between hospitals is crucial in building regional medical transport services in public health. Although the epidemiological situation varies by nation and region, it has not been well documented in Japan. In this report we described the number of pediatric interhospital transportations and examined the regional variations and trends in the recent decade. METHODS: We performed repeated, cross-sectional analyses of children (<15 years) undergoing interhospital transportation in 2010, 2013, and 2016-19, using the national database of public ambulances of the Fire and Disaster Management Agency in Japan. We stratified the cases into critical care transport (CCT) or non-critical care transport (NonCCT) by the illness/injury severity of the transported children. We calculated the national population-adjusted number of CCTs and described prefectural variations in CCT numbers with analytical thinking. RESULTS: There were 23,506 CCTs and 138,347 NonCCTs. The national average of population-adjusted CCT numbers was 255 per 1,000,000 person-years. The statistics varied by prefectures, ranging from 25-536 per 1,000,000 person-years. The annual trends were also diverse across prefectures, increasing in nine, decreasing in six, and static in 31 prefectures. In analytical thinking of regional variations, potential contributing factors included available interhospital transport services and the threshold of direct admission and referral to tertiary-care hospitals, whereas regional variations were not well associated with geographical patterns or population size. CONCLUSIONS: Public ambulance services were substantially used for CCTs and NonCCTs in Japan. Regional variations should be taken into account for the future policymaking on pediatric interhospital transportation.

Descriptive statistics and risk factor analysis of children with community-acquired septic shock.

BACKGROUND: Children with community-acquired septic shock can rapidly deteriorate and die in acute-care hospitals. This study aimed to describe the mortality, timing, and risk factors in children with community-acquired septic shock. METHODS: This is a retrospective cohort study using a national inpatient database in Japan. The study population included children (age < 20 years) who were admitted to acute-care hospitals with a diagnosis of sepsis from July 2010 to March 2020, who were treated with antibiotics, and who were supported with vasoactive drugs within three days of hospitalization. We used a Cox proportional-hazards regression model to identify risk factors for earlier death. RESULTS: Among 761 eligible children, the median age was 3 (interquartile range, 0-11) years and 57.2% had underlying conditions. Among these, 67.1% were admitted to accredited intensive care units within three days of hospitalization and 38.6% were transported from other hospitals. The median hospital volume, defined as the number of eligible children in each hospital over the study period, was 4 (interquartile range, 2-11). Overall, 244 children died (in-hospital mortality rate, 32.1%). Among them, 77 (31.6%) died on the first day, and 156 (63.9%) died within three days of hospitalization. A Cox proportional-hazards regression model showed that earlier death was associated with lower hospital volume and age 1-5 years, whereas it was inversely associated with admission to an accredited intensive care unit and transport from other hospitals. Among 517 survivors, 178 (34.4%) were discharged with comorbidities. CONCLUSIONS: Children with community-acquired septic shock had high mortality, and early death was common. Our findings may warrant future efforts to enhance the quality of initial resuscitation for sepsis in low-volume hospitals and to ensure a healthcare system in which children with sepsis can be treated in accredited intensive care units.

ARDS Clinical Practice Guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html ). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

ARDS clinical practice guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D); we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D); we suggest against routinely implementing NO inhalation therapy (GRADE 2C); and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jrs.or.jp/publication/jrs_guidelines/). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020).

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020).

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Clinical impact of implementing humidified high-flow nasal cannula on interhospital transport among children admitted to a PICU with respiratory distress: a cohort study.

BACKGROUND: There is a limited evidence for humidified high-flow nasal cannula (HHFNC) use on inter-hospital transport. Despite this, its use during transport is increasing in children with respiratory distress worldwide. In 2015 HHFNC was implemented on a specialized pediatric retrieval team serving for Victoria. The aim of this study is to investigate the effect of the HHFNC implementation on the retrieval team on the paediatric intensive care unit (PICU) length of stay and respiratory support use. METHODS: We performed a cohort study using a comparative interrupted time-series approach controlling for patient and temporal covariates, and population-adjusted analysis. We studied 3022 children admitted to a PICU in Victoria with respiratory distress January 2010-December 2019. Patients were divided in pre-intervention era (2010-2014) and post-intervention era (2015-2019). RESULTS: 1006 children following interhospital transport and 2016 non-transport children were included. Median (IQR) age was 1.4 (0.7-4.5) years. Pneumonia (39.1%) and bronchiolitis (34.3%) were common. On retrieval, HHFNC was used in 5.0% (21/420) and 45.9% (269/586) in pre- and post-intervention era. In an unadjusted model, median (IQR) PICU length of stay was 2.2 (1.1-4.2) and 1.7 (0.9-3.2) days in the pre- and post-intervention era in transported children while the figures were 2.4 (1.3-4.9) and 2.1 (1.2-4.5) days in non-transport children. In the multivariable regression model, the intervention was associated with the reduced PICU length of stay (ratio 0.64, 95% confidential interval 0.49-0.83, p = 0.001) with the predicted reduction of PICU length of stay being - 10.6 h (95% confidential interval - 16.9 to - 4.3 h), and decreased respiratory support use (- 25.1 h, 95% confidential interval - 47.9 to - 2.3 h, p = 0.03). Sensitivity analyses including a model excluding less severe children showed similar results. In population-adjusted analyses, respiratory support use decreased from 4837 to 3477 person-hour per year in transported children over the study era, while the reduction was 594 (from 9553 to 8959) person-hour per year in non-transport children. With regard to the safety, there were no escalations of respiratory support mode during interhospital transport. CONCLUSIONS: The implementation of HHFNC on interhospital transport was associated with the reduced PICU length of stay and respiratory support use among PICU admissions with respiratory distress.

Recurrent Extubation Failure Following Neonatal Cardiac Surgery Is Associated with Increased Mortality.

Extubation failure (EF) following neonatal cardiac surgery is associated with increased mortality. Neonates who experienced EF twice or more (recurrent EF) may have worse outcomes than those who have a single EF or no-EF. The aims of this study are to investigate the in hospital mortality for neonates with recurrent EF compared to those with single or no-EF, and determine factors associated with recurrent EF. Neonates' ≤ 28 days who underwent cardiac surgery from January 2008 to December 2019 were included. EF was defined as unplanned reintubation within 72 h after a planned extubation. 1187 (18 recurrent EF, 84 single EF and 1085 no-EF) neonates were included. Recurrent EF occurred in 18 (17.6%) of 102 neonates undergoing a second extubation. The median time (IQR) to reintubation after the first and second extubations were similar, being 20.9 (3.3-45.2) versus 19.4 (5.5-47) h. The reason for a second-time EF was respiratory in 39% and cardiovascular in 33%. Recurrent EF and single EF was associated with increased mortality (odds ratio, 95% confidence interval (CI) 23.5, 6.9-79.9) and (odds ratio, 95% CI 5.2, 2.3-12.0) compared to no-EF. Based on the final model with risk adjustment, predicted mortality was 29.0% in recurrent EF, 6.5% in single EF, and 1.2% in no-EF. First-time EF due to cardiovascular compromise was associated with recurrent EF (odds ratio, 95% CI 3.1, 1.0-9.7). This study confirmed that patients with recurrent EF have a high morality. Neonates with a cardiovascular reason for first-time EF are more likely to have a recurrent EF than those with other causes.

Extubation Failure and Major Adverse Events Secondary to Extubation Failure Following Neonatal Cardiac Surgery.

OBJECTIVES: To describe the prevalence and consequences of major adverse events secondary to extubation failure after neonatal cardiac surgery. DESIGN: A single-center cohort study. SETTING: A medical-surgical, 30-bed PICU in Victoria, Australia. PATIENTS: One thousand one hundred eighty-eight neonates less than or equal to 28 days old who underwent cardiac surgery from January 2007 to December 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Extubation failure was defined as unplanned reintubation within 72 hours after a planned extubation. Major adverse event was defined as one or more of cardiac arrest, emergency chest reopening, extracorporeal membrane oxygenation, or death within 72 hours after extubation. One hundred fifteen of 1,188 (9.7%) neonates had extubation failure. Hospital mortality was 17.4% and 2.0% in neonates with and without extubation failure. Major adverse event occurred in 12 of 115 reintubated neonates (10.4%). major adverse event included cardiac arrest (n = 10), chest reopening (n = 8), extracorporeal membrane oxygenation (n = 5), and death (n = 0). Cardiovascular compromise accounted for major adverse event in eight: ventricular dysfunction (n = 3), pulmonary overcirculation (n = 2), coronary ischemia (n = 2), cardiac tamponade (n = 1). In a multivariable logistic regression, factors associated with major adverse event were high complexity in cardiac surgery (odds ratio 5.9; 95% CI: 1.1-32.2) and airway anomaly (odds ratio 6.0; 95% CI: 1.1-32.6). Hospital morality was 25% and 17% in reintubated neonates with and without major adverse event. CONCLUSIONS: Around 10% of reintubated neonates suffered major adverse event within 72 hours of extubation. Neonates suffering major adverse event had high mortality. Major adverse event should be monitored and reported in future studies of extubation failure. Along with tracking of extubation failure rates, major adverse event secondary to extubation failure may also serve as a key performance indicator for ICUs and registries.

Normal Baseline Function Is Associated With Delayed Rehabilitation in Critically Ill Children.

BACKGROUND: Early mobilization of patients in the adult intensive care unit (ICU) is associated with improved functional outcomes and shorter ICU stay. Although emerging evidence suggests that early mobilization in pediatric ICUs (PICUs) is safe and feasible, physical therapist (PT) consultation may be delayed because of perceptions that patient acuity precludes mobilization activities. Factors that influence timely involvement of PTs to facilitate acute rehabilitation in critically ill children have not been characterized. The aim of this study was to identify patient-level factors for early PT consultation in a tertiary care PICU before large-scale implementation of a multicomponent early mobilization program. METHODS: We conducted a retrospective analysis of data from the PICU Up! Quality Improvement Initiative. The primary outcome was early rehabilitation, defined as PT consultation within the first 3 days of PICU admission. Patients (n = 100) were divided into 2 groups by outcome, and predictive factors for early rehabilitation were analyzed with logistic regression. RESULTS: Of 100 children, 54% received early rehabilitation. In univariate analyses, higher pediatric risk of mortality (PRISM) score (P < .001), baseline motor impairment (P < .01), developmental delay (P = .04), mechanical ventilation (P = .1), and number of devices (P = .01) were associated with early rehabilitation. In a logistic regression model, predictive factors for early rehabilitation included baseline motor impairment (adjusted odds ratio = 5.36, 95% confidence interval [CI] = 1.3-22.0) and higher PRISM score (adjusted odds ratio = 1.17, 95% CI = 1.02-1.34). CONCLUSIONS: Critically ill children with normal baseline function or lower acuity of illness are less likely to have initiation of early rehabilitation with PT prior to implementation of a unit-wide early mobilization program. Baseline motor impairment and higher PRISM scores were independently associated with early rehabilitation. These findings highlight the need for streamlined criteria for PT consultation to meet the rehabilitation needs of all critically ill patients.

Contrast Echocardiogram for the Evaluation of Streaming in a Single-Ventricle Patient.

In cases involving single ventricles, predicting streaming characteristics is difficult. Unfavorable streaming can cause decreased oxygen saturation. Judging whether desaturation results from decreased pulmonary flow or unfavorable streaming is critical. A 20-day-old infant with a single left ventricle underwent ductus arteriosus ligation and pulmonary artery banding to control high pulmonary flow. Severe desaturation presented postoperatively, which worsened to 68% despite pure-oxygen ventilation. A bedside contrast echocardiogram helped determine whether unfavorable streaming caused desaturation. It revealed systemic venous streaming predominantly directed to the aorta. Emergent balloon atrial septostomy facilitated mixing at the atrial level. Oxygen saturation promptly increased to 85%.

Extubation Failure in Neonates After Cardiac Surgery: Prevalence, Etiology, and Risk Factors.

BACKGROUND: The purpose of this study was to explore the prevalence, etiology, and risk factors of extubation failure (EF) in post-cardiac surgery neonates. METHODS: Neonates (30 days old or younger) who underwent cardiac surgery and were admitted to the cardiac intensive care unit between September 2010 and February 2016 were included. The prevalence and etiology of EF, defined as reintubation within 48 hours, were reviewed. Demographic, operative, and perioperative data were retrospectively collected. Multiple logistic regression models were constructed to identify the risk factors for EF. RESULTS: The median age at surgery was 10 days. Extubation failure occurred in 25 of 156 cases (16.0%; 95% confidence interval: 10.6% to 22.7%), because of respiratory dysfunction (n = 16), hemodynamic instability (n = 4), upper airway obstruction (n = 4), or gastrointestinal bleeding (n = 1). Subsequent extubations were successful in 17 cases (68%) because of medical optimization of the causes of reintubation. The remaining 8 cases needed surgical reintervention, including tracheostomy and cardiac surgery. The inhospital mortality rate was 2.6%. In a bivariate analysis, younger age, airway diseases, ventilation before surgery, prolonged mechanical ventilation, and delayed sternal closure were associated with EF. The multivariable analysis identified airway diseases (adjusted odds ratio 18.2, 95% confidence interval: 3.8 to 88.6, p = 0.0003) and mechanical ventilation longer than 7 days (adjusted odds ratio 8.2, 95% confidence interval: 1.9 to 34.9, p = 0.0046) as risk factors for EF. CONCLUSIONS: The prevalence of EF is relatively high in neonatal cardiac surgery. The etiologies can be diverse. Extubation of neonates at high risk after cardiac surgery, based on these possible risk factors, requires more diligent approaches.

Auxin depletion in barley plants under high-temperature conditions represses DNA proliferation in organelles and nuclei via transcriptional alterations.

Many plant species are susceptible to high-temperature (HT) injury during reproductive development. We recently demonstrated that HT represses the expression of YUCCA auxin biosynthesis genes and reduces endogenous auxin in the developing anthers of barley and Arabidopsis. Here, we show that DNA proliferation in mitochondria, chloroplasts and nuclei of developing panicles is inhibited with increasing temperatures in barley. Following DNA proliferation suppression, terminal abnormalities were observed in the organelles of anther wall cells, including mitochondrial swelling and overdevelopment of chloroplasts. Comprehensive transcriptome analyses using both reproductive organs and vegetative tissues showed high and positive pairwise correlations between the expression profiles of auxin-induced genes, DNA replication-related genes and mitochondrial-related genes. In contrast, the expression profiles of auxin-repressed protein genes and photosynthesis-/chloroplast-related genes were negatively correlated with those of the previously mentioned genes. Under HT conditions, the former was repressed and the latter was up-regulated in the developing panicles. Furthermore, application of exogenous auxin promoted the expression of DNA replication-related genes under HT conditions, inducing anther cell proliferation. These suggest that compromised auxin biosynthesis/IAA level under HT condition results in nuclear and organellar DNA proliferation arrest due to co-transcriptional alterations.

Cytosolic calcium elevation induced by orexin/hypocretin in granule cell domain cells of the rat cochlear nucleus in vitro.

Using rat brain slice preparations, we examined the effect of orexin on cytosolic Ca(2+) concentrations ([Ca(2+)](i)) in the granule cell domain (GCD) cells of the cochlear nucleus that carry non-auditory information to the dorsal cochlear nucleus. Application of orexin concentration-dependently increased [Ca(2+)](i), and in two thirds of GCD cells these increases persisted in the presence of tetrodotoxin. There was no significant difference between the dose-response curve for orexin-A and that for orexin-B. Extracellular Ca(2+) removal abolished the [Ca(2+)](i) elevation induced by orexin-B, whereas depletion of intracellular Ca(2+) stores had no effect. The orexin-B-induced elevation of [Ca(2+)](i) was not blocked by inhibitors of reverse-mode Na(+)/Ca(2+) exchanger (NCX) and nonselective cation channel, whereas it was blocked by lowering the extracellular Na(+) or by applying inhibitors of forward-mode NCX and voltage-gated R- and T-type Ca(2+) channels. The ORX-B-induced increase in [Ca(2+)](i) was also blocked by inhibitors of adenylcyclase (AC) and protein kinase A (PKA), but not by inhibitors of phosphatidylcholine-specific and phosphatidylinositol-specific phospholipase C. In electrophysiological experiments using whole-cell patch clamp recordings, half of GCD cells were depolarized by orexin-B, and the depolarization was abolished by a forward-mode NCX inhibitor. These results suggest that orexin increases [Ca(2+)](i) postsynaptically via orexin 2 receptors, and the increase in [Ca(2+)](i) is induced via the AC-PKA-forward-mode NCX-membrane depolarization-mediated activation of voltage-gated R- and T-type Ca(2+) channels. The results further support the hypothesis that the orexin system participates in integrating neural systems that are involved in arousal, sensory processing, energy homeostasis and autonomic function.

Auxins reverse plant male sterility caused by high temperatures.

With global warming, plant high temperature injury is becoming an increasingly serious problem. In wheat, barley, and various other commercially important crops, the early phase of anther development is especially susceptible to high temperatures. Activation of auxin biosynthesis with increased temperatures has been reported in certain plant tissues. In contrast, we here found that under high temperature conditions, endogenous auxin levels specifically decreased in the developing anthers of barley and Arabidopsis. In addition, expression of the YUCCA auxin biosynthesis genes was repressed by increasing temperatures. Application of auxin completely reversed male sterility in both plant species. These findings suggest that tissue-specific auxin reduction is the primary cause of high temperature injury, which leads to the abortion of pollen development. Thus, the application of auxin may help sustain steady yields of crops despite future climate change.

[Multidisciplinary strategy for lung cancer patients with bone metastasis].

The fall of QOL by bone metastasis poses a problem with the increase in lung cancer. The examples of long-term survival of lung cancer are also increasing by progress of chemotherapy or molecular-targeted therapy. Now, in addition to the conventional radiotherapy, the multidisciplinary treatment including a newer bisphosphonates or an orthopedic operation has been needed to bone metastasis of lung cancer. We presented the lung cancer case who showed the symptoms in transcervical pathologic fracture and whose QOL was improved by orthopedic surgery, radiotherapy to bone metastasis, chemotherapy, gamma knife surgery, and treatment with zoledronic acid and gefitinib.