OX2R-selective orexin agonism is sufficient to ameliorate cataplexy and sleep/wake fragmentation without inducing drug-seeking behavior in mouse model of narcolepsy.

Acquired loss of hypothalamic orexin (hypocretin)-producing neurons causes the chronic sleep disorder narcolepsy-cataplexy. Orexin replacement therapy using orexin receptor agonists is expected as a mechanistic treatment for narcolepsy. Orexins act on two receptor subtypes, OX1R and OX2R, the latter being more strongly implicated in sleep/wake regulation. However, it has been unclear whether the activation of only OX2R, or both OX1R and OX2R, is required to replace the endogenous orexin functions in the brain. In the present study, we examined whether the selective activation of OX2R is sufficient to rescue the phenotype of cataplexy and sleep/wake fragmentation in orexin knockout mice. Intracerebroventricular [Ala11, D-Leu15]-orexin-B, a peptidic OX2R-selective agonist, selectively activated OX2R-expressing histaminergic neurons in vivo, whereas intracerebroventricular orexin-A, an OX1R/OX2R non-selective agonist, additionally activated OX1R-positive noradrenergic neurons in vivo. Administration of [Ala11, D-Leu15]-orexin-B extended wake time, reduced state transition frequency between wake and NREM sleep, and reduced the number of cataplexy-like episodes, to the same degree as compared with orexin-A. Furthermore, intracerebroventricular orexin-A but not [Ala11, D-Leu15]-orexin-B induced drug-seeking behaviors in a dose-dependent manner in wild-type mice, suggesting that OX2R-selective agonism has a lower propensity for reinforcing/drug-seeking effects. Collectively, these findings provide a proof-of-concept for safer mechanistic treatment of narcolepsy-cataplexy through OX2R-selective agonism.

Effect of sevoflurane preconditioning on sleep reintegration after alteration by lipopolysaccharide.

Despite extensive evidence on the organ protective effects of sevoflurane, its effect on disturbed sleep remains unclear. We hypothesised that sevoflurane preconditioning positively impacts disturbed sleep caused by systemic inflammation. A prospective, randomised laboratory investigation was conducted in C57BL/6J mice. A mouse model of lipopolysaccharide (LPS)-induced systemic inflammation was employed to investigate the effects of sevoflurane on sleep recovery. Symptom recovery was evaluated through electroencephalography/electromyography (EEG/EMG) and histological studies. The mice were exposed to 2% sevoflurane before and after peritoneal injection of LPS. The EEG and EMG were recorded for 24 h after the procedure. Brain tissue was harvested after the sevoflurane/LPS procedure and was immunostained using individual antibodies against choline acetyltransferase (ChAT) and Fos. The ChAT-positive and ChAT/Fos double-positive cells were analysed quantitatively in the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus (PPTg/LDTg). Compared with control mice, mice preconditioned with sevoflurane but not post-conditioned showed a significant increase in rapid eye movement (REM) sleep during EEG recording following the LPS challenge. They also demonstrated a shorter REM latency, indicating an early recovery from LPS-altered sleep. The bouts of REM episodes were retained with sevoflurane preconditioning. More ChAT/Fos double-positive cells were observed in the PPTg/LDTg in the sevoflurane preconditioning plus LPS group than in the LPS-only group. Sevoflurane preconditioning promotes recovery from altered sleep induced by systemic inflammation. Activation of PPTg/LDTg is considered a mechanism underlying sleep reintegration. The recovery phenomenon shows potential for clinical application in cases of sleep disturbances induced by systemic inflammation.

Usefulness of the whole-body counter for infants and small children (BABYSCAN) as a risk communication tool after the Fukushima Daiichi nuclear power plant incident.

Responding to the radiation-related concerns of parents/guardians with infants/small children is an important public health issue for regional recovery after radioactive contamination. This study summarizes the results of a systematic internal contamination screening of infants/small children, aged 0-6 years, using BABYSCAN and individual counselling sessions with physicians about radiation concerns from 2014 to 2018 in Minamisoma City. Of 3,114 participants, no one was found to have internal contamination with radioactive caesium with a detection limit of 50 Bq/body. The questionnaire survey showed a decreasing trend of concerns about food contamination and playing outside as possible causes of internal contamination over time. Because people's concerns were diverse in counselling sessions, individual responses are required. This study showed that examinations using BABYSCAN provide an opportunity for direct dialogue between the parents/guardians of infants/small children and experts. This can be considered a model case for risk communication conducted by the local government after a radioactive contamination incident.

Absence of Relatives Impairs the Approach of Nurses to Cardiopulmonary Resuscitation in Non-Cancer Elderly Patients without a Do-Not-Attempt-Resuscitation Order: A Vignette-Based Questionnaire Study.

A Do-Not-Attempt-Resuscitation (DNAR) order solely precludes performing cardiopulmonary resuscitation (CPR) following cardiopulmonary arrest. A patient's personal status is known to influence a range of clinical practices, not only CPR, when a DNAR order is given. We assessed whether the absence of supporting relatives or a diagnosis of dementia can influence nurses' perceptions of clinical practices for elderly patients with non-malignant and chronic diseases. A vignette-based questionnaire was used to evaluate nurses' beliefs both before and after issuance of a DNAR order. Three vignettes were developed: the control vignette described an 85-year-old woman with repeated heart failure, the second and third incorporated a lack of relatives and a dementia diagnosis, respectively. The survey assessed the approach of nurses to 10 routine medical procedures, including CPR, clinical laboratory testing and nursing care, using a 5-base Likert-scale, for six vignette scenarios. A questionnaire was completed by 186 nurses (64% response). The pre-DNAR non-relative vignette showed significantly lower scores for CPR, indicating a deterioration in willingness to perform CPR, compared to the pre-DNAR control (median [interquartile]; 3 [2-4] and 4 [3-4] in the non-relative and control vignettes, respectively, p < 0.001). No significant differences were observed between the dementia and control vignettes. Absence of contactable relatives and resultant lack of communication can diminish the perception of nurses regarding the provision of CPR, even when a DNAR does not exist. This result suggests a necessity for comprehensive training all medical staff about issuance of DNAR orders and what care should be provided thereafter.

The importance of family caregiving to achieving palliative care at home: a case report of end-of-life breast cancer in an area struck by the 2011 Fukushima nuclear crisis: A case report.

RATIONALE: The primary setting of palliative care has shifted from inpatient care to patients' residences. Family caregiving is essential for patients with life-limiting illnesses to receive palliative care at home, however little information is available regarding potential interventions to achieve palliative homecare for those without sufficient support from family members in various settings, including disasters. PATIENT CONCERNS: In March 2011, Fukushima, Japan experienced an earthquake, tsunami and nuclear disaster. In August 2015, a 59-year-old Japanese female presented to our hospital, located 23 km north of Fukushima Daiichi Nuclear Power Plant, with a right breast ulcer. DIAGNOSES: The patient was diagnosed with stage IV breast cancer. INTERVENTIONS: The patient's general condition gradually worsened despite a one-year course of chemotherapy, and she became bedridden after a fall in October 2016. Although the patient wished to receive palliative homecare, this appeared challenging to achieve because she resided alone in a temporary housing shelter. Although she originally lived with her family in Odaka District, Fukushima, she relocated outside of the city following evacuation orders after the disaster. The evacuation orders for Odaka District were still in effect when she returned to the city alone in 2014. We contacted her sister who moved apart from her during the evacuation, and explained the necessity of family caregiving to enable her palliative homecare. OUTCOMES: The sister decided to move back to their original residence in Odaka District and live with the patient again. The patient successfully spent her end-of-life period and died at home. LESSONS: Health care providers and community health workers may need to take a pro-active approach to communicating with family members to draw informal support to enable patients' end-of-life management according to their values and preferences. This is a lesson which may be applicable to broader healthcare settings beyond cancer, or disaster contexts, considering that population ageing and social isolation may continue to advance worldwide.

Breast cancer patient delay in Fukushima, Japan following the 2011 triple disaster: a long-term retrospective study.

BACKGROUND: Little information is available concerning how patient delay may be affected by mass disasters. The main objectives of the present study are to identify whether there was a post-disaster increase in the risk of experiencing patient delay among breast cancer patients in an area affected by the 2011 triple disaster in Fukushima, Japan, and to elucidate factors associated with post-disaster patient delay. Sociodemographic factors (age, employment status, cohabitant status and evacuation status), health characteristics, and health access- and disaster-related factors were specifically considered. METHODS: Records of symptomatic breast cancer patients diagnosed from 2005 to 2016 were retrospectively reviewed to calculate risk ratios (RRs) for patient delay in every year post-disaster compared with the pre-disaster baseline. Total and excessive patient delays were respectively defined as three months or more and twelve months or more from symptom recognition to first medical consultation. Logistic regression analysis was conducted for pre- and post-disaster patient delay in order to reveal any factors potentially associated with patient delay, and changes after the disaster. RESULTS: Two hundred nineteen breast cancer patients (122 pre-disaster and 97 post-disaster) were included. After adjustments for age, significant post-disaster increases in RRs of experiencing both total (RR: 1.66, 95% Confidence Interval (CI): 1.02-2.70, p < 0.05) and excessive patient delay (RR: 4.49, 95% CI: 1.73-11.65, p < 0.01) were observed. The RRs for total patient delay peaked in the fourth year post-disaster, and significant increases in the risk of excessive patient delay were observed in the second, fourth, and fifth years post-disaster, with more than five times the risk observed pre-disaster. A family history of any cancer was the only factor significantly associated with total patient delay post-disaster (odds ratio: 0.38, 95% CI: 0.15-0.95, p < 0.05), while there were no variables associated with delay pre-disaster. CONCLUSIONS: The triple disaster in Fukushima appears to have led to an increased risk of patient delay among breast cancer patients, and this trend has continued for five years following the disaster.

Non-communicable diseases in decontamination workers in areas affected by the Fukushima nuclear disaster: a retrospective observational study.

OBJECTIVES: To assess the prevalence of non-communicable diseases (NCDs), and whether NCDs were treated or not, among hospitalised decontamination workers who moved to radio-contaminated areas after Japan's 2011 Fukushima Daiichi Nuclear Power Plant disaster. METHODS: We retrospectively extracted records of decontamination workers admitted to Minamisoma Municipal General Hospital between 1 June 2012 and 31 August 2015, from hospital records. We investigated the incidence of underlying NCDs such as hypertension, dyslipidaemia and diabetes among the decontamination workers, and their treatment status, in addition to the reasons for their hospital admission. RESULTS: A total of 113 decontamination workers were admitted to the hospital (112 male patients, median age of 54 years (age range: 18-69 years)). In terms of the demographics of underlying NCDs in this population, 57 of 72 hypertensive patients (79.2%), 37 of 45 dyslipidaemic patients (82.2%) and 18 of 27 hyperglycaemic patients (66.7%) had not been treated for their NCDs before admission to the hospital. CONCLUSIONS: A high burden of underlying NCDs was found in hospitalised decontamination workers in Fukushima. Managing underlying diseases such as hypertension, hyperlipidaemia and diabetes mellitus is essential among this population.

Asymptomatic hepatic portal venous gas with gastric emphysema as a chronic complication of gastrostomy tube placement: a case report.

BACKGROUND: Percutaneous endoscopic gastrostomy feeding is widely used as a route for enteral feeding for patients with impaired swallowing ability, particularly in older patients. Hepatic portal venous gas is a condition that may arise from several causes. Hepatic portal venous gas that develops after an endoscopic procedure is generally reported to be nonfatal, yet there is little information available concerning the characteristics of hepatic portal venous gas as a chronic complication of percutaneous endoscopic gastrostomy feeding. CASE PRESENTATION: We experienced a case of hepatic portal venous gas that happened to be detected in an 81-year-old Japanese man with long-term percutaneous endoscopic gastrostomy use who was admitted to our hospital with aspiration pneumonia. While aspiration pneumonia was treated with antibiotics and suspension of tube feedings, he recovered from hepatic portal venous gas without any treatment. CONCLUSIONS: The presence of a percutaneous endoscopic gastrostomy tube may have induced hepatic portal venous gas through a mechanism in which vomiting led to increased abdominal pressure and eventually gastric emphysema. This case suggests that hepatic portal venous gas without any signs of bowel ischemia or emphysematous gastritis can resolve without treatment, which is a finding that could be helpful for clinicians who deal with those supported by percutaneous endoscopic gastrostomy feeding.

Klebsiella Pneumoniae sepsis deteriorated by uncontrolled underlying disease in a decontamination worker in Fukushima, Japan.

OBJECTIVES: Patients with underlying conditions are at a higher risk of developing sepsis, a systematic response to infection, which has a high mortality rate. After the March 2011 Fukushima Daiichi nuclear power plant accident, there has been an influx of migrant decontamination workers; however, little is known about their health status. CASE: A Japanese 55-year-old male decontamination worker, who had several underlying diseases, was transferred to our hospital in cardiopulmonary arrest. He had a history of diabetes mellitus and hypertension and a past history of tuberculosis. Control of underlying conditions was poor, with HbA1c of 13.8% at presentation. He was diagnosed with pneumonia-induced bacteremia and sepsis due to Klebsiella pneumoniae. Although spontaneous circulation returned in emergency room, he died a day after admission. CONCLUSION: The poor control of underlying diseases seen in this patient could have been influenced by his recent job transfer and engagement in decontamination work and additionally related to his socioeconomic status (SES). This case highlights the need for further research to elucidate the underlying diseases, working conditions, and SES of this population.

[Umbilical Hernia Complicated by Gastrointestinal Stromal Tumor of the Small Intestine - A Case Report].

Intraabdominal tumors can cause umbilical hernia and may lead to serious consequences, such as incarcerated or necrotized intestine. However, little information is available concerning how the location and characteristics of tumors may affect the process of umbilical hernia development. A 46-year-old Japanese man presented at the department of surgery with abdominal pain and abdominal retention, which appeared on the day of presentation and 4 years before the presentation, respectively. Abdominal computed tomography revealed a suspected gastrointestinal stromal tumor(GIST)and an umbilical hernia close to the tumor, both of which were clinically diagnosed. Surgical tumor resection and hernia repair were conducted successfully. The patient was pathologically diagnosed with high-risk GIST. Adjuvant therapy with imatinib was administered with no recurrence as of 1 year post-surgery. This is a case of GIST complicated by umbilical hernia. Small solid tumors may cause umbilical hernia if they are in close proximity to vulnerable parts of the abdominal wall.

Whole-body counter surveys of over 2700 babies and small children in and around Fukushima Prefecture 33 to 49 months after the Fukushima Daiichi NPP accident.

BABYSCAN, a whole-body counter (WBC) for small children was developed in 2013, and units have been installed at three hospitals in Fukushima Prefecture. Between December, 2013 and March, 2015, 2707 children between the ages of 0 and 11 have been scanned, and none had detectable levels of radioactive cesium. The minimum detectable activities (MDAs) for (137)Cs were ≤ 3.5 Bq kg(-1) for ages 0-1, decreasing to ≤ 2 Bq kg(-1) for ages 10-11. Including the (134)Cs contribution, these translate to a maximum committed effective dose of ∼ 16 µSv y(-1) even for newborn babies, and therefore the internal exposure risks can be considered negligibly small.Analysis of the questionnaire filled out by the parents of the scanned children regarding their families' food and water consumption revealed that the majority of children residing in the town of Miharu regularly consume local or home-grown rice and vegetables, while in Minamisoma, a majority avoid tap water and produce from Fukushima. The data show, however, no correlation between consumption of locally produced food and water and the children's body burdens.

Whole-body counter survey results 4 months after the Fukushima Dai-ichi NPP accident in Minamisoma City, Fukushima.

Using the first WBC unit installed in Fukushima Prefecture after the accident, the radiocesium body burdens of 566 high-risk residents of Minamisoma city were measured in July 2011 at the Minamisoma Municipal General Hospital. The analysis of the data was challenging because this chair-type, WBC unit, did not have sufficient shielding against background gamma rays and methods had to be developed to reliably compensate for the body-attenuated background radiation. Fortunately, data for repeated tests of hospital staff members using both the chair-type and well-shielded FASTSCAN WBC units, installed in September 2011, were available and could be used to check the validity of the analysis. The CEDs of all subjects, estimated under the assumption of acute inhalation in March 2011, were found to be less than 1 mSv.

Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer.

BACKGROUND: This study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU). METHODS: A total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1M tegafur--0.4 M 5-chloro-2,4-dihydroxypyridine--1 M potassium oxonate (S-1 [TS-1]) were also compared, using three human gastric cancer xenografts in nude mice. RESULTS: There was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity. CONCLUSION: DPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.