Stress upregulates 2-arachidonoylglycerol levels in the hypothalamus, midbrain, and hindbrain, and it is sustained by green nut oil supplementation in SAMP8 mice revealed by DESI-MSI.

The endocannabinoid 2-arachidonoylglycerol (2AG) is an important modulator of stress responses. Its level in the brain increases in response to stress, but region-specific effects of stress on brain 2AG are not well known yet. Moreover, green nut oil (GNO), oil extracted from the seeds of Plukenetia volubilis has several health benefits, but its effects on brain 2AG levels are unknown. Therefore, we conducted this study to explore the effects of stress and GNO supplementation on 2AG levels in specific brain regions of senescence-accelerated mouse prone 8 (SAMP8). In this study, desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) revealed that water-immersion stress for three days significantly increased 2AG levels in several brain regions of SAMP8 mice, including the hypothalamus, midbrain, and hindbrain. No significant change was observed in the relative abundance of brain 2AG in stress given SAMP8 mice after eighteen days of removing stress load compared to control SAMP8 mice. GNO supplementation also increased brain 2AG in SAMP8 mice without stress load. Additionally, GNO supplementation sustained the increased brain 2AG levels in stress given SAMP8 mice after eighteen days of removing stress load. Among all brain regions, a relatively higher accumulation of 2AG was noted in the hypothalamus, midbrain, and hindbrain of GNO-fed SAMP8. Our data explored the potentiality of GNO supplementation to improve brain 2AG levels which might be used to treat anxiety and depressive behaviors.

Dietary Intake of Green Nut Oil or DHA Ameliorates DHA Distribution in the Brain of a Mouse Model of Dementia Accompanied by Memory Recovery.

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, has significant healthbenefits. Previous studies reported decreased levels of DHA and DHA-containing phosphatidylcholines inthe brain of animals suffering from Alzheimer's disease, the most common type of dementia; furthermore,DHA supplementation has been found to improve brain DHA levels and memory efficiency in dementia. Oilextracted from the seeds of Plukenetia volubilis (green nut oil; GNO) is also expected to have DHA like effectsas it contains approximately 50% α-linolenic acid, a precursor of DHA. Despite this, changes in the spatialdistribution of DHA in the brain of animals with dementia following GNO or DHA supplementation remainunexplored. In this study, desorption electrospray ionization imaging mass spectrometry (DESI-IMS) wasapplied to observe the effects of GNO or DHA supplementation upon the distribution of DHA in the brain ofmale senescence-accelerated mouse-prone 8 (SAMP8) mice, a mouse model of dementia. DESI-IMS revealedthat brain DHA distribution increased 1.85-fold and 3.67-fold in GNO-fed and DHA-fed SAMP8 mice,respectively, compared to corn oil-fed SAMP8 mice. Memory efficiency in SAMP8 mice was also improvedby GNO or DHA supplementation. In summary, this study suggests the possibility of GNO or DHAsupplementation for the prevention of dementia.

Interactive effect of sleep duration and physical activity on anxiety/depression in adolescents.

Although effects of sleep duration and physical activity (PA) have been demonstrated on mental health in adolescents, their interactive effect has not been studied. This cross-sectional study first examines this interactive effect on anxiety/depression in adolescents. A total of 983 Japanese students aged 12-17 were studied, using a self-report questionnaire. The interaction of sleep duration and amount of PA and their main effects on anxiety/depression, assessed using the 12-item General Health Questionnaire (GHQ-12), were investigated employing multiple regression, adjusting for grade and sex. Sleep duration and amount of PA were classified as being adequate or not, according to the duration and amount recommended by the National Sleep Foundation and World Health Organization, respectively. As a result, the interaction between sleep duration and amount of PA and their main effects were statistically significant. GHQ-12 score was significantly better in adolescents with either adequate sleep or adequate PA, not both, than those with neither adequate sleep nor adequate PA. The score, however, seemed no further improved in those with both adequate sleep and PA. The present study suggests that effects of sleep and PA on mental health need to be studied with consideration to their interaction.

The association between changes in depression/anxiety and trajectories of psychotic-like experiences over a year in adolescence.

BACKGROUND: Recent cross-sectional studies suggest that psychotic-like experiences (PLEs) are associated with depression and anxiety in adolescents. While longitudinal studies have observed that adolescents suffer more severe symptoms of depression/anxiety when PLEs persist, it remains unclear whether depression/anxiety worsens or improves with PLE emergence or remission, respectively. In this prospective school-based study, we investigated the association between longitudinal changes in depression/anxiety and one-year PLE trajectories in adolescence. METHODS: Nine hundred and twelve adolescents participated in the baseline assessment of PLEs and depression/anxiety; 887 (97.3%) adolescents completed the follow-up assessment one year later. Multilevel analysis was conducted to evaluate the change in depression/anxiety, evaluated using the General Health Questionnaire-12 (GHQ-12), during the year according to PLE trajectory, adjusting for baseline depression/anxiety, gender, age, substance use and victimization. RESULTS: Sixteen percent of adolescents reported PLEs at baseline, with 56% of them remitting at follow-up. At follow-up, PLEs were experienced by 6.6% of adolescents not experiencing PLEs at baseline (incident PLE group). After adjusting for covariates, GHQ-12 score worsened significantly during the year in students with incident trajectories (regression coefficient for time, α1=1.91, 95% CI: 1.04-2.77), but in those showing remission, GHQ-12 score did not significantly improve (α1=-0.20, 95% CI: -0.97-0.56). CONCLUSIONS: Greater awareness about PLEs and their trajectories in school health care settings may be a key towards the prevention and treatment of adolescent depression and anxiety.

Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa.

Salmonella Typhi is the causative agent of typhoid. Typhoid is diagnosed by blood culture, a method that lacks sensitivity, portability and speed. We have previously shown that specific metabolomic profiles can be detected in the blood of typhoid patients from Nepal (Näsström et al., 2014). Here, we performed mass spectrometry on plasma from Bangladeshi and Senegalese patients with culture confirmed typhoid fever, clinically suspected typhoid, and other febrile diseases including malaria. After applying supervised pattern recognition modelling, we could significantly distinguish metabolite profiles in plasma from the culture confirmed typhoid patients. After comparing the direction of change and degree of multivariate significance, we identified 24 metabolites that were consistently up- or down regulated in a further Bangladeshi/Senegalese validation cohort, and the Nepali cohort from our previous work. We have identified and validated a metabolite panel that can distinguish typhoid from other febrile diseases, providing a new approach for typhoid diagnostics.

An evaluation of purified Salmonella Typhi protein antigens for the serological diagnosis of acute typhoid fever.

OBJECTIVES: The diagnosis of typhoid fever is a challenge. Aiming to develop a typhoid diagnostic we measured antibody responses against Salmonella Typhi (S. Typhi) protein antigens and the Vi polysaccharide in a cohort of Bangladeshi febrile patients. METHODS: IgM against 12 purified antigens and the Vi polysaccharide was measured by ELISA in plasma from patients with confirmed typhoid fever (n = 32), other confirmed infections (n = 17), and healthy controls (n = 40). ELISAs with the most specific antigens were performed on plasma from 243 patients with undiagnosed febrile disease. RESULTS: IgM against the S. Typhi protein antigens correlated with each other (rho > 0.8), but not against Vi (rho < 0.6). Typhoid patients exhibited higher IgM against 11/12 protein antigens and Vi than healthy controls and those with other infections. Vi, PilL, and CdtB exhibited the greatest sensitivity and specificity. Specificity and sensitivity was improved when Vi was combined with a protein antigen, generating sensitivities and specificities of 0.80 and >0.85, respectively. Applying a dynamic cut-off to patients with undiagnosed febrile disease suggested that 34-58% had an IgM response indicative of typhoid. CONCLUSIONS: We evaluated the diagnostic potential of several S. Typhi antigens; our assays give good sensitivity and specificity, but require further assessment in differing patient populations.

A prospective study of the importance of enteric fever as a cause of non-malarial febrile illness in patients admitted to Chittagong Medical College Hospital, Bangladesh.

BACKGROUND: Fever is a common cause of hospital admission in Bangladesh but causative agents, other than malaria, are not routinely investigated. Enteric fever is thought to be common. METHODS: Adults and children admitted to Chittagong Medical College Hospital with a temperature of ≥38.0 °C were investigated using a blood smear for malaria, a blood culture, real-time PCR to detect Salmonella Typhi, S. Paratyphi A and other pathogens in blood and CSF and an NS1 antigen dengue ELISA. RESULTS: We enrolled 300 febrile patients with a negative malaria smear between January and June 2012: 156 children (aged ≤15 years) and 144 adults with a median (interquartile range) age of 13 (5-31) years and median (IQR) illness duration before admission of five (2-8) days. Clinical enteric fever was diagnosed in 52 patients (17.3 %), lower respiratory tract infection in 48 (16.0 %), non-specific febrile illness in 48 (16.0 %), a CNS infection in 37 patients (12.3 %), urinary sepsis in 23 patients (7.7 %), an upper respiratory tract infection in 21 patients (7.0 %), and diarrhea or dysentery in 21 patients (7.0 %). Malaria was still suspected in seven patients despite a negative microscopy test. S. Typhi was detected in blood by culture or PCR in 34 (11.3 %) of patients. Of note Rickettsia typhi and Orientia tsutsugamushi were detected by PCR in two and one patient respectively. Twenty-nine (9 %) patients died during their hospital admission (15/160 (9.4 %) of children and 14/144 (9.7 %) adults). Two of 52 (3.8 %) patients with enteric fever, 5/48 (10.4 %) patients with lower respiratory tract infections, and 12/37 (32.4 %) patients with CNS infection died. CONCLUSION: Enteric fever was confirmed in 11.3 % of patients admitted to this hospital in Bangladesh with non-malaria fever. Lower respiratory tract and CNS infections were also common. CNS infections in this location merit more detailed study due to the high mortality.

Annual longitudinal survey at up to five time points reveals reciprocal effects of bedtime delay and depression/anxiety in adolescents.

OBJECTIVE: To investigate the longitudinal relationship between sleep habits and mental health in adolescents. METHODS: Multipoint observation data of up to five years were employed from a prospective cohort study of sleep habits and mental health status conducted from 2009 to 2013 in a unified junior and senior high school (grades 7-12) in Tokyo, Japan. A total of 1078 students answered a self-report questionnaire, including items on usual bed and wake-up times on school days, and the Japanese version of the 12-item General Health Questionnaire (GHQ-12). RESULTS: Latent growth model (LGM) analysis, which requires three or more time point data, showed that longitudinal changes in bedtime and GHQ-12 score (or score for depression/anxiety) were significantly and moderately correlated (correlation coefficient = 0.510, p < 0.05). Another result of interest was that, using an autoregressive cross-lagged (ARCL) model, bedtime and the depression/anxiety score had reciprocal effects the following year: ie, bedtime significantly affects the following year's depression/anxiety, and vice versa. In addition, the analysis provided estimates of mutually predicted changes: one-hour bedtime delay may worsen the GHQ-12 score by 0.2 points, and one-point worsening of the score may delay bedtime by 2.2 minutes. CONCLUSIONS: By using up to five multiple time point data, the present study confirms the correlational and reciprocally longitudinal relationship between bedtime delay and mental health status in Japanese adolescents. The results indicate that preventing late bedtime may have a significant effect on improving mental health in adolescents.

The diagnostic accuracy of three rapid diagnostic tests for typhoid fever at Chittagong Medical College Hospital, Chittagong, Bangladesh.

OBJECTIVE: To determine the diagnostic accuracy of three rapid diagnostic tests (RDTs) for typhoid fever in febrile hospitalised patients in Bangladesh. METHODS: Febrile adults and children admitted to Chittagong Medical College Hospital, Bangladesh, were investigated with Bact/Alert(®) blood cultures and real-time PCR to detect Salmonella enterica Typhi and Paratyphi A and assays for Rickettsia, leptospirosis and dengue fever. Acute serum samples were examined with the LifeAssay (LA) Test-it™ Typhoid IgM lateral flow assay detecting IgM antibodies against S. Typhi O antigen, CTKBiotech Onsite Typhoid IgG/IgM Combo Rapid-test cassette lateral flow assay detecting IgG and IgM antibodies against S. Typhi O and H antigens and SD Bioline line assay for IgG and IgM antibodies against S. Typhi proteins. RESULTS: In 300 malaria smear-negative febrile patients [median (IQR) age of 13.5 (5-31) years], 34 (11.3%) had confirmed typhoid fever: 19 positive by blood culture for S. Typhi (three blood PCR positive) and 15 blood culture negative but PCR positive for S. Typhi in blood. The respective sensitivity and specificity of the three RDTs in patients using a composite reference standard of blood culture and/or PCR-confirmed typhoid fever were 59% and 61% for LifeAssay, 59% and 74% for the CTK IgM and/or IgG, and 24% and 96% for the SD Bioline RDT IgM and/or IgG. The LifeAssay RDT had a sensitivity of 63% and a specificity of 91% when modified with a positive cut-off of ≥2+ and analysed using a Bayesian latent class model. CONCLUSIONS: These typhoid RDTs demonstrated moderate diagnostic accuracies, and better tests are needed.

Thalassemia major is a major risk factor for pediatric melioidosis in Kota Kinabalu, Sabah, Malaysia.

BACKGROUND: Melioidosis is an important cause of community-acquired infection in Southeast Asia and northern Australia. Studies from endemic countries have demonstrated differences in the epidemiology and clinical features among children diagnosed with melioidosis. This suggests that local data are needed to determine the risk factors and outcome in specific areas. METHODS: This was a retrospective study of all children admitted to Likas Women's and Children Hospital, Kota Kinabalu, Sabah, Malaysia, with a blood or clinical sample positive for Burkholderia pseudomallei from 2001 to 2012. RESULTS: Of 28 children with confirmed melioidosis, 27 records were reviewed including 11 (41%) children with thalassemia major. Twenty of the children had bacteremia, and 16 (59%) had a fatal outcome. Six children had chronic disease, and none died. Empiric use of antibiotics not specific for B. pseudomallei was associated with increased risk of death (P < .001). The annual incidence of melioidosis in children with thalassemia major from 2001 to 2010 was 140 per 100 000/year vs 0.33 per 100 000/year for other children (P < .001). After institution of iron chelation therapy in 2010, no child with thalassemia major was diagnosed with melioidosis in 2011 or 2012. CONCLUSIONS: Pediatric melioidosis in Sabah is associated with a high proportion of bacteremia and death. Thalassemia major was a major risk factor for melioidosis among children from 2001 to 2010, but infections decreased markedly from 2011 to 2012 after universal availability of iron chelation therapy. Inappropriate empiric therapy was associated with an increased risk of death.

Associations between sleep habits and mental health status and suicidality in a longitudinal survey of monozygotic twin adolescents.

Several epidemiological studies have indicated that there is a relationship between sleep habits, such as sleep duration, bedtime and bedtime regularity, and mental health status, including depression and anxiety in adolescents. However, it is still to be clarified whether the relationship is direct cause-and-effect or mediated by the influence of genetic and other traits, i.e. quasi-correlation. To examine this issue, we conducted a twin study using a total of 314 data for monozygotic twins from a longitudinal survey of sleep habits and mental health status conducted in a unified junior and senior high school (grades 7-12), located in Tokyo, Japan. Three-level hierarchical linear model analysis showed that both bedtime and sleep duration had significant associations with the Japanese version of the 12-item General Health Questionnaire (GHQ-12) score, suicidal thoughts and the experience of self-harm behaviours when genetic factors and shared environmental factors, which were completely shared between co-twins, were controlled for. These associations were statistically significant even after controlling for bedtime regularity, which was also associated significantly with the GHQ-12 score. These suggest that the associations between sleep habits and mental health status were still statistically significant after controlling for the influence of genetic and shared environmental factors of twins, and that there may be a direct cause-and-effect in the relationship in adolescents. Thus, late bedtime and short sleep duration could predict subsequent development of depression and anxiety, including suicidal or self-injury risk. This suggests that poor mental health status in adolescents might be improved by health education and intervention concerning sleep and lifestyle habits.

Long-term oral intake of aluminium or zinc does not accelerate Alzheimer pathology in AßPP and AßPP/tau transgenic mice.

Whether or not the oral intake of metals such as aluminium (Al) and zinc (Zn) is a risk for Alzheimer's disease (AD) has been a matter of controversy. Lack of AD pathology in patients with Al encephalopathy indicates Al does not cause AD. On the other hand, some epidemiological studies have suggested high Al increases the occurrence of AD. Our purpose is to test if high Al in drinking water is a risk factor for AD. We administered Al and Zn in drinking water to Tg2576, a transgenic mouse model for amyloid ß-protein (Aß) deposition with the Aß precursor protein (AßPP) mutations (K670N/M671L), and Tg2576/tau(P301L), a model for Aß and tau deposition. Deionized water was given to the control Tg2576 and Tg2576/tau. After administration for 4-10 months of approximately 100 mg/kg body weight Al or Zn per day, we were not able to find by quantitative immunohistochemical analyses differences in the deposition of Aß and tau between the treated and untreated groups. Nor did the Al or Zn treatment affect the amount of soluble Aß and Aß*56, an Aß oligomer, measured by ELISA or immunoblot. The oral intake of excess Al or Zn does not accelerate AD pathology in the transgenic mouse models for Aß and tau accumulation. Such results do not seem to support the notion that excessive oral intake of Al or Zn is a risk factor for AD.

Psychotic-like experiences (PLEs) and mental health status in twin and singleton Japanese high school students.

AIM: Studying what factors and behaviours to work on may be a key to develop the effective prevention of future mental disorder in both high-risk and general young subjects. This study aimed to investigate whether twins are more vulnerable to mental health problems including psychotic-like experiences (PLEs) than singletons and what factors on lifestyle and social environment are associated with poor mental health. METHODS: Subjects comprised 341 Japanese high-school students (173 males and 168 females) including 62 twins. We examined PLEs, general psychological distress, length and regularity of sleep, domestic violence, being bullied and other environmental factors using questionnaires including the 12-item General Health Questionnaire (GHQ-12). The variables were compared between twins and singletons. Whether variables on lifestyle and social environment affect PLEs and GHQ-12 scores were studied by logistic regression. RESULTS: Significant difference was observed in PLEs and GHQ-12 between twins and singletons. Experiencing PLEs was negatively associated with being a twin (OR = 0.293, 95% CI = 0.101-0.847) and length of sleep (OR = 0.685, 95% CI = 0.519-0.903). GHQ-12 > 4 was significantly associated with irregular sleep schedule (OR = 3.042, 95% CI = 1.818-5.090), being bullied (OR = 3.677, 95% CI = 1.317-10.266) and having no people to confide in (OR = 2.615, 95% CI = 1.249-5.475). CONCLUSION: Poor mental health status including experiencing PLEs might be less frequent in twins than in singletons. Problems in sleep length, its schedule and human relationships were significantly associated with mental health in high-school students as we hypothesized. Early identification programmes and mental health education focused on these factors may be helpful.

Successful treatment of chronic granulomatous disease with fludarabine-based reduced-intensity conditioning and unrelated bone marrow transplantation.

Allogeneic hematopoietic stem-cell transplantation (HSCT) for chronic granulomatous disease (CGD) with a reduced-intensity conditioning regimen can be expected to lead to less therapy-related mortality and late-onset impairment, whereas it has also been reported to increase the risk of unsustained mixed donor chimerism and late rejection after transplantation. Herein, we report a 4-year-old boy with CGD who was successfully treated with unrelated bone marrow transplantation with a reduced-intensity conditioning regimen (RIC). Fludarabine-based RIC, 4 Gy of total body irradiation, 120 mg/kg of cyclophosphamide, and 125 mg/m(2) of fludarabine, was adopted for transplantation, followed with 8.9 x 10(8)/kg mononucleated donor cells infused without T-cell depletion. Although hematopoietic engraftment was rapidly obtained by day +17, he developed unstable donor chimerism. After tacrolimus withdrawal, the patient showed grade III acute graft-versus-host disease (GVHD), and subsequently reached full donor chimerism by day +61. Twelve months post-transplant, the patient has remained well with stable and durable engraftment, 100% donor chimerism, and normal superoxide production, without the requirement of donor lymphocyte infusions (DLI).