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It has been established for a long time that brain glucose metabolism is impaired in Alzheimer's disease. Recent studies have demonstrated that impaired brain glucose metabolism precedes the appearance of clinical symptoms, implying its active role in the development of Alzheimer's disease. However, the molecular mechanism by which this impairment contributes to the disease is not known. In this study, we demonstrated that protein O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins with beta-N-acetyl-glucosamine and a process regulated by glucose metabolism, was markedly decreased in Alzheimer's disease cerebrum. More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease. We also found that hyperphosphorylated tau contained 4-fold less O-GlcNAc than non-hyperphosphorylated tau, demonstrating for the first time an inverse relationship between O-GlcNAcylation and phosphorylation of tau in the human brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with decreased glucose metabolism induced by fasting, but not those in rat brains when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation patterns under various conditions suggests that abnormal tau hyperphosphorylation in Alzheimer's disease brain may result from downregulation of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein phosphatase 2A activity may offer promising therapeutic targets for treating Alzheimer's disease. [ABSTRACT FROM AUTHOR]

In palliative care, steroids are often used to alleviate symptoms such as pain, fatigue, anorexia, nausea, and vomiting. Steroids occasionally induce psychiatric adverse effects. It has been reported that treatment of the steroid-induced psychiatric symptoms involves dosage reduction or discontinuation of steroid, and concomitant administration of psychotropics. There were few reports on effectiveness of treatment of steroid-induced psychiatric symptoms by switching from one steroid to the other. We experienced the case of 67-year-old man with malignant pleural mesothelioma and pulmonary emphysema who developed psychiatric symptoms after switching from oral prednisolone 10 mg/day to intravenous betamethasone 2 mg/day. He began to complain that 'time repeats cycles of going and coming' and that he was 'unable to distinguish between daytime and night,' and his face became expressionless. He gazed at familiar healthcare professionals as if seeing them for the first time, complaining: 'I feel something obscure or strange in my head.' He was unable to remember events on the same or the previous day at all, and made no verbal response to questions by healthcare professionals. He did not know how to eat or use the toilet, and thus required assistance in daily life activities. He did not respond even when talked to by his family members. He continued gazing at them, sometimes saying: 'Where am I now? Am I sick?' He behaved restlessly, repeating cycles of lying and sitting. The symptoms disappeared gradually after re-switching from intravenous betamethasone 2 mg/day to oral prednisolone 10mg/day. 'Steroid switching' may serve as a valid alternative treatment. [ABSTRACT FROM AUTHOR]

The mRNA expression of presenilin-1 (PS1) and β-amyloid precursor protein (βAPP) was investigated in the embryonic day 20 rat olfactory bulb, nasal cavity, and inner ear using in situ hybridization histochemistry. In the olfactory bulb, PS1 mRNA was strongly expressed in both olfactory bulb neuroepithelium and the differentiating olfactory bulb. In contrast, βAPP mRNA was preferentially expressed in differentiating fields. In the nasal cavity, PS1 mRNA was strongly expressed throughout the olfactory epithelium, while βAPP mRNA expression was concentrated in the middle part of the epithelium. In the membrane labyrinth of the inner ear, although PS1 mRNA was evenly distributed in both sensory epithelium and supporting cells, βAPP mRNA was exclusively expressed in the sensory epithelium. These data suggest that PS1 is expressed earlier than βAPP, and that PS1 and βAPP co-operatively play pivotal roles in the development of the olfactory and vestibulocochlear systems. [ABSTRACT FROM AUTHOR]

The article examines a study that investigate the effects of large doses of various amino acids in combination with a monoamine oxidase inhibitor on the behavior of schizophrenics. The researchers found bufotenin both in free and conjugated forms in the urine of four schizophrenic patients under dietary control. Bufotenin was also excreted in some patients in the absence of monoamine oxidase blockade. Furthermore, increases of urinary bufotenin and other N-methylated indoleamines were observed before the mental and behavioral symptoms of the patients worsened.

The chitinase 3-like 1 (CHI3L1) gene acts as a cellular survival factor in response to several environmental and psychosocial stresses. The expression level of CHI3L1 was increased in the hippocampus and prefrontal cortex regions of patients with schizophrenia. Genetic variants of the CHI3L1 gene have been significantly associated with schizophrenia in two distinct ethnic groups, the Chinese and Irish populations. The aims of this study are to confirm the association between the CHI3L1 gene and schizophrenia in a Japanese population using the largest sample size to date (1463 cases and 1795 controls) and perform a meta-analysis of the combined samples (3005 cases, 3825 controls and 601 trios). We found significant associations between single nucleotide polymorphism (SNP) 4/rs4950928 (p=0.009), which is located in the promoter region of the CHI3L1 gene, and haplotypes including this SNP and schizophrenia (the most significant global p<0.001). As the meta-analysis of the combined samples showed significant heterogeneity among studies of SNP3/rs10399805 (p=0.026) and SNP4 (p<0.001), we performed meta-analyses separately in the Japanese (2033 cases and 2365 controls) and Chinese populations (412 cases, 464 controls and 601 trios), the major groups analyzed in association studies of the CHI3L1 gene. The meta-analysis in Japanese populations showed stronger evidence for the association of schizophrenia with SNP4 (p=0.003), while the meta-analysis in Chinese populations showed an association with a different variant (SNP3) (p=0.003). We conclude that the genetic variants in the CHI3L1 gene have ethnic heterogeneity and confer a susceptibility to schizophrenia in Asian populations. [ABSTRACT FROM AUTHOR]

Context: Cultural adaptation is essential for optimizing programs centered around autonomy, such as the Serious Illness Care Program (SICP), especially for populations valuing family-involved decision-making., Objectives: We aimed to evaluate the feasibility and efficacy of a culturally adapted SICP-based nurse-physician collaborative Advance Care Planning (ACP) intervention tailored for patients with advanced cancer who prefer family-involved decision-making., Methods: Oncology nurses, extensively trained and closely collaborating with physicians, conducted structured discussions with patients in the intervention group. The culturally adapted SICP-based ACP intervention was supplemented with trust-building, family involvement, and understanding of patient values. Primary inclusion criteria included patients within six weeks of initiating first-line palliative chemotherapy. Primary endpoints were achieving a 70% completion rate and assessing spiritual well-being (FACIT-Sp) at six months. Secondary endpoints included anxiety (GAD-7), depression (PHQ-9), quality of life (QOL) (CoQoLo), and ACP progress (ACP Engagement Scale) at the same interval., Results: Forty-one patients (67.2%) completed the six-month follow-up, falling short of the targeted completion rate. The least-squares mean change from baseline in spiritual well-being at six months was 3.00 in the intervention group and -2.22 in the standard care group (difference, 5.22 points; 95% confidence interval, 1.38-9.06; P = 0.009). Similar superiority of the intervention was observed in QOL and ACP progress., Conclusion: Despite not meeting the targeted completion rate, the intervention group demonstrated enhanced spiritual well-being, QOL, and ACP progress. Our findings suggest revisions to the intervention manual to improve feasibility and to progress to an efficacy-focused randomized controlled trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Antipsychotics are commonly used to treat delirium but can adversely affect the extrapyramidal and cardiac conduction systems. Antipsychotic use has also been reported to be associated with increased mortality in older adults. Therefore, alternative and adjunct medications for delirium are necessary. We retrospectively assessed the efficacy and safety of gabapentin (GBP) as an alternative and adjunct medication for delirium., Methods: We retrospectively investigated the records of patients with delirium treated with GBP (71 patients; median age, 81 years; interquartile range, 76-87.5 years; 54.9% males) at a general hospital. We examined duration to delirium improvement, as assessed by the Intensive Care Delirium Screening Checklist (ICDSC) and DSM-5 criteria, as well as adverse events., Results: The median (interquartile range) GBP dose was 200 mg (150-350 mg) /day. A total of 71.8% and 85.9% of the patients failed to meet the diagnostic criteria for delirium at 2 days and 5 days after initial administration, respectively (p<0.05). In subgroup analysis, patients with a history of epilepsy or cerebrovascular disease responded better to GBP than did those without such histories, suggesting that patients with abnormal/borderline neuronal activity respond to GBP even though they do not exhibit seizures. GBP did not induce extrapyramidal symptoms, cardiac conduction disturbances, hyperglycemia, or epilepsy but caused sleepiness and myoclonus., Conclusions: GBP may improve delirium with fewer adverse effects and may be a safe alternative or adjunct treatment for delirium. Dosage adjustment may be necessary to prevent sleepiness.

Objective: The Japanese Psycho-Oncology Society and the Japanese Association of Supportive Care in Cancer have recently revised the clinical practice guidelines for delirium in adult cancer patients. This article reports the process of developing the revised guidelines and summarizes the recommendations made., Methods: The guidelines were developed in accordance with the Medical Information Network Distribution Service creation procedures. The guideline development group, consisting of multi-disciplinary members, created three new clinical questions: non-pharmacological intervention and antipsychotics for the prevention of delirium and trazodone for the management of delirium. In addition, systematic reviews of nine existing clinical questions have been updated. Two independent reviewers reviewed the proposed articles. The certainty of evidence and the strength of the recommendations were graded using the grading system developed by the Medical Information Network Distribution Service, following the concept of The Grading of Recommendations Assessment, Development, and Evaluation system. The modified Delphi method was used to validate the recommended statements., Results: This article provides a compendium of the recommendations along with their rationales, as well as a short summary., Conclusions: These revised guidelines will be useful for the prevention, assessment and management of delirium in adult cancer patients in Japan., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: Although treatment outcomes for childhood cancer have improved in recent years, some patients continue to experience physical symptoms and psychological stress several years after the end of treatment. This study aimed to examine the correlation between the quality-of-life (QOL) scores of childhood cancer survivors (CCSs) aged 18-39 and (1) their families and (2) the time since the end of treatment. Methods: Measuring the QOL of CCSs attending the long-term follow-up (LTFU) and those of their families. The Short-Form Health Survey (SF-36) was used for CCSs and the Caregiver Quality of Life Index-Cancer (CQOLC) for their families. Spearman's rank correlation analyses were used to examine the relationship between the CCSs' and their families' QOL and the time since the end of treatment. Results: Twenty-nine CCSs (mean age, 24.2 years; mean the time since the end of treatment, 13.9 years), each paired with one family member, were included. Time since the end of treatment was positively correlated with the CCSs' QOL on the physical component score ( ρ  = 0.42, p  = 0.03) and negatively correlated with mental health (MH) ( ρ  = -0.50, p  = 0.01), a subscale of the mental component score (MCS). Furthermore, the CCSs' QOL on the MCS was positively correlated with their families' QOL scores ( ρ  = 0.58, p  < 0.01). Conclusion: Psychological stress may persist in CCSs long after treatment, even when physical symptoms improve. Therefore, it is necessary to establish a comprehensive support system for the LTFU of CCSs, including MH care and QOL monitoring for patients and their families.

Background: Unique cognitive impairments related to chronic obstructive pulmonary diseases (COPD) have been increasingly reported. Considering the dementia risk and medication management, older patients with COPD should be evaluated for cognitive impairment. This study aimed to examine whether specific cognitive impairments related to COPD could be detected by an assessment tool using a touchscreen personal computer (PC) in older patients with COPD., Methods: This study included 28 older male patients with COPD and 30 healthy older male individuals. A touchscreen PC-based cognitive assessment application called CogEvo was used to assess and compare the cognitive function according to five domains: spatial cognition, orientation, working memory, executive function, and attention., Results: Analysis of variance showed an interaction effect on the indices of cognitive function based on five domains between the two groups, indicating differences in the characteristics of cognitive function in such groups. Betweengroup comparisons as a subtest showed that attention, executive function, and working memory were significantly lower in the COPD group than in the healthy group., Conclusions: CogEvo can detect specific cognitive impairments associated with COPD, suggesting that it can be potentially used as a screening tool for cognitive impairment in older patients with COPD., (©Copyright: the Author(s).)

Delirium is a condition in which the main symptom is a mild disturbance of consciousness caused by a physical abnormality or medication, and various symptoms such as cognitive dysfunction, hallucinations, delusions, and mood swings appear with any disease. Delirium is frequently observed in patients with cancer, especially in the terminal stage, and is observed in about 90% of patients just before death. Hypercalcemia due to bone metastases, brain metastases, and the use of opioids and steroids for symptom relief are direct factors in the development of delirium. Furthermore, there are many opportunities to encounter delirium at the end of life caused by conditions that are difficult to recover from, such as brain metastasis, liver failure, and hypoxic encephalopathy. In the management of delirium, "search for the cause(s)and its treatment"and"environmental adjustment"are the most important. Then, pharmacotherapy is considered to reduce the severity of delirium. Antipsychotics are the basic medication of choice. The route of administration, half-life, dosage form, adverse events of medication, as well as patient factors such as the presence or absence of diabetes and the subtype of delirium should be comprehensively considered when selecting a medication. The timing of medication discontinuation should also be kept in mind once medication therapy is initiated. On the other hand, when delirium is caused by factors that are difficult to recover from, the goal of treatment is to alleviate the painful symptoms caused by delirium, and it is important to take a holistic approach for patients and family members.

Young adult survivors of childhood cancer may have a perception gap with their families. Patients aged 18-39 years after treatment of cancer and their families (28 pairs) completed a survey that contained questions on health-related quality of life using the 36-item short form survey. There was a significant difference in the role-social component score (mean difference -2.23; p  = 0.04) with family reporting higher scores than patients. Families may overestimate the social function of cancer survivors, emphasizing the importance of the long-term follow-up by taking into account the risk of a gap (IRB approval No.: R2257-1).

Background: Clinical usefulness of trazodone for delirium in patients receiving palliative care is unclear. Objectives: To examine the safety and effectiveness of trazodone for delirium. Design: A secondary analysis of a multicenter prospective observational study. Setting/Subjects: The setting involves nine psycho-oncology consultation services and 14 inpatient palliative care units in Japan. Measurements: The measurement involves the Delirium Rating Scale (DRS) Revised-98 for effectiveness and the CTCAE (Common Terminology Criteria for Adverse Events) version 4 for safety assessments. Results: Thirty-eight patients enrolled the study. Mean age was 75 years. After three-day observation, the DRS total score (11.6 ± 5.3 to 8.7 ± 6.5 [difference -2.9, 95% confidence interval -5.3 to -0.5, p  = 0.02]); sleep-wake cycle disturbance ( p  = 0.047), lability of affect ( p  < 0.001), and motor agitation subscales ( p  < 0.001) were significantly decreased. The most frequent adverse event was somnolence ( n  = 9). Conclusions: Low-dose trazodone treatment was generally safe and may be effective in reducing delirium severity.

Importance: The Assessment of Quality of Activities (A-QOA) is an observation-based tool for assessing the strength of engagement in an activity by the person performing it in a natural context. By quantifying the quality of engagement, the A-QOA can help occupational therapy practitioners be better able to select meaningful activities and more clearly understand the effectiveness of various choices., Objective: To examine use of the A-QOA as a valid unidimensional scale and to clarify preliminary results on its internal scale validity and item reliability using the Rasch model., Participants: One hundred thirty-one participants with dementia performing 262 activities., Outcomes and Measures: We used the Rasch model to clarify the psychometric properties of A-QOA's measurement quality., Results: Rasch analysis revealed that 21 of the 25 items reached an acceptable level of fit, and 4 did not. After eliminating the 4 misfitting items, the resulting A-QOA was determined to have both acceptable internal scale validity and item separation reliability, which are fundamental psychometric properties of a clinical observational instrument., Conclusions and Relevance: The A-QOA can be used to quantitatively assess the strength of engagement in an activity by the person performing it by using the observational method., What This Article Adds: In clinical settings, the A-QOA can be used both to select activities for clients with dementia and to quantitatively show the effects of occupational therapy interventions., (Copyright © 2021 by the American Occupational Therapy Association, Inc.)

Introduction: This study is aimed at understanding how practicing the use of public transportation can affect the self-efficacy and perceptions of occupational enablement among patients with physical disabilities in a recovery rehabilitation hospital., Method: We recruited 21 inpatients with physical disabilities caused by stroke or orthopedic diseases from a recovery rehabilitation hospital in Japan and used a multimethod design including an intervention study and a follow-up survey. The intervention study utilized a before-after trial and provided hands-on training in the use of public transportation as the intervention. How self-efficacy and perceptions of occupational enablement changed before and after the intervention was measured using the visual analog scale (VAS). The follow-up survey was conducted to investigate whether patients used public transportation postdischarge., Results: Only differences in the VAS scores regarding self-efficacy were significant between before and after the hands-on training in the use of public transportation, whereas differences regarding the perceptions of occupation enablement were not. Self-efficacy after the intervention was higher than that before the intervention. In the follow-up survey, both VAS scores of the psychological factors were significantly higher in the group that used public transportation postdischarge than in the group that did not., Conclusion: Providing hands-on training in the use of public transportation for inpatients with physical disabilities increased their self-efficacy, indicating that psychological factors should be evaluated to predict their occupational skill improvement and to verify the outcomes of an occupational therapeutic intervention., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of the article., (Copyright © 2020 Masahiro Ogawa et al.)

We investigated the periods from symptom onset to the first visit to the psychiatric consultation and the factors that influence psychiatric help-seeking behavior in university students. Students who first visited the psychiatric department of university health care center were the study participants. We surveyed the elicited information such as age, sex, period from symptom onset to the first visit, main symptoms, General Health Questionnaire GHQ-12, and perception of stigma associated with receiving a psychiatric consultation. We analyzed the factors affecting the duration until a psychiatric consultation was made using logistic regression analysis, examining age, sex, contents of the problem, GHQ-12, and stigma as independent variables. Of the participants, 48.2 % did not consult with a psychiatrist for more than 6 months and 51 participants (36.7 %) took more than a year before a consultation. We divided the study participants into two groups: early examinees and delayed examinees. In order to investigate the factors affecting the two groups, logistic regression analysis was performed. Of the independent variables, one consultation content (physical symptoms; odds ratio (OR) = 9.21, 95 % CI (confidence interval) = 2.00-42.62, p = 0.004) and the GHQ-12 (OR = 1.17, 95 % CI = 1.05-1.31, p = 0.005) were significant factors. It became clear that physical symptoms significantly accelerated consultation with psychiatry. When various problems occurred, the decision to seek a psychiatry consultation required a long time. Health education focusing on the values of seeking an early consultation is required so that when students have mental health problems they will seek psychiatric services in a timely manner., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest to report., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aims: Psychologic stress can affect the pathogenesis of inflammatory bowel disease (IBD), but the precise contribution of psychologic stress to IBD remains unclear. We investigated the association of psychologic stress with disease activity in patients with IBD, especially in terms of mental state and sleep condition., Methods: This was a multi-center observational study comprising 20 institutions. Data were collected using survey forms for doctors and questionnaires for patients, and the association of psychologic stress with clinical parameters was investigated. Mental state was evaluated using the Center for Epidemiologic Studies Depression (CES-D) scale, and sleep condition was evaluated by querying patients about the severity of insomnia symptoms., Results: A total of 1078 IBD patients were enrolled, including 303 patients with Crohn's disease and 775 patients with ulcerative colitis. Seventy-five percent of IBD patients believed that psychologic stress triggered an exacerbation of their disease (PSTE group) and 25% did not (non-PSTE group). The CES-D scores were significantly higher for patients with clinically active disease than for those in remission in the PSTE group (median (interquartile range) = 7 (4-9.5) vs. 5 (3-7), p < .0001), but not in the non-PSTE group (5 (2-8) vs. 4 (3-7), p = 0.78). Female sex and disease exacerbation by factors other than psychologic stress were independent factors of psychologic stress-triggered disease exacerbation. Also, patients with insomnia had higher disease activity than those without insomnia, especially in the PSTE group., Conclusions: A worsened mental state correlates with disease activity in IBD patients, especially those who believe that their disease is exacerbated by psychologic stress., Competing Interests: The author has declared that no competing interests exist. The authors have no competing interests which can alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The Japanese Psycho-Oncology Society and Japanese Association of Supportive Care in Cancer recently launched the clinical practice guidelines for delirium in adult cancer patients. The aim of the guidelines was to provide evidence-based recommendations for the clinical assessment and management of delirium in cancer patients. This article reports the process of developing the guideline and summarizes the recommendations made., Methods: The guidelines were developed in accordance with the Medical Information Network Distribution Service creation procedures. The guideline development group, consisting of multidisciplinary members, formulated nine clinical questions. A systematic literature search was conducted to identify relevant articles published prior to through 31 May 2016. Each article was reviewed by two independent reviewers. The level of evidence and the strength of the recommendations were graded using the grading system developed by the Medical Information Network Distribution Service, following the concept of The Grading of Recommendations Assessment, Development and Evaluation system. The modified Delphi method was used to validate the recommendation statements., Results: This article provides a summary of the recommendations with rationales for each, as well as a short summary., Conclusions: These guidelines will support the clinical assessment and management of delirium in cancer patients. However, additional clinical studies are warranted to further improve the management of delirium., (© The Author(s) 2020. Published by Oxford University Press.)

Background: This study aimed to investigate the use of psychosocial support services, the intention to use these services, and to elucidate the characteristics of survivors most likely to use support services among Japanese breast cancer survivors., Methods: We invited breast cancer survivors to complete an online questionnaire via an email sent to subscribers of a non-profit organization mailing list. We asked participants questions related to demographics, opinions on the state of psychosocial support services, and their interest in using these services. Participants were also asked to complete the Hospital Anxiety and Depression Scale and the Brief Cancer Worry Inventory (BCWI)., Results: We analyzed the data of 171 participants. Those who used some form of psychosocial support service constituted 50.9% of the participant population. Participants used cancer consulting and support center services (13.5%), hospital and non-hospital support groups (12.9%, respectively), psychiatry (11.1%), hospital and non-hospital cancer salons (8.8%, respectively), psychosomatic medicine (8.2%), therapist counseling (6.4%) and psycho-oncology department services (4.1%). Non-users who suffered from adjustment disorders or major depression (52.1%) reported higher total BCWI and the subscale scores had no concrete plans to use psychosocial support services., Conclusions: The usage levels of psychiatry, psychosomatic medicine and psycho-oncology services in our study were higher than those reported in any previous Japanese study within the psycho-oncology field. Participants joining a breast cancer survivors' mailing list, or their being female, may have led to a higher use of such services. A high degree of distress does not necessarily lead cancer survivors to seek psychosocial support services., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

To compare the efficacy of antipsychotics (APs) for delirium treatment in patients with cancer, 27 patients treated with 1 of the 4 APs, haloperidol (HPD), risperidone (RIS), olanzapine (OLZ), and quetiapine (QTP), were divided into 2 groups: long half-life (T1/2; HPD, RIS, and OLZ) versus short T1/2 (QTP) or the multiacting receptor-targeted APs (MARTAs; OLZ and QTP) versus the non-MARTA (HPD and RIS). The symptom severity was evaluated by the memorial delirium rating scale (MDAS) on days 0, 3, and 7 following intervention. Significant improvements in total MDAS scores were found in all groups on day 3. However, on day 7, only the short T1/2 group and MARTA group showed significant improvement. Consideration of an AP's pharmacological properties may be helpful for improving the outcomes of pharmacological delirium intervention in patients with cancer., (© The Author(s) 2014.)

Paclitaxel (Px) is an effective chemotherapeutic agent for the treatment of various cancers. However, it is often associated with neurological side effects, including chemotherapy-associated cognitive impairment (CACI), such as "chemobrain". Previously, we reported that endoplasmic reticulum (ER) stress is involved in Px-induced neurotoxicity, and immunoglobulin heavy chain binding protein (BiP) inducer X (BIX) alleviates Px-induced neurotoxicity. However, BIX has not been used in clinical practice yet. We recently reported that fluvoxamine (Flv) alleviates ER stress via induction of sigma-1 receptor (Sig-1R). The purpose of this study was to investigate whether Flv could alleviate Px-induced neurotoxicity in vitro . SK-N-SH cells were pre-treated for 12 h with or without 10 μg/ml Flv followed by treatment with 1 μM Px with or without co-existence of 10 μg/ml Flv for 24 h. To investigate the involvement of Sig-1R in alleviation effect on Px-induced neurotoxicity,1 μM NE100, an antagonist of Sig-1R, was added for 24 h. Neurotoxicity was assessed using the MTS viability assay and ER stress-mediated neurotoxicity was assessed by evaluating the expression of C/EBP homologous protein (CHOP), cleaved caspase 4, and cleaved caspase 3. Pre-treatment with Flv significantly alleviated the induction of CHOP, cleaved caspase 4, and cleaved caspase 3 in SK-N-SH cells. At the same time, pre-treatment with Flv significantly induced Sig-1R in SK-N-SH cells. In addition, viability was significantly higher in Flv-treated cells than in untreated cells, which was reversed by treatment with NE100. Our results suggest that Flv alleviates Px-induced neurotoxicity in part through the induction of Sig-1R. Our findings should contribute to one of the novel approaches for the alleviation of Px-induced neurotoxicity, including chemobrain.

Purpose: Bereaved families often suffer from insomnia and depression. However, the associations between depressive state and changes in sleep condition during the grieving process have not been investigated. This study aimed to clarify the prevalence of insomnia symptoms and to explore associations between present depressive state and changes in sleep condition in the grieving process in bereaved families of Japanese patients with cancer., Methods: A cross-sectional, multicenter survey was conducted in 103 certified palliative care units. A questionnaire asking insomnia symptoms and depressive symptoms by the Center for Epidemiological Studies Depression Scale (CES-D) was mailed to bereaved families (N = 987). The association between present depressive state (CES-D ≥7) and sleep conditions in the grieving process were analyzed., Results: A total of 561 families were enrolled for analysis. Fifty-three percent of family members were considered to be in a depressive state at the time of the investigation. Prevalence of past insomnia was 86.5% at "within a few weeks before the patient's death" (T1) and 84.5% at "within 6 months after the patient's death" (T2) in all bereaved family members. However, in contrast to decreased severity of insomnia between T1 and T2 in the non-depressive group (p < 0.05), severity of insomnia was unchanged in the depressive group during this period (p = 0.139)., Conclusions: Insomnia symptoms are highly prevalent and may be associated with posthumous depressive state in bereaved Japanese families. These results suggest the need for careful observation of changes in sleep condition during the grieving process.

Cancer patients often suffer from various distresses, including cognitive impairment. Cognitive impairment during and after cancer diagnosis and treatment are collectively called "Cancer-related cognitive impairment (CRCI)". The number of publications about cognitive impairment due to cancer therapy, especially chemotherapy, hormonal therapy, and radiotherapy, has been growing. Patients often worry not only about their disease condition and therapies, but also experience concerns regarding their memory, attention, and ability to concentrate. Even subtle CRCI can have a significant impact on social relationships, the ability to work, undergo treatment, accomplish meaningful goals, and the quality of life. Longitudinal studies of cancer patients indicated that up to 75% experience CRCI during treatment. Furthermore, CRCI may persist for many years following treatment. However, it is not well understood by most physicians and medical staff. CRCI can be mediated through increased inflammatory cytokines and hormonal changes. In addition, the biology of the cancer, stress, and attentional fatigue can also contribute to CRCI. Genetic factors and co-occurring symptoms may explain some of the inter-individual variability in CRCI. Researchers and patients are actively trying to identify effective interventional methods and useful coping strategies. Many patients are willing to discuss their disease condition and future treatment with medical staff and/or their families. Some patients also hope to discuss their end-of-life care. However, it is difficult to express their will after developing cognitive impairment. Advance care planning (ACP) can help in such situations. This process involves discussion between a patient, their family, and clinicians to clarify and reflect on values, treatment preferences, and goals to develop a shared understanding of how end-of-life care should proceed. The number of cancer patients with cognitive impairment has been increasing owing to the super-aging of society. Psychiatrists need to develop appropriate care for them and understand the value of ACP. In this review, an outline of CRCI is given, especially related to cancer therapy such as chemotherapy, hormonal therapy, and radiation therapy. In addition, the importance of ACP to facilitate a living will for patients likely to develop impaired cognitive functions in the future is described.

Patients with cancer frequently suffer from insomnia symptoms, and additionally, their family members also often experience these symptoms. The aim of this study was to investigate the prevalence of insomnia symptoms in both family members and patients with hematological malignancies. We conducted an observational cross-sectional study using a clinical self-reported questionnaire for sleep conditions, depressive symptoms (two-question method), and worries (five items that originated from the Brief Cancer Worry Inventory). One hundred twelve family members and 153 patients were investigated. A t test and Chi-square test were used to compare the prevalence of insomnia and depressive symptoms between family members and patients. Logistic regression was used to determine whether insomnia symptoms or worries related to patients' disease had an impact on depressive symptoms. The presence of insomnia symptoms in family members (87 %) was significantly higher than that in patients (60 %, p < 0.001). The prevalence of depressive mood and anhedonia in family members were 55 and 34 %, respectively, and these values were higher than those in patients (43 and 28 %, respectively). Insomnia symptoms and worries about present/prospective disease conditions were significantly associated with depressive mood (insomnia symptoms, odds ratios (OR) 4.3, confidence intervals (CI) 1.2-15.2, p = 0.025; worries, OR 4.4, CI 1.0-19.3, p = 0.048). Taken together, our results demonstrated that insomnia symptoms and depressive symptoms are highly prevalent in family members as well as in patients with hematological malignancies.

We recently demonstrated that endoplasmic reticulum (ER) stress induces sigma-1 receptor (Sig-1R) expression through the PERK pathway, which is one of the cell's responses to ER stress. In addition, it has been demonstrated that induction of Sig-1R can repress cell death signaling. Fluvoxamine (Flv) is a selective serotonin reuptake inhibitor (SSRI) with a high affinity for Sig-1R. In the present study, we show that treatment of neuroblastoma cells with Flv induces Sig-1R expression by increasing ATF4 translation directly, through its own activation, without involvement of the PERK pathway. The Flv-mediated induction of Sig-1R prevents neuronal cell death resulting from ER stress. Moreover, Flv-induced ER stress resistance reduces the infarct area in mice after focal cerebral ischemia. Thus, Flv, which is used frequently in clinical practice, can alleviate ER stress. This suggests that Flv could be a feasible therapy for cerebral diseases caused by ER stress.

Background: Ketamine is often used to manage neuropathic pain in patients with cancer. However, it occasionally causes psychotomimetic effects such as vivid dreams, nightmares, illusions, hallucinations, and altered body image., Objective: To examine whether gradual dose titration of ketamine for management of neuropathic pain prevents psychotomimetic effects in patients with advanced cancer., Methods: This was a retrospective chart review. We administered ketamine when neuropathic pain in patients with advanced cancer became refractory to opioids and oral adjuvant analgesics. The starting dose of ketamine was 10 mg/d by continuous intravenous infusion. The dose was gradually increased by 10 mg/d every 4 to 6 hours to 50 mg/d or until the pain was relieved. It was subsequently increased by 25 mg/d every 12 to 24 hours until the pain was relieved., Results: For this study, we enrolled 46 patients with advanced cancer. The mean age was 52.2 ± 16.9 years. The mean dose at onset of action and maximum dose of ketamine were 56 ± 58 and 272 ± 214 mg/d, respectively. The mean pain intensity (numerical rating scale) decreased significantly from 7.3 ± 2.0 to 3.5 ± 2.2 after the administration of ketamine (P < .01). The effectiveness was 69.5%. No psychotomimetic effect of less than 300 mg/d was observed during the introduction phase even though psychotropic drugs were not prescribed. Mild sedation was observed in 3 patients (7%) as the only adverse effect during the introduction phase., Conclusion: Gradual dose titration of ketamine for management of neuropathic pain can prevent psychotomimetic effects in patients with advanced cancer.

Due to chemotherapy, the majority of breast cancer patients survive, but frequently complain of chemotherapy-associated cognitive impairment. This phenomenon is termed "chemobrain" or "chemofog" in the literature. However, its mechanisms are unclear. The objective of this study was to investigate the mechanisms of paclitaxel (Px)-induced neurotoxicity, with a focus on endoplasmic reticulum (ER) stress. To investigate Px-induced neurotoxicity and ER stress induction, SK-N-SH cells were treated with 1, 10, 50, and 100 μM Px for 24 h. Neurotoxicity was assessed using MTS viability assays, and ER stress was assessed by evaluating the expression of phosphorylated elF2α (phospho-eIF2α), C/EBP homologous protein (CHOP), and cleaved caspase 4 and caspase 3 (the active form of each caspase). Furthermore, to investigate whether immunoglobulin heavy-chain binding protein (BiP) inducer X (BIX), which induces the molecular chaperone BiP, could attenuate Px-induced neurotoxicity, SK-N-SH cells were pre-treated for 12 h with 3.5 μM BIX before Px treatment. Neurotoxicity was observed in SK-N-SH cells treated with Px in a dose-dependent manner compared with vehicle control. Furthermore, phospho-eIF2α, CHOP, and activated caspase 4 and caspase 3 were significantly induced in Px-treated cells. In addition, pre-treatment with BIX significantly attenuated the induction of CHOP and activated caspase 4 and caspase 3. The viability of BIX pre-treated cells prior to Px treatment was significantly increased compared with cells that were not treated with BIX. Our results suggest that Px induces neurotoxicity in part through activating the ER stress response. Our findings should contribute to novel approaches regarding the mechanism of Px-induced neurotoxicity, including chemobrain., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Patients with cancer often experience insomnia. Nightmares are also a strong factor that interferes with the maintenance of comfortable and satisfying sleep. However, the prevalence and standard treatment of nightmares in patients with cancer have not been established yet. We aimed to treat insomnia and nightmares with trazodone. From 2008 to 2011, trazodone was prescribed to 30 patients with cancer who reported experiencing insomnia with or without nightmares to the palliative care team in Osaka University Hospital. Effective treatment was seen in 15 patients (50%). Four patients with cancer reported having severe nightmares and 2 patients had beneficial effects, with frightening dreams transformed into acceptable ones. Trazodone may be an effective drug for the treatment of insomnia and nightmares in patients with advanced cancer.

Objectives: A meta-analysis of the associations between genetic variants in the AKT1 gene and schizophrenia found that a single nucleotide polymorphism (SNP5; rs2494732) was associated with schizophrenia in Asian populations., Methods: In this study, we investigated the effects of this SNP on memory and attentional performance and brain structure using magnetic resonance imaging in a Japanese population (117 patients with schizophrenia and 189 healthy subjects)., Results: The memory performance, particularly attention/concentration score, measured by the Wechsler Memory Scale-Revised in A carriers of SNP5, which was found to be enriched in patients with schizophrenia, was lower than that in individuals with the G/G genotype. We confirmed the association of the SNP with attentional performance using the Continuous Performance Test, which assessed sustained attention and vigilance of attentional function. Patients with A allele demonstrated lower attentional performance than patients with the G/G genotype. Patients with the A allele had smaller gray matter volumes in the right inferior parietal lobule related to attentional processes and in the frontostriatal region related to different SNPs in AKT1 than patients with the G/G genotype., Conclusions: Our results suggest that a genetic variant of AKT1 might be associated with attentional deficits and brain morphological vulnerability in patients with schizophrenia.

Tauopathy is a pathological condition with an abnormal intracellular accumulation of tau protein in neurons and glias, which is a feature of Alzheimer's disease (AD) as well as frontotemporal lobar degenerations (FTLD). Recent reports showed that tauopathy occupies an important position for pathological process of dementia generally. Previously, we reported that endoplasmic reticulum (ER) stress has an influence on the onset of AD. In addition, some reports on brain autopsy findings suggest that ER stress is associated with AD and tauopathy. However, the mechanism underlying the association between ER stress and tauopathy is still unknown. Here, we show that ER stress, induced by glucose deprivation or chemicals, increases total endogenous tau protein in cultured neurons and primary cultured neurons. Under ER stress, no significant differences were observed in the transcription of tau, and no differences were observed in the translation of tau with or without the 5'-untranslated region (5'UTR) of tau. In contrast, the degradation rate of tau was decreased by 20% under ER stress. ER stress reduced the binding between tau and carboxyl terminus of Hsc70-interacting protein (CHIP), ubiquitin E3 ligase for tau. These results suggest that ER stress increases total tau protein and its mechanism is due to the decrease in the binding between tau and CHIP, which delays the degradation of tau protein through the ubiquitin-proteasome pathway. This mechanism may provide clue to treatment for tauopathy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Agitated delirium is often observed in terminal patients with cancer. To clarify the risk factors for agitated delirium in terminal patients with cancer, we conducted a retrospective chart review of 126 patients with cancer who died at a university hospital in 2008., Method: As a working definition, we define agitated delirium as a score of 2 or more in item 9 of the Memorial Delirium Assessment Scale with diurnal variation., Results: The results were as follows: agitated delirium was observed in 49 (42%) of the 115 patients, and it occurred within the last week before death in 49% of the patients. Univariate analysis revealed older age, male gender, smoking history, lung cancer, diabetes, and high C-reactive protein (CRP) value as major risk factors, while dendritic analysis revealed lung cancer, high CRP value, diabetes, older age, and smoking history as key factors for predicting agitation., Conclusion: It is necessary to consider risk factors in order to categorize terminal patients with cancer into high- and low-risk groups and undertake possible counter-measures.

Sigma-1 receptors (Sig-1Rs) are the ER resident proteins. Sig-1Rs in the brain have been reported to be significantly reduced in patients with schizophrenia. The impediment of regulating Sig-1Rs expression levels increases the risk for schizophrenia. Thus elucidating the mechanism regulating Sig-1Rs expression might provide the strategy to prevent mental disorders. In this study, we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. Moreover, ATF4 directly bounds to the 5' flanking region of Sig-1R gene. The reporter activities using this region were enhanced in ER stress, or by ATF4 alone. The reporter activities with the pathogenic polymorphisms (GC-241-240TT, T-485A) were reduced. In addition, the processing of Caspase-4 was inhibited by Sig-1Rs. These results indicate that Sig-1Rs are transcriptionally upregulated via the PERK/eIF2α/ATF4 pathway and ameliolate cell death signaling. This study is the first report identifying the transcription factor regulating Sig-1Rs expression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Milnacipran is one of the classes of drugs that are serotonin and norepinephrine reuptake inhibitors (SNRIs). It is a promising drug for the treatment of neuropathic pain in patients with advanced cancer. However, we found that neuromuscular and somatosensory disorders occurred when milnacipran was used as an adjuvant analgesic., Case Report: A 66-year-old woman with a history of neuropathic pain was given 15 mg of milnacipran after dinner. The next morning she developed stiffness of the fingers, numbness in the mandible, and the soles of her feet felt swollen. Milnacipran was discontinued and her symptoms disappeared immediately. We managed this case, which was becoming severe, by discontinuing milnacipran on early detection of symptoms., Discussion: This is the first report that demonstrates an adverse reaction of milnacipran when used as an analgesic adjuvant, and not as an antidepressant drug, for neuropathic pain in patients with advanced cancer. The analgesic effect of SNRIs will likely be used in the management of neuropathic pain in the future; however, clinicians should be aware of the early adverse reactions to these agents.

A recent genome-wide association study showed that a variant (rs1344706) in the ZNF804A gene was associated with schizophrenia and bipolar disorder. Replication studies supported the evidence for association between this variant in the ZNF804A gene and schizophrenia and that this variant is the most likely susceptibility variant. Subsequent functional magnetic resonance imaging studies in healthy subjects demonstrated the association of the high-risk ZNF804A variant with neural activation during a memory task and a theory of mind task. As these cognitive performances are disturbed in patients with schizophrenia, this gene may play a role in cognitive dysfunction in schizophrenia. The aim of the current study was to investigate the potential relationship between this ZNF804A polymorphism and memory function. The effects of the high-risk ZNF804A genotype, diagnosis, and genotype-diagnosis interaction on verbal memory, visual memory (VisM), attention/concentration, and delayed recall (measured by the Wechsler Memory Scale-Revised) were analyzed by two-way analysis of covariance in 113 patients with schizophrenia and 184 healthy subjects. Consistent with previous studies, patients with schizophrenia exhibited poorer performance on all indices as compared to healthy control subjects (P < 0.001). A significant ZNF804A genotype-diagnosis interaction was found for VisM performance (P = 0.0012). Patients with the high-risk T/T genotype scored significantly lower on VisM than G carriers did (P = 0.018). In contrast, there was no genotype effect for any index in the healthy control subjects (P > 0.05). Our data suggest that rs1344706 may be related to memory dysfunction in schizophrenia. © 2010 Wiley-Liss, Inc., (Copyright © 2010 Wiley-Liss, Inc.)

The patient was a 57-year-old woman with malignant pleural mesothelioma. She had a past history of anxiety neurosis but not had any history of otological diseases. On admission to our hospice (day 1), she complained of dyspnea and wheezing associated with the progression of her underlying disease. After we started oral betamethasone (2 mg/d), dyspnea was alleviated and the frequency of wheezing was reduced. On day 3, she began to experience musical hallucinations that were manifested in opera/piano concert music and a child's voice. The episodes of musical hallucinations occurred approximately 10 times a day and disappeared spontaneously within several minutes. She had not experienced these symptoms before. We reduced the dose of betamethasone to 1 mg/d, but the musical hallucinations continued. Then on day 11, we switched betamethasone (1 mg/d) to prednisolone (10 mg/d) and we then gradually tapered off prednisolone. The frequency of musical hallucinations decreased and she ceased to experience musical hallucinations on day 29. However, on day 40, her dyspnea was aggravated again, so we started treatment with prednisolone (5 mg/d). Dyspnea was alleviated and no musical hallucinations occurred. On Day 51, dyspnea was worsened and we switched prednisolone to betamethasone (4 mg/d), which she hoped to use. The betamethasone alleviated the dyspnea but she developed musical hallucinations that were similar to the previous episodes. The musical hallucinations disappeared spontaneously 4-5 days later without changing the betamethasone. Musical hallucinations never occurred thereafter. She later died due to the exacerbation of disease.

Background: During intramembrane proteolysis of β-amyloid protein precursor (βAPP) by presenilin (PS)/γ-secretase, ε-cleavages at the membrane-cytoplasmic border precede γ-cleavages at the middle of the transmembrane domain. Generation ratios of Aβ42, a critical molecule for Alzheimer's disease (AD) pathogenesis, and the major Aβ40 species might be associated with ε48 and ε49 cleavages, respectively. Medicines to downregulate Aβ42 production have been investigated by many pharmaceutical companies. Therefore, the ε-cleavages, rather than the γ-cleavage, might be more effective upstream targets for decreasing the relative generation of Aβ42. Thus, one might evaluate compounds by analyzing the generation ratio of the βAPP intracellular domain (AICD) species (ε-cleavage-derived), instead of that of Aβ42., Methods: Cell-free γ-secretase assays were carried out to observe de novo AICD production. Immunoprecipitation/MALDI-TOF MS analysis was carried out to detect the N-termini of AICD species. Aβ and AICD species were measured by ELISA and immunoblotting techniques., Results: Effects on the ε-cleavage by AD-associated pathological mutations around the ε-cleavage sites (i.e., βAPP V642I, L648P and K649N) were analyzed. The V642I and L648P mutations caused an increase in the relative ratio of ε48 cleavage, as expected from previous reports. Cells expressing the K649N mutant, however, underwent a major ε-cleavage at the ε51 site. These results suggest that ε51, as well as ε48 cleavage, is associated with Aβ42 production. Only AICDε51, though, and not Aβ42 production, dramatically changed with modifications to the cell-free assay conditions. Interestingly, the increase in the relative ratio of the ε51 cleavage by the K649N mutation was not cancelled by these changes., Conclusion: Our current data show that the generation ratio of AICDε51 and Aβ42 do not always change in parallel. Thus, to identify compounds that decrease the relative ratio of Aβ42 generation, measurement of the relative level of Aβ42-related AICD species (i.e., AICDε48 and AICDε51) might not be useful. Further studies to reveal how the ε-cleavage precision is decided are necessary before it will be possible to develop drugs targeting ε-cleavage as a means for decreasing Aβ42 production., (© 2010 The Authors. Psychogeriatrics © 2010 Japanese Psychogeriatric Society.)

Background: Appropriate use of anti-infective drugs is essential in clinical practice. No evidence-based guidelines or protocols have been published on the appropriate use of anti-infective drugs in patients receiving palliative care as yet., Methods: The medical records, which included the demographic data of patients, anti-infective drug use, bacteriologic findings, symptoms, and hematologic findings were reviewed retrospectively to determine the potential factors that contribute to symptom improvement of patients in terminal phase., Results: Seventy-one patients (64%) who received anti-infective drugs and had a total of 326 episodes of infection were assessed. Symptom improvement was seen in 33.1%. A total of 22.6% of episodes were started on anti-infective drugs during the last week of life and the symptom improvement in these episodes was 9.2%. Symptom improvement was hardly observed when the anti-infective drug was administered during the last week of life. The association between the decrease in the C-reactive protein (CRP) levels, the decrease of the leukocyte count, reduction of fever, and symptom improvement was determined. The decrease of CRP levels was 42.4%; leukocyte, 56.7%; and reduction of fever was 28.4%. The symptom improvement of individual treatment history was also investigated. The symptom improvement of the group who took positive treatment such as chemotherapy, radiotherapy, surgery, and catheter placement was significantly lower than that of no-treatment group., Conclusions: Active cancer treatment probably induces the symptoms related to infection and the use of anti-infective drugs. Unnecessary and excessive treatment should be avoided, and the symptoms should be managed with consideration of the patient's state of mind in order to improve the quality of life of terminally ill patients.

Background/aims: A single-nucleotide polymorphism (SNP) in the KIBRA gene, rs17070145, was reported to be significantly associated with episodic memory in cognitively normal cohorts. This observation has expanded genetic studies on KIBRA to Alzheimer's disease (AD). Importantly, the association between KIBRA and episodic memory in AD has never been addressed. In this study, we investigated whether the KIBRA rs17070145 SNP influences AD episodic memory and the disease in a Japanese cohort., Methods: Blood samples from 346 AD patients and 375 normal cognitive controls were collected and genotyped for rs17070145. Episodic memory was measured in 32 AD patients, diagnosed for the first time, by use of the Rivermead Behavioral Memory Test (RBMT)., Results: We found that KIBRA C allele carriers scored significantly lower than KIBRA non-C carriers on both RBMT total profile score (p = 0.042, effect size = 0.84) and RBMT total screening score (p < 0.001, effect size = 1.42). The KIBRA gene did not show association with AD in our Japanese cohort., Conclusion: Our results evidence a strong association between the KIBRA gene and episodic memory impairment in AD, but show no influence on AD in our Japanese cohort. We propose that KIBRA might have an effect similar to cognitive reserve., (Copyright © 2010 S. Karger AG, Basel.)

The activity of protein phosphatase 2A (PP2A) is compromised and believed to be the cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain. Activity of PP2A is regulated by two endogeneous inhibitor proteins, called as I(1)(PP2A) and I(2)(PP2A). Previously, we reported that: (i) I(1)(PP2A) and I(2)(PP2A) are upregulated with cleavage of I(2)(PP2A) holoprotein and translocation of its amino terminal fragment from the nucleus to the cytoplasm in neuronal cells in AD brains; and (ii) translocated I(2)(PP2A) colocalized not only with the PP2A catalytic subunit, but also with phosphorylated tau in neuronal cytoplasm. Furthermore, according to preliminary data, the cleavage site of I(2)(PP2A) is located between amino acids 175 and 176 of the I(2)(PP2A) sequence. Because the sequence from amino acids 168 to 181 on I(2)(PP2A) presumably functions as a nuclear localization signal (NLS), inhibition of break down of the NLS in I(2)(PP2A) is expected to be a novel therapeutic target for the treatment of Alzheimer's disease.

G72 is one of the most widely tested genes for association with schizophrenia. As G72 activates the D-amino acid oxidase (DAO), G72 is termed D-amino acid oxidase activator (DAOA). The aim of this study is to investigate the association between G72 and schizophrenia in a Japanese population, using the largest sample size to date (1774 patients with schizophrenia and 2092 healthy controls). We examined eight single nucleotide polymorphisms (SNPs), which had been associated with schizophrenia in previous studies. We found nominal evidence for association of alleles, M22/rs778293, M23/rs3918342 and M24/rs1421292, and the genotype of M22/rs778293 with schizophrenia, although there was no association of allele or genotype in the other five SNPs. We also found nominal haplotypic association, including M15/rs2391191 and M19/rs778294 with schizophrenia. However, these associations were no longer positive after correction for multiple testing. We conclude that G72 might not play a major role in the risk for schizophrenia in the Japanese population.

Late-onset Alzheimer's disease (LOAD) is significantly associated with a single nucleotide polymorphism located in the dynamin (DNM) 2 gene, especially in non-carriers of the apolipoprotein E-epsilon4 allele. In this study we used real-time PCR to show that DNM2 mRNA is significantly reduced in the cortex of AD brains and in the peripheral blood of dementia patients. Neuroblastoma cells transfected with a dominant negative DNM2 had increased amyloid beta protein (Abeta) secretion and most of the amyloid precursor protein (APP) in these cells was localized to the plasma membrane. In addition, these cells were rich in flotillin, which is a component of lipid rafts. These data suggest that DNM2 expression is reduced in LOAD, which results in the accumulation of APP in lipid raft-rich plasma membranes. Consequently, Abeta secretion may increase in LOAD neurons.

Prepulse inhibition (PPI) and habituation of the acoustic startle reflex (ASR) are considered to be candidate endophenotypes of schizophrenia. However, to our knowledge, only one group has investigated these startle measures in Asian patients with schizophrenia. In the present study, we evaluated these startle measures in 51 Japanese patients with schizophrenia and compared them with those of 55 healthy age- and sex-matched Japanese controls. A human startle response monitoring system was used to deliver acoustic startle stimuli, and record and score the electromyographic activity of the orbicularis oculi muscle. The startle measures examined were mean magnitude of ASR to pulse alone trials in initial block (SR), habituation of ASR during the session (HAB), and PPI at prepulse intensities of 82 dB (PPI82), 86 dB (PPI86), and 90 dB (PPI90) sound pressure level. SR was not significantly different between the patients and controls. Patients displayed significantly reduced HAB and PPI for all prepulse intensities compared to controls. The greatest statistical difference in PPI between patients and controls was found with PPI86. This did not correlate with any clinical variable in each group. Our results indicate that PPI and habituation of ASR are impaired in Asian patients with schizophrenia.

The dentate gyrus, an important anatomic structure of the hippocampal formation, is one of the major areas in which neurogenesis takes place in the adult mammalian brain. Neurogenesis in the dentate gyrus is thought to play an important role in hippocampus-dependent learning and memory. Neurogenesis has been reported to be increased in the dentate gyrus of patients with Alzheimer disease, but it is not known whether the newly generated neurons differentiate into mature neurons. In this study, the expression of the mature neuronal marker high molecular weight microtubule-associated protein (MAP) isoforms MAP2a and b was found to be dramatically decreased in Alzheimer disease dentate gyrus, as determined by immunohistochemistry and in situ hybridization. The total MAP2, including expression of the immature neuronal marker, the MAP2c isoform, was less affected. These findings suggest that newly generated neurons in Alzheimer disease dentate gyrus do not become mature neurons, although neuroproliferation is increased.

Nausea and vomiting are distressing symptoms in advanced cancer patients. The causes of nausea and vomiting are multifactorial. Among the causes is opioid therapy, the mainstay of cancer pain management. When nausea or other opioid side effects occur, it may hamper pain management and undermine the quality of life of cancer patients. Risperidone exerts an antiemetic effect in animals, but there has been no clinical report on its antiemetic activity. We conducted a retrospective chart review to examine whether risperidone is useful for opioid-induced nausea and vomiting in advanced cancer patients (n=20). Risperidone was given as doses of 1mg once a day. Complete response was observed in 50% of patients (10/20) for nausea and 64% (7/11) for vomiting. Sedation (n=2) was documented as an adverse effect. This observation suggests that risperidone can be an effective antiemetic drug in the treatment of refractory opioid-induced nausea and vomiting in advanced cancer patients.