RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases.

The conversion of adenosine to inosine in RNA editing (A-to-I RNA editing) is recognized as a critical post-transcriptional modification of RNA by adenosine deaminases acting on RNAs (ADARs). A-to-I RNA editing occurs predominantly in mammalian and human central nervous systems and can alter the function of translated proteins, including neurotransmitter receptors and ion channels; therefore, the role of dysregulated RNA editing in the pathogenesis of neurological diseases has been speculated. Specifically, the failure of A-to-I RNA editing at the glutamine/arginine (Q/R) site of the GluA2 subunit causes excessive permeability of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors to Ca2+, inducing fatal status epilepticus and the neurodegeneration of motor neurons in mice. Therefore, an RNA editing deficiency at the Q/R site in GluA2 due to the downregulation of ADAR2 in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients suggests that Ca2+-permeable AMPA receptors and the dysregulation of RNA editing are suitable therapeutic targets for ALS. Gene therapy has recently emerged as a new therapeutic opportunity for many heretofore incurable diseases, and RNA editing dysregulation can be a target for gene therapy; therefore, we reviewed neurological diseases associated with dysregulated RNA editing and a new therapeutic approach targeting dysregulated RNA editing, especially one that is effective in ALS.

Extracellular RNAs as Biomarkers of Sporadic Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases.

Recent progress in the research for underlying mechanisms in neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) has led to the development of potentially effective treatment, and hence increased the need for useful biomarkers that may enable early diagnosis and therapeutic monitoring. The deposition of abnormal proteins is a pathological hallmark of neurodegenerative diseases, including ß-amyloid in AD, α-synuclein in PD, and the transactive response DNA/RNA binding protein of 43kDa (TDP-43) in ALS. Furthermore, progression of the disease process accompanies the spreading of abnormal proteins. Extracellular proteins and RNAs, including mRNA, micro RNA, and circular RNA, which are present as a composite of exosomes or other forms, play a role in cell-cell communication, and the role of extracellular molecules in the cell-to-cell spreading of pathological processes in neurodegenerative diseases is now in the spotlight. Therefore, extracellular proteins and RNAs are considered potential biomarkers of neurodegenerative diseases, in particular ALS, in which RNA dysregulation has been shown to be involved in the pathogenesis. Here, we review extracellular proteins and RNAs that have been scrutinized as potential biomarkers of neurodegenerative diseases, and discuss the possibility of extracellular RNAs as diagnostic and therapeutic monitoring biomarkers of sporadic ALS.

Age is the Most Significantly Associated Risk Factor With the Development of Delirium in Patients Hospitalized for More Than Five Days in Surgical Wards: Retrospective Cohort Study.

OBJECTIVE: The primary purpose of this study was to assess risk factors for delirium in patients staying in a surgical ward for more than 5 days. The secondary purpose was to assess outcomes in patients with delirium. BACKGROUND: Delirium is a syndrome characterized by acute fluctuations in mental status. Patients with delirium are at increased risk of adverse inpatient events, higher mortality and morbidity rates, prolonged hospital stays, and increased health care costs. METHODS: Participants in this study were 2168 patients who had been admitted to the surgical ward of St. Luke's International Hospital for 5 days or more between January 2011 and December 2014. Data on these patients were collected retrospectively from hospital medical records. Firstly, univariate and multivariate analyses were conducted to identify risk factors for delirium. Secondly, morbidity and mortality associated with delirium were analyzed. RESULTS: Delirium occurred in 205 of 2168 patients (9.5%). Age, physical restraint, past history of a cerebrovascular disorder, malignancy, intensive care unit stay, pain, and high blood urea nitrogen value were significant risk factors for delirium in the multivariate analysis. Among these, age was the strongest factor, with an odds ratio for delirium of 12.953 in patients 75 years of age or older. The length of hospital stays and the mortality rates were higher in patients with delirium. CONCLUSIONS: Results showed that age, and also physical restraint, past history of cerebrovascular disorder, malignancy, intensive care unit stay, pain, and high serum blood urea nitrogen were important factors associated with delirium in patients hospitalized for more than 5 days in a surgical ward.

A novel frameshift GRN mutation results in frontotemporal lobar degeneration with a distinct clinical phenotype in two siblings: case report and literature review.

BACKGROUND: Progranulin gene (GRN) mutations are major causes of frontotemporal lobar degeneration. To date, 68 pathogenic GRN mutations have been identified. However, very few of these mutations have been reported in Asians. Moreover, some GRN mutations manifest with familial phenotypic heterogeneity. Here, we present a novel GRN mutation resulting in frontotemporal lobar degeneration with a distinct clinical phenotype, and we review reports of GRN mutations associated with familial phenotypic heterogeneity. CASE PRESENTATION: We describe the case of a 74-year-old woman with left frontotemporal lobe atrophy who presented with progressive anarthria and non-fluent aphasia. Her brother had been diagnosed with corticobasal syndrome (CBS) with right-hand limb-kinetic apraxia, aphasia, and a similar pattern of brain atrophy. Laboratory blood examinations did not reveal abnormalities that could have caused cognitive dysfunction. In the cerebrospinal fluid, cell counts and protein concentrations were within normal ranges, and concentrations of tau protein and phosphorylated tau protein were also normal. Since similar familial cases due to mutation of GRN and microtubule-associated protein tau gene (MAPT) were reported, we performed genetic analysis. No pathological mutations of MAPT were identified, but we identified a novel GRN frameshift mutation (c.1118_1119delCCinsG: p.Pro373ArgX37) that resulted in progranulin haploinsufficiency. CONCLUSION: This is the first report of a GRN mutation associated with familial phenotypic heterogeneity in Japan. Literature review of GRN mutations associated with familial phenotypic heterogeneity revealed no tendency of mutation sites. The role of progranulin has been reported in this and other neurodegenerative diseases, and the analysis of GRN mutations may lead to the discovery of a new therapeutic target.

Psychological impact of breast cancer screening in Japan.

OBJECTIVE: The purpose of this study was to evaluate the psychological impact of breast cancer screening by use of mammography and/or ultrasound, and to reveal factors related to psychological distress. METHODS: Three hundred and twenty women were recalled to our hospital because of suspicious malignant findings from breast cancer screening between March and November 2012. They were asked to complete three questionnaires: the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression, the Brief Coping Orientations to Problems Experienced scale (Brief COPE) for coping styles, and an original questionnaire for personal information. RESULTS: Complete data were available for 312 of 320 women (97.5 %). The median age was 45 years (range 23-73). The HADS revealed borderline or clinically significant anxiety for 70 % of the women. Family history of breast cancer, area of residence, number of times screened, number of recalls, and the period before the first visit were significantly related to psychological distress (p < 0.05). Brief COPE scores showed that self-blame, behavioral disengagement, self-distraction, use of emotional support, venting, denial, and less acceptance were related to increased anxiety. CONCLUSION: Seventy percent of women who were recalled after breast cancer screening experienced psychological distress. Thus, negative psychological impact should be regarded as an adverse effect of breast cancer screening.

Roles of Aging, Circular RNAs, and RNA Editing in the Pathogenesis of Amyotrophic Lateral Sclerosis: Potential Biomarkers and Therapeutic Targets.

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease caused by upper and lower motor neuron death. Despite advances in our understanding of ALS pathogenesis, effective treatment for this fatal disease remains elusive. As aging is a major risk factor for ALS, age-related molecular changes may provide clues for the development of new therapeutic strategies. Dysregulation of age-dependent RNA metabolism plays a pivotal role in the pathogenesis of ALS. In addition, failure of RNA editing at the glutamine/arginine (Q/R) site of GluA2 mRNA causes excitotoxicity due to excessive Ca2+ influx through Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors, which is recognized as an underlying mechanism of motor neuron death in ALS. Circular RNAs (circRNAs), a circular form of cognate RNA generated by back-splicing, are abundant in the brain and accumulate with age. Hence, they are assumed to play a role in neurodegeneration. Emerging evidence has demonstrated that age-related dysregulation of RNA editing and changes in circRNA expression are involved in ALS pathogenesis. Herein, we review the potential associations between age-dependent changes in circRNAs and RNA editing, and discuss the possibility of developing new therapies and biomarkers for ALS based on age-related changes in circRNAs and dysregulation of RNA editing.

Some people living with HIV might need to pay attention to their mental health during the COVID-19 two years pandemic in Tokyo until the Omicron variant occur.

People living with HIV (PLWH) have a higher prevalence of psychiatric disorders than the general population. We retrospectively examined the medical records of PLWH who underwent the Kessler Psychological Distress Scale-10, the Patient Health Questionnaire-9, and the Generalized Anxiety Disorder-7 at an HIV referral hospital during the COVID-19 pandemic. Some PLWH who were unemployed with a history of psychiatric visits may remain in poor mental health during the prolonged COVID-19 pandemic until the Omicron variant occurs, so they may need to pay attention to their mental health.

Tracheoarterial fistula in a patient with amyotrophic lateral sclerosis successfully managed by overinflation of the tracheostomy tube cuff alone: a case report.

BACKGROUND: Tracheoarterial fistula is the most devastating complication after tracheostomy, and its mortality, without definitive treatment, approaches 100%. In general, the combination of bedside emergency management, that is, overinflation of the tracheostomy tube cuff, and definitive treatment such as surgical or endovascular intervention is necessary to prevent the poor outcome. Patients with neuromuscular diseases such as amyotrophic lateral sclerosis are susceptible to tracheoarterial fistula because of long-term mechanical ventilation and muscle weakness. CASE PRESENTATION: We describe a case of tracheoarterial fistula in a Japanese 39-year-old patient with amyotrophic lateral sclerosis with long-term ventilator management. The patient was clinically diagnosed with a tracheoarterial fistula because of massive bleeding following sentinel hemorrhage. The massive hemorrhage was controlled by overinflation of the tracheostomy tube cuff alone, without definitive treatment. CONCLUSIONS: This case suggests overinflation of the tracheostomy tube cuff alone plays an important role, semi-permanently, in the management of tracheoarterial fistula, especially in cases where surgical or endovascular intervention is not indicated. Clinicians taking care of patients with tracheostomy undergoing long-term mechanical ventilation should be aware that tracheoarterial fistula might occur following tracheostomy.

[The relevance of occupational physician for physicians].

The Japan Medical Association launched a project team to examine health conditions of physicians working at hospitals in 2008. First, cross-sectional study was conducted among total number of 10,000 physicians, who were randomly selected from the Japan Medical Association (JMA). They were asked to fill in a basic questionnaire that was used to collect demographic data and to complete the Japanese version of Quick Inventory of Depressive Symptomatology (QIDS-SR-16). As a result, an adjusted response rate was 40.5%. Fifty-three % of the respondents did not consult with the colleagues about their unhealthy conditions, 46% had less than 4 holidays in a month, and 41% slept for less than 6 hours. More importantly, from a psychiatric point of view, 6% thought of committing suicide several times a week, 9% showed lack of interest, and 6% felt lack of energy. The QIDS-SR-16 also indicated 8.7% were in a moderately depressed state and 1.9% suffered from severe depression. Secondly, the project team provided a consulation service through E-mail and telephone to listen and advice to JMA members who had the needs. However, there were only few consultations that took place. Thirdly, the project team held several workshops in 12 different locations targeting occupational physicians working in hospitals. The workshops included case conferences and lectures on mental health. From 2010 to 2011, there were total of 450 participants. Finally, in addition to these attempts, the author has been working as an occupational physician for a major department of a University hospital. The author thinks from these experiences that the location of an external occupational physician would be most effective for prevention and early detection of mental problems among physicians working in hospitals.

Association of depression and suicidal ideation with unreasonable patient demands and complaints among Japanese physicians: a national cross-sectional survey.

BACKGROUND: Physicians' mental health can be affected by unreasonable demands and complaints made by patients. PURPOSE: The purpose of this study is to determine the association between depressive symptoms and suicidal ideation among physicians working in hospitals in Japan and unreasonable patient demands and complaints. METHODS: We sent an anonymous questionnaire to 10,000 randomly selected physicians working at hospitals who were members of the Japan Medical Association. The anonymous self-report questionnaire sought to determine the number of unreasonable demands and complaints made by patients or their family members reported by physicians in the previous 6 months. Depressive symptoms and suicidal ideation were measured using the Japanese version of the Quick Inventory of Depressive Symptomatology (QIDS). Logistic regression analysis was used to explore the associations of depressive symptoms and suicidal ideation with reported unreasonable demands and complaints. RESULTS: Among the 3,864 respondents, men (46.3%) reported experiencing unreasonable patient demands and complaints more frequently than women (40.4%). Depressive symptoms were indicated in 8.3% of men and 10.5% of women, and 5.7% of men and 5.8% women were determined to exhibit suicidal ideation. The number of unreasonable demands and complaints in the previous 6 months was significantly associated with depressive symptoms and suicidal ideation for both men and women (P for trend <0.01). CONCLUSIONS: Physicians should recognize the health risks of unreasonable demands and complaints, and hospitals should provide support for physicians dealing with these stressors.

Japanese version of the Delirium Rating Scale, Revised-98 (DRS-R98-J): reliability and validity.

BACKGROUND: Delirium is a common neuropsychiatric disorder in medical and surgical inpatients of all ages. It is associated with increased long-term mortality, longer length of hospital stay, poor functional recovery, and increased likelihood of nursing home placement. OBJECTIVE: The aim of this study was to investigate the reliability and the validity of the Japanese translation of the Delirium Rating Scale, Revised-98 (DRS-R-98). METHOD: Psychiatric-consultation patients were assessed to compare groups of delirium, dementia, and non-delirium. RESULTS: Mean Total and Severity scores significantly distinguished delirium from the other groups. The scale had high interrater reliability and high internal consistency. Mean Severity scores during delirium differed from the posttreatment scores. Stratum-specific likelihood ratios showed that the DRS-R98-J is a reliable diagnostic tool. CONCLUSION: This study indicates that the Japanese version of the DRS-R-98 has high reliability and validity, and is a useful tool for assessing delirium among Japanese medically ill populations.

National survey of the association of depressive symptoms with the number of off duty and on-call, and sleep hours among physicians working in Japanese hospitals: a cross sectional study.

BACKGROUND: Physicians' mental health may be adversely affected by the number of days of work and time spent on-call, and improved by sleep and days-off. The aim of this study was to determine the associations of depressive symptoms with taking days of off duty, hours of sleep, and the number of days of on-call and overnight work among physicians working in Japanese hospitals. METHODS: A cross-sectional study as a national survey was conducted by mail. The study population was 10,000 randomly selected physicians working in hospitals who were also members of the Japan Medical Association (response rate 40.5%). Self-reported anonymous questionnaire was sent to assess the number of days off-duty, overnight work, and on-calls, and the average number of sleep hours on days not working overnight in the previous one month. Depressive state was determined by the Japanese version of the Quick Inventory of Depressive Symptomatology. Logistic regression analysis was used to explore the associations between depressive symptoms and the studied variables. RESULTS: Among the respondents, 8.3% of men and 10.5% of women were determined to be depressed. For both men and women, depressive state was associated with having no off-duty days and averaging less than 5 hours of sleep on days not doing overnight work. Depressive state was positively associated with being on-call more than 5 days per month for men, and more than 8 days per month for women, and was negatively associated with being off-duty more than 8 days per month for men. CONCLUSION: Some physicians need some support to maintain their mental health. Physicians who do not take enough days-off, who reduced sleep hours, and who have certain number of days on-calls may develop depressive symptoms.

Effects of a structured group intervention on obesity among breast cancer survivors.

BACKGROUND: Obesity is associated with an increased risk for developing breast cancer and poor cancer-related outcomes. Endocrine therapy is a key part of treatment for breast cancer, but can result in weight gain. This study examined the efficacy of a structured group intervention during adjuvant endocrine therapy for obese patients with breast cancer. The intervention involved a combination of proper nutrition, exercise, and group coaching. METHODS: Participants were patients with breast cancer who were undergoing adjuvant endocrine therapy and exhibited apparent weight gain while undergoing therapy, or had a diagnosis of abnormal lipid metabolism. We conducted a single-arm prospective study with a combined intervention. The intervention comprised 15 min of nutrition education, a 30-min group health coaching program, and three 45-min group aerobic exercise sessions. We evaluated participants' parameters (e.g., body weight, body mass index [BMI], cholesterol, psychological distress) at baseline, and at 1, 3, and 6 months after the intervention. RESULTS: At 1 month after the intervention, there were significant reductions in body weight (p < 0.01), BMI (p < 0.01), triglyceride levels (p < 0.05), total cholesterol levels (p < 0.01), psychological distress (p < 0.05), and cancer-related fatigue (p < 0.01). At 3 and 6 months after the intervention, we observed further reductions in body weight, BMI, and triceps skinfold thickness. CONCLUSION: Our study showed that a short-term structured intervention helped modify dietary and exercise behaviors and promote health among breast cancer survivors, and resulted in favorable changes in participants' body weight.

Cancer patients' reluctance to discuss psychological distress with their physicians was not associated with underrecognition of depression by physicians: a preliminary study.

OBJECTIVE: To investigate the association between cancer patients' reluctance for emotional disclosure to their physician and underrecognition of depression by physicians. METHODS: Randomly selected ambulatory patients with lung cancer were evaluated by the Hospital Depression and Anxiety Scale (HADS), and those with scores over the validated cutoff value for adjustment disorder or major depressive disorder were included in this analysis. The data set included the responses to the 13-item questionnaire to assess four possible concerns of patients in relation to emotional disclosure to the treating physician ("no perceived need to disclose emotions," "fear of the negative impact of emotional disclosure," "negative attitude toward emotional disclosure," "hesitation to disturb the physician with emotional disclosure"). The attending physicians rated the severity of depression in each patient using 3-point Likert scales (0 [absent] to 2 [clinical]). Depression was considered to be underrecognized when the patients had a HADS score above the cutoff value, but in whom the depression rating by the attending physician was 0. RESULTS: The HADS score was over the cutoff value in the 60 patients. The mean age was 65.1 +/- 10.0, and 82% had advanced cancer (Stage IIIb or IV or recurrence). Depression was underrecognized in 44 (73%) patients. None of the four factors related to reluctance for emotional disclosure was associated with the underrecognition of depression by the physicians. None of the demographic or cancer-related variables were associated with depression underrecognition by physicians. SIGNIFICANCE OF RESULTS: The results did not support the assumption that patients' reluctance for emotional disclosure is associated with the underrecognition of depression by physicians.

ADAR2-dependent A-to-I RNA editing in the extracellular linear and circular RNAs.

Currently, no reliable biomarkers of amyotrophic lateral sclerosis (ALS) exist. In sporadic ALS, RNA editing at the glutamine/arginine site of GluA2 mRNA is specifically reduced in the motor neurons due to the downregulation of adenosine deaminase acting on RNA 2 (ADAR2). Furthermore, TDP-43 pathology, the pathological hallmark of ALS, is observed in the ADAR2-lacking motor neurons in ALS patients and conditional ADAR2 knockout mice, suggesting a pivotal role of ADAR2 downregulation in the ALS pathogenesis. Extracellular RNAs were shown to represent potential disease biomarkers and the editing efficiencies at their ADAR2-dependent sites may reflect cellular ADAR2 activity, suggesting that these RNAs isolated from the body fluids may represent the biomarkers of ALS. We searched for ADAR2-dependent sites in the mouse motor neurons and human-derived cultured cells and found 10 sites in five host RNAs expressed in SH-SY5Y cells and their culture medium. Of these, the arginine/glycine site of SON mRNA was newly identified as an ADAR2-dependent site. Furthermore, we detected a circular RNA with an ADAR2-dependent site in the SH-SY5Y cells and their culture medium. Therefore, the changes in the editing efficiencies at the identified host RNA sites isolated from the body fluids may represent potential biomarkers of ALS.

GDF-15, a mitochondrial disease biomarker, is associated with the severity of multiple sclerosis.

GDF-15, a member of the transforming growth factor beta superfamily, regulates inflammatory and apoptotic pathways in various diseases, such as heart failure, kidney dysfunction, and cancer. We aimed to clarify potentially confounding variables affecting GDF-15 and demonstrate its utility as a mitochondrial biomarker using serum samples from 15 patients with mitochondrial diseases (MD), 15 patients with limbic encephalitis (LE), 10 patients with multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), and 19 patients with amyotrophic lateral sclerosis (ALS). GDF-15 and FGF-21 were significantly elevated in MD. GDF-15 and FGF-21 showed a good correlation in MD but not in LE, MS, and ALS. GDF-15 was potentially influenced by age in LE, MS/NMOSD, and ALS but not in MD. FGF-21 was not correlated with age in MS/NMOSD, ALS, LE, and MD. GDF-15 was not correlated with clinical features in LE or BMI or body weight in ALS. GDF-15 positively correlated with the Expanded Disability Status Scale (EDSS) in MS/NMOSD, while EDSS showed no correlation with age. In conclusion, the results revealed that GDF-15 may be influenced by EDSS in MS/NMOPSD and by age in LE, MS/NMOSD, and ALS but not in MD. Mitochondrial damage in MS/NMOSD is a potentially confounding variable affecting GDF-15.