A distal axonal cytoskeleton forms an intra-axonal boundary that controls axon initial segment assembly.

AnkyrinG (ankG) is highly enriched in neurons at axon initial segments (AISs) where it clusters Na(+) and K(+) channels and maintains neuronal polarity. How ankG becomes concentrated at the AIS is unknown. Here, we show that as neurons break symmetry, they assemble a distal axonal submembranous cytoskeleton, comprised of ankyrinB (ankB), αII-spectrin, and ßII-spectrin, that defines a boundary limiting ankG to the proximal axon. Experimentally moving this boundary altered the length of ankG staining in the proximal axon, whereas disruption of the boundary through silencing of ankB, αII-spectrin, or ßII-spectrin expression blocked AIS assembly and permitted ankG to redistribute throughout the distal axon. In support of an essential role for the distal cytoskeleton in ankG clustering, we also found that αII and ßII-spectrin-deficient mice had disrupted AIS. Thus, the distal axonal cytoskeleton functions as an intra-axonal boundary restricting ankG to the AIS.

The effect of off-label use of reduced-dose direct oral anticoagulants therapy in the treatment of pulmonary embolism comparable to standard-dose therapy.

Direct oral anticoagulants (DOACs) have been shown to be effective and safe in preventing pulmonary embolism recurrence. In this single-center retrospective observational study, we aimed to evaluate the efficacy and safety of reduced-dose DOACs in 86 consecutive patients with acute pulmonary embolism. Patients were divided into standard-dose and reduced-dose DOACs groups. Initial clot volume did not significantly differ between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 18.8 [Q1-Q3 7.3-30.8] mL vs. 10.0 [Q1-Q3 3.2-27.9] mL, p = 0.1). Follow-up computed tomography (CT) within 30 days showed a higher rate of clot volume reduction or disappearance in the standard-dose group compared to the reduced-dose group (standard-dose DOACs vs. reduced-dose DOACs, 81.6% vs. 53.9%, p = 0.02). However, at the final follow-up CT, there was no significant difference in clot volume change between the two groups (standard-dose DOACs vs. reduced-dose DOACs, 91.5% vs. 82.0%, p = 0.19). Major bleeding occurred in two patients in the standard-dose group (4.3%) and three patients in the reduced-dose DOACs group (7.7%) (p = 0.5). In conclusion, while standard-dose DOACs demonstrated superior efficacy in early clot reduction, reduced doses of apixaban and edoxaban showed comparable efficacy and safety profiles in long-term treatment of acute pulmonary embolism in certain patients.

Histamine H1 Receptor-Mediated JNK Phosphorylation Is Regulated by Gq Protein-Dependent but Arrestin-Independent Pathways.

Arrestins are known to be involved not only in the desensitization and internalization of G protein-coupled receptors but also in the G protein-independent activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), to regulate cell proliferation and inflammation. Our previous study revealed that the histamine H1 receptor-mediated activation of ERK is dually regulated by Gq proteins and arrestins. In this study, we investigated the roles of Gq proteins and arrestins in the H1 receptor-mediated activation of JNK in Chinese hamster ovary (CHO) cells expressing wild-type (WT) human H1 receptors, the Gq protein-biased mutant S487TR, and the arrestin-biased mutant S487A. In these mutants, the Ser487 residue in the C-terminus region of the WT was truncated (S487TR) or mutated to alanine (S487A). Histamine significantly stimulated JNK phosphorylation in CHO cells expressing WT and S487TR but not S487A. Histamine-induced JNK phosphorylation in CHO cells expressing WT and S487TR was suppressed by inhibitors against H1 receptors (ketotifen and diphenhydramine), Gq proteins (YM-254890), and protein kinase C (PKC) (GF109203X) as well as an intracellular Ca2+ chelator (BAPTA-AM) but not by inhibitors against G protein-coupled receptor kinases (GRK2/3) (cmpd101), ß-arrestin2 (ß-arrestin2 siRNA), and clathrin (hypertonic sucrose). These results suggest that the H1 receptor-mediated phosphorylation of JNK is regulated by Gq-protein/Ca2+/PKC-dependent but GRK/arrestin/clathrin-independent pathways.

Histopathological characteristics of the arrhythmogenic right ventricular cardiomyopathy presenting the electrocardiographic characteristics with Brugada syndrome.

INTRODUCTION: The histopathological characteristics of the overlapping disease states of Brugada syndrome (BrS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) have not been fully elucidated. METHODS: A 71-year-old man showed coved-type ST-segment elevation with the right precordial leads, and the echocardiography demonstrated right ventricular (RV) dilatation. After 11 months, he died of a polymorphic VT storm. RESULTS: The pathological tissue demonstrated fibrofatty degeneration in the free wall of the RV outflow tract based on the heart autopsy. CONCLUSION: The overlapping disease states of BrS and ARVC showed histopathological characteristics consistent with ARVC.

Aspects of Rest-Activity Rhythms Associated With Behavioral and Psychological Symptoms in Moderate and Severe Dementia: Results of a Cross-sectional Analysis.

OBJECTIVE: Disturbances in rest-activity rhythms (RAR) are commonly observed in patients with dementia; however, the influence thereof on behavioral and psychological symptoms of dementia (BPSD) remains unexplored. This study aimed to determine whether there is an association between RAR and BPSD among patients with moderate and severe dementia. METHODS: RAR analyses of 64 participants were performed using actigraphy. BPSD was assessed using the Neuropsychiatric Inventory-Nursing Home (NPI-NH) scale, and other clinical variables were assessed by the Mini-Mental State Examination, Cognitive Test for Severe Dementia, and Hyogo Activities of Daily Living Scale. Correlations among RAR, sleep time, and BPSD were analyzed. A stepwise multiple linear regression analysis was conducted to examine the association of RAR and sleep time with BPSD. The demographic variables were also adjusted. Variables were compared between two groups with aberrant and nonaberrant activity peak timing. RESULTS: Correlation analysis showed that longer maximum durations of activity and shorter daytime sleep were associated with higher NPI-NH scores. Stepwise multiple linear regression analysis showed that maximum activity duration predicted the NPI-NH score after adjustment for the demographic variables. There was no significant difference in any variables between the groups with aberrant and nonaberrant activity peak timing. CONCLUSION: RAR is associated with BPSD in moderate-to-severe dementia, which should be considered with regard to treatment.

Short coupling interval with high burden of atrial ectopy predicts recurrence after atrial fibrillation ablation.

Atrial ectopy (AE) with a short coupling interval (S-AE) causes atrial fibrillation (AF). A higher burden of AE is associated with recurrence after AF ablation. However, a few reports have evaluated the prognostic impact of both AE burden and S-AE after the acute phase of ablation. This study aimed to assess the characteristics of AE beyond the blanking period in predicting the recurrence. We retrospectively analyzed 173 patients who underwent first catheter ablation for AF and 24-h Holter recording following a 3-month blanking period. AE was defined as a narrow QRS complex occurring < 75% earlier than the prior reference R-R interval. We investigated the relationship between the AE's characteristics in Holter recordings and atrial arrhythmia recurrence. Forty-two patients (24%) had a recurrence during a median 488-day follow-up. Patients with S-AE (minimum coupling interval ratio of AE ≤ 45%) had a higher recurrence rate than those without S-AE (44.9% vs. 16.1%, p < 0.001). Moreover, patients with AE ≥ 241/day exhibited a significantly higher recurrence rate than those with AE < 241/day (44.3% vs. 10.7%, p < 0.001). In multivariate analysis, S-AE with a higher AE burden was an independent predictor of recurrence (hazard ratio 5.82, 95% confidence interval: 2.64-12.82, p < 0.001). Kaplan-Meier analysis showed that patients with S-AE and a higher AE burden had the worst prognosis for recurrence (p < 0.001). The combination of a higher AE burden with S-AE could be an efficient predictor of recurrence. These results can help to develop follow-up strategies after AF ablation.

Factors influencing the quality of life in patients with severe dementia.

BACKGROUND: A comprehensive understanding of the relevant factors involved in improving quality of life (QoL) is essential in patients with severe dementia; however, rating scales used in previous studies may not adequately reflect the factors that affect these patients. The purpose of this study was to identify factors that contribute to QoL using an evaluation scale suitable for patients with severe dementia. METHODS: The current cross-sectional study was conducted at a hospital for recuperation in Hyogo prefecture in Japan. The measurement scales included the QoL in Late-Stage Dementia Japanese version (QUALID-J), Cognitive Test for Severe Dementia, Neuropsychiatric Inventory-Nursing Home (NPI-NH), Physical Self-Maintenance Scale (PSMS), Pain Assessment in Advanced Dementia (PAINAD), and Special Care Unit Environment Quality Scale (SCUEQS). Multiple regression analyses were performed. RESULTS: We assessed a total of 105 patients with severe dementia (80 women; aged 87.3 ± 6.3 years). Multiple regression demonstrated that the QUALID-J total score was significantly affected by the NPI-NH and PAINAD scores. Factors 1 (expression of comfort) and 2 (expression of discomfort) of the QUALID-J were significantly affected by the PSMS and PAINAD, and the NPI-NH and PAINAD scores, respectively. CONCLUSION: Our results indicate that behavioural and psychological symptoms of dementia and pain are important factors in influencing the QoL of patients with severe dementia.

Impact of Disturbed Rest-activity Rhythms on Activities of Daily Living in Moderate and Severe Dementia Patients.

PURPOSE: People with dementia exhibit disturbed rest-activity rhythms and extended sleep duration issues throughout their disease. Little is known about the effects of these issues on clinical problems for those with moderate and severe dementia. This cross-sectional study aimed to examine the associations of disturbed rest-activity rhythms and extended sleep duration with activities of daily living (ADL). METHODS: Sleep parameters were measured using an actigraphy device. Cognitive function was assessed using the Mini-Mental State Examination and Cognitive Test for Severe Dementia, the Hyogo Activities of Daily Living Scale was used to assess ADL, and behavioral and psychological symptoms of dementia were assessed using the Neuropsychiatric Inventory-Nursing Home scale. Associations among rest-activity rhythms, sleep duration, and other clinical variables were analyzed with multiple linear regression. Clinical variables were compared between 2 groups categorized by onset timing of rest peak. PATIENTS: Sixty-four participants with moderate and severe dementia were assessed. RESULTS: In the correlation analysis, unstable daily rest-activity rhythm was associated with lower ADL. In the multiple linear regression analysis, low intradaily variability, and long daytime sleep duration were associated with low ADL. Aberrant rest peak timing showed lower ADL compared with nonaberrant timing. CONCLUSIONS: Abnormal rest-activity rhythm and sleep duration in persons with moderate and severe dementia may affect ADL.

Novel protocol combining physical and nutrition therapies, Intensive Goal-directed REhabilitation with Electrical muscle stimulation and Nutrition (IGREEN) care bundle.

BACKGROUND: Although the combination of rehabilitation and nutrition may be important for the prevention of intensive care unit (ICU)-acquired weakness, a protocolized intervention of this combination has not yet been reported. We herein developed an original combined protocol and evaluated its efficacy. METHODS: In this single-center historical control study, we enrolled adult patients admitted to the ICU. Patients in the control group received standard care, while those in the intervention group received the protocol-based intervention. The ICU mobility scale was used to set goals for early mobilization and a neuromuscular electrical stimulation was employed when patients were unable to stand. The nutritional status was assessed for nutritional therapy, and target calorie delivery was set at 20 or 30 kcal/kg/day and target protein delivery at 1.8 g/kg/day in the intervention group. The primary endpoint was a decrease in femoral muscle volume in 10 days assessed by computed tomography. RESULTS: Forty-five patients in the control group and 56 in the intervention group were included in the analysis. Femoral muscle volume loss was significantly lower in the intervention group (11.6 vs 14.5%, p = 0.03). The absolute risk difference was 2.9% (95% CI 0.1-5.6%). Early mobilization to a sitting position by day 10 was achieved earlier (p = 0.03), and mean calorie delivery (20.1 vs. 16.8 kcal/kg/day, p = 0.01) and mean protein delivery (1.4 vs. 0.8 g/kg/day, p < 0.01) were higher in the intervention group. CONCLUSION: The protocolized intervention, combining early mobilization and high-protein nutrition, contributed to the achievement of treatment goals and prevention of femoral muscle volume loss. TRIAL REGISTRATION NUMBER: The present study is registered at the University Hospital Medical Information Network-clinical trials registry (UMIN000040290, Registration date: May 7, 2020).

Insight Into Illness and Psychological Defense Attitudes in People With Chronic Schizophrenia Using Markova's Insight Scale.

ABSTRACT: Insight into illness is a multidimensional phenomenon, and various assessments are available. We focused on Markova's Insight Scale (IS) and investigated the relationship between insight, psychological defenses, and neurocognition in 38 patients with schizophrenia. Results showed that insight was significantly correlated with an immature defense style. Moreover, IS was significantly predicted by immature defense style after adjusting for clinical variables. Although insight is often assumed to be multidetermined with potential contributions from factors such as cognitive function and psychological defensive mechanisms, our results indicated that better insight assessed with the IS is more likely to reflect immature defenses. This may also be reflected in our result that a higher insight score correlated with earlier onset of illness. The insight score may reflect the immature psychological defensive attitudes of schizophrenia and may lead such patients to wish to comply with the views of clinicians.

Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine: Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine.

The D-nor-nalfurafine derivatives, which were synthesized by contraction of the six-membered D-ring in nalfurafine (1), had no affinity for orexin 1 receptors (OX1Rs). The 17N-lone electron pair in 1 oriented toward the axial direction, while that of D-nor-derivatives was directed in the equatorial configuration. The axial lone electron pair can form a hydrogen bond with the 14-hydroxy group, which could push the 6-amide side chain toward the downward direction with respect to the C-ring. The resulting conformation would be an active conformation for binding with OX1R. The dual affinities of 1 for OX1R and κ opioid receptor (KOR) led us to elucidate the mechanism by which only 1 showed no aversion but U-50488H. Actually, 1 selectively induced severe aversion in OX1R knockout mice, but not in wild-type mice. These results well support that OX1R suppresses the aversion of 1. This is the elucidation of long period puzzle which 1 showed no aversion in KOR.

Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group.

The morphinan-type orexin 1 receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

Reduced exercise capacity and clinical outcomes following acute myocardial infarction.

Reduced exercise capacity is known to be an important predictor of poor prognosis and disability in patients with cardiovascular diseases and chronic heart failure, and even members of the general population. However, data about exercise capacity assessed by cardiopulmonary exercise testing (CPX) in acute myocardial infarction (AMI) patients who underwent primary percutaneous coronary intervention (PCI) is scarce. Among 594 consecutive AMI patients who underwent primary PCI, we examined 136 patients (85.3% men, 64.9 ± 11.9 years) who underwent CPX during hospitalization for AMI. CPX was usually performed 5 days after the onset of AMI. Reduced exercise capacity was defined as peak VO2 ≤ 12. Clinical outcomes including all-cause death, myocardial infarction, and hospitalization due to heart failure were followed. Among 136 patients, reduced exercise capacity (peak VO2 ≤ 12) was seen in 38 patients (28%). Patients with reduced exercise capacity were older, more likely to have hypertension, and had lower renal function. In echocardiography, patients with reduced exercise capacity had higher E/e' and larger left atrial dimension. Multivariate logistic analysis showed that E/e' (OR 1.19, 95% CI 1.09-1.31, p < 0.001) was an independent predictor of reduced exercise capacity (peak VO2 ≤ 12). Median follow-up term was 12 months (IQR 9-22). The occurrence of composite endpoints of all-cause death, myocardial infarction, and hospitalization due to heart failure was significantly higher in patients with peak VO2 ≤ 12 than those with peak VO2 > 12 (p < 0.001). Reduced exercise capacity following primary PCI in AMI patients is associated with diastolic dysfunction and may lead to poorer clinical outcomes.

Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models.

Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice. Peripherally administered YNT-185 also promotes wakefulness without affecting body temperature in wild-type mice. Further, there was no immediate rebound sleep after YNT-185 administration in active phase in wild-type and orexin-deficient mice. No desensitization was observed after repeated administration of YNT-185 with respect to the suppression of cataplexy-like episodes. These results provide a proof-of-concept for a mechanistic therapy of narcolepsy-cataplexy by OX2R agonists.

Clinical factors associated with activities of daily living and their decline in patients with severe dementia.

BACKGROUND: To identify the clinical factors affecting activities of daily living (ADL) at baseline and after 6 months. METHODS: We conducted a single-centre observational study at two time points across 6 months (baseline and after 6 months) from April 2015 to March 2017. in a 270-bed rural recuperation hospital at Hyogo prefecture in Japan. The total number of participants was 131 (male 33, female 98; mean age: 87.0 ± 7.0; mild and moderate dementia, 38; severe dementia, 93). Measurement scales used were Personal Self-Maintenance Scale (PSMS) for assessing ADL, Mini-Mental State Examination and Cognitive Test in Severe Dementia (CTSD) for cognitive function, Neuropsychiatric Inventory-Nursing Home version and Cornell Scale for Depression in Dementia (CSDD) for behavioural/psychological symptoms of dementia, Mini Nutritional Assessment Short form (MNA-SF) for nutritional status, Pain Assessment in Advanced Dementia for pain, and Charlson comorbidity index (CCI) and the number of illness categories based on Cumulative Illness Rating Scale Geriatrics for comorbidities. Multiple regression analyses identified the association between PSMS score as the dependent variable and other variables as independent variables. RESULTS: In participants with severe dementia, the PSMS scores at baseline were significantly associated with CTSD, CCI, MNA-SF, and CSDD scores. In the longitudinal analysis, only CTSD score was significantly associated with PSMS score after 6 months. It is noteworthy that for participants with severe dementia, the only factor associated with ADL after 6 months was cognitive function, as assessed by CTSD score. CONCLUSIONS: The most important factor predicting functional decline is cognitive function, even at the severe and profound stage.

Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity.

The orexin 1 receptor (OX1R) antagonists carrying a morphinan skeleton such as YNT-707 (2) and YNT-1310 (3) showed potent and extremely high selective antagonistic activity against OX1R. In the course of our study of the essential structure of YNT-707 for high binding affinity against OX1R, we prepared derivatives of 2 without the D- and 4,5-epoxy rings to clarify the roles of these structural determinants toward OX1R antagonistic activity. The D- and 4,5-epoxy rings played important roles for the active orientation of the 17-sulfonamide and 6-amide side chains. Finally, we identified the simple structure required for selective OX1R antagonistic activity in the complex morphinan skeleton, which is expected to be a useful scaffold for further design of OX1R ligands.

Essential structure of orexin 1 receptor antagonist YNT-707, part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring.

Morphinan derivatives lacking the 4,5-epoxy ring were synthesized to examine the participation of the 14-OH group, the 3-OMe group, and the aromaticity of the A-ring in the activity and selectivity for the orexin 1 receptor (OX1R). The assay results and the conformational analyses of the 14-dehydrated and 14-H derivatives suggested that the orientations of the 6-amide side chain and the 17-benzenesulfonyl group would play important roles in the activity for OX1R. In the 6ß-derivatives, removal of the 3-OMe group and the reduction of the A-ring significantly decreased the activity toward the OX1R, but these changes did not affect the 6α-derivatives. These results indicate that the 3-OMe group and the A-ring would be essential structural moieties for the 6ß-derivatives.

Insight Into Illness and Defense Styles in Schizophrenia.

Although the psychological denial model argues that poor insight is a result of defense mechanisms, the direct relationship between the two remains unclear. This study aimed to examine the relationship between insight into illness and defense mechanisms while considering cognitive dysfunction in schizophrenia. A total of 38 patients with schizophrenia were evaluated for level of insight (Schedule for the Assessment of Insight), defense mechanisms (Defense Style Questionnaire), neurocognitive function (Brief Assessment of Cognition in Schizophrenia), and psychotic symptoms (Brief Psychiatric Rating Scale). Regarding level of insight, partial correlation analysis controlling neurocognitive and psychotic variables showed that "recognition of illness" was positively correlated with immature defense styles and negatively correlated with mature defense styles. Stepwise regression analyses revealed that "recognition of illness" was significantly predicted by immature defense styles. Our findings suggest that patients who tend to use immature defense styles are more likely to accept their own mental illness.

Inhibition of astrocytic adenosine receptor A2A attenuates microglial activation in a mouse model of Sandhoff disease.

Astrocyte-microglia communication influences the onset and progression of central nervous system (CNS) disorders. In this study, we determined how chronic inflammation by activated astrocytes affected and regulated CNS functions in Sandhoff disease (SD), a CNS lysosomal storage disorder. SD triggers intense CNS inflammation such as microglial activation and astrogliosis. It is caused by mutation of the HEXB gene, which reduces ß-hexosaminidase (Hex) enzymatic activity in lysosomes, leading to accumulation of the substrate GM2 ganglioside in neuronal cells. Hexb-/- mice display a phenotype similar to human patients that suffer from chronic inflammation characterized by activation of astrocytes and microglia. In Hexb-/- mice, tremors and loss of muscle coordination begins at ~12 weeks. Interestingly, we found that reactive astrocytes expressed adenosine A2A receptor in the cerebral cortices of Hexb-/- mice at the later inflammatory phase. In cultured astrocytes, expression of A2A receptor could be induced by astrocyte defined medium, and then the activation of the A2A receptor induced ccl2 expression. In Hexb-/- mice, inhibition of the A2A receptor antagonized by istradefylline decreased the number of activated microglial cells and inflammatory cytokines/chemokines at 13 weeks. Thus, the astrocytic A2A receptor is an important sensor that regulates microglial activation in the late phase of inflammation.

Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity.

The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX1R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX1R.