Does administration of hydroxychloroquine/amiodarone affect the efficacy of enzyme replacement therapy for Fabry mice?

As a standard therapy for Fabry disease, enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (α-Gal) has been successfully used, and the instructions for this drug state that "it should not be co-administrated with cationic amphiphilic drugs such as hydroxychloroquine (HCQ) and amiodarone (AMI), since these drugs have the potential to inhibit intracellular α-Gal activity". However, there would be cases in which HCQ or AMI is required for patients with Fabry disease, considering their medical efficacy and application. Thus, we examined the impact of HCQ/AMI on recombinant human α-Gal by in vitro, cellular, and animal experiments. The results revealed that HCQ/AMI affected the enzyme activity of α-Gal incorporated into cultured fibroblasts from a Fabry mouse when the cells were cultured in medium containing these drugs and the enzyme, although their direct inhibitory effect on the enzyme is not strong. These lysosomotropic drugs may be trapped and concentrated in lysosomes, followed by inhibition of α-Gal. On the other hand, no reduction of α-Gal activity incorporated into the organs and tissues, or acceleration of glycoshingolipid accumulation was observed in Fabry mice co-administered with HCQ/AMI and the enzyme, compared with in the case of usual ERT. As HCQ/AMI administered are catabolized in the liver, these drugs possibly do not affect ERT for Fabry mice, different from in the case of cultured cells in an environment isolated from the surroundings.

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.

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.

Radiofrequency Ablation of Re-entrant Atrial Tachycardia Originating from the Superior Vena Cava with a High-resolution, 3-dimensional Mapping System.

An 80-year-old man with no previous history of catheter ablation or cardiac surgery underwent catheter ablation for atrial tachycardia (AT). We suspected that the mechanism causing AT was re-entry indicated by the entrainment phenomenon during AT and through activation mapping with a 3-dimensional mapping system (EnSite™ X EP system; Abbott, Chicago, IL, USA). We used a multipolar catheter (Advisor™ HD Grid Mapping Catheter; Abbott) inserted into the superior vena cava (SVC) to accomplish activation mapping. The AT circuit was localized inside the SVC with a fractionated potential recorded on its right lateral wall. A similar fractionated potential was observed in the surrounding area. These areas functioned as the critical isthmus of the AT. Radiofrequency (RF) catheter ablation at these sites eliminated the tachycardia. After RF delivery, no tachycardia was induced by programmed stimulation, even during isoproterenol infusion. Consequently, there was no recurrence of tachycardia even after catheter ablation.

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.

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.

Characteristics of hypersomnia due to inflammatory demyelinating diseases of the central nervous system.

Background: Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case-control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin-A (CSF-OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF-OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI. Methods: This ancillary retrospective case-control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF-OX level and MRI hypothalamus-to-caudate-nucleus-intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF-OX levels ≤200 pg/mL. Results: The hypersomnia group (n=50) had significantly more cases of NMOSD (p<0.001), diencephalic syndrome (p=0.006), corticosteroid use (p=0.011), hypothalamic lesions (p<0.023) and early treatment (p<0.001). No cataplexy occurred. In the hypersomnia group, the median CSF-OX level was 160.5 (IQR 108.4-236.5) pg/mL and median MRI hypothalamus-to-caudate-nucleus-intensity ratio was 127.6% (IQR 115.3-149.1). Significant risk factors were hypersomnolence (adjusted OR (AOR) 6.95; 95% CI 2.64 to 18.29; p<0.001) and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p<0.001, V=0.59). Conclusions: Considering orexin as reflected by CSF-OX levels and MRI hypothalamus-to-caudate-nucleus-intensity ratio may help diagnose hypersomnia with diencephalic syndrome.

Differential regulation of histamine H1 receptor-mediated ERK phosphorylation by Gq proteins and arrestins.

Gq protein-coupled histamine H1 receptors play crucial roles in allergic and inflammatory reactions, in which the phosphorylation of extracellular signal-regulated kinase (ERK) appears to mediate the production of inflammatory cytokines. ERK phosphorylation is regulated by G protein- and arrestin-mediated signal transduction pathways. Here, we aimed to explore how H1 receptor-mediated processes of ERK phosphorylation might be differentially regulated by Gq proteins and arrestins. For this purpose, we evaluated the regulatory mechanism(s) of H1 receptor-mediated ERK phosphorylation in Chinese hamster ovary cells expressing Gq protein- and arrestin-biased mutants of human H1 receptors, S487TR and S487A, in which the Ser487 residue in the C-terminal was truncated and mutated to alanine, respectively. Immunoblotting analysis indicated that histamine-induced ERK phosphorylation was prompt and transient in cells expressing Gq protein-biased S487TR, whereas it was slow and sustained in cells expressing arrestin-biased S487A. Inhibitors of Gq proteins (YM-254890) and protein kinase C (PKC) (GF109203X), and an intracellular Ca2+ chelator (BAPTA-AM) suppressed histamine-induced ERK phosphorylation in cells expressing S487TR, but not those expressing S487A. Conversely, inhibitors of G protein-coupled receptor kinases (GRK2/3) (cmpd101), ß-arrestin2 (ß-arrestin2 siRNA), clathrin (hypertonic sucrose), Raf (LY3009120), and MEK (U0126) suppressed histamine-induced ERK phosphorylation in cells expressing S487A, but not those expressing S487TR. These results suggest that H1 receptor-mediated ERK phosphorylation might be differentially regulated by the Gq protein/Ca2+/PKC and GRK/arrestin/clathrin/Raf/MEK pathways to potentially determine the early and late phases of histamine-induced allergic and inflammatory responses, respectively.

Coagulopathy correlates with muscle titin injury in critically ill patients.

PURPOSE: We hypothesized that coagulopathy independently contributes to muscle injury focusing to titin fragmentation, and investigated their correlations. MATERIAL AND METHODS: We conducted a post-hoc analysis of an observational study, in which we evaluated muscle injury with the biomarker titin. Coagulopathy was assessed on the first day using the Japanese diagnostic criteria of acute-phase disseminated intravascular coagulopathy (JAAM-DIC). Mean N-titin/Cre measured on days 1, 3, 5, and 7 was assigned as the primary outcome. RESULTS: Overall, 111 eligible patients were included. Mean N-titin/Cre were significantly higher in the JAAM-DIC group. A multivariable analysis identified JAAM-DIC as independent risk factors for mean N-titin/Cre while other severity scores were not. CONCLUSIONS: Coagulopathy correlated with muscle titin fragmentation, as an independent risk factor. TRIAL REGISTRATION NUMBER: The present study is registered at the University Hospital Medical Information Network-clinical trials registry (UMIN000040290, Registration date: May 7, 2020).

Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinane bearing multiple effective residues (TriMER) library.

Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (-)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.

Reduced CSF orexin levels in rats and patients with systemic inflammation: a preliminary study.

OBJECTIVE: Sepsis is a lethal condition characterized by systemic inflammation and multiple organ failure; this condition was initially defined as systemic inflammatory response syndrome (SIRS) due to infection. We previously reported that the hypothalamic neuropeptide orexin improved survival in a murine model of sepsis by mainly acting in the medullary raphe nucleus through orexin type-2 receptors. We hypothesized that orexin treatment enhances recovery from sepsis by reversing the reduction in orexin levels in the cerebrospinal fluid (CSF). We recently reported a case in which CSF orexin levels were reduced in a patient with sepsis. Herein, we attempted to further investigate CSF orexin levels in rats and patients with systemic inflammation. This patient study was a single-center, retrospective observational study. RESULTS: CSF orexin levels were low in rats with lipopolysaccharide-induced systemic inflammation. We enrolled 14 patients with meningitis/encephalitis. Six patients were diagnosed with SIRS, of whom 5 patients had infections ("sepsis" by the previous definition). CSF orexin levels were low in SIRS patients. The results support the hypothesis that orexin treatment enhances recovery from sepsis by reversing the reduction in CSF orexin levels.

Assessment of clinical conditions associated with Mondor disease.

BACKGROUND: Mondor disease is superficial thrombophlebitis of the thoracoabdominal wall, mid-upper arm, and penis. Although it is usually a benign disease requiring no specific treatment, little is known about this disease owing to its rarity. OBJECTIVE: The aim of this retrospective observational study was to investigate the epidemiology and prognosis of Mondor disease. METHODS: We conducted a single-center observational study of patients with Mondor disease. Patients who received a diagnosis of Mondor disease between 2015 and 2020 were analyzed. The patients' medical records were manually reviewed to obtain the following variables: date of diagnosis, patient's age, sex, department of diagnosing physicians, underlying diseases, medications, surgery, and time until resolution of the lesion. We also reviewed the 1-year mortality, 1-year occurrence of malignancy, and recurrence of Mondor disease. RESULTS: 20 patients were included in the study. The age of the patients ranged from 7 to 83 years, with a median of 47.5 years. Most of the patients presented with thoracoabdominal wall lesions. The underlying conditions included skin diseases, surgical procedures, breast cancer, smoking, and collagenous diseases, although more than half of the patients did not have plausible predisposing factors. About three-quarters of the patients saw a spontaneous resolution of the lesions within 4 weeks without medical or surgical treatments. CONCLUSIONS: Considering the good prognosis of this disease, it is essential to avoid unnecessary invasive tests or treatment once the diagnosis is confirmed.

Copper and zinc deficiency in an alcoholic patient: a case report of a therapeutic dilemma.

Copper deficiency often manifests with anemia and ataxia. The risk factors associated with the deficiency include gastrointestinal surgery, excessive zinc supplementation, and malabsorptive conditions. Little is known about the relationship between copper deficiency and alcohol consumption. Here we report a case of copper deficiency in a patient with alcohol use disorder who also had zinc deficiency, thereby posing a therapeutic dilemma because copper and zinc are competitively absorbed into the small intestine. Early recognition of copper deficiency is essential when treating zinc deficiency in such patients.

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.

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).

Case Report: Reduced CSF Orexin Levels in a Patient With Sepsis.

Sepsis is a potentially lethal condition characterized by systemic inflammation and multiple organ failure, and sepsis-associated encephalopathy (SAE) is an independent risk factor for mortality in patients with sepsis. We previously reported that orexin improved survival in an animal model of sepsis by acting in the brain. Peripherally administered orexin entered the brain under the conditions of systemic inflammation because of BBB dysfunction and produced survival-related effects. As a therapeutic concept, we hypothesized that orexin treatment enhances recovery from sepsis by restoring reduced orexin levels in cerebrospinal fluid (CSF). Here, we report that CSF orexin levels were reduced in a 63-year-old woman with sepsis. The patient presented with coma, fever, headache, vomiting, and seizures upon arrival at the emergency room. She had a history of subarachnoid hemorrhage which led to the development of hydrocephalus, and as a consequence, a ventriculoperitoneal shunt (VP shunt) tube had been installed to ameliorate the complication. Physical examinations showed dehydration and abnormality of circulation, arterial blood gas analysis showed insufficient oxygenation, blood tests showed an inflammatory response, liver injury, kidney injury, hyperkalemia, and hyperglycemia, and radio graphical examinations showed mild hydrocephalus and several old microinfarctions. She was diagnosed with sepsis because her Sequential Organ Failure Assessment (SOFA) score was 13 and Enterococcus faecalis was isolated form her blood and CSF. Status epilepticus, hyperglycemia, and sepsis-associated encephalopathy were considered possible causes of coma. Her CSF could be safely sampled because she had a VP shunt, although it is ethically difficult to sample CSF routinely from patients with sepsis. Reduced CSF orexin levels gradually recovered as she recovered from sepsis. Unexpectedly, orexin was detected in the blood, which is unusual in healthy humans. Blood orexin was not detected after recovery from sepsis. This result may imply that orexin leaks into the blood because of BBB dysfunction. To the best of our knowledge, this is the first report investigating orexin levels in the CSF and blood of a patient with sepsis, and the data obtained from this case may provide a new understanding of the pathophysiology of SAE.

Usefulness of P-wave duration in patients with sick sinus syndrome as a predictor of atrial fibrillation.

BACKGROUND: This study aimed to clarify P-wave duration (PWD) ability before pacemaker implantation to predict worsening atrial fibrillation (AF) burden after the procedure. METHODS: We retrospectively investigated 75 patients who underwent permanent pacemaker implantation due to sick sinus syndrome (SSS) at Komaki City Hospital between January 2006 and May 2019. Worsening AF burden was defined as an increase in the number of AF episodes, each lasting ≥5.5 hours a day. RESULTS: In the study population, 17 patients (23%) had worsening AF burden during the follow-up period. These patients had significantly longer PWD in lead Ⅱ (117.9 ± 19.9 ms vs 101.3 ± 20.0 ms, P = .002) than the patients without worsening AF burden. The best discriminative cutoff value for PWD in lead Ⅱ was 108 ms (sensitivity, 77%; specificity, 67%). In multivariate analysis, PWD in lead II ≥108 ms (hazard ratio, 5.395; 95% confidence interval, 1.352-21.523; P = .017) was an independent predictor of worsening AF burden. Patients with PWD in lead II <108 ms showed a significantly higher event-free rate against worsening AF burden than those with PWD in lead II ≥108 ms (81% vs 9%, P = .005). CONCLUSIONS: Prolonged PWD before pacemaker implantation was the most important independent predictor of worsening AF burden after the procedure. In patients with SSS, prolonged PWD can be a useful marker for predicting worsening of AF burden after pacemaker implantation.

[Glial cells and pharmacological targets in Sandhoff disease].

Sandhoff disease (SD) is a genetic disorder caused by a mutation in the ß-hexosaminidase B (HexB) gene in humans. This results in the massive accumulation of GM2 gangliosides in the nervous system, causing progressive neurodegeneration. The symptoms of SD include muscle weakness, seizures, and mental illness;along with loss of muscle coordination, vision, and hearing. In the most severe form, the onset begins during early infancy, and death usually occurs within 3-5 years of age. The established animal model, Hexb-deficient (Hexb-/-) mouse, shows abnormalities that resemble the severe phenotype found in human infants. We have previously reported that activated microglia causes astrogliosis in Hexb-/- mouse at the early stage of development that can be ameliorated via immunosuppression. Moreover, within the cerebral cortices of Hexb-/- mouse, reactive astrocytes were found to express adenosine A2A receptors in later inflammatory phases. Inhibiting this receptor with istradefylline decreases the number of activated microglial cells and inflammatory cytokines/chemokines. Thus, we underline the importance of the astrocytic A2A receptor as a sensor, in regulating microglial activation in the late phase of inflammation.

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.