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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.

Abstract 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.

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 (p130% (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

Abstract 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

Abstract 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

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.

Drug-induced lysosomal storage disease (DILSD) caused by cationic amphiphilic drugs (CADs), which exhibits toxic manifestations and pathological findings mimicking Fabry disease (α-galactosidase A deficiency), has attracted the interests of clinicians and pathologists. Although the affected region is lysosomes in both the diseases, DILSD is characterized by intralysosomal accumulation of phospholipids and Fabry disease that of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). However, it is unknown whether administration of CADs affects the catabolism of Gb3 and Lyso-Gb3 in Fabry disease. In this study, we independently administered hydroxychloroquine/amiodarone to wild-type and Fabry mice and examined the effects of the drugs on the enzyme activity and substrates accumulated in organs and tissues. The results revealed that the administration of the drugs induced accumulation of phosphatidylcholine in both the wild-type and Fabry mice. However, reduction of α-galactosidase A activity in the organs and tissues of the wild-type mice was not found, and the storage of Gb3 and Lyso-Gb3 was not accelerated by these drugs in the Fabry mice. This suggests that hydroxychloroquine/amiodarone do not have any significant impact on the catabolism of Gb3 and Lyso-Gb3 in organs and tissues of both wild-type and Fabry mice.

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 β-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.

Aims: This study sought to conduct additional analyses of the Cognitive Test for Severe Dementia (CTSD) using the COSMIN checklist to ensure the development of adequate outcome measures. Methods: The following analyses were conducted: (1) factor analyses were used to evaluate construct validity; (2) the standard error of measurement (SEM) and minimal detectable change (MDC) were assessed to evaluate reliability and interpretability; and (3) longitudinal change was assessed to evaluate responsiveness. Results: The CTSD factor analysis yielded 2 factors, each of which was dichotomized by the passage rate of each item. We calculated a SEM and MDC of 1.6 and 3.6 points, respectively. Finally, the mean CTSD score showed a significant reduction (p < 0.001) over time, and the change in score exceeded the SEM and MDC. Conclusion: Our results indicate that the CTSD could provide a reliable outcome measure in severe dementia.

In Sandhoff disease (SD), the activity of the lysosomal hydrolytic enzyme, β-hexosaminidase (Hex), is lost due to a Hexb gene defect, which results in the abnormal accumulation of the substrate, GM2 ganglioside (GM2), in neuronal cells, causing neuronal loss, microglial activation, and astrogliosis. We established induced pluripotent stem cells from the cells of SD mice (SD-iPSCs). In the present study, we investigated the occurrence of abnormal differentiation and development of a neural lineage in the asymptomatic phase of SD in vitro using SD mouse fetus-derived neural stem cells (NSCs) and SD-iPSCs. It was assumed that the number of SD mouse fetal brain-derived NSCs was reduced and differentiation was promoted, resulting in the inhibition of differentiation into neurons and enhancement of differentiation into astrocytes. The number of SD-iPSC-derived NSCs was also reduced, suggesting that the differentiation of NSCs was promoted, resulting in the inhibition of differentiation into neurons and enhancement of that into astrocytes. This abnormal differentiation of SD-iPSCs toward a neural lineage was reduced by the glucosylceramide synthase inhibitor, miglustat. Furthermore, abnormal differentiation toward a neural lineage was reduced in SD-iPSCs with Hexb gene transfection. Therefore, differentiation ability along the time axis appears to be altered in SD mice in which the differentiation ability of NSCs is promoted and differentiation into neurons is completed earlier, while the timing of differentiation into astrocytes is accelerated. These results clarified that the abnormal differentiation of SD-iPSCs toward a neural lineage in vitro was shown to reflect the pathology of SD.

This paper, which aims to increment the vocabulary of an existing thesaurus using hyponymy relations, focuses on an agricultural thesaurus called AGROVOC. Our main goal is to acquire AGROVOC-qualified candidates from the hyponymy relations of legal texts and tables. We propose a pattern-based approach to hyponymy relation acquisition. Our experimental result showed that 222 and 868 candidates are extracted from statutory sentences with 67.1% precision and tables with 37.0% precision, respectively.