The N-acetylglucosaminyltransferase Radical fringe contributes to defects in JAG1-dependent turnover and signaling of NOTCH3 CADASIL mutants.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic vascular dementia characterized by age-related degeneration of vascular mural cells and accumulation of a NOTCH3 mutant protein. NOTCH3 functions as a signaling receptor, activating downstream gene expression in response to ligands like JAG1 and DLL4, which regulate the development and survival of mural cells. This signal transduction process is thought to be connected with NOTCH3 endocytic degradation. However, the specific cellular circumstances that modulate turnover and signaling efficacy of NOTCH3 mutant protein remain largely unknown. Here, we found elevated NOTCH3 and Radical fringe (RFNG) expression in senescent human pericyte cells. We then investigated impacts of RFNG on glycosylation, degradation, and signal activity of three NOTCH3 CADASIL mutants (R90C, R141C, and C185R) in EGF-like repeat-2, 3, and 4, respectively. Liquid chromatography with tandem mass spectrometry analysis showed that RFNG modified NOTCH3 WT and C185R to different degrees. Additionally, coculture experiments demonstrated that RFNG significantly promoted JAG1-dependent degradation of NOTCH3 WT but not that of R141C and C185R mutants. Furthermore, RFNG exhibited a greater inhibitory effect on JAG1-mediated activity of NOTCH3 R141C and C185R compared to that of NOTCH3 WT and R90C. In summary, our findings suggest that NOTCH3 R141C and C185R mutant proteins are relatively susceptible to accumulation and signaling impairment under cellular conditions of RFNG and JAG1 coexistence.

Novel sialidase inhibitors suppress mumps virus replication and infection.

The prevalent human pathogen, mumps virus (MuV; orthorubulavirus parotitidis) causes various complications and serious sequelae, such as meningitis, encephalitis, deafness, and impaired fertility. Direct-acting antivirals (DAAs) targeting MuV which can prevent mumps and mumps-associated complications and sequelae are yet to be developed. Paramyxoviridae family members, such as MuV, possess viral surface hemagglutinin-neuraminidase (HN) protein with sialidase activity which facilitates efficient viral replication. Therefore, to develop DAAs targeting MuV we synthesized MuV sialidase inhibitors. It is proposed that the viral HN has a single functional site for N-acetylneuraminic acid (Neu5Ac) binding and sialidase activity. Further, the known MuV sialidase inhibitor is an analog of Neu5Ac-2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA)-which lacks potency. DANA derivatives with higher MuV sialidase inhibitory potency are lacking. The MuV-HN-Neu5Ac binding site has a hydrophobic cavity adjacent to the C4 position of Neu5Ac. Exploiting this, here, we synthesized DANA derivatives with increasing hydrophobicity at its C4 position and created 3 novel sialidase inhibitors (Compounds 1, 2, and 3) with higher specificity for MuV-HN than DANA; they inhibited MuV replication step to greater extent than DANA. Furthermore, they also inhibited hemagglutination and the MuV infection step. The insight-that these 3 novel DANA derivatives possess linear hydrocarbon groups at the C4-hydroxyl group of DANA-could help develop highly potent sialidase inhibitors with high specificity for MuV sialidase, which may function as direct-acting MuV-specific antivirals.

Prolonged extracellular low sodium concentrations and subsequent their rapid correction modulate nitric oxide production dependent on NFAT5 in microglia.

Hyponatremia is the most common clinical electrolyte disorder. Chronic hyponatremia has been recently reported to be associated with falls, fracture, osteoporosis, neurocognitive impairment, and mental manifestations. In the treatment of chronic hyponatremia, overly rapid correction of hyponatremia can cause osmotic demyelination syndrome (ODS), a central demyelinating disease that is also associated with neurological morbidity and mortality. Using a rat model, we have previously shown that microglia play a critical role in the pathogenesis of ODS. However, the direct effect of rapid correction of hyponatremia on microglia is unknown. Furthermore, the effect of chronic hyponatremia on microglia remains elusive. Using microglial cell lines BV-2 and 6-3, we show here that low extracellular sodium concentrations (36 mmol/L decrease; LS) suppress Nos2 mRNA expression and nitric oxide (NO) production of microglia. On rapid correction of low sodium concentrations, NO production was significantly increased in both cells, suggesting that acute correction of hyponatremia partly directly contributes to increased Nos2 mRNA expression and NO release in ODS pathophysiology. LS also suppressed expression and nuclear translocation of nuclear factor of activated T cells-5 (NFAT5), a transcription factor that regulates the expression of genes involved in osmotic stress. Furthermore, overexpression of NFAT5 significantly increased Nos2 mRNA expression and NO production in BV-2 cells. Expressions of Nos2 and Nfat5 mRNA were also modulated in microglia isolated from cerebral cortex in chronic hyponatremia model mice. These data indicate that LS modulates microglial NO production dependent on NFAT5 and suggest that microglia contribute to hyponatremia-induced neuronal dysfunctions.

Clinical practice guidelines for multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease 2023 in Japan.

BACKGROUND: The previous Japanese clinical practice guidelines for multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) were published in 2017. Recently, for the first time in 6 years, the MS and NMOSD guideline development committee revised the Japanese guidelines for MS, NMOSD, and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: The committee utilized the Grading of Recommendations Assessment, Development, and Evaluation system based on the "Minds Handbook for Clinical Practice Guideline Development 2020 Ver. 3.0″ with a focus on clinical questions (CQs). The committee also discussed clinical issues other than CQs, categorizing them as a question-and-answer (Q&A) section, including "issues on which experts' opinions agree to a certain extent" and "issues that are important but not included in the CQ". RESULTS: The committee identified 3, 1, and 1 key CQs related to MS, NMOSD, and MOGAD, respectively, and presented recommendations. A Q&A session regarding disease-modifying therapies and relapse prevention therapies for MS, NMOSD, and MOGAD was conducted. The revised guidelines were published in September 2023. CONCLUSIONS: The Japanese guidelines for clinical practice on MS, NMOSD, and MOGAD were updated. Treatment strategies for MS, NMOSD, and MOGAD are changing, and these updated guidelines may assist with treatment decisions for these diseases in clinical practice.

VP1 of human and murine noroviruses recognizes glycolipid sulfatide via the P domain.

Noroviruses are a prevalent cause of human viral gastroenteritis, yet the precise mechanisms underlying their infection cycle, particularly their interactions with and entry into cells, remain poorly understood. Human norovirus (HuNoV) primarily targets human small intestinal epithelial cells, within which 3-O-sulfogalactosylceramide (sulfatide) ranks among the most abundant glycosphingolipids (GSLs). While sulfatide involvement in the binding and infection mechanism of several viruses has been documented, its interaction with noroviruses remains underexplored. This study investigated whether noroviruses interact with sulfatide. We found that the recombinant viral capsid protein VP1 of HuNoV (genogroups I and II) and murine norovirus (genogroup V) exhibited robust binding to sulfatide compared with other tested GSLs using enzyme-linked immunosorbent assay, thin-layer chromatography binding assay and real-time quantitative reverse transcription polymerase chain reaction binding assay. VP1 also bound 3-O-sulfated lactosylceramide, which shares the 3-O-sulfated galactose moiety with sulfatide. However, both VP1 and its P domain, identified as the sulfatide-binding domain, exhibited limited binding to structural analogues of sulfatide and other sulfated compounds. These findings suggest a specific recognition of the 3-O-sulfated galactose moiety. Notably, we found that sulfatide is a novel binding target for norovirus particles. Overall, our findings reveal a previously unknown norovirus-sulfatide interaction, proposing sulfatide as a potential candidate for norovirus infection receptors.

Effects of hypernatremia on the microglia.

Signs and symptoms of hypernatremia largely indicate central nervous system dysfunction. Acute hypernatremia can cause demyelinating lesions similar to that observed in osmotic demyelination syndrome (ODS). We have previously demonstrated that microglia accumulate in ODS lesions and minocycline protects against ODS by inhibiting microglial activation. However, the direct effect of rapid rise in the sodium concentrations on microglia is largely unknown. In addition, the effect of chronic hypernatremia on microglia also remains elusive. Here, we investigated the effects of acute (6 or 24 h) and chronic (the extracellular sodium concentration was increased gradually for at least 7 days) high sodium concentrations on microglia using the microglial cell line, BV-2. We found that both acute and chronic high sodium concentrations increase NOS2 expression and nitric oxide (NO) production. We also demonstrated that the expression of nuclear factor of activated T-cells-5 (NFAT5) is increased by high sodium concentrations. Furthermore, NFAT5 knockdown suppressed NOS2 expression and NO production. We also demonstrated that high sodium concentrations decreased intracellular Ca2+ concentration and an inhibitor of Na+/Ca2+ exchanger, NCX, suppressed a decrease in intracellular Ca2+ concentrations and NOS2 expression and NO production induced by high sodium concentrations. Furthermore, minocycline inhibited NOS2 expression and NO production induced by high sodium concentrations. These in vitro data suggest that microglial activity in response to high sodium concentrations is regulated by NFAT5 and Ca2+ efflux through NCX and is suppressed by minocycline.

The Dual-Pseudotyped Lentiviral Vector with VSV-G and Sendai Virus HN Enhances Infection Efficiency through the Synergistic Effect of the Envelope Proteins.

A gene delivery system utilizing lentiviral vectors (LVs) requires high transduction efficiency for successful application in human gene therapy. Pseudotyping allows viral tropism to be expanded, widening the usage of LVs. While vesicular stomatitis virus G (VSV-G) single-pseudotyped LVs are commonly used, dual-pseudotyping is less frequently employed because of its increased complexity. In this study, we examined the potential of phenotypically mixed heterologous dual-pseudotyped LVs with VSV-G and Sendai virus hemagglutinin-neuraminidase (SeV-HN) glycoproteins, termed V/HN-LV. Our findings demonstrated the significantly improved transduction efficiency of V/HN-LV in various cell lines of mice, cynomolgus monkeys, and humans compared with LV pseudotyped with VSV-G alone. Notably, V/HN-LV showed higher transduction efficiency in human cells, including hematopoietic stem cells. The efficient incorporation of wild-type SeV-HN into V/HN-LV depended on VSV-G. SeV-HN removed sialic acid from VSV-G, and the desialylation of VSV-G increased V/HN-LV infectivity. Furthermore, V/HN-LV acquired the ability to recognize sialic acid, particularly N-acetylneuraminic acid on the host cell, enhancing LV infectivity. Overall, VSV-G and SeV-HN synergistically improve LV transduction efficiency and broaden its tropism, indicating their potential use in gene delivery.

Astroglial connexin 43 is a novel therapeutic target for chronic multiple sclerosis model.

In chronic stages of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalitis (EAE), connexin (Cx)43 gap junction channel proteins are overexpressed because of astrogliosis. To elucidate the role of increased Cx43, the central nervous system (CNS)-permeable Cx blocker INI-0602 was therapeutically administered. C57BL6 mice with chronic EAE initiated by MOG35-55 received INI-0602 (40 mg/kg) or saline intraperitoneally every other day from days post-immunization (dpi) 17-50. Primary astroglia were employed to observe calcein efflux responses. In INI-0602-treated mice, EAE clinical signs improved significantly in the chronic phase, with reduced demyelination and decreased CD3+ T cells, Iba-1+ and F4/80+ microglia/macrophages, and C3+GFAP+ reactive astroglia infiltration in spinal cord lesions. Flow cytometry analysis of CD4+ T cells from CNS tissues revealed significantly reduced Th17 and Th17/Th1 cells (dpi 24) and Th1 cells (dpi 50). Multiplex array of cerebrospinal fluid showed significantly suppressed IL-6 and significantly increased IL-10 on dpi 24 in INI-0602-treated mice, and significantly suppressed IFN-γ and MCP-1 on dpi 50 in the same group. In vitro INI-0602 treatment inhibited ATP-induced calcium propagations of Cx43+/+ astroglial cells to similar levels of those of Cx43-/- cells. Astroglial Cx43 hemichannels represent a novel therapeutic target for chronic EAE and MS.

Role of modified Glasgow Prognostic Score in patients with achalasia who underwent laparoscopic Heller-myotomy with Dor-fundoplication.

BACKGROUND: Systemic inflammatory response is significant prognostic indicator in patients with various diseases. The relationship between prognostic scoring systems based on the modified Glasgow Prognostic Score (mGPS) and achalasia in patients treated with laparoscopic Heller­myotomy with Dor­fundoplication (LHD) remains uninvestigated. This study aimed to examine the role of mGPS in patients with achalasia. METHODS: 457 patients with achalasia who underwent LHD as the primary surgery between September 2005 and December 2020 were included. We divided patients into the mGPS 0 and mGPS 1 or 2 groups and compared the patients' background, pathophysiology, symptoms, surgical outcomes, and postoperative course. RESULTS: mGPS was 0 in 379 patients and 1 or 2 in 78 patients. Preoperative vomiting and pneumonia were more common in patients with mGPS of 1 or 2. There were no differences in surgical outcomes. Postoperative upper gastrointestinal endoscopy revealed that severe esophagitis was more frequently observed in patients with mGPS of 1 or 2 (P < 0.01). The clinical success was 91% and 99% in the mGPS 0 and mGPS 1 or 2 groups, respectively (P < 0.01). CONCLUSIONS: Although severe reflux esophagitis was more common in patients with achalasia with a high mGPS, good clinical success was obtained regardless of the preoperative mGPS.

Characterization of galactosyltransferase and sialyltransferase genes mediating the elongation of the extracellular O-GlcNAc glycans.

O-GlcNAc is a unique post-translational modification found in cytoplasmic, nuclear, and mitochondrial proteins. In a limited number of extracellular proteins, O-GlcNAc modifications occur through the action of EOGT, which specifically modifies subsets of epidermal growth factor-like (EGF) domain-containing proteins such as Notch receptors. The abnormalities due to EOGT mutations in mice and humans and the increased EOGT expression in several cancers signify the importance of EOGT pathophysiology and extracellular O-GlcNAc. Unlike intracellular O-GlcNAc monosaccharides, extracellular O-GlcNAc extends to form elongated glycan structures. However, the enzymes involved in the O-GlcNAc glycan extension have not yet been reported. In our study, we comprehensively screened potential galactosyltransferase and sialyltransferase genes related to the canonical O-GlcNAc glycan pathway and revealed the essential roles of B4GALT1 and ST3GAL4 in O-GlcNAc glycan elongation in human HEK293 cells. These findings were confirmed by sequential glycosylation of Drosophila EGF20 in vitro by EOGT, ß4GalT-1, and ST3Gal-IV. Thus, the findings from our study throw light on the specific glycosyltransferases that mediate O-GlcNAc glycan elongation in human HEK293 cells.

Is it meaningful to add mesh reinforcement to laparoscopic fundoplication for esophageal hiatal hernias in the patients with high risk of hiatal hernia recurrence?

BACKGROUND: While laparoscopic fundoplication is a standard surgical procedure for patients with esophageal hiatal hernias, the postoperative recurrence of esophageal hiatal hernias is a problem for patients with giant hernias, elderly patients, or obese patients. Although there are some reports indicating that reinforcement with mesh is effective, there are differing opinions regarding the use thereof. The aim of this study is to investigate whether mesh reinforcement is effective for laparoscopic fundoplication in patients with esophageal hiatus hernias. METHODS: The subjects included 280 patients who underwent laparoscopic fundoplication as the initial surgery for giant esophageal hiatal hernias, elderly patients aged 75 years or older, and obese patients with a BMI of 28 or higher, who were considered at risk of recurrent hiatal hernias based on the previous reports. Of the subject patients, 91 cases without mesh and 86 cases following the stabilization of mesh use were extracted to compare the postoperative course including the pathology, symptom scores, surgical outcome, and recurrence of esophageal hiatus hernias. RESULTS: The preoperative conditions indicated that the degree of esophageal hiatal hernias was high in the mesh group (p = 0.0001), while the preoperative symptoms indicated that the score of heartburn was high in the non-mesh group (p = 0.0287). Although the surgical results indicated that the mesh group underwent a longer operation time (p < 0.0001) and a higher frequency of intraoperative complications (p = 0.037), the rate of recurrence of esophageal hiatal hernia was significantly low (p = 0.049), with the rate of postoperative reflux esophagitis also tending to be low (p = 0.083). CONCLUSIONS: Mesh reinforcement in laparoscopic fundoplication for esophageal hiatal hernias contributes to preventing the recurrence of esophageal hiatal hernias when it comes to patient options based on these criteria.

RNA Foci in Two bi-Allelic RFC1 Expansion Carriers.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, autosomal recessive neurodegenerative disorder caused by biallelic AAGGG/ACAGG repeat expansion (AAGGG-exp/ACAGG-exp) in RFC1. The recent identification of patients with CANVAS exhibiting compound heterozygosity for AAGGG-exp and truncating variants supports the loss-of-function of RFC1 in CANVAS patients. We investigated the pathological changes in 2 autopsied patients with CANVAS harboring biallelic ACAGG-exp and AAGGG-exp. RNA fluorescence in situ hybridization of the 2 patients revealed CCTGT- and CCCTT-containing RNA foci, respectively, in neuronal nuclei of tissues with neuronal loss. Our findings suggest that RNA toxicity may be involved in the pathogenesis of CANVAS. ANN NEUROL 2024;95:607-613.

Visualizing intracellular sialidase activity of influenza A virus neuraminidase using a fluorescence imaging probe.

In influenza A virus-infected cells, newly synthesized viral neuraminidases (NAs) transiently localize at the host cell Golgi due to glycosylation, before their expression on the cell surface. It remains unproven whether Golgi-localized intracellular NAs exhibit sialidase activity. We have developed a sialidase imaging probe, [2-(benzothiazol-2-yl)-5-(non-1-yn-1-yl) phenyl]-α-D-N-acetylneuraminic acid (BTP9-Neu5Ac). This probe is designed to be cleaved by sialidase activity, resulting in the release of a hydrophobic fluorescent compound, 2-(benzothiazol-2-yl)-5-(non-1-yn-1-yl) phenol (BTP9). BTP9-Neu5Ac makes the location of sialidase activity visually detectable by the BTP9 fluorescence that results from the action of sialidase activity. In this study, we established a protocol to visualize the sialidase activity of intracellular NA at the Golgi of influenza A virus-infected cells using BTP9-Neu5Ac. Furthermore, we employed this fluorescence imaging protocol to elucidate the intracellular inhibition of laninamivir octanoate, an anti-influenza drug. At approximately 7 h after infection, newly synthesized viral NAs localized at the Golgi. Using our developed protocol, we successfully histochemically stained the sialidase activity of intracellular viral NAs localized at the Golgi. Importantly, we observed that laninamivir octanoate effectively inhibited the intracellular viral NA, in contrast to drugs like zanamivir or laninamivir. Our study establishes a visualization protocol for intracellular viral NA sialidase activity and visualizes the inhibitory effect of laninamivir octanoate on Golgi-localized intracellular viral NA in infected cells.

Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice.

Nogo-Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS.

Effects of 10-Hydroxy-2-decenoic Acid and 10-Hydroxydecanoic Acid in Royal Jelly on Bone Metabolism in Ovariectomized Rats: A Pilot Study.

Although previous studies have demonstrated that royal jelly (RJ) may have estrogenic properties and prevent postmenopausal bone loss, the underlying mechanisms are not fully understood. This animal study aimed to investigate the effects of specific fatty acids of RJ, 10-hydroxy-2-decenoic acid (10H2DA) and 10-hydroxydecanoic acid (10HDAA), in ovariectomized rats. Ten-week-old female Wistar rats were divided into the Baseline, Sham, Ovx, Ovx + 10H2DA, and Ovx + 10HDAA groups. Rats in the Baseline group were sacrificed immediately, whereas those in the other groups were subjected to either a sham operation or bilateral ovariectomy. The animals in the Ovx + 10H2DA and Ovx + 10HDAA groups were fed diets containing 10H2DA and 10HDAA, respectively. Twelve weeks after surgery, the rats were sacrificed, and indices of bone mass and bone mechanics were analyzed. Femoral bone mineral density was significantly lower in the Ovx group than in the Sham group (p < 0.01). Administration of 10H2DA or 10HDAA did not ameliorate bone loss after ovariectomy. In addition, administration of these fatty acids diminished femur bone stiffness in ovariectomized rats (p < 0.01 and p < 0.05, respectively). These findings suggest that the favorable effects of RJ may not be exerted solely by 10H2DA or 10HDAA. However, these effects may be exhibited in combination with other RJ constituents.

Special Issue: New Insights into Protein Glycosylation.

Protein glycosylation is a general post-translational modification pathway that controls various biological functions including protein trafficking, cell adhesion, and protein-ligand interaction [...].

Reduced likelihood of the Poggendorff illusion in cerebellar strokes: a clinical and neuroimaging study.

This study aimed to test our hypothesis that the cerebellum plays an important role in the generation of the optical-geometric illusion known as the Poggendorff illusion, the mechanism of which has been explained by accumulated experience with natural scene geometry. A total of 79 participants, comprising 28 patients with isolated cerebellar stroke, 27 patients with isolated cerebral stroke and 24 healthy controls, performed Poggendorff illusion tasks and 2 different control tasks. We also investigated core brain regions underpinning changes in the experience of the illusion effect using multivariate lesion-symptom mapping. Our results indicate that patients with isolated cerebellar stroke were significantly less likely to experience the Poggendorff illusion effect than patients with isolated cerebral stroke or healthy controls (74.6, 90.5 and 89.8%, respectively; F(2,76) = 6.675, P = 0.002). However, there were no inter-group differences in the control tasks. Lesion-symptom mapping analysis revealed that the brain lesions associated with the reduced frequency of the Poggendorff illusion effect were mainly centred on the right posteromedial cerebellar region, including the right lobules VI, VII, VIII, IX and Crus II. Our findings demonstrated, for the first time, that patients with cerebellar damage were significantly less likely to experience the Poggendorff illusion effect and that right posteromedial cerebellar lesions played an important role in this effect. These results provide new insight into alterations of a geometric illusion effect in patients with cerebellar disorders and pave the way for future clinical use of the illusion task to detect cerebellar abnormalities.

The pathological conditions and surgical outcomes depending on the degree of hernia in the intra-thoracic stomach.

BACKGROUND: In recent years, the number of patients requiring surgery for intra-thoracic stomach (ITS) has been increasing due to the effects of obesity and gibbus due to aging. The aim of this study is to assess the effects of the degree of hernia on the pathological conditions and surgical outcomes in ITS patients. METHODS: ITS was defined as cases in which over 50% of the stomach had deviated into the mediastinum by esophagogastric fluoroscopy and/or computed tomography, with 65 patients who underwent laparoscopic surgery as the initial surgery included. We compared the pathological conditions and surgical outcomes by dividing the subjects into 3 groups: Group A: 50%- < 75%; Group B: 75%- < 100%; and Group C: 100% (upside-down stomach), depending on the degree of deviation into the mediastinum of the stomach. RESULTS: The breakdown of patients was 33 in Group A, 21 in Group B, and 11 in Group C. Regarding the preoperative pathological conditions, Group C had a high body mass index (BMI) and a low score for factor V according to upper gastrointestinal endoscopy (p = 0.0109, p = 0.0062, respectively). While the surgical results indicated that the operation time was extended depending on the degree of hernia (p = 0.0051), there was no marked difference in other surgical outcomes or the postoperative course among the three groups, with a high degree of satisfaction. CONCLUSIONS: In the case of ITS, although the operation time was extended depending on the degree of the hernia, the surgical outcomes were the same, and overall good results were obtained.

Health-related quality of life in Japanese patients with multiple sclerosis.

OBJECTIVES: Neurological disabilities, especially physical issues, can adversely affect the daily lives of people with multiple sclerosis (MS) and negatively impact their health-related quality of life (HRQOL). On the other hand, physical and psychiatric symptoms are variable in people with MS, and QOL can be influenced by cultural and educational background. This study aimed to evaluate the association of HRQOL with disabilities, fatigue, and depression in Japanese subjects with MS. METHODS: Evaluation of HRQOL, fatigue, and depression was performed in 184 Japanese individuals with MS, using the Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II), respectively. RESULTS: Multiple linear regression analysis demonstrated negative correlations of the Expanded Disability Status Scale (EDSS) with scores on the FAMS subscales of mobility, symptoms, thinking and fatigue, total FAMS, and additional concerns. The FSS score had negative correlations with mobility, symptoms, emotional well-being, thinking and fatigue, total FAMS, and additional concerns. There were negative correlations between BDI-II scores and all items of FAMS. CONCLUSIONS: HRQOL had relatively close correlations with disabilities and fatigue, and depression had an especially close relationship with HRQOL.

Ameliorating Effect of the Edible Mushroom Hericium erinaceus on Depressive-Like Behavior in Ovariectomized Rats.

Estrogen deficiency during menopause causes a variety of neurological symptoms, including depression. The edible Lion's Mane mushroom, Hericium erinaceus (Bull.: Fr.) Pers. (HE), is a medicinal mushroom that has the potential for a neuroprotective effect and ameliorating neurological diseases, such as depression, anxiety, and neurodegenerative diseases. HE contains phytoestrogens, including daidzein and genistein. However, the ameliorating effect of HE on menopausal symptoms is not well understood. Here we investigated the impact of methanol extract of the HE fruiting body on depressive-like behavior in postmenopausal model rats. The activation of estrogen receptor alpha (ERα) causes body weight loss and uterine weight gain. Body weight gain and uterine weight loss by estrogen deficiency in ovariectomized (OVX) rats were reversed with 17ß-estradiol (E2) but not with HE. Thus, the phytoestrogens in HE may hardly activate ERα. Estrogen receptor beta (ERß) is expressed in the brain, and activation of ERß ameliorates menopausal depressive symptoms. Notably, depressive-like behavior in OVX rats evaluated in forced swim test was reduced by administration of not only E2 but also HE for 92 d. Long-term activation of ERα increases the risk of breast and uterine cancers. HE, therefore, may be effective in treating menopausal depression without the risk of carcinogenesis caused by ERα activation.