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Recently, various magnetic resonance imaging (MRI) modalities have been developed to easily detect carotid and aortic plaques, but these techniques are time-consuming and vulnerable to motion artifacts. We investigated the utility of a gradient echo MRI technique known as liver acquisition with volume acceleration flexible (LAVA-Flex) to detect carotid and aortic atherosclerotic plaques. Ten patients who underwent carotid endarterectomy (CEA) were assessed regarding the correspondence between LAVA-Flex findings and the histopathology of excised carotid plaques. In addition, 47 patients with cryptogenic ischemic stroke underwent LAVA-Flex and transesophageal echocardiography (TEE) for detection of embolic sources in the thoracic aorta. We analyzed the relationship between the thickness of the aortic plaque measured by TEE and the presence of high-intensity lesions on LAVA-Flex. Nine of 10 patients (90.0%) who underwent CEA showed a high-intensity carotid lesion on LAVA-Flex, which corresponded pathologically to plaques containing large lipid cores and hemorrhage. Twenty-four (51.1%) of 47 cryptogenic stroke patients showed a high-intensity lesion in the thoracic aorta on LAVA-Flex; of these, 21 (87.5%) also demonstrated a large plaque (thickness ≥4 mm) on TEE. Twenty-two (95.7%) of 23 patients without a high-intensity lesion on LAVA-Flex demonstrated no large plaque on TEE. LAVA-Flex had a sensitivity of 95.5% and a specificity of 88.0% in patients with large plaques. This study showed that LAVA-Flex successfully detected carotid and aortic plaques. This imaging technique may be useful to rapidly diagnose and evaluate carotid and aortic plaques, which are critical risk factors for aortogenic stroke.

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. Purpose: We investigated whether mesh reinforcement is effective for laparoscopic fundoplication in patients with esophageal hiatus hernias. Patients and 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 in order 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 (pConclusions: 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.

Derangement of thoracoabdominal pressure gradient (TAPG) associates with gastroesophageal reflux disease (GERD). High-resolution esophageal manometry (HRM) is the gold standard to assess pathophysiology of GERD. Starlet HRM is widely used in Japan; however, TAPG values on Starlet HRM system have been unstudied. The aim of this study is to propose the cutoff value of TAPG to discriminate GERD on Starlet HRM system. We included patients who underwent both Starlet HRM and 24-hour multichannel intraluminal impedance pH study (MII-pH) at our hospital between July 2018 and February 2022. Patients were divided into 3 groups; control group (both HRM and MII-pH were within normal limits), GERD group (acid exposure time [AET] ≥4.0% and/or DeMeester score ≥ 14.72), and non-pathological reflux group. Normal MII-pH values were defined according to our previous study using healthy Japanese volunteers (Yano, et al. Esophagus, 2017); AET Total 102 patients met the study criteria (mean age 53.0 ± 16.0 years, 32 females). Thirty-four patients were categorized into the control group, 31 patients were into the GERD group, and 37 patients were into the non-pathological reflux group. In the control group, 5th and 95th percentiles of TAPG were − 3.4 and 24.3 mmHg, and those of adjusted TAPG were − 50.7 and 1.6 mmHg. TAPG poorly correlated with acid exposure time (AET) (rs = 0.287, p = 0.003); however, adjusted TAPG well-correlated with AET (rs = 0.505, p Adjusted TAPG is associated with antireflux competency across the esophagogastric junction. Estimated cutoff value of adjusted TAPG was −11.1 mmHg in the study cohort. Further study is warrantied.

O-glycosylation is a post-translational protein modification essential to life. One of the enzymes involved in this process is protein O-fucosyltransferase 1 (POFUT1), which fucosylates threonine or serine residues within a specific sequence context of epidermal growth factor-like domains (EGF-LD). Unlike most inverting glycosyltransferases, POFUT1 lacks a basic residue in the active site that could act as a catalytic base to deprotonate the Thr/Ser residue of the EGF-LD acceptor during the chemical reaction. Using quantum mechanics/molecular mechanics (QM/MM) methods on recent crystal structures, as well as mutagenesis experiments, we uncover the enzyme catalytic mechanism, revealing that it involves proton shuttling through an active site asparagine, conserved among species, which undergoes tautomerization. This mechanism is consistent with experimental kinetic analysis of Caenorhabditis elegans POFUT1 Asn43 mutants, which ablate enzyme activity even if mutated to Asp, the canonical catalytic base in inverting glycosyltransferases. These results will aid inhibitor development for Notch-associated O-glycosylation disorders.

The epidermal growth factor-like (EGF) domain is an evolutionarily conserved motif found widely distributed among numerous secreted and membrane-anchored proteins, including the Notch receptors. Notch receptors include numerous EGF repeats tandemly connected in the extracellular domain. These EGF repeats must be properly folded in order for them to undergo the three different types of O-glycosylation associated with these extracellular proteins: O-fucose, O-glucose, and O-N-acetylglucosamine via glycosyltransferases POFUT1, POGLUT1, and EOGT. The O-glycosylation of the EGF repeats in the Notch receptors regulates the activation of Notch signaling and mutations in POFUT1, POGLUT1, and EOGT have been linked to specific human diseases. A large amount of EGF repeat and glycosyltransferase protein is required to construct an in vitro O-glycosylation system. Here, we describe how we prepared properly folded EGF repeats using two different bacterial expression vectors, generated recombinant glycosyltransferases, and performed in vitro O-glycosylation and subsequent product analysis by mass spectrometry. The methods described here are useful for investigating the enzymatic activities of mutated glycosyltransferases, revealing the structural basis of the O-glycosylation mechanism by co-crystallization of the glycosyltransferase-EGF repeat complexes, or identifying potential inhibitors of these glycosyltransferases.

The basal ganglia and related dopaminergic cortical areas are important neural systems underlying motor learning and are also implicated in impulse control disorders (ICDs). Motor learning impairments and ICDs are frequently observed in Parkinson's disease (PD). Nevertheless, the relationship between motor learning ability and ICDs has not been elucidated.We examined the relationship between motor learning ability and gambling propensity, a possible symptom for prodromal ICDs, in PD patients. Fifty-nine PD patients without clinical ICDs and 43 normal controls (NC) were administered a visuomotor rotation perturbation task and the Iowa Gambling Task (IGT) to evaluate motor learning ability and gambling propensity, respectively. Participants also performed additional cognitive assessments and underwent brain perfusion SPECT imaging.Better motor learning ability was significantly correlated with lower IGT scores, i.e., higher gambling propensity, in PD patients but not in NC. The higher scores on assessments reflecting prefrontal lobe function and well-preserved blood perfusion in prefrontal areas were correlated with lower IGT scores along with better motor learning ability.Our findings suggest that better motor learning ability and higher gambling propensity are based on better prefrontal functions, which are in accordance with the theory that the prefrontal cortex is one of the common essential regions for both motor learning and ICDs.

Neuroinflammation by activated microglia and astrocytes plays a critical role in progression of amyotrophic lateral sclerosis (ALS). Interleukin-19 (IL-19) is a negative-feedback regulator that limits pro-inflammatory responses of microglia in an autocrine and paracrine manner, but it remains unclear how IL-19 contributes to ALS pathogenesis. We investigated the role of IL-19 in ALS using transgenic mice carrying human superoxide dismutase 1 with the G93A mutation (SOD1G93A Tg mice). We generated IL-19–deficient SOD1G93A Tg (IL-19−/−/SOD1G93A Tg) mice by crossing SOD1G93A Tg mice with IL-19−/− mice, and then evaluated disease progression, motor function, survival rate, and pathological and biochemical alternations in the resultant mice. In addition, we assessed the effect of IL-19 on glial cells using primary microglia and astrocyte cultures from the embryonic brains of SOD1G93A Tg mice and IL-19−/−/SOD1G93A Tg mice. Expression of IL-19 in primary microglia and lumbar spinal cord was higher in SOD1G93A Tg mice than in wild-type mice. Unexpectedly, IL-19−/−/SOD1G93A Tg mice exhibited significant improvement of motor function. Ablation of IL-19 in SOD1G93A Tg mice increased expression of both neurotoxic and neuroprotective factors, including tumor necrosis factor-α (TNF-α), IL-1β, glial cell line–derived neurotrophic factor (GDNF), and transforming growth factor β1, in lumbar spinal cord. Primary microglia and astrocytes from IL-19−/−/SOD1G93A Tg mice expressed higher levels of TNF-α, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms.

Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral–pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA. Supplementary Information The online version contains supplementary material available at 10.1186/s13041-021-00770-1.

In Japan, disease-modifying drugs for multiple sclerosis have amounted to eight, to date, providing us with various therapeutic choices. However, we still encounter difficult cases resistant to these drugs. This review summarizes the diagnostic and therapeutic strategies for refractory multiple sclerosis by presenting suggestive cases.

The Notch pathway represents evolutionarily conserved intercellular signaling essential for cell-to-cell communication during development. Dysregulation of Notch signaling has been implicated in various diseases, and its control represents a potential cancer treatment strategy. Notch signaling is initiated by the interaction of NOTCH receptors with their ligands on neighboring cells. Therefore, the truncated NOTCH ectodomain, composed mainly of tandem repeats of epidermal growth factor-like (EGF) domains, serves as a decoy molecule that competes for ligand binding and thus inhibits ligand-dependent Notch signaling. Although full-length NOTCH EGF repeats exhibited potent Notch inhibitory activity, they were poorly produced in the transfected cells. This study evaluated the effect of EGF domain-modifying glycosyltransferases on the secretion of NOTCH EGF repeats. Our results in HEK293T cells revealed that, unlike the effect on endogenous NOTCH receptors, overexpressed EGF domain-specific O-GlcNAc transferase (EOGT) markedly enhanced the secretion of NOTCH1 EGF repeats in an enzyme activity-dependent manner. The co-expression of protein O-glucosyltransferase 1 further manifested the effect of EOGT. The resultant changes in O-glycosylation of NOTCH3 were evaluated by label-free glycopeptide quantification. This study provides an experimental strategy to efficiently generate NOTCH EGF repeats by manipulating the expression of glycosyltransferases that alter the O-glycosylation of EGF domains.

Siponimod, which is approved to treat active secondary progressive multiple sclerosis, acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P

Guillain-Barré syndrome (GBS) has occasionally occurred in people who have received coronavirus disease 2019 (COVID-19) vaccines. Dysgeusia is rare symptom of GBS. We herein report a rare case of sensory ataxic GBS with dysgeusia just after the second dose of the Pfizer-BioNTech COVID-19 vaccine. Although autoantibodies against glycolipids were not detected, immunotherapy with intravenous immunoglobulin and methylprednisolone pulse therapy effectively ameliorated the symptoms. Our report suggests that the COVID-19 vaccine may induce various clinical subtypes of GBS, including a rare variant with sensory ataxia and dysgeusia.

Introduction We report a case of sustained complete response in unfavorable cancer of unknown primary site (CUP) successfully treated with chemotherapy combining pembrolizumab, pemetrexed and platinum. Case presentation A 66-year-old man was presented with weight loss and cough for 3 months. Contrast-enhanced computed tomography (CT) confirmed a mass in the superior anterior mediastinum and multiple enlarged mediastinal and axillary lymph nodes. Positron emission tomography-CT (PET-CT) showed abnormal uptake in the corresponding lesions. Histopathological analysis of the left axillary nodule revealed poorly differentiated adenocarcinoma. Immunohistochemistry showed the tumor cells were positive for cytokeratin 7 and thyroid transcription factor-1 and negative for cytokeratin 20. Thus, the patient was diagnosed as poorly differentiated adenocarcinoma of unknown primary, and treated as non-small-cell lung cancer. Additional genetic testing revealed the patient was negative for EGFR, ALK fluorescence in situ hybridization, ROS1, BRAF, and PD-L1 22C3 IHC with Tumor Proportion Score (TPS) was less than 1%. The patient received six cycles of pembrolizumab, platinum, and pemetrexed intravenously. Cisplatin was switched to carboplatin because of cisplatin nephrotoxicity in one course. PET-CT after six cycles showed all lesions disappeared; complete response was considered to have been achieved. Maintenance therapy of pembrolizumab and pemetrexed has been continued for 6 months after the induction therapies to prevent progressive disease. Complete response has been maintained. Discussion Chemotherapy with pembrolizumab, platinum and pemetrexed could be valuable for treating unfavorable CUP. Conclusion Chemotherapy with pembrolizumab, platinum, and pemetrexed helped achieved sustained complete response in a patient with unfavorable CUP., Highlights • The prognosis of patients with unfavorable CUP remains poor. • Pembrolizumab's addition to standard chemotherapy resulted in significantly longer overall survival for patients with NSCLC. • Chemotherapy with pembrolizumab, platinum, and pemetrexed helped achieved sustained complete response in a patient with unfavorable CUP.

Background Patients with a history of gastrectomy have a higher incidence of cholecystocholedocholithiasis (CCL) and related morbidities than the general population. However, the management of common bile duct (CBD) stones with endoscopic retrograde cholangiopancreatography is challenging in patients after Roux‐en‐Y or Billroth II reconstruction because of the altered gastrointestinal anatomy. The aim of the current study was to evaluate the safety and efficacy of one‐stage laparoscopic transcystic papillary balloon dilation and laparoscopic cholecystectomy (LTPBD+LC) in patients with previous gastrectomy for gastric cancer. Methods This retrospective cohort study included five patients with CCL who had previously undergone gastrectomy. All five underwent LTPBD+LC between May 2015 and February 2020 at our institution. The primary end‐point was complete clearance of the CBD stones. Results Of the 311 patients who had undergone gastrectomy for gastric cancer from December 2009 to December 2018 at our institution, six (1.9%) were later diagnosed with CCL. Five of the six patients did not need emergency biliary drainage and underwent conservative therapy and subsequent elective LTPBD+LC. LTPBD+LC was successfully performed in all cases. None of the patients required conversion to open surgery. The rate of complete clearance of the CBD stones was 100%. The mean operative time of the entire procedure was 126 minutes (range, 102‐144 minutes), and the mean blood loss was 12.4 mL (range, 1‐50 mL). There were no major perioperative complications, and the mean length of postoperative hospital stay was 4.2 days (range, 3‐7 days). Conclusion One‐stage LTPBD+LC may be a feasible procedure for patients with CCL who have previously undergone gastrectomy for gastric cancer.

Background In colorectal laparoscopic surgery, accuracy of tumor marking has been an important but not fully resolved issue. The tattoo marking technique or intraoperative endoscopy have been used but they either carry the risk of accidental intestinal puncture or require either longer operation times, a skilled endoscopist and/or intraoperative colon insufflation. We supposed that tumor site marking with the near-infrared fluorescent clips, ZEOCLIP FS clips (Zeon Medical Co., Ltd., Tokyo, Japan) might overcome disadvantages of both tattoo marking and intraoperative endoscopy-based tumor localization methods. This is the first report on the case series using near-infrared fluorescent marking clip. We summarize the early results in 30 patients, who underwent colorectal laparoscopic surgery; we focus particularly on effectiveness and safety of the method. Materials and methods Thirty consecutive patients, who underwent laparoscopic surgery for colorectal cancer after previous endoscopic ZEOCLIP FS placement were enrolled from May 2019 till October 2019. The primary endpoint was the rate of intraoperative clip detection and the secondary endpoints were: the rate of adverse effects, percentage of slipped clips and usefulness of plain abdominal radiography to preoperatively confirm the clip retention. Locations of fluorescent clips were identified with a full-color fluorescence laparoscope. All operations and clip placements were performed by the same senior surgeon with sufficient experience in both procedures. Results Fluorescent clips could be detected in 94.1% of tumor lesions. Three (2.1%) clips dropped before surgery. Plain abdominal radiography was sufficient to assess clip retention in all cases. No adverse effects related to either clip placement or clip detection were observed. Conclusion The ZEOCLIP FS could be easily detected from the serosal side of the intestinal tract when placed 1–2 days before surgery. Fluorescent clip-guided laparoscopy may be considered a safe and effective method for localization of colorectal tumor sites. The Research Registry UIN: researchregistry5400.

Epidermal growth factor (EGF) domain-specific O-GlcNAc transferase (EOGT) is an endoplasmic reticulum (ER)-resident protein that modifies EGF repeats of Notch receptors and thereby regulates Delta-like ligand-mediated Notch signaling. Several EOGT mutations that may affect putative N-glycosylation consensus sites are recorded in the cancer database, but the presence and function of N-glycans in EOGT have not yet been characterized. Here, we identified N-glycosylation sites in mouse EOGT and elucidated their molecular functions. Three predicted N-glycosylation consensus sequences on EOGT are highly conserved among mammalian species. Within these sites, we found that Asn-263 and Asn-354, but not Asn-493, are modified with N-glycans. Lectin blotting, endoglycosidase H digestion, and MS analysis revealed that both residues are modified with oligomannose N-glycans. Loss of an individual N-glycan on EOGT did not affect its endoplasmic reticulum (ER) localization, enzyme activity, and ability to O-GlcNAcylate Notch1 in HEK293T cells. However, simultaneous substitution of both N-glycosylation sites affected both EOGT maturation and expression levels without an apparent change in enzymatic activity, suggesting that N-glycosylation at a single site is sufficient for EOGT maturation and expression. Accordingly, a decrease in O-GlcNAc stoichiometry was observed in Notch1 co-expressed with an N263Q/N354Q variant compared with WT EOGT. Moreover, the N263Q/N354Q variant exhibited altered subcellular distribution within the ER in HEK293T cells, indicating that N-glycosylation of EOGT is required for its ER localization at the cell periphery. These results suggest critical roles of N-glycans in sustaining O-GlcNAc transferase function both by maintaining EOGT levels and by ensuring its proper subcellular localization in the ER.

The Notch signaling pathway is highly conserved and essential in animal development and tissue homeostasis. Regulation of Notch signaling is a crucial process for human health. Ligands initiate a signal cascade by binding to Notch receptors expressed on the neighboring cell. Notch receptors interact with ligands through their epidermal growth factor-like repeats (EGF repeats). Most EGF repeats are modified by O-glycosylation with residues, such as O-linked N-acetylglucosamine (O-GlcNAc), O-fucose, and O-glucose. A recent study revealed the distinct roles of these O-glycans in ligand binding, processing, and trafficking of Notch receptors. In particular, O-GlcNAc glycans are essential for Delta-like (DLL) ligand-mediated Notch signaling. In this study, we showed that O-GlcNAc promotes Notch1 trafficking to the cell surfaces under the condition that O-fucose and O-glucose are removed from consecutive EGF repeats of Notch1. Through in vitro experiments, we showed that O-GlcNAc mediates the stability of EGF domains in the same manner as O-fucose and O-glucose. Thus, O-GlcNAc on EGF domains possesses a shared function in the stability of EGF domains and Notch1 trafficking.

Introduction This is the first report on near-infrared fluorescent (NIRF) clip-guided gastrectomy. The NIRF clip, ZEOCLIP FS, emits NIRF signals when excited. We hypothesized that preoperative placement of the ZEOCLIP FS near a gastric lesion would allow fluorescence laparoscopic localization of the clip, and hence, the lesion, during surgery. We report this technique in two cases. Case presentation Case 1: An 81-year-old female was diagnosed with early gastric cancer and a pedunculated 4 cm large hyperplastic polyp that had prolapsed into the duodenum, and was scheduled for laparoscopy-assisted distal gastrectomy, due to the potential risk of dissection of the polyp with the duodenal wall. On the day before surgery, ZEOCLIP FS clips were endoscopically placed at the cancer site and the polyp. The locations of the fluorescent clips were confirmed intraoperatively using a full-color fluorescence laparoscope. Case 2 An 81-year-old male was scheduled for laparoscopy-assisted total gastrectomy for gastric cancer under fluorescent clip-guidance. Clip locations could not be confirmed during initial intraoperative observation. However, when the stomach wall was raised using forceps during a second observation attempt, the fluorescent clip locations were confirmed. Discussion In case 1, it was easy to confirm clip location, facilitating complete resection of early gastric cancer without dissecting the polyp. In case 2, the fluorescent clip was located by raising the stomach and adjusting the angle between the stomach wall and the fluorescence laparoscope. Conclusion The positive results of these two cases warrant conducting feasibility studies for use of this method., Highlights • This is the first case series on near-infrared fluorescent clip guided gastrectomy. • It was possible to observe the position by devising the angle between the stomach wall and the fluorescent laparoscope. • The near-infrared clip method may be useful as a method for confirming an intraoperative lesion site in gastrectomy.

Highlights • We have reported the case that underwent laparoscopic total gastrectomy with photodynamic diagnosis based on 5-aminolevulinic acid induced protoporphyrinIX by using PINPOINT®. • PINPOINT®, a brightfield color fluorescence camera, could be used for 5-ALA-PDD. • Administration of 5-ALA through PTEG for a patient with pyloric stenosis was successfully performed., Introduction Photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) has been used as a diagnostic procedure for malignant diseases. Dedicated laparoscopes (e.g., an IMAGE1 Camera System®) are used for this procedure. We report a case treated with laparoscopic total gastrectomy with 5-ALA-PDD using the PINPOINT® system. Presentation of case A patient in his 80 s with diffuse-type gastric cancer with pyloric stenosis and ascites was admitted to our hospital. Double percutaneous transesophageal gastrotubing (dPTEG) for both gastric decompression and enteral nutrition and two cycles of preoperative chemotherapy with S-1 plus oxaliplatin were performed preoperatively. Additionally, we preoperatively performed an ex vivo experiment that confirmed that the PINPOINT® system can be used to observed protoporphyrin IX (PpIX) fluorescence. Three hours before surgery, 5-ALA hydrochloride was administered through dPTEG. Observation was performed by PINPOINT®, and Aladuck® was used as an excitation light source. Peritoneal nodules and sampled lymph nodes with red fluorescence were observed by 5-ALA-PDD. Accordingly, we gave up a radical operation and laparoscopic total gastrectomy without systematic lymphadenectomy to improve anemia and release pyloric stenosis was performed. The patient’s postoperative course was uneventful. Discussion It is possible that the connection with each of the scopes and an exclusive light source (Aladuck®) enable the easy use of 5-ALA-PDD without dedicated laparoscopy. It is expected that 5-ALA-PDD would show the further spread of gastrointestinal cancer if it could be performed with many types of laparoscopes. Conclusion We found that 5-ALA-PDD-guided surgery can be easily performed in a short time using the PINPOINT® system.

Recently, a recessively inherited intronic repeat expansion in replication factor C1 (RFC1) was identified in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Here, we describe a Japanese case of genetically confirmed CANVAS with autonomic failure and auditory hallucination. The case showed impaired uptake of iodine-123-metaiodobenzylguanidine and 123I-ioflupane in the cardiac sympathetic nerve and dopaminergic neurons, respectively, by single-photon emission computed tomography. Long-read sequencing identified biallelic pathogenic (AAGGG)n nucleotide repeat expansion in RFC1 and heterozygous benign (TAAAA)n and (TAGAA)n expansions in brain expressed, associated with NEDD4 (BEAN1). Enrichment of the repeat regions in RFC1 and BEAN1 using a Cas9-mediated system clearly distinguished between pathogenic and benign repeat expansions. The haplotype around RFC1 indicated that the (AAGGG)n expansion in our case was on the same ancestral allele as that of European cases. Thus, long-read sequencing facilitates precise genetic diagnosis of diseases with complex repeat structures and various expansions.

A 65-year-old man was followed up after undergoing Hartmann's operation for the treatment of obstructive colon cancer 1 year earlier. He presented with bloody stool and underwent examination, including lower gastrointestinal endoscopy, and he was diagnosed with rectal cancer. Since he had a history of multiple abdominal surgeries, including Hartmann's operation, severe pelvic adhesions were expected. Thus, in consideration of surgical safety and curability, transanal total mesorectal excision (Ta-TME) was performed. The duration of the surgery was 3 h, and there was minimal blood loss. Histopathological findings did not reveal remnants of cancer in the resected margin, and the patient was discharged on hospital day 7. Rectal cancer has a higher rate of local recurrence than colon cancer. To prevent local recurrence, ensuring a rectal circumferential resection margin (CRM) with TME is essential, which is, however, challenging in obese patients and in those with giant tumors, contracted pelvis, prostatic hypertrophy, etc., since these conditions complicate pelvic surgery. The same is true for patients with a history of multiple abdominal surgeries. It is expected that these problems can be resolved by Ta-TME. In the present case, Ta-TME was extremely useful in rectal cancer surgery for a patient with a history of multiple abdominal surgeries, including Hartmann's operation.

Highlights • VISION SENSE® is a new near-infrared fluorescence laparoscope, and allows adjustment of the intensity of excitation light and quantification of the intensity of ICG fluorescence during observation. • Using VISION SENSE®, when many ICG-positive lymph nodes are observed, we can select lymph nodes by quantifying ICG fluorescence during surgery. • This procedure might improve SN mapping for early gastric cancer., Introduction One of the drawbacks of indocyanine green (ICG) fluorescence sentinel node (SN) mapping is the impossibility of quantifying lymph node fluorescence during surgery. VISION SENSE® is a new near-infrared fluorescence laparoscope for bright-field full-color observation, and provides the ability to adjust the intensity of excitation light and quantify the intensity of ICG fluorescence during observation. We report the case of a patient who underwent ICG SN mapping for early gastric cancer using VISION SENSE®. Presentation of case A woman in her 60 s was diagnosed with cType0-IIc early gastric cancer located in the anterior wall of the middle gastric body (25 mm in diameter, cT1b, cN0, cM0, cStage IA). Contrast-enhanced computed tomography showed no metastases. Laparoscopy assisted distal gastrectomy with D1+ lymph node dissection and SN mapping with ICG fluorescence using the VISION SENSE® were successfully performed. Using VISION SENSE®, we could select those lymph nodes objectively showing high intensity by quantifying ICG fluorescence during surgery. The pathological diagnosis was well-differentiated adenocarcinoma, pT1a, N0, M0, pStage IA. No ICG-positive lymph nodes (8 nodes) contained metastases. Postoperative course was good, with no complications. Discussion The use of VISION SENSE® allowing adjustment of excitation light and quantification of ICG fluorescence intensity might decreased the false-negative rate for SNs and increased the sensitivity of the ICG for detecting SNs. Conclusion We successfully performed ICG SN mapping for early gastric cancer using VISION SENSE®.

Highlights • NIR overlay threshold function of VISIONSENSE® allows us to set a floor for the NIR signal to be included in the overlay. • We report the case of a patient who underwent indocyanine green fluorescence-guided parathyroidectomy using the threshold-adjustment function of VISIONSENSE®. • The threshold-adjustment function of VISIONSENSE® may be useful to readily identify the PG in parathyroid surgery., Introduction VISIONSENSE® is a new near-infrared (NIR) fluorescence laparoscope and has an NIR overlay threshold function that allows us to set a floor for the NIR signal to be included in the overlay. We report the case of a patient who underwent indocyanine green (ICG) fluorescence-guided parathyroidectomy for primary hyperparathyroidism due to parathyroid adenoma using the threshold-adjustment function of VISIONSENSE®. Presentation of case A 40-year-old man was referred to our department for examination and treatment of hypercalcemia. ICG fluorescence-guided parathyroidectomy using VISIONSENSE® was planned on diagnosis of primary hyperparathyroidism due to parathyroid tumor. In the operation, we were unable to readily recognize the parathyroid gland (PG). After intravenous injection of ICG, fluorescence from ICG appeared from the left thyroid lobe to the PG, but PG contours remained unclear. We therefore used the threshold-adjustment function of VISIONSENSE® to discard NIR signal values

Notch signaling is an evolutionarily conserved signaling pathway and is essential for cell-fate specification in metazoans. Dysregulation of Notch signaling results in various human diseases, including cardiovascular defects and cancer. In 2000, Fringe, a known regulator of Notch signaling, was discovered as a Notch-modifying glycosyltransferase. Since then, glycosylation-a post-translational modification involving literal sugars-on the Notch extracellular domain has been noted as a critical mechanism for the regulation of Notch signaling. Additionally, the presence of diverse O-glycans decorating Notch receptors has been revealed in the extracellular domain epidermal growth factor-like (EGF) repeats. Here, we concisely summarize the recent studies in the human diseases associated with aberrant Notch glycosylation.

The O-GlcNAc modification of Notch receptors regulates Notch ligand interactions in a manner distinct from other forms of O-glycans on epidermal growth factor-like (EGF) repeats of Notch receptors. Although many proteins, besides Notch receptors, are expected to be O-GlcNAcylated by EGF domain-specific O-GlcNAc transferase (EOGT), only a small number of proteins have been reported to be modified in vivo, and elongated O-GlcNAc glycans have not been extensively explored. To extend our view of the specificity and variety of the glycan modification, we conducted a comprehensive analysis of O-GlcNAc glycans on NOTCH1 in mammals. Mass spectrometric analysis of NOTCH1 fragments expressed in HEK293T cells revealed that several EGF domains with putative O-GlcNAcylation sites were hardly modified with O-GlcNAc. Although amino acid residues before the modification site are preferentially occupied with aromatic residues, Phe and Tyr are preferable to Trp for the apparent modification with O-GlcNAc. Furthermore, a minor form of fucosylated O-GlcNAc glycans was detected in a subset of EGF domains. Fucosylation of O-GlcNAc glycans was enhanced by FUT1, FUT2, or FUT9 expression. The FUT9-dependent Lewis X epitope was confirmed by immunoblotting using an anti-Lewis X antibody. As expected from the similarity in the glycan structures, the Lexis X antigen was detected on O-fucose glycans. Our results refined the putative consensus sequence for the EOGT-dependent extracellular O-GlcNAc modification in mammals and revealed the structural diversity of functional Notch O-glycans.

Objective Simultanagnosia is a rare neuropsychological symptom characterized by difficulty recognizing global structures while preserving perception of local detail. The condition is classified into ventral and dorsal types. Clinical presentation of ventral simultanagnosia includes a reduced ability to recognize multiple visual stimuli rapidly, that is, part-by-part recognition. Here, we report a case of ventral simultanagnosia with a unique presentation; when short-duration visual stimuli were presented, the patient could perform global recognition by improving his part-by-part approach. To investigate the relationship between local and global perception bias and the duration of the present stimulus, we conducted a visual perception test using hierarchically organized Navon figures. Methods/Results The patient was a 62-year-old right-handed man who suffered from cerebral infarction in the right occipitotemporal lobe. He had no language dysfunction but exhibited left unilateral neglect, prosopagnosia, and ventral-type simultanagnosia. We conducted a visual perception test using the Navon figures and control figures as a visual stimulus. We randomly presented the figures for intervals of 0.2 or 20 s and let the patient report all the letters (global and/or local element) that he recognized. Global elements of the Navon letter were recognized a rate of 0% and 78.3% at intervals of 20 and 0.2 s, respectively, indicating that shorter presentation made the part-by-part approach less likely to manifest. Conclusions We assumed that the simultanagnosia in this case was caused by failure to maintain the initially perceived global information for a long period of time during visual presentation, due to right occipitotemporal damage.

Background : This study aimed to evaluate the association between cognitive impairment and health-related quality of life (HRQOL), fatigue, and depression in Japanese patients with multiple sclerosis (MS). Methods : The Brief International Cognitive Assessment for MS (BICAMS) was performed in 184 Japanese patients with MS. The Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II) were used to evaluate HRQOL, fatigue, and depression, respectively. Results : Multiple linear regression analysis demonstrated positive correlations of the Symbol Digit Modalities Test (SDMT) with the scores on the FAMS subscales of mobility, symptoms, emotional well-being, and additional concerns and with the total FAMS score even after controlling for the Expanded Disability Status Scale score, age at examination, and duration of education. The SDMT score in the BICAMS battery had negative correlations with the BDI-II score, as revealed by multiple linear regression analysis. None of the three tests in the BICAMS had any correlation with the FSS score. Conclusion : The SDMT has a significant relationship with HRQOL and depression in Japanese patients with MS.

O-Linked glycosylation such as O-fucose, O-glucose, and O-N-acetylglucosamine are considered to be unusual. As suggested by the high levels of evolutional conservation, these O-glycans are fundamentally important for life. In the last two decades, our understanding of the importance of these glycans has greatly advanced. In particular, identification of the glycosyltransferases responsible for the biosynthesis of these glycans has accelerated basic research on the functional significance and molecular mechanisms by which these O-glycans regulate protein functions as well as clinical research on human diseases due to changes in these types of O-glycosylation. Notably, Notch receptor signaling is modified with and regulated by these types of O-glycans. Here, we summarize the current view of the structures and the significance of these O-glycans mainly in the context of Notch signaling regulation and human diseases.

Background: Mild cognitive impairment (MCI) in Parkinson’s disease (PD) is considered a risk factor for PD with dementia (PDD). Verbal fluency tasks are widely used to assess executive function in PDD. However, in cases of PD with MCI (PD-MCI), the relative diagnostic accuracy of different qualitative verbal fluency measures and their related neural mechanisms remain unknown. Objective: This study aimed to investigate the relative diagnostic accuracy of qualitative (clustering and switching) verbal fluency strategies and their correlates with functional imaging in PD-MCI. Methods: Forty-five patients with PD (26 with MCI and 19 without MCI) and 25 healthy controls underwent comprehensive neurocognitive testing and resting-state functional magnetic resonance imaging. MCI in patients with PD was diagnosed according to established clinical criteria. The diagnostic accuracy of verbal fluency measures was determined via receiver operating characteristic analysis. Changes in brain functional connectivity between groups and across clinical measures were assessed using seed-to-voxel analyses. Results: Patients with PD-MCI generated fewer words and switched less frequently in semantic and phonemic fluency tasks compared to other groups. Switching in semantic fluency showed high diagnostic accuracy for PD-MCI and was associated with reduced functional connectivity in the salience network. Conclusion: Our results indicate that reduced switching in semantic fluency tasks is a sensitive and specific marker for PD-MCI. Qualitative verbal fluency deficits and salience network dysfunction represent early clinical changes observed in PD-MCI.

Neuro-Behçet's disease accounts for 10-20% cases of Behçet's disease, and patients manifest neurological symptoms due to parenchymal inflammation in the central nervous system. Neuro-Behçet's disease is classified into two types (acute and chronic progressive) based on clinical symptoms and therapeutic responsiveness. This review aimed to summarize the acute type of neuro-Behçet's disease according to the guidelines of the Japanese Behçet's Disease Research Committee.

Anticoagulation therapy, especially using heparin or recently developed oral direct factor Xa inhibitors (DiXals), is recommended as first-line treatment for cancer-related venous thromboembolism (VTE). However, the preventive efficacy of these anticoagulants for cancer-associated ischemic stroke is still unknown. We retrospectively investigated the efficacy of subcutaneous unfractionated heparin (UFH) and DiXals for preventing the recurrence of cancer-associated cryptogenic ischemic stroke with VTE., We retrospectively studied consecutive patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE who received subcutaneous UFH or oral DiXaIs at 9 hospitals., Fifty-three patients (24 treated with UFH and 29 treated with DiXaIs) were enrolled. Of these, 47 demonstrated systemic metastasis (cancer stage IV). During 30-day follow-up after initiation of anticoagulation therapy, recurrent ischemic stroke was observed in only 1 patient (4%) in the UFH group and in 9 patients (31%) in the DiXal group. The incidence of major bleeding complications was similar between the 2 groups (4% and 10%, respectively). The cumulative risk of ischemic stroke recurrence within 30days was lower with UFH than with DiXals (competing risk analysis, p=0.008). In the DiXal group, patients who experienced recurrence showed significantly higher D-dimer levels than those without recurrence., In patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE, UFH demonstrated a lower rate of recurrent ischemic stroke than DiXaIs, and there were no differences in bleeding risk between the 2 treatments. D-dimer levels at stroke onset increased the risk of recurrence in the DiXal group but not in the UFH group.

Interleukin-19 (IL-19) acts as a negative-feedback regulator to limit proinflammatory response of macrophages and microglia in autocrine/paracrine manners in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system (CNS), but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17-producing helper T cell (Th17 cell) infiltration into the CNS. In addition, IL-19-deficient splenic macrophages expressed elevated levels of major histocompatibility complex (MHC) class II, co-stimulatory molecules, and Th17 cell differentiation-associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.

Notch signaling receptors, ligands, and their downstream target genes are dysregulated in pancreatic ductal adenocarcinoma (PDAC), suggesting a role of Notch signaling in pancreatic tumor development and progression. However, dysregulation of Notch signaling by post-translational modification of Notch receptors remains poorly understood. Here, we analyzed the Notch-modifying glycosyltransferase involved in the regulation of the ligand-dependent Notch signaling pathway. Bioinformatic analysis revealed that the expression of epidermal growth factor (EGF) domain-specific O-linked N-acetylglucosamine (EOGT) and Lunatic fringe (LFNG) positively correlates with a subset of Notch signaling genes in PDAC. The lack of EOGT or LFNG expression inhibited the proliferation and migration of Panc-1 cells, as observed by the inhibition of Notch activation. EOGT expression is significantly increased in the basal subtype, and low expression of both EOGT and LFNG predicts better overall survival in PDAC patients. These results imply potential roles for EOGT- and LFNG-dependent Notch signaling in PDAC.

Primary gastrointestinal lymphoma is relatively rare and typically treated by chemotherapy. In some cases, surgery for obstruction in the proximal small intestine is challenging and has a high risk for anastomotic leakage. An 80-year-old woman presented to our hospital with vomiting and abdominal distension. Enteroscopy showed a type 2 circumferential tumor in the proximal jejunum 6 cm on the anal side from Treitz ligament. Biopsy showed solid and diffuse proliferation of large atypical cells with round and irregular nuclei. On immunohistochemistry, these cells were positive for CD20, CD79a, and CD138. Diffuse large B-cell lymphoma (DLBCL) was diagnosed and classified as Ann Arbor stage IIE and Lugano classification stage II 2 and scored 1 point on the International Prognostic Index (i.e., low risk). Given the risk of anastomotic leakage due to lesions and residual obstructive enteritis, surgery was not performed. The patient received double percutaneous transesophageal gastrotubing (dPTEG) to facilitate decompression and enteral nutrition. Enteral nutrition and chemotherapy were initiated immediately after dPTEG insertion. After one course of rituximab plus cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (R–CHOP), the tumor showed a partial response, and the obstruction was improved. Oral ingestion was started, and the dPTEG tube was removed. After six courses of R–CHOP, enhanced CT, positron emission tomography-CT, and serum interleukin-2 levels indicated complete treatment response. During treatment, gastrointestinal perforation did not occur, oral intake was good, and careful follow-up will be continued. dPTEG for obstructive small intestinal DLBCL could help avoid high-risk surgery, and a complete response to chemotherapy was achieved., Highlights • ・Surgery for obstruction in the proximal small intestine is challenging and has a high risk for anastomotic leakage. • ・Double percutaneous transesophageal gastrotubing is a novel treatment that can achieve both intestinal decompression and enteral nutrition. • ・Performing dPTEG for obstructive small intestinal DLBCL precluded the use of high-risk surgery and facilitated a complete response to chemotherapy.

Surgical site infections (SSI) are one of the most frequent complications following stoma reversal (SR-SSI) and lead to multiple problems such as decreased mobility of the patients or increased hospital costs. Several risk factors for SR-SSI have been reported, but there are no risk scoring systems for predicting SR-SSI. The current study aimed to analyze the risk factors for SR-SSI and develop a scoring system.Multivariate analysis of risk factors for SR-SSI was performed in patients who underwent elective SR and were followed-up during the first month after surgery. A logistic regression model was used to identify risk factors and construct a predictive score.Of the 182 patients, 53 (29.1%) developed SSI. In multivariate analysis, three variables as preoperative risk factors were associated with increased SR-SSI incidence: subcutaneous fat thickness (≥ 20 mm) (odds ratio [OR]: 8.46 [95% confidence interval (CI): 3.45-20.7], P0.001), period from stoma creation (≤ 20 weeks) (OR: 2.88 [95% CI: 1.14-7.28], P = 0.025), and SSI after the primary operation (OR: 3.06 [95% CI: 1.19-7.90], P = 0.021). Each of these variables contributed 2,1, and 1 points to the risk score, respectively. The SR-SSI rate was 2.9%, 20.3%, 34.2%, 54.5%, and 81.8% for the scores of 0,1,2,3, and 4 points, respectively. The area under the receiver operating characteristic curve was 0.773 (95% CI: 0.703-0.844).A simple clinical scoring system based on three preoperative variables may be useful in predicting the risk of SR-SSI.

Background Extended excision of the permeation organ neighborhood is often performed in locally invasive colon cancer, and it is reported to have a survival benefit. In addition, some cases of secondary lymph node metastases in a permeation organ were reported. However, they are reports of synchronous secondary lymph node metastases, not metachronous secondary lymph node metastases. To the best of our knowledge, there are no cases of metachronous secondary lymph node metastases after the resection of a primary colorectal cancer in PubMed. Case presentation The case was a 67-year-old man who underwent colonoscopy because of weight loss. Sigmoid colon cancer with all circumference-related stenosis was found by examination, and the patient was transferred to our hospital for the purpose of scrutiny and treatment. The small intestine ileus caused by the invasion of sigmoid colon cancer developed after the transfer. Laparoscopic high anterior resection and extended excision of small intestine segmental resection was performed after the intestinal tract decompression with a nasal ileus tube. Histopathological analysis revealed a pathological diagnosis of pT4b (ileal submucosal invasion) N0 (0/11) M0 f Stage II, tub2, ly1, v2, PN0. Although adjuvant chemotherapy with capecitabine after the operation was planned for half a year, treatment was suspended in the first course by the patient’s self-judgment. No recurrence was observed for a year after the operation, but metastasis recurrence in the para-aortic lymph node was found by a computed tomography (CT) one and a half years after the operation. 18 F-fluorodeoxyglucose (FDG) positron emission tomography revealed that FDG was accumulated only in the para-aortic lymph node. Laparoscopic metastasis lymphadenectomy was performed due to the diagnosis of metachronous metastasis to the para-aortic lymph node alone. Intraoperative findings revealed that lymph node metastasis occurred in the mesentery of the ileum. No adjuvant treatment was done after the secondary operation, and he is still alive with no recurrence 1 year and 9 months after the operation. Conclusions We report a rare case of a laparoscopic resection of a metachronous secondary lymph node metastasis in the mesentery of the ileum after surgery for sigmoid colon cancer with ileum invasion.

O-Linked glycosylation such as O-fucose, O-glucose, and O-N-acetylglucosamine are considered to be unusual. As suggested by the high levels of evolutional conservation, these O-glycans are fundamentally important for life. In the last two decades, our understanding of the importance of these glycans has greatly advanced. In particular, identification of the glycosyltransferases responsible for the biosynthesis of these glycans has accelerated basic research on the functional significance and molecular mechanisms by which these O-glycans regulate protein functions as well as clinical research on human diseases due to changes in these types of O-glycosylation. Notably, Notch receptor signaling is modified with and regulated by these types of O-glycans. Here, we summarize the current view of the structures and the significance of these O-glycans mainly in the context of Notch signaling regulation and human diseases.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of Collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion inSOD1G93Amice using Crmp1S522A(Ser522→Ala) knock-in (Crmp1ki/ki) mice in which the S522 phosphorylation site was abolished andCrmp1knock-out (Crmp1−/−) mice, respectively.Crmp1ki/ki/SOD1G93Amice showed longer latency to fall in a rotarod test whileCrmp1−/−/SOD1G93Amice showed shorter latency compared withSOD1G93Amice. Survival was prolonged inCrmp1ki/ki/SOD1G93Amice but not inCrmp1−/−/SOD1G93Amice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved inCrmp1ki/ki/SOD1G93Amice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects inCrmp1ki/ki/SOD1G93AandCrmp1−/−/SOD1G93Amice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.

Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet’s disease, and myositis. Here we present the first report of anti–signal recognition particle antibody–associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.

Intracellular aggregates are a common pathological hallmark of neurodegenerative diseases such as polyglutamine (polyQ) diseases, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and multiple system atrophy (MSA). Aggregates are mainly formed by aberrant disease-specific proteins and are accompanied by accumulation of other aggregate-interacting proteins. Although aggregate-interacting proteins have been considered to modulate the formation of aggregates and to be involved in molecular mechanisms of disease progression, the components of aggregate-interacting proteins remain unknown. In this study, we showed that small glutamine-rich tetratricopeptide repeat-containing protein alfa (SGTA) is an aggregate-interacting protein in neurodegenerative diseases. Immunohistochemistry showed that SGTA interacted with intracellular aggregates in Huntington disease (HD) cell models and neurons of HD model mice. We also revealed that SGTA colocalized with intracellular aggregates in postmortem brains of patients with polyQ diseases including spinocerebellar ataxia (SCA)1, SCA2, SCA3, and dentatorubral–pallidoluysian atrophy. In addition, SGTA colocalized with glial cytoplasmic inclusions in the brains of MSA patients, whereas no accumulation of SGTA was observed in neurons of PD and ALS patients. In vitro study showed that SGTA bound to polyQ aggregates through its C-terminal domain and SGTA overexpression reduced intracellular aggregates. These results suggest that SGTA may play a role in the formation of aggregates and may act as potential modifier of molecular pathological mechanisms of polyQ diseases and MSA.

Fucosylated glycans critically regulate the physiological functions of proteins and cells. Alterations in levels of fucosylated glycans are associated with various diseases. For detection and functional modulation of fucosylated glycans, chemical biology approaches using fucose (Fuc) analogs are useful. However, little is known about how efficiently each unnatural Fuc analog is utilized by enzymes in the biosynthetic pathway of fucosylated glycans. We show here that three clickable Fuc analogs with similar but distinct structures labeled cellular glycans with different efficiency and protein specificity. For instance, 6-alkynyl (Alk)-Fuc modified O-Fuc glycans much more efficiently than 7-Alk-Fuc. The level of GDP-6-Alk-Fuc produced in cells was also higher than that of GDP-7-Alk-Fuc. Comprehensive in vitro fucosyltransferase assays revealed that 7-Alk-Fuc is commonly tolerated by most fucosyltransferases. Surprisingly, both protein O-fucosyltransferases (POFUTs) could transfer all Fuc analogs in vitro, likely because POFUT structures have a larger space around their Fuc binding sites. These findings demonstrate that labeling and detection of fucosylated glycans with Fuc analogs depend on multiple cellular steps, including conversion to GDP form, transport into the ER or Golgi, and utilization by each fucosyltransferase, providing insights into design of novel sugar analogs for specific detection of target glycans or inhibition of their functions.

Interleukin-19 (IL-19) acts as an anti-inflammatory cytokine in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system, but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17–producing helper T cell (Th17 cell) infiltration into the central nervous system. In addition, IL-19–deficient splenic macrophages expressed elevated levels of major histocompatibility complex class II, co-stimulatory molecules, and Th17 cell differentiation–associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.

Background Postoperative non-anastomotic stenosis of the proximal jejunum after total gastrectomy with Roux-en-Y reconstruction is a rare complication. If endoscopic balloon dilation proves ineffective, patients need re-operation under general anesthesia and experience a high rate of postoperative complications. Magnetic compression anastomosis is a nonsurgical procedure that can create an anastomosis similar to that obtained through surgery. We report a case in which magnetic compression anastomosis was successfully performed to avoid re-operation for non-anastomotic stenosis of the proximal jejunum after total gastrectomy with Roux-en-Y reconstruction. Case presentation A 70-year-old woman was admitted to our hospital for treatment of non-anastomotic stenosis of the proximal jejunum. Open total gastrectomy and Roux-en-Y reconstruction were performed 2 years previously for advanced gastric cancer at another hospital. She complained of anorexia and obstructed passage of food. No recurrence of gastric cancer was identified. Esophagogastroduodenoscopy showed circumferential membranous stenosis of the jejunum 3 cm distal to the esophago-jejunal anastomosis. Endoscopic balloon dilation was performed three times, but proved ineffective. Magnetic compression anastomosis was planned because the stenosis existed near the esophago-jejunal anastomosis and re-operation was a highly invasive procedure requiring intrathoracic anastomosis. Endoscopic balloon dilation preceded placement of the parent magnet on the anal side of the stenosis. Confirming the improvement of stenosis, the parent magnet was placed on the anal side of the stenosis during esophagogastroduodenoscopy. The parent magnet attached to nylon thread was fixed to the cheek to prevent magnet migration. A week after placing the parent magnet, restenosis was confirmed and the daughter magnet was placed via nylon thread on the oral side of the stenosis. The two magnets were adsorbed in the end-to-end direction across the stenosis. Magnets adsorbed in the end-to-end direction moved to the anal side 11 days after placement. Wide anastomosis was confirmed by esophagogastroduodenoscopy. Endoscopic balloon dilation was regularly performed to prevent restenosis after magnetic compression anastomosis. No complications were observed postoperatively. The patient was able to eat normally and successfully reintegrated into society. Conclusions Magnetic compression anastomosis could be a feasible procedure to avoid surgery for non-anastomotic stenosis of the proximal jejunum after gastrectomy with Roux-en-Y reconstruction.