Neuronal SAM68 differentially regulates alternative last exon splicing and ensures proper synapse development and function.

Alternative splicing in the 3'UTR of mammalian genes plays a crucial role in diverse biological processes, including cell differentiation and development. SAM68 is a key splicing regulator that controls the diversity of 3'UTR isoforms through alternative last exon (ALE) selection. However, the tissue/cell type-specific mechanisms underlying the splicing control at the 3' end and its functional significance remain unclear. Here, we show that SAM68 regulates ALE splicing in a dose-dependent manner and the neuronal splicing is differentially regulated depending on the characteristics of the target transcript. Specifically, we found that SAM68 regulates interleukin-1 receptor-associated protein splicing through the interaction with U1 small nuclear ribonucleoprotein. In contrast, the ALE splicing of protocadherin-15 (Pcdh15), a gene implicated in several neuropsychiatric disorders, is independent of U1 small nuclear ribonucleoprotein but modulated by the calcium/calmodulin-dependent protein kinase signaling pathway. We found that the aberrant ALE selection of Pcdh15 led to a conversion from a membrane-bound to a soluble isoform and consequently disrupted its localization into excitatory and inhibitory synapses. Notably, the neuronal expression of the soluble form of PCDH15 preferentially affected the number of inhibitory synapses. Moreover, the soluble form of PCDH15 interacted physically with α-neurexins and further disrupted neuroligin-2-induced inhibitory synapses in artificial synapse formation assays. Our findings provide novel insights into the role of neuron-specific alternative 3'UTR isoform selections in synapse development.

Case study observational research: inflammatory cytokines in the bronchial epithelial lining fluid of COVID-19 patients with acute hypoxemic respiratory failure.

BACKGROUND: In this study, the concentrations of inflammatory cytokines were measured in the bronchial epithelial lining fluid (ELF) and plasma in patients with acute hypoxemic respiratory failure (AHRF) secondary to severe coronavirus disease 2019 (COVID-19). METHODS: We comprehensively analyzed the concentrations of 25 cytokines in the ELF and plasma of 27 COVID-19 AHRF patients. ELF was collected using the bronchial microsampling method through an endotracheal tube just after patients were intubated for mechanical ventilation. RESULTS: Compared with those in healthy volunteers, the concentrations of interleukin (IL)-6 (median 27.6 pmol/L), IL-8 (1045.1 pmol/L), IL-17A (0.8 pmol/L), IL-25 (1.5 pmol/L), and IL-31 (42.3 pmol/L) were significantly greater in the ELF of COVID-19 patients than in that of volunteers. The concentrations of MCP-1 and MIP-1ß were significantly greater in the plasma of COVID-19 patients than in that of volunteers. The ELF/plasma ratio of IL-8 was the highest among the 25 cytokines, with a median of 737, and the ELF/plasma ratio of IL-6 (median: 218), IL-1ß (202), IL-31 (169), MCP-1 (81), MIP-1ß (55), and TNF-α (47) were lower. CONCLUSIONS: The ELF concentrations of IL-6, IL-8, IL-17A, IL-25, and IL-31 were significantly increased in COVID-19 patients. Although high levels of MIP-1 and MIP-1ß were also detected in the blood samples collected simultaneously with the ELF samples, the results indicated that lung inflammation was highly compartmentalized. Our study demonstrated that a comprehensive analysis of cytokines in the ELF is a feasible approach for understanding lung inflammation and systemic interactions in patients with severe pneumonia.

Long-term outcome of cervical lymph node metastasis in superficial pharyngeal squamous cell carcinoma after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Superficial pharyngeal squamous cell carcinoma (PSCC) has received increasing attention as a therapeutic target in the GI field with recent innovations in endoscopic submucosal dissection (ESD). However, there are currently no defined criteria for the application of ESD to superficial PSCC. One of the problems encountered during follow-up after ESD is cervical lymph node metastasis (LNM). Identifying the clinicopathologic predictors of cervical LNM can help to provide a basis for the refinement of therapeutic strategies for superficial PSCC. METHODS: The risk of cervical LNM was evaluated in 331 patients with superficial PSCC who underwent initial ESD between 2008 and 2021. Since tumor size, rather than depth, is the dominant factor in the current TNM classification for PSCC, the correlation between tumor size and thickness was investigated. RESULTS: The median follow-up period was 4.8 years. The cumulative 5-year cervical LNM rate was 6.1%. Multivariate Cox proportional hazards regression analysis identified tumor thickness ≥1000 µm and lymphatic invasion as significant independent predictors. Among 204 cases with subepithelial invasion, both factors were also revealed to be significant independent predictors, suggesting that tumor thickness was superior to tumor size in predicting cervical LNM. Despite the positive correlation between tumor thickness and size, there was noticeable variability in the values (R = .20), and the current staging was inadequate to identify groups at high risk for cervical LNM. CONCLUSIONS: Tumor thickness and lymphatic invasion are validated as significant independent predictors for cervical LNM and can be useful indicators to optimize the therapeutic strategies for superficial PSCC.

Safety of Cold Snare Polypectomy during Continuous Use of Antithrombotic Drugs for Delayed Post-Polypectomy Bleeding: A Pilot Study.

BACKGROUND: Cold snare polypectomy is a high-risk endoscopic procedure with a low delayed post-polypectomy bleeding rate. However, it is unclear whether delayed post-polypectomy bleeding rates increase during continuous antithrombotic treatment. This study aimed to determine the safety of cold snare polypectomy during continuous antithrombotic treatment. METHODS: This single-center, retrospective cohort study enrolled patients who underwent cold snare polypectomy during antithrombotic treatment between January 2015 and December 2021. Patients were divided into continuation and withdrawal groups based on whether they continued with antithrombotic drugs or not. Propensity score matching was performed using age, sex, Charlson comorbidity index, hospitalization, scheduled treatment, type of antithrombotic drugs used, multiple medications used, indication for antithrombotic drugs, and gastrointestinal endoscopist qualifications. The delayed polypectomy bleeding rates were compared between the groups. Delayed polypectomy bleeding was defined as the presence of blood in stools and requiring endoscopic treatment or a decrease in hemoglobin level by 2 g/dL or more. RESULTS: The continuation and withdrawal groups included 134 and 294 patients, respectively. Delayed polypectomy bleeding was observed in 2 patients (1.5%) and 1 patient (0.3%) in the continuation and withdrawal groups, respectively (p = 0.23), before propensity score matching, with no significant difference. After propensity score matching, delayed polypectomy bleeding was observed in 1 patient (0.9%) in the continuation group but not in the withdrawal group, with no significant difference. CONCLUSION: Cold snare polypectomy during continuous antithrombotic treatment did not significantly increase delayed post-polypectomy bleeding rates. Therefore, this procedure may be safe during continuous antithrombotic treatment.

Metachronous Multiple Gastric Cancer Discovered as Endoscopic Curability C2 during Regular Follow-Up after Gastric Endoscopic Submucosal Dissection.

INTRODUCTION: The objective of this study was to clarify characteristics of metachronous endoscopic curability C2 (eCura C2) cancer during post-endoscopic submucosal dissection (ESD) follow-up. METHODS: Of 4,355 gastric lesions treated by ESD at our hospital during 2005-2021, 657 were metachronous. After excluding lesions found ≥2 years since the prior examination or in the gastric remnant, the remaining 515 were analyzed. Study 1: We compared 35 eCura C2 cancers and 480 eCura A-C1 cancers. Study 2: Endoscopic findings of the 35 lesions were examined to determine why they had been missed. RESULTS: Mean tumor size was larger (34.0 mm vs. 12.1 mm, p < 0.01) and the proportions of mixed-type and poorly differentiated cancers were higher (highly:mixed:poorly, 34.3:57.1:8.6 vs. 94.2:5.0:0.8, p < 0.01) in the eCura C2 group. Study 2: At the prior examination, 4 lesions were noticed but considered benign, 2 lacked sufficient imaging, 19 were detectable on imaging but missed, and 10 were not detectable on imaging. Over half the lesions that were detectable but missed at the prior examination were in the lesser curvature, many being type IIa-IIb lesions with color similar to the background mucosa. All lesions not detectable on imaging at the prior examination were mixed-type or poorly differentiated type. DISCUSSION: Metachronous cancer detected as eCura C2 cancers was significantly larger, and a significantly higher proportion was mixed-type or poorly differentiated cancers, compared with eCura A-C1 cancers. Possible reasons why these lesions were missed include rapid progression of mixed-type and poorly differentiated cancers, and poor recognition that lesions showing only slight color changes may be present at the lesser curvature.

Evaluation of the fully automated urine particle analyzer UF-1500.

BACKGROUND AND AIMS: This study primarily assessed the performance of the UF-1500, the novel and compact model of the fully automated urine particle analyzer and evaluated its performance against the existing UF-5000 instrument. MATERIALS AND METHODS: A total of 648 residual urine specimens were randomly collected and examined using both the UF-1500 and UF-5000 instruments as well as manual microscopy. For each parameter, the concordance rates and detection accuracy of the UF-1500 against manual microscopy were compared with the UF-5000. RESULTS: The concordance rates between the UF-1500 and manual microscopy were 75.3%-98.5%. The UF-1500 concordance rates within one group agreement were observed to be >90%, for all parameters except for YLCs. The differences within one group agreement between the UF-1500 and manual microscopy were insignificant, in comparison to the UF-5000, with exceptions noted for ECs and YLCs. The sensitivity and specificity of the UF-1500 for RBCs, WBCs, Squa.ECs, and BACT exceeded 80%, while the positive predictive values of ECs and CASTs were below 70%. CONCLUSION: The UF-1500 exhibited a performance that was comparable to the existing instrument, the UF-5000, and was suitable to be introduced in clinical practice. For the samples with suspected false-positive or false-negative results, a manual microscopic examination is required for accurate testing.

Pathogenesis, Clinical Features, and Treatment of Patients with Myelin Oligodendrocyte Glycoprotein (MOG) Autoantibody-Associated Disorders Focusing on Optic Neuritis with Consideration of Autoantibody-Binding Sites: A Review.

Although there is a substantial amount of data on the clinical characteristics, diagnostic criteria, and pathogenesis of myelin oligodendrocyte glycoprotein (MOG) autoantibody-associated disease (MOGAD), there is still uncertainty regarding the MOG protein function and the pathogenicity of anti-MOG autoantibodies in this disease. It is important to note that the disease characteristics, immunopathology, and treatment response of MOGAD patients differ from those of anti-aquaporin 4 antibody-positive neuromyelitis optica spectrum disorders (NMOSDs) and multiple sclerosis (MS). The clinical phenotypes of MOGAD are varied and can include acute disseminated encephalomyelitis, transverse myelitis, cerebral cortical encephalitis, brainstem or cerebellar symptoms, and optic neuritis. The frequency of optic neuritis suggests that the optic nerve is the most vulnerable lesion in MOGAD. During the acute stage, the optic nerve shows significant swelling with severe visual symptoms, and an MRI of the optic nerve and brain lesion tends to show an edematous appearance. These features can be alleviated with early extensive immune therapy, which may suggest that the initial attack of anti-MOG autoantibodies could target the structures on the blood-brain barrier or vessel membrane before reaching MOG protein on myelin or oligodendrocytes. To understand the pathogenesis of MOGAD, proper animal models are crucial. However, anti-MOG autoantibodies isolated from patients with MOGAD do not recognize mouse MOG efficiently. Several studies have identified two MOG epitopes that exhibit strong affinity with human anti-MOG autoantibodies, particularly those isolated from patients with the optic neuritis phenotype. Nonetheless, the relations between epitopes on MOG protein remain unclear and need to be identified in the future.

Effect of Helicobacter pylori infection on malignancy of undifferentiated-type gastric cancer.

BACKGROUND: Although almost all cases of gastric cancer are caused by Helicobacter pylori (HP) infection, there are some rare exceptions. Furthermore, the clinicopathological characteristics of gastric cancer may differ depending on HP infection status. This study aimed to determine the clinicopathological characteristics of undifferentiated-type gastric cancer (UD-GC) according to HP status. METHODS: The study involved 83 patients with UD-GC who were selected from 1559 patients with gastric cancer who underwent endoscopic resection at our hospital and whose HP infection status was confirmed. Clinicopathological characteristics were evaluated according to HP status (eradicated, n = 28; infected, n = 32; not infected, n = 23). RESULTS: In patients without HP infection, UD-GCs were < 20 mm and intramucosal with no vascular invasion. In patients with eradicated HP, there was no correlation between development of UD-GC and time since eradication. Nine of twelve patients with a tumor detected ≥ 5 years after eradication had undergone yearly endoscopy. Submucosal invasion was observed in two of four patients and lymphovascular invasion in three of four patients whose UD-GC was detected ≥ 10 years after eradication. There was no significant between-group difference in the frequency of lesions with invasion into the submucosal layer or deeper (14.3%, 10.5%, and 0% in the UD-E, UD-I, and UD-U groups, respectively). CONCLUSION: The clinicopathological characteristics of UD-GC were similar between HP-infected patients and HP-eradicated patients. Three of four patients with eradicated HP whose UD-GC developed ≥ 10 years after eradication were not eligible for endoscopic treatment and required additional surgery resection. In contrast, UD-GC was curable by endoscopic resection in all patients without HP infection.

Factors Associated with Coronary In-Stent Restenosis after Drug-Eluting Stent Implantation in Patients on Chronic Hemodialysis.

AIMS: Recently, drug-eluting stents (DESs) have been widely adopted for patients on chronic hemodialysis (HD). However, whether DES implantation is associated with a reduced rate of in-stent restenosis (ISR) is unclear. We investigated the incidence of ISR and its predictors in patients on HD after DES implantation. METHODS AND RESULTS: We analyzed 194 consecutive patients (331 lesions) on HD who underwent follow-up angiography after DES implantation. ISR was observed in 74 lesions (22.4%). Angiographically, the relative incidence of AHA/ACC type C lesion was increased (47 vs. 32%; p = 0.043), the minimal lumen diameter (MLD) before DES implantation was smaller (0.82 ± 0.49 vs. 0.97 ± 0.45 mm; p < 0.01), and the lesion length (LL) was increased (30.2 ± 16.1 vs. 24.4 ± 12.1 mm; p = 0.023) in lesions with ISR compared to those without ISR. The rate of rotational atherectomy use was also increased in lesions with ISR compared to those without ISR (50% vs. 25%; p < 0.01). In a multivariate analysis, the MLD before DES implantation (odds ratio [OR] = 0.50, 95% confidence interval [CI] 0.27-0.91, p = 0.024), LL (OR = 1.02, 95% CI 1.00-1.04, p = 0.030) and the use of rotational atherectomy (OR = 2.71, 95% CI 1.55-4.72, p < 0.01) were independent predictors of ISR. The incidence of ISR was similar between lesions treated with the first-generation (25.8%) and the second-generation DESs (20.4%). CONCLUSIONS: ISR was observed in 74 lesions (22.4%). A small MLD, long LL, and the use of rotational atherectomy were independent predictors of ISR after DES implantation in patients on HD. There was no significant difference in the ISR rate between the first- and the second-generation DESs.

Comprehensive risk evaluation for metachronous carcinogenesis after endoscopic submucosal dissection of superficial pharyngeal squamous cell carcinoma.

BACKGROUND: Pharyngeal squamous cell carcinoma (PSCC) is associated with a high likelihood of metachronous carcinogenesis, which is known to have a poor prognosis. This study aimed to identify comprehensive risk evaluation indicators for metachronous carcinogenesis after endoscopic submucosal dissection (ESD) of superficial PSCC. METHODS: The risk of metachronous carcinogenesis was evaluated in 144 patients with superficial PSCC (with no history of PSCC or esophageal squamous cell carcinoma) who underwent initial ESD from 2008 to 2020. Multiple lugol-voiding lesions (LVLs) in the background pharyngeal and esophageal epithelium were evaluated as endoscopic indicators. The hemoglobin, albumin, lymphocyte, and platelet (HALP) score was analyzed as a serum marker. RESULTS: The median follow-up period was 4.3 years. The coincidence rate for pharyngeal and esophageal LVL grade was 55%. The cumulative 3-year metachronous PSCC rate was 18.9%. The cumulative 3-year second metachronous PSCC rate was 43.9%. Forward stepwise multivariate Cox proportional hazards regression analysis identified pharyngeal LVL grade and a lower HALP score as significant independent predictors. Pharyngeal LVL grade was superior to esophageal LVL grade as a predictor of metachronous PSCC. A lower HALP score was significantly associated with younger age in forward stepwise multivariate logistic regression analysis. CONCLUSIONS: Patients with a history of superficial PSCC remain at risk for metachronous carcinogenesis over time, and long-term follow-up is imperative. Comprehensive evaluation of endoscopic features with a novel serum marker, namely, the HALP score, can help predict metachronous carcinogenesis.

Clinical relevance of endoscopic treatment for superficial pharyngeal cancer: feasibility of techniques corresponding to each location and long-term outcomes.

BACKGROUND AND AIMS: Superficial pharyngeal cancers are being detected and treated using endoscopy in many medical facilities with increasing frequency. However, the reports focus on the hypopharynx. We identified reliable treatments by adapting the method for each region of the pharynx. Here, we introduce our methods for treating various pharyngeal regions and show their long-term results. METHODS: Of 308 consecutive patients who underwent pharyngeal endoscopic submucosal dissection between February 2007 and December 2018 at our institution, we selected 293 patients who were diagnosed histologically with squamous cell carcinoma. The patients were divided into 4 groups based on the specific location of superficial pharyngeal lesions and the short- and long-term outcomes, such as technical success, adverse events, overall survival, and case-specific survival, were evaluated. RESULTS: The procedure time was 51 minutes at location A where cancer develops most commonly. The rate of en bloc resection was 99.4%, and the R0 resection rate was 82.6%. With regard to adverse events, there were 2 cases of postoperative hemorrhage, both treated with endoscopic hemostasis. The average observation period was 61.2 months overall, with 14 cases of recurrent lymph node metastasis. The 5-year survival rate was 84.1%, and cause-specific survival was 100%. CONCLUSIONS: Adaptation of the treatment method according to the location of the lesion led to good results. Endoscopic treatment of superficial pharyngeal cancer is both feasible and beneficial.

Efficacy of Vonoprazan for Refractory Reflux Esophagitis after Esophagectomy.

BACKGROUND: Refractory reflux esophagitis (RRE), unresponsive to conventional proton-pump inhibitors (PPIs), is a complication in esophagectomy with gastric pull-up. Vonoprazan (VPZ), a novel potassium-competitive acid blocker, has been available in Japan since 2015. Here, we investigated the efficacy of VPZ on PPI-resistant RRE after esophagectomy with gastric pull-up. METHODS: This was a single-center retrospective study. We used the revised Los Angeles (r-LA) classification based on the Los Angeles classification and the modified Los Angeles classification to evaluate abnormal forms of mucosal breaks such as lateral spreading consistently. Patients who underwent esophagectomy with gastric pull-up and had RRE grade B-D as per the r-LA classification, despite using standard-dose PPIs or double dose of rabeprazole, were included. Sixteen patients who switched to VPZ (20 mg/day) and 14 patients who continued PPIs were assigned to the VPZ and PPI groups, respectively. Endoscopic observations were reviewed by 3 endoscopists using the r-LA classification to ensure consistent diagnosis, while the treatment arm and patient information were blinded to evaluators. We defined mucosal breaks that improved by at least one grade after treatment as improved mucosa and recovery to grade M or N as mucosal healing. RESULTS: The percentage of patients with improved mucosa in the VPZ and PPI groups was 81.3 and 14.3%, respectively (p < 0.001). The rate of mucosal healing was 68.8 and 7.1%, respectively (p = 0.001). CONCLUSION: VPZ significantly improved PPI-resistant RRE after esophagectomy with gastric pull-up.

Effectiveness of Chemoradiotherapy for Metachronous Esophageal Squamous Cell Carcinoma.

INTRODUCTION: Multiple Lugol-voiding lesions (LVLs) in the esophagus increase the risk of synchronous and metachronous development of esophageal squamous cell carcinoma (ESCC). Chemoradiotherapy (CRT) following endoscopic submucosal dissection (ESD) may reduce the incidence of metachronous ESCC, but few studies have investigated this. Therefore, we retrospectively examined the effect of CRT on metachronous ESCC and multiple esophageal dysplasias visible as multiple LVLs. METHODS: This study reviewed 146 patients who underwent esophageal ESD and were determined pathologically to have noncurative resection. They were divided into 2 groups: those who received additional CRT (CRT group; n = 64) and those without additional treatment (control group; n = 82). Incidence of metachronous ESCC was analyzed using propensity scores to adjust for patient characteristics. The number of multiple LVLs was also examined. RESULTS: The CRT group was significantly younger than the control group (mean 66.6 vs. 70.6 years, p = 0.011), had significantly deeper tumor invasion (p = 0.013), and had a significantly higher rate of lymphovascular invasion (47.8 vs. 12.2%, p < 0.001). The CRT group also had a significantly higher improvement rate of multiple LVLs (58.1 vs. 2.0%, p < 0.001). The LVLs after CRT had a distinctive irregular crack-shaped appearance. Metachronous ESCC was found in 7 patients (10.9%) in the CRT group and in 17 patients (20.7%) in the control group (p = 0.113). In propensity score-adjusted logistic regression analysis, the odds ratio for metachronous ESCC in the CRT group was 0.316 (p = 0.023). The occurrence rate was significantly lower in the CRT group than in the control group. DISCUSSION/CONCLUSION: CRT may be effective in preventing metachronous ESCC.

Management and outcomes of resectable gastric conduit cancer: a retrospective comparative study of 51 cases.

PURPOSE: Although gastric conduit cancer (GCC) arising after esophagectomy is increasingly being reported, therapeutic strategies for resectable GCC have yet to be optimized. We investigated clinicopathological features of patients undergoing endoscopic versus more invasive surgical treatments for GCC and compared their outcomes. METHODS: Fifty-one patients, who had a history of esophagectomy with gastric conduit reconstruction for esophageal cancer and underwent resection for metachronous GCC, were identified. Their characteristics and outcomes were retrospectively reviewed. RESULTS: There were 48 males and three females, ranging in age from 46-86 years. Twelve patients underwent surgery for GCC (group S) and 39 underwent only endoscopic resection (group E). The most common cause of death was pneumonia (10/51, 19.6%). Neither overall survival nor cumulative incidence of pneumonia-caused death differed significantly between the two groups (P = 0.60, 0.84, respectively). In group S, partial gastrectomy was performed in four cases and total gastrectomy in seven. Partial resections, including three antrectomy without sternotomy or intrathoracic procedures, were completed with significantly shorter operative durations than total resections (median 208 vs 513 min, P = 0.012). GCC recurrence was experienced in two cases: one undergoing open approach partial resection of the corpus and the other thoracoscopic total gastrectomy. CONCLUSION: Even compared with endoscopic treatment, outcomes following surgery for GCC appeared to be acceptable. Open approach total gastric gastrectomy could be the most radical modality, while other less invasive alternatives, e.g., antrectomy, are also an option. Clinicians may select a treatment strategy balancing radicality and patient status, reflecting tolerance to invasive procedures.

Metachronous carcinogenesis of superficial esophagus squamous cell carcinoma after endoscopic submucosal dissection: incidence and risk stratification during long-term observation.

BACKGROUND: This study aimed to reveal long-term outcomes, such as incidence of metachronous esophageal and head and neck squamous cell carcinomas and overall survival rate, through long-term observation of patients with esophageal carcinoma post-endoscopic submucosal dissection. METHODS: Risk of metachronous carcinogenesis was evaluated in 88 patients with intramucosal esophageal carcinoma (without history of metachronous esophageal or head and neck squamous cell carcinomas) who underwent endoscopic submucosal dissection from 2007 to 2008 and were endoscopically observed for > 3 years. Histologically, the papillary vessel is defined as the clock gear-like structure composed of capillaries directly penetrating the epithelium (starting from the lamina propria) and covering at least two-thirds of it, around which the tumor cells are arranged in a spiral pattern. RESULTS: Median endoscopic follow-up period was 11.0 years. Cumulative 2-, 5-, and 10-year metachronous esophageal carcinoma rates were 11.4%, 20.6%, and 39.3%, respectively. Stepwise multivariate Cox proportional hazard regression analysis identified multiple Lugol-voiding lesions (LVLs) as the single significant independent predictor. Cumulative 2-, 5-, and 10-year metachronous head and neck squamous cell carcinoma rates were 6.9%, 10.4%, and 19.6%, respectively. Stepwise multivariate Cox proportional hazard regression analysis identified multiple LVLs, Brinkman index, papillary vessel, and younger age as significant predictive factors. Overall post-endoscopic submucosal dissection survival rates were 98.8% and 87.5% at 5 and 10 years, respectively. CONCLUSION: Patients with a history of esophageal carcinoma remain at risk for metachronous carcinogenesis even > 5 years after endoscopic submucosal dissection. Thus, long-term follow-up is important.

Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod. METHODS: We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped. RESULTS: HLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). CONCLUSIONS: HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

Utility of Valsalva maneuver in the endoscopic pharyngeal observation.

BACKGROUND: Metachronous cancer rate in the pharynx is high before and after the treatment of esophageal cancer. Endoscopic observation is difficult in the pharynx especially in the postcricoid area. Pharyngeal cancer in the postcricoid area has been often found in advanced stage. Valsalva maneuver has been reported to improve the visibility. METHODS: From May 2017 we introduced a dedicated mouthpiece to conduct Valsalva maneuver. One hundred consecutive patients who had been observed throughout the pharynx by one endoscopist were enrolled. A total of 200 image files before and after introduction were made and reviewed by three endoscopists. We retrospectively evaluated the utility and safety of Valsalva maneuver. RESULTS: The visibility before introduction was Good in three cases, Moderate in 12 cases and Poor in 85 cases. Meanwhile, the visibility after introduction was Good in 58 cases, Moderate in 23 cases, and Poor in 19 cases (P < 0.05). Nine lesions including hypopharyngeal cancer were found and adverse events were not observed in this study. CONCLUSION: The Valsalva maneuver was considered to be a safe and effective method in endoscopic observation of the pharynx.

Hypertension as a Metabolic Disorder and the Novel Role of the Gut.

PURPOSE OF REVIEW: Hypertension is related to impaired metabolic homeostasis and can be regarded as a metabolic disorder. This review presents possible mechanisms by which metabolic disorders increase blood pressure (BP) and discusses the importance of the gut as a novel modulator of BP. RECENT FINDINGS: Obesity and high salt intake are major risk factors for hypertension. There is a hypothesis of "salt-induced obesity"; i.e., high salt intake may tie to obesity. Heightened sympathetic nervous system (SNS) activity, especially in the kidney and brain, increases BP in obese patients. Adipokines, including adiponectin and leptin, and renin-angiotensin-aldosterone system (RAAS) contribute to hypertension. Adiponectin induced by a high-salt diet may decrease sodium/glucose cotransporter (SGLT) 2 expression in the kidney, which results in reducing BP. High salt can change secretions of adipokines and RAAS-related components. Evidence has been accumulating linking the gastrointestinal tract to BP. Glucagon-like peptide-1 (GLP-1) and ghrelin decrease BP in both rodents and humans. The sweet taste receptor in enteroendocrine cells increases SGLT1 expression and stimulates sodium/glucose absorption. Roux-en-Y gastric bypass improves glycemic and BP control due to reducing the activity of SGLT1. Na/H exchanger isoform 3 (NHE3) increases BP by stimulating the intestinal absorption of sodium. Gastrin functions as an intestinal sodium taste sensor and inhibits NHE3 activity. Intestinal mineralocorticoid receptors also regulate sodium absorption and BP due to changing ENaC activity. Gastric sensing of sodium induces natriuresis, and gastric distension increases BP. Changes in the composition and function of gut microbiota contribute to hypertension. A high-salt/fat diet may disrupt the gut barrier, which results in systemic inflammation, insulin resistance, and increased BP. Gut microbiota regulates BP by secreting vasoactive hormones and short-chain fatty acids. BP-lowering effects of probiotics and antibiotics have been reported. Bariatric surgery improves metabolic disorders and hypertension due to increasing GLP-1 secretion, decreasing leptin secretion and SNS activity, and changing gut microbiome composition. Strategies targeting the gastrointestinal system may be therapeutic options for improving metabolic abnormalities and reducing BP in humans. SNS, brain, adipocytes, RAAS, the kidney, the gastrointestinal tract, and microbiota play important roles in regulating BP. Most notably, the gut could be a novel target for treatment of hypertension as a metabolic disorder.

Operational effectiveness of three-dimensional flexible endoscopy: an ex vivo study using a new model.

BACKGROUND AND OBJECTIVES: Two-dimensional (2D) images lack depth information and thus provide probabilistic recognition that do not completely match the actual three-dimensional (3D) information. Here, we investigated the operability of 3D endoscopes. METHODS: A 3D operation model was developed by passing 20 silk threads through upper and lower plates at 2-mm intervals in front and back rows separated by 1 mm. We evaluated accuracy and time of operating an electrosurgical knife. A successful operation was defined as pulling only a front-row thread; an unsuccessful operation was defined as pulling no thread (miss) or simultaneously pulling front- and back-row threads. Endoscopists (four experts, six trainees) repeated the operation under 2D and 3D conditions until individually accumulating 10 successful attempts under each condition. RESULTS: Operation accuracy was significantly higher for 3D compared with 2D in all endoscopists (88.5% vs. 61.3%; p < 0.01) and in both experience groups (trainees: 84.5% vs. 61.2%; experts: 95.2% vs. 61.5%; both p < 0.01). Operation time was significantly shorter for 3D compared with 2D in all endoscopists (12.5 ± 4.1 s vs. 14.8 ± 4.7 s; p < 0.01) and in both experience groups (trainees: 12.8 ± 4.2 s vs. 15.2 ± 4.9 s; experts: 12.1 ± 4.0 s vs. 14.3 ± 4.3 s; both p < 0.01). DISCUSSION: Compared with 2D endoscopy, 3D endoscopy significantly improved operation accuracy and shortened operation time, suggesting that 3D endoscopy enables accurate operation by depth information, aiding spatial recognition.

Comparison of 3D endoscopy and conventional 2D endoscopy in gastric endoscopic submucosal dissection: an ex vivo animal study.

BACKGROUND AND OBJECTIVES: Conventional endoscopy provides two-dimensional (2D) information without depth information. This study compared three-dimensional (3D) endoscopy and 2D endoscopy using an endoscopic submucosal dissection (ESD) training model to evaluate the utility of 3D endoscopy. METHODS: Porcine stomach specimens (7 × 7 cm) were prepared from commercially available resected porcine stomachs and a 10-mm hypothetical lesion was marked at the center of each specimen. Specimens were individually placed in an ESD training model, and subjected to either 2D or 3D ESD. En bloc resection rate, perforation rate, incision time, dissection time, and levels of five eyestrain symptoms (fatigue, pain, blurred vision, head-heaviness, and headache; 100-mm visual analog scale) were compared between the 2D and 3D procedures. In a crossover design, 8 endoscopists each performed two 2D and two 3D procedures. RESULTS: All 32 lesions were resected en block, but perforation occurred in one 2D procedure. Incision time was significantly shorter in 3D ESD than in 2D ESD (102.8 ± 42.1 s vs. 135.8 ± 65.7 s, p < 0.05). Dissection time was also significantly shorter in 3D ESD than in 2D ESD (366.3 ± 187.6 s vs. 517.8 ± 282.3 s, p < 0.05). Differences in levels of all symptoms except blurred vision between before and after ESD were larger in 3D ESD than in 2D ESD. CONCLUSIONS: Incision time and dissection time were significantly shorter in 3D ESD compared with 2D ESD, but eyestrain was increased. Depth information from 3D images appears to facilitate rapid and stable ESD maneuvers.