Search

Objectives: Recently, a genetic risk for chronic pancreatitis (CP) was found to be conferred by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 6 ( TRPV6 ). Interestingly, 20%-57% of patients with functionally defective TRPV6 variants have other susceptibility genes such as cationic trypsinogen, serine protease inhibitor Kazal type 1, chymotrypsin C, cystic fibrosis transmembrane conductance regulator, and carboxypeptidase A1. In this study, we focused on pediatric patients with acute recurrent pancreatitis or CP with at least 1 variant in these 5 genes and investigated the presence of coexisting TRPV6 mutations., Methods: Ninety Japanese pediatric patients (median age at first onset, 8.0 years) who had at least 1 variant of these 5 genes were enrolled in this study. DNA samples were extracted for analysis from peripheral blood leukocytes. Coding regions of TRPV6 were screened by Sanger sequencing., Results: Regardless of functional defects or non-defects in TRPV6 variants, 14 of the 90 patients (15.6%) were trans-heterozygous for TRPV6 variants [p.A18S (n = 3), p.C197R (n = 3), p.I223T (n = 3), p.D324N (n = 4), p.M418V (n = 3), p.V540F (n = 1), p.A606T (n = 1), and p.M721T (n = 3)] and the 5 susceptibility genes noted above. Of these variants, p.D324N, p.V540F, and p.A606T are associated with pancreatitis. Three patients had the ancestral haplotype [p.C197R + p.M418V + p.M721T]., Conclusions: Overall, 4 of 90 patients (4.4%) had the coexistence of clearly pathogenic TRPV6 variants with pancreatitis-associated variants. The cumulative accumulation of these genetic factors may contribute to the development of pancreatitis at a young age., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Obstructive sleep apnea syndrome (OSAS) can cause sudden death during sleep. Previous findings have suggested that OSAS development is related to maxillofacial morphology. Evaluation of facial morphology can determine the risk of developing the disease, and establishing an objective method to assess the underlying etiology of OSAS-related death would be advantageous., Objective: The objective of this study is to determine the key features of obstructive sleep apnea syndrome (OSAS) using postmortem oral and pharyngeal computed tomography (CT)., Methods: We retrospectively assessed autopsy cases of patients with (n=25) and without (n=25) OSAS-related death. We used oral and pharyngeal CT images to compare the oral and pharyngeal cavity volume (OPCV), oral and pharyngeal soft tissue volume (OPSV), oral and pharyngeal air space volume (OPAV), and OPAV to OPCV ratio (%air). Receiver operating curve (ROC) analysis was used to determine the accuracy of OSAS prediction. We assessed participants with body mass index (BMI) values within the normal range., Results: Among the 50 subjects, we observed significant between-group differences in OPSV, OPAV, and % air, whereas there were significant between-group differences in OPSV and %air among 28 subjects with normal BMI values. Both comparisons suggested that OSAS-related death was associated with low %air and high OPSV values., Conclusion: The %air and OPSV are useful for assessing postmortem oropharyngeal CT images. OSAS-related sudden death is likely when %air and OPSV values are ≤20.1% and ≥127.2 ml, respectively. Among those with normal BMI values, % air and OPSV values of ≤22.8% and ≥111.5 ml, respectively, predict OSAS-related sudden death., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: To elucidate the effectiveness of extracorporeal membrane oxygenation (ECMO) in accidental hypothermia (AH) patients with and without cardiac arrest (CA), including details of complications., Methods: This study was a multicentre, prospective, observational study of AH in Japan. All adult (aged ≥18 years) AH patients with body temperature ≤32 °C who presented to the emergency department between December 2019 and March 2022 were included. Among the patients, those with CA or circulatory instability, defined as severe AH, were selected and divided into the ECMO and non-ECMO groups. We compared 28-day survival and favourable neurological outcomes at discharge between the ECMO and non-ECMO groups by adjusting for the patients' background characteristics using multivariable logistic regression analysis., Results: Among the 499 patients in this study, 242 patients with severe AH were included in the analysis: 41 in the ECMO group and 201 in the non-ECMO group. Multivariable analysis showed that the ECMO group was significantly associated with better 28-day survival and favourable neurological outcomes at discharge in patients with CA compared to the non-ECMO group (odds ratio [OR] 0.17, 95% confidence interval [CI]: 0.05-0.58, and OR 0.22, 95%CI: 0.06-0.81). However, in patients without CA, ECMO not only did not improve 28-day survival and neurological outcomes, but also decreased the number of event-free days (ICU-, ventilator-, and catecholamine administration-free days) and increased the frequency of bleeding complications., Conclusions: ECMO improved survival and neurological outcomes in AH patients with CA, but not in AH patients without CA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the "acidic pathway" of cholesterol metabolism. Previously, we demonstrated that an inability to upregulate CYP7B1 in the setting of insulin resistance leads to the accumulation of cholesterol metabolites such as ( 25R )26-hydroxycholesterol (26HC) that initiate and promote hepatocyte injury; followed by an inflammatory response. The current study demonstrates that dietary coffee improves insulin resistance and restores Cyp7b1 levels in a well-characterized Western diet (WD)-induced nonalcoholic fatty liver disease (NAFLD) mouse model. Ingestion of a WD containing caffeinated (regular) coffee or decaffeinated coffee markedly reduced the serum ALT level and improved insulin resistance. Cyp7b1 mRNA and protein levels were preserved at normal levels in mice fed the coffee containing WD. Additionally, coffee led to upregulated steroid sulfotransferase 2b1 (Sult2b1) mRNA expression. In accordance with the response in these oxysterol metabolic genes, hepatocellular 26HC levels were maintained at physiologically low levels. Moreover, the current study provided evidence that hepatic Cyp7b1 and Sult2b1 responses to insulin signaling can be mediated through a transcriptional factor, hepatocyte nuclear factor (HNF)-4α. We conclude coffee achieves its beneficial effects through the modulation of insulin resistance. Both decaffeinated and caffeinated coffee had beneficial effects, demonstrating caffeine is not fundamental to this effect. The effects of coffee feeding on the insulin-HNF4α-Cyp7b1 signaling pathway, whose dysregulation initiates and contributes to the onset and progression of NASH as triggered by insulin resistance, offer mechanistic insight into approaches for the treatment of NAFLD. NEW & NOTEWORTHY This study demonstrated dietary coffee prevented the accumulation of hepatic oxysterols by maintaining Cyp7b1/Sult2b1 expression in a diet-induced NAFLD mice model. Lowering liver oxysterols markedly reduced inflammation in the coffee-ingested mice. Caffeine is not fundamental to this effect. In addition, this study showed Cyp7b1/Sult2b1 responses to insulin signaling can be mediated through a transcriptional factor, HNF4α. The insulin-HNF4α-Cyp7b1/Sult2b1 signaling pathway, which directly correlates to the onset of NASH triggered by insulin resistance, offers insight into approaches for NAFLD treatment.

Background: In nasal or sinonasal tumors, orbital invasion beyond periorbita by the tumor is one of the important criteria in the selection of the surgical procedure. We investigated the usefulness of the convolutional neural network (CNN)-based deep learning technique for the diagnosis of orbital invasion, using computed tomography (CT) images., Methods: A total of 168 lesions with malignant nasal or sinonasal tumors were divided into a training dataset (n = 119) and a test dataset (n = 49). The final diagnosis (invasion-positive or -negative) was determined by experienced radiologists who carefully reviewed all of the CT images. In a CNN-based deep learning analysis, a slice of the square target region that included the orbital bone wall was extracted and fed into a deep-learning training session to create a diagnostic model using transfer learning with the Visual Geometry Group 16 (VGG16) model. The test dataset was subsequently tested in CNN-based diagnostic models and by two other radiologists who were not specialized in head and neck radiology. At approx. 2 months after the first reading session, two radiologists again reviewed all of the images in the test dataset, referring to the diagnoses provided by the trained CNN-based diagnostic model., Results: The diagnostic accuracy was 0.92 by the CNN-based diagnostic models, whereas the diagnostic accuracies by the two radiologists at the first reading session were 0.49 and 0.45, respectively. In the second reading session by two radiologists (diagnosing with the assistance by the CNN-based diagnostic model), marked elevations of the diagnostic accuracy were observed (0.94 and 1.00, respectively)., Conclusion: The CNN-based deep learning technique can be a useful support tool in assessing the presence of orbital invasion on CT images, especially for non-specialized radiologists., (© 2022. The Author(s).)

Background: The aim of the study was to investigate a prevalence of sarcopenia in patients with gynecological cancer in accordance with current diagnostic criteria of sarcopenia., Methods: A series of 513 patients with gynecological cancer who were intended to newly receive initial or salvage treatment were recruited in a prospective study. Eligible patients were examined with dual energy X-ray absorptiometry and underwent handgrip strength test and the Short Physical Performance Battery before treatment. Sarcopenia was defined as both low skeletal muscle mass (skeletal muscle mass index) and low muscle strength (handgrip strength of <18.0 kg) or both low skeletal muscle mass index and low physical performance (Short Physical Performance Battery score of ≤9)., Results: A total of 475 patients (92.6%) were completely assessed in this study. Eligible patients' median age was 60 years (range: 29-89 years). Frequencies of patients with low skeletal muscle mass index, low hand grip strength and low Short Physical Performance Battery were 118 (24.8%), 70 (14.7%) and 80 (16.8%), respectively. Sarcopenia was finally identified in 45 patients (9.5%), which accounted for 38.1% of patients with low skeletal muscle mass index, 64.3% of the patients with low hand grip strength and 56.3% of the patients with low physical performance, respectively., Conclusions: The prevalence of sarcopenia of 9.5% in patients with gynecological malignancy who were scheduled to newly receive an initial or a salvage treatment. A large-scale, nation-wide study might be planned to elucidate an accurate prevalence of sarcopenia among gynecologic cancer patients., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

In Japan, a decrease in cardiovascular mortality has coincided with reduced population salt intake since the 1950s. The purpose of this study was to quantify the effect of reduced population salt intake on the long-term trends of cardiovascular mortality. Using government statistics and epidemiological study results in people of 20-69 years old from 1950 to 2017, including the National Health and Nutrition Survey, we developed a system dynamics model of age-specific cardiovascular mortality and salt intake. We estimated the period and cohort effects on mortality and calibrated the model for the historical mortality rate. We then simulated the counterfactual scenario of no decrease in salt intake to estimate the reduction in cardiovascular deaths associated with decreased mean salt intake. Compared with the base run and calibrated to the actual data, approximately 298,000 and 118,000 excess deaths were observed in men and women, respectively, assuming no change in salt intake over the entire period. The model suggests that the decline in salt intake since the 1950s has contributed to a non-negligible reduction in cardiovascular mortality., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Background: Few prospective reports of universal screening for Lynch syndrome exist for patients with endometrial cancer. In this study, we performed immunohistochemical staining for DNA mismatch repair-related genes (MLH1, MSH2, MSH6 and PMS2), to determine the extent to which Lynch syndrome can be diagnosed in endometrial cancer patients through universal screening., Methods: We recruited 116 consecutive patients assumed to have uterine corpus malignancy from October 2019 to February 2021 in a prospective observational study. We performed immunohistochemical for mismatch repair-related proteins on samples from 100 patients who had surgicopathologically confirmed diagnoses of endometrial cancer. Samples with missing immunohistochemical results for any of the proteins had subsequent universal screening tests for microsatellite instability, DNA methylation of the MLH1 promoter region and mismatch repair genetics., Results: We identified 19 (19.0%) patients with lost results for any of the proteins. All 19 patient samples had subsequent screening tests. We identified the microsatellite instability-high phenotype in 84.2% (16/19) of these patients and MLH1 methylation in 57.9% (11/19). Mismatch repair genetic testing detected two pathological variants, in MSH2 and MSH6, which indicated that the prevalence of Lynch syndrome was 2.0% in our cohort. Two cases of unclassified variant (MSH6) and one case of benign variant (PMS2) were also detected., Conclusions: Initial screening by immunohistochemical is an effective method in universal screening for Lynch syndrome in endometrial cancer patients., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Internal tibial torsion is more common in the Asian population than in Western populations. Generally, surgery should be considered for the treatment of severe internal tibial torsion. As an alternative approach, the usefulness of a tibia counter rotator (TCR), a corrective orthosis based on the theory of the tibia torsional transformer, has been demonstrated, but the evidence is limited. In the present study, the efficacy and safety of TCR treatment were investigated in pediatric patients with internal tibial torsion. The subjects were 124 pediatric patients with internal tibial torsion who were between 3 and 15 years of age and had no underlying diseases. The severity of tibial intorsion was evaluated by the tibial transmalleolar angle (TMA). A TMA less than 5° was defined as internal tibial torsion, and less than −20° was defined as severe in this study. The median duration of TCR use was 11 (9, 12) (median (IQR: interquartile range)) months, and the treatment completion rate was 94.4% (117/124). The TMA at 12 months from the start of treatment in patients who completed treatment was 5° (0°, 10°) on the right (n = 66) (p < 0.01 vs. pretreatment) and 0° (−5°, 8°) on the left (n = 71) (p < 0.01 vs. pretreatment). The tibial torsional transformer used in this study is effective in the initial treatment of mild to severe internal tibial torsion, with no adverse effects. Although internal tibial torsion is generally expected to resolve spontaneously, TCR treatment may be an effective alternative to surgical therapy in the Asian pediatric population.

Post-transcriptional modifications have critical roles in tRNA stability and function 1-4 . In thermophiles, tRNAs are heavily modified to maintain their thermal stability under extreme growth temperatures 5,6 . Here we identified 2'-phosphouridine (U p ) at position 47 of tRNAs from thermophilic archaea. U p 47 confers thermal stability and nuclease resistance to tRNAs. Atomic structures of native archaeal tRNA showed a unique metastable core structure stabilized by U p 47. The 2'-phosphate of U p 47 protrudes from the tRNA core and prevents backbone rotation during thermal denaturation. In addition, we identified the arkI gene, which encodes an archaeal RNA kinase responsible for U p 47 formation. Structural studies showed that ArkI has a non-canonical kinase motif surrounded by a positively charged patch for tRNA binding. A knockout strain of arkI grew slowly at high temperatures and exhibited a synthetic growth defect when a second tRNA-modifying enzyme was depleted. We also identified an archaeal homologue of KptA as an eraser that efficiently dephosphorylates U p 47 in vitro and in vivo. Taken together, our findings show that U p 47 is a reversible RNA modification mediated by ArkI and KptA that fine-tunes the structural rigidity of tRNAs under extreme environmental conditions., (© 2022. The Author(s).)

Background: Concurrent chemoradiotherapy has limited therapeutic efficacy for stage III-IV cervical cancer. We aimed to identify a subgroup of patients with stage III-IV cervical cancer who benefit from concurrent chemoradiotherapy with additional treatment., Methods: We retrospectively reviewed 120 patients with stage III-IV cervical cancer who were treated with concurrent chemoradiotherapy from 2002 to 2018. We compared overall survival between patients treated with concurrent chemoradiotherapy alone and those who received concurrent chemoradiotherapy with additional conventional treatments (systemic chemotherapy before and/or after concurrent chemoradiotherapy and/or extended-field radiation). Prognostic factors were statistically analysed., Results: Overall, 44 (36.7%) and 21 (17.5%) patients were radiologically diagnosed with pelvic and para-aortic lymph node enlargement, respectively. The median tumour diameter was 5.7 cm. A total of 69 (57.5%) patients received no additional treatment, and 51 (42.5%) received additional treatment. Cox regression analysis identified the following prognostic factors: histological non-squamous cell carcinoma (hazard ratio, 3.9; 95% confidence interval, 1.8-8.2), tumour diameter of ≥6 cm (hazard ratio, 2.1; 95% confidence interval, 1.2-3.7), radiological pelvic lymph node enlargement (hazard ratio, 2.1; 95% confidence interval, 1.1-4.0) and radiological para-aortic lymph node enlargement (hazard ratio, 2.1; 95% confidence interval, 1.1-4.1). Even in the lowest risk group (no risk factors), the 5-year overall survival rate was lower in the additional treatment group than in the concurrent chemoradiotherapy alone group (78.7% vs. 80.9%, respectively; log-rank test, P = 0.79)., Conclusions: Addition of conventional treatments to concurrent chemoradiotherapy might not improve survival in patients with advanced cervical cancer. Novel treatment strategies including immune checkpoint inhibitors should be considered for such patients., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Acute pancreatitis (AP) develops in approximately 2% of patients with the diagnosis of inflammatory bowel disease (IBD), but the characteristics and frequency of childhood-onset IBD-associated AP in Japan have not been studied. The present study aimed to clarify the characteristics of IBD-associated AP in Japan., Methods: A nationwide survey of pediatric patients with IBD (age, <17 years) was conducted from December 2012 to March 2013 at 683 hospitals and medical centers in Japan. A secondary survey was also sent to the centers with the target patients to evaluate their characteristics., Results: The response rate to the first part of the survey was 61.2% (n = 418). In total, 871 patients with Crohn disease and 1671 patients with ulcerative colitis were enrolled. The second part of the survey found that 11 (1.3%) patients with Crohn disease and 23 (1.4%) patients with ulcerative colitis experienced IBD-associated AP caused by medication (n = 18, 53%), a primary disease (n = 11, 32%), autoimmune pancreatitis (n = 1, 3%), or an anatomical abnormality (n = 1, 3%). All the patients had only mild AP., Conclusions: IBD-associated AP was not very frequent and was generally mild. The major cause of the pancreatitis was the medication used to treat the IBD., Competing Interests: The authors report no conflicts of interest. Translational Impact: Because the most common cause of inflammatory bowel disease–associated acute pancreatitis is drugs (thiopurine or aminosalicylic acid), the potential for acute pancreatitis should be considered whenever gastrointestinal symptoms appear during the course of inflammatory bowel disease treatment using these medications., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Obstructive sleep apnea syndrome (OSAS) induces upper airway occlusion and may cause sudden death during sleep. This study sought to clarify the relationship between oral air space volume and OSAS onset, which is influenced by multiple factors, such as jawbone, dentition morphology, and oral soft-tissue volume., Methods: (1) 50 subjects from deceased cases were divided into two groups: OSAS (25 subjects) and controls (25 subjects). (2) 28 subjects from clinical cases were divided into two groups: OSAS (9 subjects) and controls (19 subjects). In all cases, the Computed Tomography (CT) images of the facial region were obtained, and four parameters of oral area volume were analyzed in deceased and clinical cases, and comparisons and analyses were performed between OSAS and control cases. In addition, the efficiency of measurement of these parameters was evaluated using Receiver Operating Characteristic (ROC) curves in OSAS., Results: (1) In deceased cases, oral soft-tissue volume (OSV), oral air-space volume (OAV), and the ratio of OAV to OSV (%air) showed a significant correlation. (2) In clinical cases, OAV and %air showed a significant correlation. In both postmortem and clinical images, a small %air value indicates a high risk of developing OSAS and a high probability of OSAS-related sudden death., Conclusions: It was shown that the %air is an index to evaluate OSAS by CT imaging of the oral region. OSAS may be indicated when the %air value is ≦ 16.0% in deceased cases and ≦ 6.6% in clinical cases., (© 2021. The Author(s), under exclusive licence to Japanese Society for Oral and Maxillofacial Radiology and Springer Nature Singapore Pte Ltd.)

In recent years, the radial incision and cutting(RIC)method has been developed as a treatment for intractable anastomotic stenosis after esophageal cancer surgery, and its usefulness is attracting attention. We report a case in which the RIC method was effective for endoscopic balloon dilatation-resistant anastomotic stenosis. The case was a 69-year-old woman. Transthoracic esophagectomy with three-field lymph node dissection, and narrow gastric tube reconstruction through antethoracic route, were performed for middle thoracic esophageal cancer. The patient suffered from Grade Ⅲa anastomotic leakage, but was discharged relieved. After discharge, the patient needed regular endoscopic balloon dilation for against intractable anastomotic stenosis. RIC was performed for the patient. Although stenosis relapsed after the RIC, the pain during balloon dilatation improved and oral intake can be continued without surgery. The required interval of dilatation was about 2 weeks before RIC, but it has been gradually extended to about 4 weeks after 1 year after the RIC. Moreover, oral intake and body weight of the patient were increased. The RIC method may be useful for intractable anastomotic stenosis after esophageal cancer surgery, and further case accumulation is needed.

Background: The current study investigated an optimal method for using CT scan in detection of low skeletal muscle mass quantity (SMQ)., Methods: In total, 82 consecutive patients with gynecological cancers were examined using computed tomography (CT) and dual-energy X-ray absorptiometry (DEXA) before treatment. Low SMQ was defined as a DEXA-based skeletal muscle mass index (SMI) of <5.40 kg/m2. Furthermore, CT-based SMI values were measured by six evaluators, and each evaluator measured SMI values two times for each subject. The first SMI value and the average SMI value were used for analyses. Receiver operating characteristic (ROC) analyses were performed to evaluate the performance of CT-based SMI measurements for detecting low SMQ. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC)., Results: In total, 23 patients (28.0%) were diagnosed with low skeletal muscle mass. All areas under the curve (AUC) values from twelve (six evaluators × two measurements) ROC curves were within the range of 0.8-0.9. AUC values based on a single measurement and those based on two measurements were almost the same. The ICC was 0.828 (95% CI 0.777-0.874, P < 0.001) when using a single measurement value and increased to 0.959 (95% CI 0.944-0.971, P < 0.001) when using the average of the two measurements., Conclusions: A single measurement CT-based SMI efficiently identified patients with low SMQ in a daily clinical setting. The reliability of SMI measurements might be further improved by using a mean value of two measurements compared with the use of a single measurement value., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We experienced a case of kidney metastasis of a gastric tumor. An 81-year-old man underwent distal gastrectomy with D2 lymph node dissection and partial hepatic resection for antral gastric tumor with hepatic infiltration in July 2019. A histological examination showed undifferentiated tubular adenocarcinoma. The final stage was pT4bN1P0H0M0, Stage ⅢB. He rejected the recommended adjuvant chemotherapy. Seven months after surgery, abdominal enhanced CT showed a hypovascular mass, 20 mm in diameter, on the right upper pole of kidney. Eleven months after surgery, CT showed that the mass had enlarged to 35 mm, infiltrated the renal pelvis, and advanced to para-aortic lymph node metastasis. We performed a retroperitoneoscopic partial right nephrectomy and diagnosed kidney metastasis of the gastric tumor. His right flank pain worsened, and radiotherapy(50 Gy)was performed for the mass and para-aortic lymph node metastasis. His right flank pain resolved. Kidney metastasis of the gastric tumor is very rare. Radiotherapy effectively relieves pain.

A 65-year-old woman underwent distal gastrectomy with D2 lymph node dissection for advanced gastric cancer in November 2016. The histopathological diagnosis was pT3N0M0, pStage ⅡA, HER2-negative. In August 2019, transverse colon stenosis due to peritoneal dissemination was detected, and an ileum-transverse colon anastomosis was performed. Postoperatively, she received chemotherapy with S-1 plus oxaliplatin. After 6 courses, CT revealed an increase in ascites and dissemination nodules. We diagnosed her with progressive disease and initiated second-line chemotherapy, a ramucirumab plus nab-paclitaxel regimen. On the 20th day during the 5th course of treatment, she visited our hospital with acute abdominal pain. CT revealed free air, and we diagnosed acute panperitonitis with a gastrointestinal perforation. Emergency surgery was performed, and perforation of the appendix end and mild cloudy ascites were observed. We performed an appendectomy and intraperitoneal drainage. Histopathological examination revealed perforation of the appendix, possibly as an adverse effect of the ramucirumab. It should be noted that angiogenesis inhibitors may cause the fatal adverse effect of gastrointestinal perforation.

Chylothorax after esophagectomy is a relatively rare complication that can be difficult to manage. Here, we report a case of refractory chylothorax after surgery for esophageal cancer treated with lymphatic duct lipiodol imaging by inguinal lymph node puncture to confirm patency of the thoracic duct and thoracic duct ligation. A 71-year-old female with esophageal cancer(cT3N0M0)underwent video-assisted thoracoscopic esophagectomy with 2-field lymph node dissection, intrathoracic gastric tube reconstruction, and an enterostomy. A chylothorax appeared when we started enteral nutrition on the day after surgery. She became markedly dehydrated due to over 2,000 mL/day of drainage from the chest drain, and we managed her general condition in the ICU. We started octreotide acetate on postoperative day(POD)6 and etilefrine on POD 8, but neither was effective. Lymphatic duct lipiodol imaging by bilateral inguinal lymph node puncture was performed, and we confirmed leakage from the main thoracic duct. On POD 11, a thoracic duct ligation performed via a thoracotomy revealed that the volume of the chylothorax was remarkably decreased. The chest tube was removed on re-POD 12.

Background: Hydroxychloroquine (HCQ) has been positioned as an anchor drug for systemic lupus erythematosus (SLE). There is evidence supporting the benefits of HCQ; however, the effect of additional HCQ in maintenance therapy remains unclear., Methods: Thirty patients with SLE who visited Juntendo University Hospital were receiving maintenance therapy before HCQ treatment and were able to complete more than 104 weeks of HCQ treatment were analyzed. Anti-DNA antibody titers, IgG and CH50 levels, the maintenance dose of corticosteroids, the SLE disease activity index (SLEDAI), and the achievement of the Lupus Low Disease Activity State (LLDAS) were evaluated at baseline and at 12, 24, 52, and 104 weeks after HCQ initiation., Results: We observed improvements in the anti-DNA antibody titers, IgG and CH50 levels, maintenance dose of corticosteroids, and SLEDAI at week 104 relative to baseline. Moreover, the LLDAS achievement rate increased over time from 10% at baseline to 43% and 80% at week 52 and week 104, respectively., Conclusion: Two years of continuous HCQ treatment led to improvements in SLE disease activity and corticosteroid dose and an increase in LLDAS achievement, thereby demonstrating the significance of the maintenance dose of HCQ for the management of SLE.

Objective: In patients with endometrial cancer, obesity is associated with favorable prognostic characteristics but not with prolonged survival. The aim of this study was to elucidate the reason for this clinical paradox., Methods: We retrospectively reviewed 1173 patients with endometrial cancer. Patients were divided into a non-obese group [body mass index (BMI) < 30 kg/m2], class I obesity group (BMI 30-35 kg/m2) and class II obesity group (BMI ≥ 35 kg/m2). The relationship between clinicopathological factors and disease-specific survival (DSS) was analyzed by Cox regression analysis. To correct for three-time significance testing, we used the Bonferroni method, giving the level of probability at which findings were considered significant as P < 0.0167., Results: Three disease-intrinsic variables-older age, advanced stage and high-risk histology-and three treatment-related variables-no hysterectomy, no lymphadenectomy and no chemotherapy-were independently associated with poor DSS. DSS was similar among the three groups of patients even though the proportion of patients with plural pretreatment-related unfavorable risk factors significantly decreased with increment of BMI category (40.1 vs. 27.5 vs. 17.6%, P = 0.0003). The proportion of patients with plural treatment-related unfavorable prognostic factors significantly increased with increment of BMI category (21.3 vs. 26.7 vs. 39.3%, P = 0.0072)., Conclusions: Poor-quality surgical staging in obese women may result in worse than expected survival outcomes., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, result in the systemic accumulation of ammonia to toxic levels. Sodium 4-phenylbutyrate (NaPB), a standard therapy for UCDs for over 20 years, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the accepted use of NaPB. However, this regimen is not based on clinical evidence. Here, an open-label, single-dose, five-period crossover study was conducted in healthy adults to investigate the effect of food on the pharmacokinetics of NaPB and determine any subsequent change in amino acid availability. Twenty subjects were randomized to one of four treatment groups. Following an overnight fast, NaPB was administered orally at 4.3 g/m 2 (high dose, HD) or 1.4 g/m 2 (low dose, LD) either 30 min before or just after breakfast. At both doses, compared with post-breakfast administration, pre-breakfast administration significantly increased systemic exposure of PB and decreased plasma glutamine availability. Pre-breakfast LD administration attenuated plasma glutamine availability to the same extent as post-breakfast HD administration. Regardless of the regimen, plasma levels of branched-chain amino acids (BCAA) were decreased below baseline in a dose-dependent manner. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of the drug and thereby its potency to consume plasma glutamine. This finding may improve poor medication compliance because of the issues with odor, taste, and pill burden of NaPB and reduce the risk of BCAA deficiency in NaPB therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to find a clinical marker for identifying refractory cancer cachexia., Methods: We analyzed computed tomography imaging data, which included the third lumbar vertebra, from 94 patients who died of uterine cervix or corpus malignancy. The time between the date of examination and date of death was the most important attribute for this study, and the computed tomography images were classified into >3 months before death and ≤ 3 months before death. Psoas muscle mass index was defined as the left-right sum of the psoas muscle areas (cm2) at the level of third lumbar vertebra, divided by height squared (m2)., Results: A data set of 94 computed tomography images was obtained at baseline hospital visit, and a data set of 603 images was obtained at other times. One hundred (16.6%) of the 603 non-baseline images were scanned ≤3 months before death. Mean psoas muscle mass index change rates at >3 months before death and ≤3 months before death were -1.3 and -20.1%, respectively (P < 0.001). Receiver operating characteristic curve analysis yielded a cutoff value of -13.0%. The area under the curve reached a moderate accuracy level (0.777, 95% confidence interval 0.715-0.838). When we used the cutoff value to predict death within 3 months, sensitivity and specificity were 74.0 and 82.1%, respectively., Conclusions: Measuring change in psoas muscle mass index might be useful for predicting cancer mortality within 3 months. It could become a potential tool for identifying refractory cancer cachexia., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: The current study evaluated the performance of psoas muscle mass measurement for detecting low skeletal muscle mass quantity., Methods: A sample of 82 consecutive patients with gynecological cancers was examined using computed tomography and dual energy X-ray absorptiometric scan before treatment. Skeletal muscle mass index was measured by dual energy X-ray absorptiometric scan and its cut-off value was set at 5.40 kg/m2 for detecting low skeletal muscle mass. Psoas muscle mass index was manually measured with cross-sectional computed tomography imaging at the level of L3 by six evaluators., Results: Low skeletal muscle mass index was identified in 23 (28.0%) patients. Two-way analysis of variance confirmed a significant main effect of skeletal muscle mass index on mean psoas muscle mass index values (P < 0.0001). A receiver operating characteristic curve obtained from a total of 492 psoas muscle mass index data points gathered from six evaluators produced an area under the curve value of 0.697 (95% confidence interval 0.649-0.744) and a cut-off value of 3.52 cm2/m2, with sensitivity of 79.0% and specificity of 59.6%. Using the cut-off value, the kappa coefficient for evaluating diagnostic agreement between skeletal muscle mass index (low vs. normal) and psoas muscle mass index (low vs. normal) was 0.308 (95% confidence interval 0.225-0.392), suggesting poor agreement. Fleiss' kappa produced a coefficient of 0.418 (95% confidence interval 0.362-0.473), suggesting moderate agreement., Conclusions: Although relevance between skeletal muscle mass index and psoas muscle mass index was confirmed, intensity of relevance between them was weak. Psoas muscle mass index measurement should be subordinated to skeletal muscle mass index measurement for detection of low skeletal muscle mass., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Several visual scoring methods are currently used to assess progression of rheumatoid arthritis (RA) on radiography. However, they are limited by its subjectivity and insufficient sensitivity. We have developed an original measurement system which uses a technique called phase-only correlation (POC). The purpose of this study is to validate the system by using a phantom simulating the joint of RA patients.A micrometer measurement apparatus that can adjust arbitrary joint space width (JSW) in a phantom joint was developed to define true JSW. The phantom was scanned with radiography, 320 multi detector CT (MDCT), high-resolution peripheral quantitative CT (HR-pQCT), cone beam CT (CBCT), and tomosynthesis. The width was adjusted to the average size of a women's metacarpophalangeal joint, from 1.2 to 2.2 mm with increments of 0.1 mm and 0.01 mm. Radiographical images were analyzed by the POC-based system and manual method, and images from various tomographical modalities were measured via the automatic margin detection method. Correlation coefficients between true JSW difference and measured JSW difference were all strong at 0.1 mm intervals with radiography (POC-based system and manual method), CBCT, 320MDCT, HR-pQCT, and tomosynthesis. At 0.01 mm intervals, radiography (POC-based system), 320MDCT, and HR-pQCT had strong correlations, while radiography (manual method) and CBCT had low correlations, and tomosynthesis had no statistically significant correlation. The smallest detectable changes for radiography (POC-based system), radiography (manual method), 320MDCT, HR-pQCT, CBCT, and tomosynthesis were 0.020 mm, 0.041 mm, 0.076 mm, 0.077 mm, 0.057 mm, and 0.087 mm, respectively. We conclude that radiography analyzed with the POC-based system might sensitively detect minute joint space changes of the finger joint.

Acute recurrent pancreatitis (ARP) is defined as two distinct episodes of acute pancreatitis (AP), whereas chronic pancreatitis (CP) is caused by persistent inflammation of the pancreas. In children they are caused by genetic mutations, autoimmune pancreatitis, congenital pancreatic abnormalities, and other conditions. Acute recurrent pancreatitis is frequently a precursor to CP, and both are thought to be on the same disease continuum. In particular, genetic factors are associated with early progression of ARP to CP. The diagnosis of CP, as in AP, is based on clinical findings, biochemical tests, and imaging studies. Findings of exocrine pancreatic dysfunction are also important in the diagnosis of CP. A step-up strategy has become increasingly standard for the treatment of patients with CP. This strategy starts with endoscopic treatment, such as pancreatic sphincterotomy and stenting, and progresses to surgery should endoscopic therapy fail or prove technically impossible. Non-opioid (e.g. ibuprofen / naproxen) and opioid (e.g. oxycodone) forms of analgesia are widely used in pediatric patients with AP or CP, whereas pancreatic enzyme replacement therapy may be beneficial for patients with abdominal pain, steatorrhea, and malnutrition. Despite the disparity in the age of onset, pediatric CP patients display some similarities to adults in terms of disease progress. To reduce the risk of developing pancreatic exocrine inefficiency, diabetes and pancreatic cancer in the future, clinicians need to be aware of the current diagnostic approach and treatment methods for ARP and CP and refer them to a pediatric gastroenterologist in a timely manner., (© 2020 Japan Pediatric Society.)

Purpose: The long-term efficacy and safety of infliximab (IFX) in children with ulcerative colitis (UC) have not been well-evaluated. Here, we reviewed the long-term durability and safety of IFX in our single center pediatric cohort with UC., Methods: This retrospective study included 20 children with UC who were administered IFX., Results: For induction, 5 mg/kg IFX was administered at weeks 0, 2, and 6, followed by every 8 weeks for maintenance. The dose and interval of IFX were adjusted depending on clinical decisions. Corticosteroid (CS)-free remission without dose escalation (DE) occurred in 30% and 25% of patients at weeks 30 and 54, respectively. Patients who achieved CS-free remission without DE at week 30 sustained long-term IFX treatment without colectomy. However, one-third of the patients discontinued IFX treatment because of a primary nonresponse, and one-third experienced secondary loss of response (sLOR). IFX durability was higher in patients administered IFX plus azathioprine for >6 months. Four of five patients with very early onset UC had a primary nonresponse. Infusion reactions (IRs) occurred in 10 patients, resulting in discontinuation of IFX in four of these patients. No severe opportunistic infections occurred, except in one patient who developed acute focal bacterial nephritis. Three patients developed psoriasis-like lesions., Conclusion: IFX is relatively safe and effective for children with UC. Clinical remission at week 30 was associated with long-term durability of colectomy-free IFX treatment. However, approximately two-thirds of the patients were unable to continue IFX therapy because of primary nonresponse, sLOR, IRs, and other side effects., Competing Interests: Conflict of Interest: Hirotaka Shimizu received honoraria from Mitsubishi Tanabe Pharma Corporation and Nippon Kayaku Co., Ltd., and a grant from Nippon Kayaku Co., Ltd. Katsuhiro Arai received honoraria from Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., AbbVie GK, and Janssen Pharmaceutical K.K., and a grant from Nippon Kayaku Co., Ltd. For the remaining authors, none was declared., (Copyright © 2021 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)

Several pancreatitis susceptibility genes have been identified to date. A relationship between a mutation in the cationic trypsinogen (protease serine 1, PRSS1 ) gene and hereditary pancreatitis (HP) was first identified in 1996. Currently, HP has been defined as either two or more individuals within a family exhibiting pancreatitis for two or more generations, or pancreatitis linked to mutation of the PRSS1 gene. In 2000, a mutation in the serine protease inhibitor gene ( Kazal type 1: SPINK1 ) was reported to be related to sporadic pancreatitis of unknown etiology. This paper reviews and summarizes the current published data on the pancreatitis susceptibility genes, mainly PRSS1 and SPINK1 genes, and introduces a diagnostic and therapeutic approach for dealing with patients with these gene mutations. Patients with these genetic predispositions, both children and adults, have often been initially diagnosed with idiopathic acute pancreatitis, in approximately 20-50% of pediatric cases and 28-80% of adult cases. In such patients, where the etiology is unknown, genetic testing, which requires pre-test and post-test genetic counselling, may prove helpful. Patients with chronic pancreatitis (CP) due to SPINK1 gene mutation and HP patients have a potentially high risk of pancreatic exocrine insufficiency, diabetes mellitus, and, of particular importance, pancreatic cancer. Thus, these patients require careful long-term follow-up and management. Specifically, symptomatic CP patients often need endoscopic therapy or surgery, often following a step-up approach beginning with endoscopic therapy and progressing to surgery if necessary, which is similar to the therapeutic approach for patients with CP due to other etiologies. It is important that clinicians are aware of the characteristics of patients with pancreatitis susceptibility genetic abnormalities.

Objective: This study aimed to establish intraoperative diagnostic criteria of sentinel lymph node (SLN) micro-/macrometastasis on the basis of tissue rinse liquid-based cytology (TRLBC) in gynecological cancer., Methods: We enrolled 214 patients with gynecological cancer who underwent rapid diagnosis of SLN metastasis on the basis of TRLBC from a total of 490 SLNs. For slides that were classified as positive for atypical cells on cytological inspection, we counted the number of clusters (an atypical cell mass consisted of three or more cells) and the number of single cells (an atypical cell other than clusters). Receiver operating characteristic (ROC) analysis was applied to determine the efficiency of predicting SLN micro-/macrometastasis., Results: On cytological inspection, 36 slides were classified as positive for atypical cells, while 21 slides (4.3%) were true positive, 15 (3.1%) were false positive, and 454 (92.6%) were true negative. There were no false negative results in this study. The area under the ROC curve for the number of cluster was superior to that for the number of single cells for distinguishing micro-/macrometastasis from negative/isolated tumor cells (0.86 vs. 0.67, P = 0.032). The optimum cut-off value of the number of clusters was 5 for distinguishing these two categories., Conclusions: TRLBC is a highly sensitive alternative for detecting SLN metastasis as a rapid intraoperative diagnosis. Counting the number of atypical cell clusters might be useful for distinguishing micro-/macrometastasis from isolated tumor cells.

In this study we investigated the relation between anterior disc displacement (ADD) and maxillomandibular morphology in skeletal anterior open bite with changes to the mandibular condyle. Thirty female patients (60 joints) with both conditions were evaluated. Magnetic resonance imaging of the temporomandibular joint (TMJ) was used to diagnose both ADD and changes to the mandibular condyle (erosion, osteophyte, and deformity). The relations among ADD, changes to the mandibular condyle, and maxillomandibular morphology were examined statistically. Changes to the mandibular condyle had a higher score than sym anterior open bite, the deviated side in asymmetric anterior open bite, and the non-deviated side. The score for disc displacement on the non-deviated side was lower than both the sym side and the deviated side. Unilateral changes to the mandibular condyle and unilateral disc displacement were not apparent in sym anterior open bite, but a unilateral non-displaced disc was seen only on the asymmetric side. Mandibular condylar changes were significantly more common on the deviated, than on the non-deviated, side. The SNB angle was significantly smaller, and the ANB, GZN, and SN-mandibular plane angles were significantly larger in sym anterior open bite. Overjet, ANB angle, GZN angle, and SN-MP angle were significantly larger, and the SNB angle was significantly smaller, in the presence of ADD without reduction and mandibular condylar deformity. We conclude that the prevalence of ADD without reduction and changes to the mandibular condyle were related to mandibular asymmetry and mandibular morphology in anterior open bite. This retrospective study suggests that ADD without reduction and mandibular condylar bone changes may be related to the progression of skeletal class II open bite and mandibular asymmetry in cases of skeletal open bite., (Copyright © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Adenosine triphosphatase phospholipid transporting 8B1 (ATP8B1) deficiency, an ultrarare autosomal recessive liver disease, includes severe and mild clinical forms, referred to as progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1), respectively. There is currently no practical method for determining PFIC1 or BRIC1 at an early disease course phase. Herein, we assessed the feasibility of developing a diagnostic method for PFIC1 and BRIC1. A nationwide Japanese survey conducted since 2015 identified 25 patients with cholestasis with ATP8B1 mutations, 15 of whom agreed to participate in the study. Patients were divided for analysis into PFIC1 (n = 10) or BRIC1 (n = 5) based on their disease course. An in vitro mutagenesis assay to evaluate pathogenicity of ATP8B1 mutations suggested that residual ATP8B1 function in the patients could be used to identify clinical course. To assess their ATP8B1 function more simply, human peripheral blood monocyte-derived macrophages (HMDMs) were prepared from each patient and elicited into a subset of alternatively activated macrophages (M2c) by interleukin-10 (IL-10). This was based on our previous finding that ATP8B1 contributes to polarization of HMDMs into M2c. Flow cytometric analysis showed that expression of M2c-related surface markers cluster of differentiation (CD)14 and CD163 were 2.3-fold and 2.1-fold lower (95% confidence interval, 2.0-2.5 for CD14 and 1.7-2.4 for CD163), respectively, in patients with IL-10-treated HMDMs from PFIC1 compared with BRIC1. Conclusion : CD14 and CD163 expression levels in IL-10-treated HMDMs may facilitate diagnosis of PFIC1 or BRIC1 in patients with ATP8B1 deficiency., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

An AU-rich element (ARE) is RNA element that enhances the rapid decay of mRNA. The RNA binding protein HuR stabilizes ARE-mRNA by exporting it to the cytoplasm. In most of cancer cells, HuR is exported to the cytoplasm and ARE-mRNA is stabilized. In addition, the viral gene product E4orf6 exports HuR to stabilize ARE-mRNA in adenovirus-infected cells and the stabilization is required for full virus replication. Previously we showed the oncolytic activity of E4orf6-deleted adenovirus dl355, which can replicate in cancer cells where ARE-mRNA is stabilized. In this study, we examined whether the further enhancement of HuR export can stimulate the replication and the oncolytic activity of dl355. We found that ethanol treatment promoted the cytoplasmic relocalization of HuR in cancer cells. In addition, the replication efficiency of dl355 increased in ethanol-treated cells, and in response, the cytolytic activity of the virus also increased in vitro and in vivo. Upregulation of a cleaved-PARP level in infected cells mediated by ethanol is suggesting that ethanol activated the apoptosis induced by dl355. IVa2 mRNA, the only ARE-mRNA among transcripts of adenovirus was augmented by ethanol treatment. These data indicate that the enhancement of ARE-mRNA stabilization as a result of ethanol treatment upregulates the oncolytic activity of dl355 and suggests that the combined use of an oncolytic adenovirus and ethanol treatment may be a good strategy for cancer therapy., Competing Interests: Declaration of competing interest The authors declared that there is no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: To evaluate and compare diffusion-weighted imaging (DWI) parameters derived from a non-Gaussian fitting model and positron-emission tomography (PET) parameters derived from 18 F-fluoromisonidazole-PET (FMISO-PET) in patients with oral squamous cell carcinoma (OSCC)., Materials and Methods: Primary sites were evaluated prospectively in 18 patients. DWI was performed using six b-values (0-2,500). Diffusion-related parameters of kurtosis value (K), the kurtosis-corrected diffusion coefficient (D K ), diffusion heterogeneity (α), distributed diffusion coefficient (DDC), the slow diffusion coefficient (D slow ), and the apparent diffusion coefficient (ADC) were calculated from four diffusion-fitting models. Maximal standardised uptake values (SUV max ), mean standardised uptake values (SUV mean ), and the tumour-to-muscle ration (TMR) of the SUV value were calculated for FMISO-PET. Spearman's correlation coefficient was used to evaluate the correlation between each non-Gaussian diffusion model parameters and PET parameter., Results: There was moderate correlation between FMISO-PET SUV max and D slow (ρ=-0.45, p=0.06). In addition, there was good correlation between TMR max and five non-Gaussian diffusion model parameters (K: ρ=0.65, p=0.004, D K : ρ=-0.72, p=0.0008, DDC: ρ=-0.75, p=0.0003, ADC: ρ=-0.74, p=0.0005, and D slow : ρ= -0.65, p=0.003), and between TMR mean and five non-Gaussian model parameters (K: ρ=0.64, p=0.005, D K : ρ=-0.61, p=0.007, DDC: ρ=-0.63, p=0.005, ADC: ρ=-0.61, p=0.007, and D slow : ρ=-0.56, p=0.015)., Conclusion: Non-Gaussian diffusion model parameters can be related to tumour hypoxia., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Tumor endothelial cells (TECs) perform tumor angiogenesis, which is essential for tumor growth and metastasis. Tumor cells produce large amounts of lactic acid from glycolysis; however, the mechanism underlying the survival of TECs to enable tumor angiogenesis under high lactic acid conditions in tumors remains poorly understood., Methodology: The metabolomes of TECs and normal endothelial cells (NECs) were analyzed by capillary electrophoresis time-of-flight mass spectrometry. The expressions of pH regulators in TECs and NECs were determined by quantitative reverse transcription-PCR. Cell proliferation was measured by the MTS assay. Western blotting and ELISA were used to validate monocarboxylate transporter 1 and carbonic anhydrase 2 (CAII) protein expression within the cells, respectively. Human tumor xenograft models were used to access the effect of CA inhibition on tumor angiogenesis. Immunohistochemical staining was used to observe CAII expression, quantify tumor microvasculature, microvessel pericyte coverage, and hypoxia., Results: The present study shows that, unlike NECs, TECs proliferate in lactic acidic. TECs showed an upregulated CAII expression both in vitro and in vivo. CAII knockdown decreased TEC survival under lactic acidosis and nutrient-replete conditions. Vascular endothelial growth factor A and vascular endothelial growth factor receptor signaling induced CAII expression in NECs. CAII inhibition with acetazolamide minimally reduced tumor angiogenesis in vivo. However, matured blood vessel number increased after acetazolamide treatment, similar to bevacizumab treatment. Additionally, acetazolamide-treated mice showed decreased lung metastasis., Conclusion: These findings suggest that due to their effect on blood vessel maturity, pH regulators like CAII are promising targets of antiangiogenic therapy. Video Abstract.

Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved regimen for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7-3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.

The cystic fibrosis transmembrane conductance regulator ( CFTR ) gene has been reported as one of the pancreatitis susceptibility genes. Although many variants of CFTR have been reported in Caucasian patients, there are few data in Japanese patients. We aimed to survey CFTR variants in Japanese children with idiopathic pancreatitis. Twenty-eight Japanese paediatric patients with idiopathic pancreatitis were enroled, who were not previously diagnosed by genetic analysis of PRSS1 and SPINK1 . The entire CFTR gene was sequenced in the patients by combining LA-PCR and next-generation sequencing analysis. To determine a splice-affecting variant, CFTR expression was investigated in the nasal epithelial cells by RT-PCR. One (3.6%) and 15 (53.6%) of 28 patients had pathogenic and functionally affected variants in the CFTR gene, respectively. Two variants, p.Arg352Gln and p.Arg1453Trp, were found more frequently in the patients compared with one in Japanese healthy controls ( p  = 0.0078 and 0.044, respectively). We confirmed skipping of exon 10 in the nasal epithelial cells in one patient having a splice-affecting variant (c.1210-12 T(5)) in intron 9. Functionally affected variants of the CFTR gene are not so rare in Japanese paediatric patients with idiopathic pancreatitis. Surveying CFTR gene variants in a Japanese sample could help identify pancreatitis risk in these children., Competing Interests: The authors declare that they have no conflict of interest.

Random mutagenesis for the hyperthermophilic archaeon Thermococcus kodakarensis was established by the insertion of an artificial transposon designed to allow easy identification of the transposon-inserted locus. The phenotypic screening was applied for the isolation of thermosensitive mutants of T. kodakarensis, which resulted in the isolation of 16 mutants showing defective growth at the supraoptimal temperature 93°C. The high occurrence of the mutants suggested that the high thermotolerance of hyperthermophiles was achieved by a combination of diverse gene functions. The transposon insertion sites in two-thirds of the mutants were identified in a group of genes responsible for tRNA modifications including 7-formamidino-7-deaza-guanosine (archaeosine), N1-methyladenosine/N1-methylinosine, N4-acetylcytidine, and N2-dimethylguanosine/N2,N2-dimethylguanosine. LC-MS/MS analyses of tRNA nucleosides and fragments exhibited disappearance of the corresponding modifications in the mutants. The melting temperature of total tRNA fraction isolated from the mutants lacking archaeosine or N1-methyladenosine/N1-methylinosine decreased significantly, suggesting that the thermosensitive phenotype of these mutants was attributed to low stability of the hypomodified tRNAs. Genes for metabolism, transporters, and hypothetical proteins were also identified in the thermosensitive mutants. The present results demonstrated the usefulness of random mutagenesis for the studies on the hyperthermophile, as well as crucial roles of tRNA modifications in cellular thermotolerance., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNA. The fate of ARE-mRNA is controlled by ARE-binding proteins. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the export and stabilization of ARE-mRNA. In the vast majority of cancer cells, HuR constitutively relocates to the cytoplasm, resulting in the stabilization of ARE-mRNA. Previously, we described that the adenovirus gene product, E4orf6, which is necessary for virus replication, participates in ARE-mRNA export and stabilization. In the present study, we showed the oncolytic potential of E4orf6-deleted adenovirus dl355, which is expected to be replicated selectively in cancer cells. Virus production and cytolytic activity of dl355 were higher in cancer cells than in normal cells. HuR-depletion downregulated dl355 replication, demonstrating that ARE-mRNA stabilization is required for the production of this virus. Tumor growth was inhibited in nude mice by an intratumoral injection of dl355. Furthermore, dl355 had a stronger oncolytic effect than E1B55k-deleted adenovirus. These results indicate that dl355 has potential as an oncolytic adenovirus for a large number of cancers where ARE-mRNA is stabilized.

A 40-year-old man who was diagnosed with bronchial asthma and eosinophilia was transferred to our hospital due to a worsening respiratory status. He was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic pneumoniae. Cardiac magnetic resonance (CMR) imaging indicated Löffler endocarditis. Treatment was initiated using intravenous methylprednisolone, cyclophosphamide, and heparin as anticoagulation therapy. Three months later, CMR showed the improvement of the LV myocardium. In this case, the early diagnosis of Löffler endocarditis by CMR could prevent systemic embolism and CMR was useful for assessing the curative effects of steroid and immunosuppressant therapy.

LC/Tribrid Orbitrap was developed to determine phosphodiesterase-5 (PDE-5) inhibitors and their analogs as adulterants in dietary supplements. High-resolution MS/MS and MS 3 spectra of PDE-5 inhibitors and their analogs were obtained by LC/Tribrid Orbitrap using both higher-energy collisional dissociation and collision-induced dissociation. We investigated dietary supplements that claim to enhance men's sexual performance, and detected PDE-5 inhibitors and their analogs. We also estimated the structures of the PDE-5 inhibitor analogs and the impurities of PDE-5 inhibitors and their analogs in the dietary supplements.

This systematic review aimed to investigate complications related to initial trocar insertion among 3 different laparoscopic techniques: Veress needle (VN) entry, direct trocar entry (DTE), and open entry (OE). A literature search was completed, and complications were assessed. Major vessel injury, gastrointestinal injury, and solid organ injury were defined as major complications. Minor complications were defined as subcutaneous emphysema, extraperitoneal insufflation, omental emphysema, trocar site bleeding, and trocar site infection. Arm-based network meta-analyses were performed to identify the differences in complications among the 3 techniques. Seventeen studies were included in the quantitative analysis. DTE resulted in fewer major complications when compared with VN entry although the difference was not significant (p = .23) as well as significantly fewer minor complications (p < .001). There were no significant differences in minor complications when comparing OE and DTE (p = .74). Fewer major complications were observed with OE compared with VN entry although the difference was not significant (p = .31). There were significantly fewer minor complications for patients who underwent OE (p = .01). DTE patients experienced the least number of minor complications followed by VN entry and OE. In conclusion, major complications are extremely rare, and all 3 insertion methods can be performed without mortality., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Laparoscopy and endoscopy cooperative surgery(LECS)is an excellent surgical procedure that utilizes the advantages of both methods. Furthermore, non-exposed endoscopic wall-inversion surgery(NEWS)is a more promising procedure that enables avoidance of tumor exposure of and dissemination to the abdominal cavity. However, NEWS has the potential risk of postoperative ulceration, leading to delayed perforation because of mucosal defect. We invented a modified NEWS, which was a safe procedure, by including the all-layer suture to close the mucosal defect. We present a case of gastrointestinal stromal tumor(GIST)near the esophagogastric junction, which was treated with modified NEWS.

Interferon-based simeprevir therapy showed high efficacy and tolerability in children with genotype 1 hepatitis C virus infection. While direct-acting antivirals (DAAs) therapy are undergoing study in children, this regimen is considered an available therapeutic option for selected patients in countries where DAAs have not yet been approved.

The aim of this study was to investigate the incidence of anterior disc displacement without reduction (ADDwoR) of the temporomandibular joint (TMJ) in patients with dentofacial deformity. Eighty-eight female patients (176 joints) with skeletal class III malocclusion and 33 female patients (66 joints) with skeletal class II malocclusion, with or without anterior open bite and asymmetry, were evaluated. Magnetic resonance imaging (MRI) of the TMJ was used to diagnose ADDwoR. A statistical analysis was performed to examine the relationship between ADDwoR and skeletal structure. ADDwoR was present in 37 of the 66 joints (56.1%) in class II compared to 34 of the 176 joints (19.3%) in class III (P<0.05). In class III, ADDwoR was significantly more common in joints with mandibular asymmetry (24/74; 32.4%) than in joints with open bite (9/62; 14.5%) and joints with open bite and without mandibular asymmetry (1/38; 2.6%). In class II, ADDwoR was significantly less common in joints with mandibular asymmetry and without open bite (1/8; 12.5%). ADDwoR was only observed on the deviated side in both class III and class II with mandibular asymmetry. The prevalence of ADDwoR differed according to the dentofacial morphology., (Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

HuR is an RNA-binding protein of the embryonic lethal abnormal vision (ELAV) family, which binds to the AU-rich element (ARE) in the 3'-untranslated region (UTR) of certain mRNAs and is involved in the nucleo-cytoplasmic export and stabilization of ARE-mRNAs. The cytoplasmic relocalization of ARE-mRNAs with several proteins such as HuR and pp32 increases in cells transformed by the adenovirus oncogene product E4orf6. Additionally, these ARE-mRNAs were stabilized and acquired the potential to transform cells. Although, the relocalization of HuR and the stabilization of ARE-mRNAs are crucial for cell transformation, evidence regarding the relationship of HuR and ARE-mRNAs with adenovirus replication is lacking. In this report, we demonstrate that adenovirus infection induces the relocation of HuR to the cytoplasm of host cells. Analysis using the luciferase-ARE fusion gene and the tetracycline (tet)-off system revealed that the process of stabilizing ARE-mRNAs is activated in adenovirus-infected cells. Heat shock treatment or knockdown-mediated depletion of HuR reduced adenovirus production. Furthermore, expression of ARE-including viral IVa2 mRNA, decreased in HuR-depleted infected cells. These results indicate that HuR plays an important role in adenovirus replication, at least in part, by up-regulating IVa2 mRNA expression and that ARE-mRNA stabilization is required for both transformation and virus replication., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study aimed to characterize serum 25-hydroxyvitamin D (25OH-D) values among Japanese children aged ≤48 mo. The study included 290 healthy infants and young children aged 0-48 mo (males/females=166/124) living in Shizuoka or Tokyo. The subjects were divided into three groups by age (Low Age: 0-5, Middle Age: 6-15, High Age: 16-48 mo). The vitamin D deficient state was defined as 25OH-D <12 ng/mL, the insufficient state as 12-20 ng/mL, and the sufficient state as >20 ng/mL. The seasonal variation of serum 25OH-D levels was also analyzed. The median serum 25OH-D levels in each group were: Low Age (n=50), 19 ng/mL; Middle Age (n=94), 30 ng/mL; and High Age (n=146), 30 ng/mL. The serum 25OH-D level was significantly lower in the Low Age group than in the other groups (p<0.01). Serum 25OH-D levels in summer and autumn (n=149) were significantly higher than in winter and spring (n=141) (33 vs. 25 ng/mL, p<0.01). In the Low Age group, there was a significant difference in serum 25OH-D levels between breast-fed infants (n=26) and formula-fed or mixed-fed infants (n=19) (12 vs. 32 ng/mL, p<0.01). However, there were no significant differences in 25OH-D levels between the two season classifications in either breast-fed or formula-fed and mixed-fed infants. Although clinical symptoms were not available, more than 75% of the breast-fed infants and 14.6% of infants and young children to whom food had been introduced were defined as having a vitamin D deficient or insufficient state. Breastfeeding seems one of the contributing factor to lower serum 25 OH-D levels among infants ≤5 mo of age.

Progressive familial intrahepatic cholestasis type 1 (PFIC1), a rare inherited recessive disease resulting from a genetic deficiency in ATP8B1, progresses to liver failure. Because of the difficulty of discriminating PFIC1 from other subtypes of PFIC based on its clinical and histological features and genome sequencing, an alternative method for diagnosing PFIC1 is desirable. Herein, we analyzed human peripheral blood monocyte-derived macrophages (HMDM) and found predominant expression of ATP8B1 in interleukin-10 (IL-10)-induced M2c, a subset of alternatively activated macrophages. SiRNA-mediated depletion of ATP8B1 in IL-10-treated HMDM markedly suppressed the expression of M2c-related surface markers and increased the side scatter (SSC) of M2c, likely via impairment of the IL-10/STAT3 signal transduction pathway. These phenotypic features were confirmed in IL-10-treated HMDM from four PFIC1 patients with disease-causing mutations in both alleles, but not in those from four patients with other subtypes of PFIC. This method identified three PFIC1 patients in a group of PFIC patients undiagnosed by genome sequencing, an identical diagnostic outcome to that achieved by analysis of liver specimens and in vitro mutagenesis studies. In conclusion, ATP8B1 deficiency caused incomplete polarization of HMDM into M2c. Phenotypic analysis of M2c helps to identify PFIC1 patients with no apparent disease-causing mutations in ATP8B1., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)