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Introduction: While genetic aberrations are becoming increasingly critical in disease classification, morphological abnormalities defined by a 10% threshold in each lineage continue to play a significant role as a diagnostic tool for myelodysplastic neoplasms (MDS). However, erythroid lineage dysplasia has been reported in some cases of aplastic anemia (AA), a phenomenon noted as common in the UK guidelines. Methods: We assessed the impact of erythroid dysplasia on the survival in AA patients enrolled in an ongoing prospective registry, central morphological review (blinded), and follow-up study of AA and MDS conducted by the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes. Furthermore, we compared the prognosis of AA patients with erythroid dysplasia with that of patients diagnosed in the same study with MDS presenting with single-lineage erythroid dysplasia (“MDS-SLED”). According to this study's definition, the criteria for excluding MDS are stringent, considering both bone marrow cellularity and megakaryocyte counts. Therefore, AA is not diagnosed when a decrease is not observed in the megakaryocyte count. Results: The study included a total of 32 cases of AA with erythroid dysplasia, 56 cases of AA without dysplasia, and 47 cases of MDS-SLED. The overall survival or leukemia-free survival showed no significant difference between AA patients with and without erythroid dysplasia (both p=0.14). Nevertheless, distinct differences were seen between AA with erythroid dysplasia and those diagnosed with MDS-SLED (both p

Background: In acetabular fracture surgery, an infra-acetabular screw (IAS) is inserted from the anterior to the posterior column through the infra-acetabular corridor to stabilize both columns. Although the IAS is useful for increasing fixation strength, proper placement requires proficiency and often results in extraosseous screw penetration. The complex anatomy of the infra-acetabular corridor and difficult intraoperative detection of the ideal insertion point and angle make proper placement of the IAS challenging. This study aimed to detect the ideal insertion point and angle of the IAS based on anatomical landmarks that can be directly identified intraoperatively., Methods: We retrospectively reviewed the pelvic CT of 50 adults who underwent serial slice CT imaging. The pelvic inlet plane (PIP), which contains the anterior border of both the sacroiliac joint and posterior superior edge of the pubic symphysis, was used as the reference plane for the pelvic coordinate system to simulate the ideal insertion of IAS. The distance from the posterior superior edge of the pubic symphysis to the ideal insertion point of the IAS (IAS distance) and the angle and length of the IAS that could be inserted from the ideal insertion point were measured., Results: The mean IAS distance was 61.0 ± 5.7 mm (57.6 ± 4.3 mm in men and 64.4 ± 4.9 mm in women). The mean angle between ideal IAS and yz-plane on the outlet view (α-angle) was 8.4 ± 6.6 ° (6.4 ± 5.6° in men and 10.5 ± 7.0° in women). The mean angle between ideal IAS and y-axis on the yz-plane (β-angle) was 86.5 ± 10.6 ° (86.0 ± 10.3° in men and 87.0 ± 10.9° in women). The length of IAS was 97.1 ± 4.7 mm in men and 89.2 ± 3.6 mm in women., Conclusion: The IAS ideal insertion point detected as a distance from the pubic symphysis may aid in the proper insertion of the IAS during surgery. The insertion angle was parallel or tilted 10 ° laterally to the longitudinal axis in the pelvic outlet plane and almost perpendicular to the PIP in the sagittal plane when inserted from the ideal insertion point., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to assess the efficacy and safety of a sheathless guiding system in patients who underwent percutaneous coronary intervention (PCI) with distal radial access (DRA)., Background: Hyperion™ Sheathless® guiding catheter (Asahi Intecc, Japan), one of the latest 6-Fr guiding systems for transradial PCI characterized by novel outer dilator, is considered to facilitate smooth insertion of the catheter to the artery and may contribute to further reduction of access site complications in DRA., Methods: Between October 2018 and January 2023, 286 patients underwent PCI with a Hyperion™ Sheathless® guiding catheter with DRA at two Japanese hospitals. Procedural success, bleeding complications, and radial artery occlusion (RAO) detected by Doppler ultrasonography were assessed., Results: Mean age of the patients was 72.7 years, and 236 patients (82.5 %) were male. The target lesions were located in the right coronary artery, left anterior descending artery, left circumflex artery, and left main trunk in 81, 44, 50 patients, and 18 patients respectively. Procedural success rate was 99.7 % with no patients requiring conversion to conventional radial access. Two patients presented with a forearm hematoma equivalent to an Early Discharge After Transradial Stenting of Coronary Arteries Study hematoma classification Grade II and 23 with Grade I. No patient presented minor or major bleeding according to the Thrombolysis in Myocardial Infarction bleeding classification. RAO at 30-day follow-up was observed in 6 out of 277 patients (2.2 %)., Conclusions: 6-Fr sheathless guiding system for PCI via DRA is feasible and associated with a low incidence of access site complications., Competing Interests: Declaration of competing interest The authors report no financial relationships or conflicts of interest regarding the content herein., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Early prediction of coronavirus disease (COVID-19) severity is crucial. Hyponatremia has been linked to poor outcomes in hospitalized COVID-19 patients, but its association with mild cases is unclear. This study aimed to investigate whether initial serum sodium level is a risk factor for COVID-19 severity in patients with mild-to-moderate disease., Methods: A multicenter retrospective cohort study was conducted in 10 hospitals in Fukui City, Japan, from July 1, 2020, to October 31, 2021. The study included 1055 adult patients with asymptomatic, mild, or moderate COVID-19 confirmed by a positive RT-PCR test. The primary outcome was the need for oxygen therapy after hospitalization, and the secondary outcome was the composite of in-hospital death and critical care interventions. The association between initial serum sodium level (at the emergency department or on admission) and outcomes was examined, adjusting for age, sex, hypertension, and pneumonia presence., Results: Of the 1267 patients diagnosed with COVID-19 during the study period, 1055 were eligible (median age: 45 years; 54 % male). Hyponatremia was observed in 5.2 % of patients upon admission. A lower initial serum sodium level was associated with an increased risk of the need for oxygen therapy after hospitalization (adjusted odds ratio [OR] per 1 mmol/L lower, 1.12 [95 % confidence interval {CI}, 1.05-1.19]) and the composite of critical care and in-hospital death (adjusted OR per 1 mmol/L lower, 1.09 [95 % CI, 0.99-1.20])., Conclusions: Among patients with mild COVID-19, lower initial serum sodium level was a risk factor for COVID-19 progression., Competing Interests: Declaration of competing interest Author Tadahiro Goto is employed by TXP Medical, Co. Ltd. Tokyo, Japan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

The rapidly growing concern of marine microplastic pollution has drawn attentions globally. Microplastic particles are normally subjected to visual characterization prior to more sophisticated chemical analyses. However, the misidentification rate of current visual inspection approaches remains high. This study proposed a state-of-the-art deep learning-based approach, Mask R-CNN, to locate, classify, and segment large marine microplastic particles with various shapes (fiber, fragment, pellet, and rod). A microplastic dataset including 3000 images was established to train and validate this Mask R-CNN algorithm, which was backboned by a Resnet 101 architecture and could be tuned in less than 8 h. The fully trained Mask R-CNN algorithm was compared with U-Net in characterizing microplastics against various backgrounds. The results showed that the algorithm could achieve Precision = 93.30%, Recall = 95.40%, F1 score = 94.34%, AP bb (Average precision of bounding box) = 92.7%, and AP m (Average precision of mask) = 82.6% in a 250 images test dataset. The algorithm could also achieve a processing speed of 12.5 FPS. The results obtained in this study implied that the Mask R-CNN algorithm is a promising microplastic characterization method that can be potentially used in the future for large-scale surveys., 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 Ltd. All rights reserved.)

Clostridium botulinum produces seven botulinum neurotoxin (BoNT) serotypes. In nature, BoNT exists as a part of the progenitor toxin complex (PTC) through associations with neurotoxin associated proteins (NAPs), including nontoxic nonhemagglutinin and hemagglutinin (HA) complex, consists of HA-70, HA-17 and HA-33. Because PTC displays higher oral toxicity than pure BoNTs, NAPs play a critical role in food poisoning. In a previous study, we demonstrated that the NAP complex in mature large-sized PTC (L-PTC) from serotypes C and D concomitantly induced cell death and cytoplasmic vacuolation in the rat intestinal epithelial cell line IEC-6. Here, we found that the serotype D NAP complex induces only cytoplasmic vacuolation in the normal rat kidney cell line NRK-52E without reducing cell viability. NAP complexes from serotype A and B L-PTCs did not affect cell viability or cytoplasmic vacuolation in IEC-6 and NRK-52E cells. Furthermore, we assessed the effect of immature L-PTCs with fewer HA-33/HA-17 trimers (two HA-33 and one HA-17) than mature L-PTCs on cell viability and cytoplasmic vacuolation in IEC-6 and NRK-52E cells. As a result, mature L-PTCs with the maximum number of HA-33/HA-17 trimers displayed the greatest potency. Consequently, the reduction in cell viability and vacuolation induction are related to the number of HA-33/HA-17 trimers in PTC. The discovery of an epithelial cell model where botulinum PTC specifically induces vacuolization may help clarify the unknown cytotoxicity of PTC, which plays an important role in the trans-epithelial transport of the toxin., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Symptomatic central venous obstruction (CVO) is sometimes observed in patients undergoing hemodialysis. Angioplasty is generally performed for salvage purposes, and stent implantation is performed as a last resort to prevent permanent venous occlusion. However, published reports about the clinical outcomes of stenting for CVO have been limited by the small number of included patients and the relatively old generation of analyzed stents. This study aimed to clarify the safety and efficacy of endovascular therapy (EVT) using stents for symptomatic CVO in contemporary practice., Methods: This retrospective review was performed between May 2012 and August 2021. We retrospectively analyzed consecutive 31 lesions (31 patients, 64 ± 10.7 years old) treated with a vascular stent for elastic recoil after balloon angioplasty or recurrent stenosis <3 months after angioplasty. The primary outcome was primary patency, defined as freedom from target lesion revascularization. The secondary outcome was assisted primary patency, defined as freedom from permanent occlusion of the target stents., Results: In all cases, stents were successfully deployed on the target lesions. No EVT-related complications were observed. Self-expandable and balloon-expandable stents were used in 26 and 5 lesions, respectively. The median follow-up period was 18 months (interquartile range, 7-40). Kaplan-Meier analysis revealed that the primary patency rates were 66.1 % at 6 months, 61.7 % at 12 months, and 38.4 % at 24 months after EVT. The assisted primary patency rate was 70.3 % 24 months after EVT. In the multivariate analysis, younger age was the only independent predictor of target lesion revascularization (hazard ratio: 0.92, 95 % CI: 0.85-0.99, p = 0.04)., Conclusions: Stent implantation for CVO that is resistant to standard angioplasty seems safe and effective., Competing Interests: Declaration of competing interest The authors have the following disclosures: Junichi Yamaguchi, Hiroyuki Arashi, and Hisao Otsuki belong to a division (Clinical Research Division for Cardiovascular Catheter Intervention) that is financially maintained by donations from Abbott Vascular, Boston Scientific, Medtronic, and Terumo. The other authors declare that they have no competing interests relevant to the contents of this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The indication of Fontan conversion (FC) from atriopulmonary connection (APC) to total cavopulmonary connection (TCPC) is unclear. We sought to analyze the mid-term outcome of prophylactic and therapeutic Fontan conversion compared with that of primary TCPC., Methods: Patients with a univentricular heart who underwent cardiac catheterization at >18 years of age between July 2005 and July 2019 were included and divided into three groups: symptomatic APC patients who underwent therapeutic FC (t-FC, n = 13), asymptomatic APC patients after prophylactic FC (p-FC, n = 15), and patients who had primary TCPC procedure (pTCPC, n = 24)., Results: The mean last follow up was at the age of 32.0 ± 7.8, 26.8 ± 3.8, and 27.3 ± 7 years (p = 0.07) in t-FC, p-FC, and pTCPC, respectively. There was no late death. All of t-FC and 12 (80%) of p-FC cases underwent concomitant arrhythmic surgery. Consequently, five and four patients in t-FC and p-FC groups required pacemaker implantations mostly due to sinus node dysfunction. Thromboembolism was seen in 2 cases in both t-FC (15%) and p-FC (13%), and 1 case in pTCPC (4%) (p = 0.50). The last cardiac catheterization was performed at the age of 29.5 ± 8.5, 24.6 ± 3.8, and 26.3 ± 7.1 years (p = 0.11) in t-FC, p-FC, and pTCPC patients, respectively. There was no significant difference in central venous pressure, aortic pressure, and cardiac index among the three groups. There was no late supraventricular tachyarrhythmic event seen in t-FC and p-FC, whereas two patients in pTCPC had newly developed atrial flutter., Conclusions: FC is a safe and feasible procedure to bring APC patients back onto the same track of primary TCPC patients in terms of hemodynamics as well as arrhythmia. The antiarrhythmic procedure should be carefully chosen because sinus node dysfunction can frequently occur and FC itself would reduce the risk of arrhythmia., Competing Interests: Declaration of Competing Interest Authors have no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Microplastics in the ocean are threatening marine ecosystems. Although plastic contaminants are ubiquitous, their distribution is thought to be heterogeneous. Here, we elucidate the spatial and temporal variations in the quanti-qualitative characteristics of microplastics near Kyushu, Japan in the East China Sea. Six surveys across nine stations were conducted over a 14-month period, and a total of 6131 plastic items were identified. The average microplastic abundance and size were 0.49 ± 0.92 (items·m -3  ± S.D.), and 1.71 ± 0.93 (mm ± S.D.), respectively. Differences between the highest and lowest abundances were 50-fold among monthly means, and 550-fold across all net tows. With respect to colour, polymer type, and shape, white and transparent polyethylene fragments were the dominant composition. There were significant differences for each of the analytical microplastic parameters among the survey months. Our results provide baseline data and lead to a more comprehensive understanding of the spatiotemporal characteristics of microplastic pollution., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is a serious complication that negatively affects the prognosis and quality of life of patients who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Antithymocyte globulin (ATG) is one of the second-line treatments for SR-aGVHD. We retrospectively evaluated Karnofsky Performance Status (KPS) recovery and clinical response in 11 patients who received the response-guided low-dose ATG treatment for SR-aGVHD after allo-HSCT using alternative donors. The median dose of ATG per cycle was 1.0 mg/kg (range, 1.0-1.25 mg/kg) and the median number of cycles of ATG was 2 (range, 1-4). The overall response rate was 63.6%, and the estimated overall survival rate at 1 year was 63.6%. Two out of seven patients who survived 1 year after the response-guided ATG treatment had KPS of 80 or higher. The remaining 5 patients had KPS of lower than 80 due to moderate chronic GVHD (cGVHD) and/or ≥grade 3 infectious complications. Based on the poor prognosis of patients with SR-aGVHD, the response-guided ATG treatment represents one therapeutic option. The present results also suggest that chronic GVHD and infectious complications after the response-guided ATG treatment were associated with decreased KPS recovery and impaired social function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recent reports have indicated that gut microbiota modulates the responses to stress through the microbiota-gut-brain axis in mice, suggesting a connection between gut microbiota and brain function. We hypothesized that the gut microbiota early in life would have an effect on aggressiveness, and examined how gut microbiota affect aggressive behaviors in mice. BALB/c mice were housed in germ-free (GF) and ex-germ-free (Ex-GF) isolators. An aggression test was performed between castrated and a non-castrated mice at 8 weeks of age; the mice were allowed to confront each other for 10 min in strictly contamination-free environments. To evaluate aggressive behavior related to gut microbiota, we orally administered diluted Ex-GF mouse feces to the offspring of GF mice at 0, 6, and 10 weeks. GF mice showed more aggression than Ex-GF mice. Furthermore, GF mice who were administered feces of the Ex-GF group at 0-week-old were less aggressive than the GF mice. These findings suggested that the gut microbiota in the early stages of development was likely to have an effect on aggressiveness. Maintenance of healthy gut microbiota early in life can affect the mitigation of aggressive behavioral characteristics throughout the lifetime., Competing Interests: Declaration of Competing Interest Natsuru Watanabe received research support from Shionogi & Co. Katsunaka Mikami received research support from Taisho Pharmaceutical, Otsuka Pharmaceutical, Shionogi & Co., Japanese Society for Probiotic Science; honoraria from Shionogi & Co., Shire Japan, Eli Lilly and Co., Meiji Holdings Co., Takeda Pharmaceutical, MIYARISAN PHARMACEUTICAL CO; and a consulting fee from Otsuka Pharmaceutical and Shionogi & Co. Tomokazu Hata received research support from Foundation of Kinoshita Memorial Enterprise. Keitaro Kimoto received research support from Otsuka Pharmaceutical, Shionogi & Co, and Taisho Pharmaceutical. Ryo Nishino received a consulting fee from Shionogi & Co. Fumiaki Akama has received research support from Otsuka Pharmaceutical and Shionogi & Co.; and honoraria from Dainippon Sumitomo Pharma, Pfizer, Shionogi & Co. and Eisai Co. KenjiYamamoto reports receiving grants and personal fees from Eisai Co., Ltd., Japan; grants and personal fees from Otsuka Pharmaceutical Co., Ltd., Japan; personal fees from Meiji Seika Pharma Co., Ltd.; personal fees from Sumitomo Dainippon Pharma Co., Ltd.; personal fees from Pfizer Japan Inc.; personal fees from Mitsubishi Tanabe Pharma Corporation; personal fees from Shionogi & Co.; personal fees from Eli Lilly and Company; personal fees from EPS Holdings, Inc.; grants from Grant-in-Aid for Scientific Research (16K10260) outside the submitted work. Nobuyuki Sudo has no conflict of interest. Yasuhiro Koga received research support from Meiji Holdings Co. Hideo Matsumoto received research support from, Dainippon Sumitomo, Otsuka Pharmaceutical, Shionogi & Co., KOIKE-YA Inc. Mental Clinic Yokohama Minatomirai, Kishi Byoin, Soushu Hospital, Kouzu Hospital, Tanzawa Hospital, Aikou Hospital, and Keyaki-no-mori Hospital; and honoraria from Eli Lilly and Co., Novartis Pharma, Yoshitomiyakuhin Corporation, GlaxoSmithKline, Dainippon Sumitomo, Pfizer, Meiji Seika Pharma, Otsuka Pharmaceutical, Janssen Pharmaceutical, Eisai Co., Shionogi & Co., Astellas Pharma, MSD and Mitsubishi Tanabe Pharma Corporation., (Copyright © 2021 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Background: T-wave inversion (TWI) is not considered useful for diagnosing pediatric arrhythmogenic right ventricular cardiomyopathy (ARVC), because right precordial TWI in ARVC resembles a normal juvenile pattern., Objectives: The aims of this study were to clarify the electrocardiographic (ECG) characteristics of pediatric ARVC to distinguish those patients from healthy children., Methods: Between 1979 and 2017, 11 ARVC patients under 18 years old were registered and compared with school screening ECGs from 48,401 healthy children., Results: The mean age at the first arrhythmic event or diagnosis was 13.3 ± 4.7 years. Nine patients were asymptomatic initially and were found by ECG screening, but 6 developed severe symptoms during the follow-up. Healthy children had a normal juvenile pattern, while ARVC children, especially symptomatic patients, had a significant tendency to have inferior and anterior TWI. The phenomenon of T-wave discontinuity (TWD) in which the TWI became deeper from V1 to V3 and suddenly turned positive in V5 was significantly more frequent in ARVC (60%) than healthy children (0.55%). Anterior TWI and TWD were also significantly more frequent in those who developed severe symptoms. The sensitivity and specificity of TWD were 60% (95% CI, 31-83%), and 99% (95% CI, 99-99%) to distinguish ARVC from healthy children, as well as 100% (95% CI, 71-100%) and 80% (95% CI, 51-80%), respectively, to predict severe symptoms in the future., Conclusions: The ECG is useful to distinguish ARVC children, even in the early phase. Anterior TWI and TWD could detect ARVC children and to predict the possible serious conditions., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Schizophrenia is probably ascribed to perinatal neurodevelopmental deficits, and its onset might be affected by environmental factors. Hypofrontality with glutamatergic and dopaminergic neuronal dysfunction are known factors, but a way to mitigate abnormalities remains unfound. An early enriched environment such as a wheel running in rodents may contribute to the prevention, but its clinical applicability is very limited. From our studies, low-intensity exercise training (LET) based on physiological indices, such as lactate threshold, easily translates to humans and positively affects the brains. Hence, LET during adolescence may ameliorate abnormalities in neurodevelopment and prevent the development of schizophrenia. In the current study, LET prevented sensitization to phencyclidine (PCP) treatment, impairment of cognition, and affective behavioral abnormalities in an animal model of schizophrenia induced by prenatal PCP treatment. Further, LET increased dopamine turnover and attenuated the impairment of phosphorylation of ERK1/2 after exposure to a novel object in the prenatal PCP-treated mice. These results suggest that LET during adolescence completely improves schizophrenia-like abnormal behaviors associated with improved glutamate uptake and the dopamine-induced ERK1/2 signaling pathway in the PFC., 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 © 2020 Elsevier Inc. All rights reserved.)

Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Epigenetic gene silencing by aberrant DNA methylation leads to loss of key cellular pathways in tumorigenesis. DNA methylation-mediated silenced genes in pancreatic cancer were searched for using the methyl-CpG targeted transcriptional activation (MeTA) method, and LHX6 (LIM homeobox 6), a transcription factor involved in embryogenesis and head development, was selected as a strong candidate gene. LHX6 was downregulated in most of the pancreatic cancer cell lines (83%, 10/12), mainly through promoter hypermethylation and histone deacetylation. Furthermore, LHX6 was methylated in primary pancreatic cancer specimens (57%, 16/28) in a tumor-specific manner. Re-expression of LHX6 inhibited colony formation and proliferation in LHX6 low-expressing pancreatic cancer cell lines, PK-1 and PK-9. In contrast, knockdown of LHX6 accelerated cell proliferation in LHX6 high-expressing pancreatic cancer cell lines, PCI-35 and MIA PaCa-2. In order to analyze LHX6 downstream genes, we performed microarray analyses using LHX6 inducible PK-1 and PK-9 and found that LHX6 induction upregulated several genes that had tumor suppressive functions. Among these, we focused on TFPI2 (Tissue factor pathway inhibitor-2) and found that TFPI2 was greatly downregulated in all twelve pancreatic cancer cell lines. Our present results suggest that epigenetic inactivation of LHX6 plays an important role in pancreatic tumorigenesis by promoting cell proliferation through aberrant transcriptional regulation of several cancer-related genes., Competing Interests: Declaration of competing interest The authors declare no financial competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: This study aimed to investigate the association between living alone at home and the care and outcomes of patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (pPCI)., Methods: In total, 557 patients with STEMI underwent pPCI between January 2008 and September 2017. Among them, we included 208 patients who were transferred directly by emergency medical services from their home to the hospital., Results: Patients were classified into two groups, namely living alone (n = 45) and living with others (n = 163). There were no significant differences in age, sex, and cardiovascular risk factors between the two groups. The onset-to-door (OTD) and onset-to-balloon times were significantly shorter in patients living with others than in those living alone (106.4 vs. 190.8 min, p < 0.01 and 152.3 vs. 236.9 min; p < 0.01, respectively). The left ventricular ejection fraction after pPCI was significantly lower in patients living alone than in those living with others (48.7 % vs. 54.9 %, p < 0.01). Multivariate logistic regression analysis indicated that living alone and the incidence of congestive heart failure were independent predictors of a longer OTD time., Conclusions: Patients living alone were less likely to arrive early at the hospital than those living with others. A greater understanding of the inter-relationships among living alone, access to acute cardiac care, and outcomes is essential., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined., Methods: Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations., Results: Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively., Conclusions: This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations., Trial Registry: UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000019691., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression., Methods: We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors-defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors-defined second progressive disease or death., Results: Among the 542 patients included, 20% and 53% showed a typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (n = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the patients who showed pseudoprogression than the PFS of the patients with a typical response (p < 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than did patients showing typical progression (p = 0.001)., Conclusions: Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed a typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

In flies, grooming serves several purposes, including protection against pathogens and parasites. Previously, we found Escherichia coli or lipopolysaccharides (LPS) can induce grooming behavior via activation of contact chemoreceptors on Drosophila wing. This suggested that specific taste receptors may contribute to this detection. In this study, we examined the perception of commercially available LPS on Drosophila wing chemoreceptors in grooming reflex. Behavioral tests conducted with bitter, sweet and salty gustation such as caffeine, sucrose and salt, using flies carrying a defect in one of their taste receptors related to the detection of bitter molecules (Gr66a, Gr33a), sugars (Gr5a, Gr64f), or salt (IR76b). LPS and tastants of each category were applied to wing sensilla of these taste defectflies and to wild-type Canton Special (CS) flies. Our results indicate that the grooming reflex induced by LPS requires a wide range of gustatory genes, and the inactivation of any of tested genes expressing cells causes a significant reduction of the behavior. This suggests that, while the grooming reflex is strongly regulated by cues perceived as aversive, other sapid cues traditionally related to sweet and salty tastes are also contributing to this behavior., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

(Aim) Bacterial infection underlies the pathogenesis of many human diseases, including acute and chronic inflammation. Here, we investigated a possible role for bacterial infection in the progression of chronic pancreatitis. (Materials and Methods) Pancreatic juice was obtained from patients with pancreatic cancer (n = 20) or duodenal cancer/bile duct cancer (n = 16) and subjected to PCR using universal primers for the bacterial 16S ribosomal RNA gene. Bacterial species were identified by PCR using bile samples from four pancreatic cancer patients. PCR products were subcloned into T-vectors, and the sequences were then analyzed. Immunohistochemical and serologic analyses for Enterococcus faecalis infection were performed on a large cohort of healthy volunteers and patients with chronic pancreatitis or pancreatic cancer and on mice with caerulein-induced chronic pancreatitis. The effect of E. faecalis antigens on cytokine secretion by pancreatic cancer cells was also investigated. (Results) We found that 29 of 36 pancreatic juice samples were positive for bacterial DNA. Enterococcus and Enterobacter species were detected primarily in bile, which is thought to be a pathway for bacterial infection of the pancreas. Enterococcus faecalis was also detected in pancreatic tissue from chronic pancreatitis and pancreatic cancer patients; antibodies to E. faecalis capsular polysaccharide were elevated in serum from chronic pancreatitis patients. Enterococcus-specific antibodies and pancreatic tissue-associated E. faecalis were detected in mice with caerulein-induced chronic pancreatitis. Addition of Enterococcus lipoteichoic acid and heat-killed bacteria induced expression of pro-fibrotic cytokines by pancreatic cancer cells in vitro. (Conclusion) Infection with E. faecalis may be involved in chronic pancreatitis progression, ultimately leading to development of pancreatic cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

During percutaneous coronary intervention performed for a stenotic lesion with heavy calcification in the left coronary artery, the microcatheter tip became transected in the vessel. The fragment was successfully retrieved using the twin guidewire method after negotiating to cross a chronic total occlusion-dedicated guidewire outside the retained tip., (Copyright © 2018 Elsevier Inc. All rights reserved.)

To obtain a better understanding of the genetic alterations of high-grade pancreatic intraepithelial neoplasia (HG-PanIN), we performed whole-genome copy number analysis by using single nucleotide polymorphism microarrays and targeted next-generation sequencing of 11 microdissected HG-PanIN and two low-grade PanIN lesions associated with HG-PanIN. HG-PanIN mutation profiles were compared with those of their associated invasive pancreatic ductal adenocarcinoma. All PanIN lesions harbored somatic KRAS mutations. The most common copy number losses in the HG-PanIN were at the CDKN2A (9p21), TP53 (17p13), and SMAD4 (18q21) loci. Chromosomal losses in HG-PanIN were also found at 6p25-p24, 6q11-q27, 12q24, and 17q23-q24. Biallelic inactivation of CDKN2A and TP53 was detected in five of eight and in three of eight evaluable PanIN lesions, respectively. None of the HG-PanIN lesions had SMAD4 mutations or homozygous deletion. Copy number gains were noted at the MYC (8q24) and CCNE1 (19q12) loci and at 1q25-q31. Four HG-PanINs and one low-grade PanIN harbored chromothripsis-like regions. Five of seven pancreatic ductal adenocarcinomas evaluated had additional mutations that were not found in their associated HG-PanIN. HG-PanIN harbors widespread copy number alterations and commonly shows evidence of biallelic inactivation of CDKN2A and TP53 but not SMAD4. Chromothripsis events contribute to the copy number alterations of HG-PanIN., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The eggs of the migratory locust, Locust migratoria, hatch in synchrony from their pod. In this study, we examined the mechanism controlling hatching synchrony. Two eggs obtained from the same pod hatched in synchrony when kept in contact with one another, whereas those separated by a few millimeters hatched less synchronously. When a screen separated the eggs, the hatching was even more sporadic, indicating that hatching synchrony might be controlled by a two-step mechanism. We hypothesize that in the first step the embryos shortly before hatching control the time to enter a standby stage using some signal from neighboring eggs. The eggs in the standby stage hatch promptly when an additional stimulus is received from neighboring eggs. Before this stage, eggs cannot respond to that stimulus by hatching but may spontaneously hatch later. Introduction of a newly hatched nymph to single eggs 1 or 2 days before hatching advanced hatching of these eggs, but hatching occurred only sporadically. Eggs kept in contact with other eggs that had been killed by freezing shortly before hatching hatched as if they had been kept singly in separate containers, providing no evidence for involvement of chemical stimuli in controlling hatching synchrony. By contrast, eggs separated by several millimeters hatched as synchronously as those kept in contact with one another when they were connected by a piece of wire. Furthermore, vibrational stimulation derived from music greatly advanced hatching of separately kept eggs; however, hatching synchrony was not achieved unless the music started shortly before hatching. These results are consistent with the two-step hypothesis and indicated that locust embryos used vibrational stimuli from neighboring eggs for synchronous hatching., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated. Telomere fusions were detected in 56 of 91 pancreatic cancers (61.5%). Telomere fusion-positive cell lines had significantly shorter telomere lengths than fusion-negative lines (P = 0.003). Telomere fusions were undetectable in normal pancreas or IPMNs with low-grade dysplasia (0.0%) and were detected in IPMN with high-grade dysplasia (HGD; 48.0%) (P < 0.001). In IPMN cyst fluids, telomere fusions were more frequent in IPMNs with HGD (26.9%) or associated invasive cancer (42.9%) than IPMN with intermediate-grade dysplasia (15.4%) or low-grade dysplasia (0%) (P = 0.025). Telomerase activity levels were higher in cyst fluids with fusions than in those without (P = 0.0414). Cyst fluid telomere fusion status was an independent predictor of HGD/invasive cancer by multivariate analysis (odds ratio, 6.23; 95% CI, 1.61-28.0). Telomere fusions are detected in later stages of IPMN progression and can serve as a marker for predicting the presence of HGD and/or invasive cancer., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The various guidelines clearly mention the treatment strategies for in patient of acute myocardial infarction (MI) presenting more than 24h from symptom onset (recent myocardial infarction, RMI). However, the appropriate timing of reperfusion for RMI is unclear., Methods: We retrospectively evaluated 525 consecutive MI patients who underwent percutaneous coronary intervention (PCI) in our hospital between January 2008 and December 2012., Results: Sixty RMI patients were more frequently associated with cardiac complications such as myocardial rupture (3.3% vs. 0%; p<0.01), ventricular septal rupture (3.3% vs. 0.4%; p<0.05), and congestive heart failure (15% vs. 2.6%; p<0.001) than 272 consecutive ST-elevation myocardial infarction (STEMI) patients. Of the 60 RMI patients, 33 (55.0%) underwent PCI within 7days (early-PCI group) and 27 (45.0%) underwent PCI after 7days (late-PCI group). Left ventricular ejection fraction measured by echocardiography at second hospital day was similar between the groups. The early-PCI group was more significantly associated with cardiogenic shock and heart failure and more frequently required intra-aortic balloon pumping (24.2% vs. 3.7%; p<0.05) than the late-PCI group. There were no significant differences in 30-day mortality, cardiac complications, and major cardiac events during long-term follow-up (12-36 months) between the groups., Conclusion: RMI patients had a higher incidence of cardiac complications than AMI patients. Clinical outcomes were similar between patients undergoing early revascularization and those undergoing late revascularization, although the former group included a higher proportion of patients with severe cardiac failure., (Copyright © 2017. Published by Elsevier B.V.)

Aims: Immune and inflammatory responses mediated by immunoglobulin (Ig) G are largely responsible for the pathogenesis of autoimmune diseases. Spleen tyrosine kinase (Syk) plays a pivotal role in the IgG-mediated responses; therefore, Syk has emerged as a new therapeutic target for the treatment of autoimmune diseases. In this study, we investigated the inhibitory actions of JTE-852, a novel Syk inhibitor, on IgG-mediated cellular responses and autoimmune reactions in vivo., Main Methods: We examined mediator secretion from human monocytes. We also conducted rat models of reversed cutaneous anaphylaxis (RCA) and reversed passive Arthus (RPA), which are classified as type II and type III hypersensitivities, respectively. In a rat collagen-induced arthritis (CIA) model, JTE-852 or methotrexate was administered preventively (before the onset of arthritis) or therapeutically (after the onset of arthritis)., Key Findings: JTE-852 blocked secretion of reactive oxygen species and tumor necrosis factor-α from monocytes stimulated by IgG crosslinking. In the RCA and RPA models, JTE-852 also suppressed edema and dye leakage, respectively. In the CIA model, JTE-852 showed both preventive and therapeutic effects against joint swelling and bone erosion; on the other hand, methotrexate did not show the therapeutic effect., Significance: JTE-852 attenuates IgG-mediated responses and signs in animal model of autoimmune diseases. JTE-852 is thus a promising candidate for a novel, orally available drug for the treatment of autoimmune diseases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The detailed pathophysiology of limb coldness in multiple system atrophy (MSA) is unknown., Methods: We evaluated cutaneous vasomotor neural function in 18 MSA patients with or without limb coldness, and in 20 healthy volunteers as controls. We measured resting skin sympathetic nerve activity (SSNA) and spontaneous changes of the sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex: SVR), as well as SVR and reflex changes of SSNA after electrical stimulation. The parameters investigated were the SSNA frequency at rest, amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and skin blood flow velocity., Results: Both the resting frequency of SSNA and the amplitude of SSNA reflex bursts were significantly lower in the MSA group than the control group (p<0.001 and p<0.05, respectively). There were no significant differences between the two groups with regard to the absolute decrease or percent reduction of SVR volume. The recovery time showed no significant difference between all MSA patients and control groups, but it was significantly prolonged in six MSA patients with limb coldness compared with that in the control group and that in MSA patients without limb coldness (p<0.01). The skin blood flow velocity was significantly slower in the MSA group than in the control group (p<0.001)., Conclusion: In MSA patients, limb coldness might occur due to impairments of the peripheral circulation based on prolongation of vasoconstriction and a decrease of skin blood flow velocity secondary to combined pre- and postganglionic skin vasomotor dysfunction., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although chronic total occlusion of the left main coronary artery (LMCA) is considered very rare, this condition could be fatal if it becomes complicated with an acute coronary syndrome lesion in the right coronary artery (RCA) which is usually the only remaining coronary artery for the myocardium. We reported a successfully treated case of a nonagenarian patient with ST-segment elevation myocardial infarction, who had subtotal occlusion of the RCA and total occlusion of the LMCA with Rentrop grade 2 collateral coronary artery supply from the RCA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

When considering the safety of ingested nanomaterials, it is important to quantitate their transfer across intestinal cells; however, little information exists about the effects of nanomaterial size or exposure side (apical versus basolateral epithelial surface) on nanomaterial transfer. Here, we examined cellular internalization and transcellular transport, and the effects of nanomaterials on Caco-2 monolayers after apical or basolateral exposure to Ag or Au nanoparticles with various sizes. After apical treatment, both internalization and transfer to the basolateral side of the monolayers were greater for smaller Ag nanoparticles than for larger Ag nanoparticles. In contrast, after basolateral treatment, larger Ag nanoparticles were more internalized than smaller Ag nanoparticles, but the transfer to the apical side was greater for smaller Ag nanoparticles. Au nanoparticles showed different rules of internalization and transcellular transport compared with Ag nanoparticles. Furthermore, the paracellular permeability of the Caco-2 monolayers was temporarily increased by Ag nanoparticles (5 μg/mL; diameters, ≤10 nm) following basolateral but not apical exposure. We conclude that the internalization, transfer, and effects of nanomaterials in epithelial cell monolayers depend on the size and composition of nanomaterials, and the exposure side., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Neonatal hemochromatosis (NH) is a rare neonatal disorder that results in liver cirrhosis with hemosiderin deposition in the liver and other organs, similarly to hereditary hemochromatosis. Excess iron is transferred from the mother to fetus through the placenta in NH. We examined the expression of iron metabolism-related substances in placental syncytiotrophoblasts (STB) by immunostaining to clarify how the transfer of iron through STB increases in NH., Methods: Immunostaining was performed using formalin-fixed, paraffin-embedded sections of placentae from three NH cases, four gestational age-matched controls, and, depending on the antibody examined, five to seven full-term controls. The reactivity of immunostaining was assessed by averages of scores assigned by 3 researchers., Results: On the microvillar surface of STB, the reactions of the antibodies against transferrin receptor 1 (TFR1), transferrin, ferritin, hepcidin, ferroportin, divalent metal transporter-1 (DMT1), hephaestin, and HFE were stronger in NH than in controls. In the cytoplasm, the reactions of antibodies against TFR1, transferrin, ferritin, hepcidin, DMT1, hephaestin, HFE, and ZIP 14 were stronger in NH than in gestational age-matched controls. Among these reactions, those of anti-TFR1 antibody on the surface of STB in NH was especially marked., Discussion: In the placenta of NH, increases in expressions of TFR1, transferrin, and ferritin of which those of TFR1 were especially marked, reflect increased iron influx from the mother to fetus. The hepcidin observed on the surface and in the cytoplasm of STB of NH is suggested to be from the mother, possibly to compensate for the decreased fetal liver-derived hepcidin., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Recently, novel calreticulin (CALR) mutations were discovered in Janus kinase 2 (JAK2) non-mutated myelofibrosis (PMF) and essential thrombocythemia (ET) cases, with a frequency of 60-80%. We examined clinical correlations and CALR mutation frequency in our myeloproliferative neoplasms (MPN) cases, and introduce an effective test method for use in clinical practice., Methods: We examined 177 samples previously investigated for the JAK2 mutation for differential diagnosis of MPN. JAK2 and CALR mutations were analyzed using melting curve analysis and microchip electrophoresis, respectively. Next, we constructed a test for simultaneous screening of the JAK2 and CALR mutations utilizing high resolution melting (HRM)., Results: Among 99 MPN cases, 60 possessed the JAK2 mutation alone. Of the 39 MPN cases without the JAK2 mutation, 14 were positive for the CALR mutation, all of which were ET. Using our novel screening test for the JAK2 and CALR mutations by HRM, the concordance rate of conventional analysis with HRM was 96% for the JAK2 mutation and 95% for the CALR mutation., Conclusion: Our novel simultaneous screening test for the JAK2 and CALR gene mutations with HRM is useful for diagnosis of MPN., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: To assess placental perfusion during spontaneous or induced uterine contraction in labor at term using placental vascular sonobiopsy (PVS) by 3D power Doppler ultrasound with the VOCAL imaging analysis program., Method: PVS was performed in 50 normal pregnancies (32 in spontaneous labor group [SLG], and 18 in induced labor group with oxytocin or prostaglandin F2α [ILG]) at 37-41 weeks of gestation to assess placental perfusion during uterine contraction in labor. Only pregnancies with an entirely visualized anterior placenta were included in the study. Data acquisition was performed before, during (at the peak of contraction), and after uterine contraction. 3D power Doppler indices such as the vascularization index (VI), flow index (FI), and vascularization flow index (VFI) were calculated in each placenta., Results: There were no abnormal fetal heart rate tracings during contraction in either group. VI and VFI values were significantly reduced during uterine contraction in both groups (SLG, -33.4% [-97.0-15.2%], and ILG, -49.6% [-78.2--4.0%]), respectively (P < 0.001). The FI value in the ILG group was significantly lower during uterine contraction (P = 0.035), whereas it did not change during uterine contraction in the SLG group. After uterine contraction, all vascular indices returned almost to the same level as that before uterine contraction. However, the FI value in ILG (-8.6%, [-19.7-16.0%]) was significantly lower than that in SLG (2.4%, [-13.4-38.1%]) after uterine contraction (P < 0.05). All 3D power Doppler indices (VI, FI, and VFI) during uterine contraction (at the peak of contraction) showed a correlation greater than 0.7, with good intra- and inter-observer agreements., Discussion: Our findings suggest that uterine contraction in both spontaneous and induced labors causes a significant reduction in placental perfusion. Reduced placental blood flow in induced uterine contraction has a tendency to be marked compared with that in spontaneous uterine contraction. To the best of our knowledge, this is the first study on the non-invasive assessment of placental perfusion during uterine contraction in labor using 3D power Doppler ultrasound. However, the data and their interpretation in the present study should be taken with some degree of caution because of the small number of subjects studied. Further studies involving a larger sample size are needed to assess placental perfusion and vascularity using PVS during normal and abnormal uterine contractions in normal and high-risk pregnancies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Claudin-1 (CLDN-1), an integral transmembrane protein, is an attractive target for drug absorption, prevention of infection, and cancer therapy. Previously, we generated mouse anti-CLDN-1 monoclonal antibodies (mAbs) and found that they enhanced epidermal absorption of a drug and prevented hepatitis C virus infection in human hepatocytes. Here, we investigated anti-tumor activity of a human-mouse chimeric IgG1, xi-3A2, from one of the anti-CLDN-1 mAbs, clone 3A2. Xi-3A2 accumulated in the tumor tissues in mice bearing with human CLDN-1-expressing tumor cells. Xi-3A2 activated Fcγ receptor IIIa-expressing reporter cells in the presence of human CLDN-1-expressing cells, suggesting xi-3A2 has a potential to exhibit antibody-dependent cellular cytotoxicity against CLDN-1 expressing tumor cells. We also constructed a mutant xi-3A2 antibody with Gly, Ser, and Ile substituted with Ala, Asp, and Arg at positions 236, 239, and 332 of the Fc domain. This mutant antibody showed greater activation of Fcγ receptor IIIa and in vivo anti-tumor activity in mice bearing human CLDN-1-expressing tumors than xi-3A2 did. These findings indicate that the G236A/S239D/I332E mutant of xi-3A2 might be a promising lead for tumor therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Old age is a prognostic risk factor for patients with ST elevation acute myocardial infarction (STEMI); however, few data exist describing STEMI patients aged over 90 years., Methods: We retrospectively evaluated the clinical indices and outcomes of 282 consecutive STEMI patients who underwent primary percutaneous coronary intervention (PCI) in our hospital between January 2008 and December 2012. Patients with acute myocardial infarction complicated by out-of-hospital cardiopulmonary arrest, patients with a left main trunk culprit lesion, and patients diagnosed more than 24h after symptom onset were excluded., Results: Of the patients treated during the study period, 11 (3.8%) were >90 years old. The mean door-to-balloon time was significantly longer for nonagenarians than younger patients (66.2 vs. 44.0minutes; p<0.001). This was mainly attributed to delays in decision-making regarding invasive treatment by both the doctors and families. Nonagenarians had multiple coronary artery stenoses more frequently (36.4% vs. 15.0%; p<0.05) and required intra-aortic balloon pumping more often (36.4% vs. 18.9%; p=0.15) compared with patients aged ≤89 years. However, the peak creatinine kinase levels and the left ventricular ejection fractions were similar between the groups. Moreover, the in-hospital and 30-day mortality rates were similar (9.1% vs. 4.6%, p=0.50; 9.1% vs. 3.6%, p=0.34, respectively) between the groups. The two-year survival rate was 81.8% in nonagenarians., Conclusions: Despite the longer door-to-balloon time, higher use of intra-aortic balloon pumping, and larger number of diseased vessels, the 30-day and 2-year survival rates of nonagenarians with STEMI were comparable to those of younger patients., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

We investigated the effect of cytochrome P450 (CYP) 2C9 polymorphism on the inhibition of methylhydroxylation activity of tolbutamide, a typical CYP2C9 substrate, by triazole antifungal agents, fluconazole and voriconazole. Although the Michaelis constants (Km), maximal velocities (Vmax), and Vmax/Km values for CYP2C9.1 (wild type) and CYP2C9.2 (Arg144Cys) were similar and CYP2C9.3 (Ile359Leu) had a higher Km and a lower Vmax than CYP2C9.1 and CYP2C9.2, the inhibition constants of fluconazole and voriconazole against CYP2C9.2 were lower than that against CYP2C9.1 and CYP2C9.3. These results suggest that more careful administration of azole antifungals to patients with the CYP2C9*2 allele might be required because of the strong inhibitory effects., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Islet autotransplantation following total pancreatectomy differs from allograft transplantation with respect to the requirement of biliary reconstruction. Although it is known that careful consideration should be given to postoperative cholestatic liver injury after biliary reconstruction, its direct effects on transplanted islets have not been completely elucidated. In this study, we developed a murine model of postoperative cholestatic liver injury after biliary reconstruction with islet autotransplantation that involved syngeneic intraportal islet transplantation into chemically induced diabetic mice and common bile duct ligation. We assessed the viability and function of the transplanted islets. The impaired viability of transplanted islets and increased blood glucose levels indicated restoration of the diabetic state after common bile duct ligation in this murine model. Furthermore, impaired islet viability and function occurred earlier in the transplanted islets than in the surrounding liver tissues, which was consistent with the faster and higher expression of oxidative stress markers in the transplanted islets. Transplanted islets may be more vulnerable to oxidative stress caused by cholestatic liver injury than the surrounding liver tissue. Therefore, patients should be intensively managed after total pancreatectomy with islet autotransplantation to preserve viability and function of the transplanted islets., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objectives: The aim of this study was to evaluate the feasibility and safety of the 6-Fr Glidesheath Slender, which has equivalent outer size to the conventional 5-Fr sheath, for use with the 6-Fr intra-aortic balloon pump (IABP) catheter., Methods: Between May 2014 and March 2015, 24 patients with acute coronary syndrome underwent percutaneous coronary intervention using a 6-Fr IABP catheter through a 6-Fr Glidesheath Slender for support. The adverse events, including access site complications, kinking of the sheath during the procedure, and any evidence of balloon pump failure, were retrospectively investigated., Results: Insertion of the IABP catheter through either the femoral or brachial artery was successful in all patients. The mean support time was 32.4±22.0h. No major hemorrhagic event or severe limb ischemia was observed. Kinking of the shaft occurred during insertion in one patient; however, the subsequent balloon pumping was well maintained and did not require exchange of the sheath or IABP catheter. No kind of IABP failure was observed., Conclusion: Although this sheath was originally designed to allow radial access, our results suggest that the use of the Glidesheath Slender is feasible for insertion of the 6-Fr IABP catheter through the brachial and femoral arteries, and may reduce vascular complications in patients who undergo percutaneous coronary intervention., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy., Patients and Methods: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety., Results: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups., Conclusion: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment., Clinical Trial Identifier: UMIN000002557., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: The mother and child technique with a deep-seated 4F Kiwami catheter has been reported to be effective for delivering stents to complex lesions., Objectives: To assess the feasibility and efficacy of a novel 4.5F child catheter for deep insertion and stent deployment into the distal coronary artery for the treatment of complex lesions., Method: We retrospectively evaluated 51 consecutive patients, who underwent percutaneous coronary intervention between January 2011 and December 2013, using a 4.5F CoKatte catheter after stent delivery failure using the conventional procedures. We evaluated the procedure success, need for an additional anchor balloon technique, and complications related to the deep insertion., Results: Stent delivery to the intended lesion was successful in all cases. For advancement and subsequent deep intubation of the catheter, 42 lesions required the additional anchor balloon technique. No complications, including proximal dissection, air embolism, and severe ischemia, were observed in relation to the deep insertion of the catheter., Conclusion: Percutaneous coronary intervention with the novel 4.5F catheter is a safe and effective method, which can facilitate stent delivery to a complex coronary lesion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Sterol regulatory element-binding protein-2 (SREBP-2) is a basic helix-loop-helix-leucine zipper transcription factor that positively regulates transcription of target genes involved in cholesterol metabolism. In the present study, we have investigated a possible involvement of SREBP-2 in human intestinal expression of fibroblast growth factor (FGF)19, which is an endocrine hormone involved in the regulation of lipid and glucose metabolism. Overexpression of constitutively active SREBP-2 decreased FGF19 mRNA levels in human colon-derived LS174T cells. In reporter assays, active SREBP-2 overexpression suppressed GW4064/FXR-mediated increase in reporter activities in regions containing the IR-1 motif (+848 to +5200) in the FGF19 gene. The suppressive effect disappeared in reporter activities in the region containing the IR-1 motif when the mutation was introduced into the IR-1 motif. In electrophoretic mobility shift assays, binding of the FXR/retinoid X receptor α heterodimer to the IR-1 motif was attenuated by adding active SREBP-2, but SREBP-2 binding to the IR-1 motif was not observed. In chromatin immunoprecipitation assays, specific binding of FXR to the IR-1-containing region of the FGF19 gene (+3214 to +3404) was increased in LS174T cells by treatment with cholesterol and 25-hydroxycholesterol. Specific binding of SREBP-2 to FXR was observed in glutathione-S-transferase (GST) pull-down assays. These results suggest that SREBP-2 negatively regulates the FXR-mediated transcriptional activation of the FGF19 gene in human intestinal cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We present a case of intra-amniotic umbilical vein varix with thrombosis using conventional two-dimensional (2D) sonography, power Doppler, three-dimensional (3D) HD-flow, and HDlive at 35 weeks of gestation. 2D sonography showed a large banana-like umbilical cord enlargement (100 × 43.3 × 45.9 mm) including umbilical vein varix (maximum vein diameter = 25.5 mm) with massive thrombosis. Power Doppler and 3D HD-flow revealed bidirectional turbulent blood flow inside the varix. The HDlive clearly demonstrated fragile massive thrombosis inside the varix. Elective cesarean section was performed on the same day in order to avoid additional risks of umbilical cord complications and umbilical venous embolism. A male infant weighing 2501 g was delivered with an umbilical artery pH of 7.334, and Apgar score of 8/9 at 1 and 5 min, respectively. The macroscopic and microscopic findings revealed umbilical cord vein varix with thrombosis. On the basis of the laboratory date of the neonate, the diagnosis of consumptive coagulopathy was made. However, the neonate followed a favorable course after delivery., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Adult T-cell leukemia/lymphoma (ATL) relapse is a serious therapeutic challenge after allogeneic hematopoietic stem cell transplantation (allo-SCT). In the present study, we retrospectively analyzed 35 patients who experienced progression of or relapsed persistent ATL after a first allo-SCT at 3 institutions in Nagasaki prefecture (Japan) between 1997 and 2010. Twenty-nine patients were treated by the withdrawal of immune suppressants as the initial intervention, which resulted in complete remission (CR) in 2 patients. As the second intervention, 9 patients went on to receive a combination of donor lymphocyte infusion and cytoreductive therapy and CR was achieved in 4 patients. Of 6 patients who had already had their immune suppressants discontinued before the relapse, 3 patients with local recurrence received local cytoreductive therapy as the initial treatment, which resulted in CR for more than 19 months. Donor lymphocyte infusion-induced remissions of ATL were durable, with 3 cases of long-term remission of more than 3 years and, interestingly, the emergence or progression of chronic GVHD was observed in all of these cases. For all 35 patients, overall survival after relapse was 19.3% at 3 years. The results of the present study suggest that induction of a graft-versus-ATL effect may be crucial to obtaining durable remission for ATL patients with relapse or progression after allo-SCT.