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The success rate of flap tissue reconstruction has increased in recent years owing to advancements in microsurgical techniques. However, complications, such as necrosis, are still more prevalent in diabetic patients compared to non-diabetic individuals, presenting an ongoing challenge. To address this issue, many previous studies have examined vascular anastomoses dilation and stability, primarily concerning surgical techniques or drugs. In contrast, in the present study, we focused on microvascular damage of the peripheral microvessels in patients with diabetes mellitus and the preventative impact of nafamostat mesylate. Herein, we aimed to investigate the effects of hyperglycemia on glycocalyx (GCX) levels in mice with type 2 diabetes. We examined the endothelial GCX (eGCX) in skin flap tissue of 9-12-week-old type 2 diabetic mice (db/db mice) using a perforator skin flap and explored treatment with nafamostat mesylate. The growth rates were compared after 1 week. Heterotype (db/+) mice were used as the control group. Morphological examination of postoperative tissues was performed at 1, 3, 5, and 7 days post-surgery. In addition, db/db mice were treated with 30 mg/kg/day of nafamostat mesylate daily and were evaluated on postoperative day 7. Seven days after surgery, all db/db mice showed significant partial flap necrosis. Temporal observation of the skin flaps revealed a stasis-like discoloration and necrosis starting from the contralateral side of the remaining perforating branch. The control group did not exhibit flap necrosis, and the flap remained intact. In the quantitative assessment of endothelial glycans using lectins, intensity scoring showed that the eGCX in the db/db group was significantly thinner than that in the db/+ group. These results were consistent with the scanning electron microscopy findings. In contrast, treatment with nafamostat mesylate significantly improved the flap engraftment rate and suppressed eGCX injury. In conclusion, treatment with nafamostat mesylate improves the disrupted eGCX structure of skin flap tissue in db/db mice, potentially ameliorating the impaired capillary-to-venous return in the skin flap tissue., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: This study aimed to determine the impact of augmented renal clearance (ARC) on anticoagulation therapy in critically ill patients with coronavirus disease 2019 (COVID-19)., Methods: This retrospective cohort study included adult patients with severe COVID-19 with ARC who had been treated at our hospital between 2020 and 2021. We measured the estimated glomerular filtration rate calculated by the Chronic Kidney Disease Epidemiology Collaboration formula (eGFR CKD-EPI ) every morning, and ARC condition was defined as eGFR CKD-EPI ≥ 130 mL/min/1.73 m 2 . Multivariate regression analysis with Huber-White sandwich estimator was performed to examine the association of unfractionated heparin (UH) dosage between blood test timings with activated partial thromboplastin time (APTT) compared with and without ARC., Results: We identified 38 enrolled patients: seven and 31 in the ARC and non-ARC groups, respectively. In the ARC coexisting condition, a higher dose of UH, which corresponded to the total dose in 24 h from the previous day, was required to achieve the same APTT prolongation, with a significant difference (p < 0.001)., Conclusions: Our study suggests that careful monitoring and consideration of higher UH doses in critically ill patients with COVID-19 is necessary because anticoagulation failure can occur during ARC., Competing Interests: Declaration of competing interest None., (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.)

Background: Knowledge of the proximal edge of the germinal matrix is essential to avoid injuries in the germinal matrix. The previous index such as terminal tendon insertion is not visible from the body surface. The purpose of this study was to examine the relationship between the proximal edge of the germinal matrix and the body surface indexes by ultrasonographic measurements., Methods: All participants underwent X-rays of the hand and were grouped based on the presence or absence of osteoarthritis in the distal interphalangeal (DIP) joint. The distance from the proximal edge of the germinal matrix to dorsal distal interphalangeal crease (parameter D1), and to ''DIP joint extension boundary line'' (parameter D2) were measured using ultrasonography., Results: Thirty middle fingers of 24 patients were enrolled; 13 fingers were in control group and 17 fingers were in Heberden's node group. The average of parameter D1 was 6.17 mm (SD 1.12) in the control group (N = 13), and was 7.04 mm (SD 1.31) in Heberden's node group (N = 17) without significant difference. The DIP joint extension boundary line was not visible in 7 fingers with severe DIP joint osteoarthritis. The average of parameter D2 was 0.00 mm (SD 0.00) in the control group (N = 13), and was 0.04 mm (SD 0.13) in Heberden's node group (N = 10)., Conclusions: We suggest that DIP joint extension boundary line and dorsal distal interphalangeal crease are valuable indexes to predict the proximal edge of the germinal matrix from the body surface. Though the DIP joint extension boundary line was not visible in some cases, once it has been sighted, the line shows where the germinal matrix exactly is., Competing Interests: Declaration of competing interest The authors declare there are no conflicts of interest directly relevant to the content of this article., (Copyright © 2022. Published by Elsevier B.V.)

Background: The present study aimed to evaluate the association between estimated functional remnant pancreatic volume (eFRPV) and postoperative malnutrition after pancreaticoduodenectomy (PD)., Methods: The medical records of 131 patients who underwent PD and preoperative computed tomography were retrospectively reviewed. Onodera's prognostic nutritional index (PNI) was assessed 6-months after PD. Patients with PNI values of at least 45 were included in the non-malnutrition group, while those with values <45 and <40 were included in the mild and severe malnutrition groups, respectively. Associations between eFRPV and postoperative nutritional status were evaluated to identify factors predictive of severe malnutrition after PD., Results: Fifty-three patients (40%) were included in the non-malnutrition group, while 38 (29%) and 40 (31%) were included in the mild and severe malnutrition groups, respectively. Overall survival was significantly shorter in the severe malnutrition group (p < 0.001). The eFRPV was significantly lower in the severe malnutrition group (p = 0.003; Jonckheere-Terpstra trend test, p < 0.001). In the multivariate analysis, eFRPV ≤55.2 mL·HU (odds ratio [OR] = 5.20; p = 0.004), preoperative PNI ≤41.9 (OR = 6.37; p = 0.010), and body mass index ≤19.1 kg/m 2 (OR = 3.43; p = 0.031) were independent predictors of severe malnutrition after PD., Conclusion: The current results indicate that eFRPV may predict low PNI values after PD., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: This study aimed to reveal the geographic accessibility of dental clinics for most municipalities in Japan in 2015 and to explore the association between dental accessibility and dental caries status in 3-year-old children., Methods: We computed the accessibility index and accessibility index rate for the population outside a 1-km radius of dental clinics using a geographic information system. We also used spatial autocorrelation analysis (Moran's I statistic) to examine the spatial clustering patterns of dental accessibility in Japanese municipalities. In addition, we adjusted the prevalence of dental caries for most municipalities using empirical Bayesian estimation. Finally, we applied multiple linear regression to scrutinise the associations between dental caries status, including the prevalence of dental caries and decayed and filled teeth (dft), and dental accessibility, with adjustments made for other sociodemographic variables., Results: The distribution of dental accessibility in Japanese municipalities is relatively unequal. Dental accessibility is decent in the 3 metropolitan areas around Tokyo, Osaka, and Nagoya but poor in the Tohoku and Kyushu regions. In addition, dental accessibility is significantly related to the prevalence of dental caries and dft after adjusting for other sociodemographic variables (P < .005)., Conclusions: This study suggests that dental accessibility is considerably connected to the dental caries status of 3-year-old children after excluding financial burden. Preschool children in areas with poor dental accessibility are likely to have poor dental caries status. We also verified the inequality of dental accessibility amongst Japanese municipalities. For the future development of primary oral health care, more attention should be paid to people with a disadvantage in terms of dental accessibility., Competing Interests: Conflict of Interest None disclosed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Snow sports are a popular recreational activity; however, the incidence of injury of snow sports can be high for skiers and snowboarders. Our hospital receives severe trauma cases from snow resorts and hospitals throughout the region. This study aimed to determine whether the risk of snow sports-related major trauma that requires emergency surgery under general anesthesia varies by the equipment and injury mechanism., Methods: This retrospective cohort study included patients with snow sports trauma referred to Gifu University Hospital, Japan between November 2010 and March 2020. We analyzed the need for emergency operation under general anesthesia within 24 h using Fisher's exact test. We identified 106 patients: (1) 90 in the snowboarders' group and 16 in the skiers' group or (2) 46 in the fall after jumping group (jumping group), 27 in the collide with other people and obstacle group (collision group), and 33 in the fall during gliding group (gliding group)., Results: Snowboarders were nearly twice as likely as skiers to require emergency surgery under general anesthesia (44% vs. 25%; p = 0.236]. No significant associations were found between emergency surgery under general anesthesia and injury mechanism, but half of the patients in the jumping group required emergency surgery., Conclusions: Snowboard as equipment and falls after jumping as a mechanism of injury tended to be associated with emergency surgery under general anesthesia, with no significant differences. In order to provide adequate resources for snow sports trauma, the cause of the patient's injury is strongly related to the urgency of the condition, and transport to a trauma center should be actively considered. Further studies are warranted with respect to the effects of personal protective equipment and skill level., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Ltd.)

Protons (H + ) are essential for most physiological functions in organelles and cells. In this study, we have demonstrated a sulfonated polyaniline (SPA) biotransducer that can modulate the intracellular pH in C6 cells with an applied potential, which is directly coupled with H + to facilitate engineering interactions with physiological processes in the cells. To modulate the pH in the intracellular fluid, we improved the performance of SPA biotransducer by coating of a carbon nanotube (CNT) supportive layer that provides high H + selectivity in the solution and also high H + capacity in the hybrid SPA electrode. The intracellular pH modulation was succeeded by applying a potential difference of less than ±0.6 V. pH modulation in the cells is effected by using the biotransducer, which drives the activity of plasma membrane potential and the flow of molecules through the permeable membrane between cells and culture medium, whereas the poly (3,4-ethylenedioxythiophene) (PEDOT)-based biotransducer, which does not have H + selectivity, was insufficient for modulation. Furthermore, the protonic biotransducer can control the increase/decrease in mitochondria membrane potential, reactive oxygen species and intracellular Ca 2+ concentration. Therefore, the protonic biotransducer provides a new perspective to transfer a H + signal into the cells for modulating the functions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

To clarify the detailed molecular mechanisms underlying the development of asthma, we assessed the potential immune effects of prenatal osteoprotegerin (OPG) inhibition in the pathogenesis of asthma. The effects of OPG deficiency on the development of asthma were evaluated using an ovalbumin-induced asthma model in OPG knockout mice. Histological analysis demonstrated that OPG was mainly detected in airway epithelial cells in wild type mice. After ovalbumin sensitization and challenge, accumulation of inflammatory cells, gene expression of T helper 2-related cytokines and mucus hypersecretion in lung tissues were inhibited by OPG deficiency. Importantly, the serum level of IgE was not increased in OPG KO mice after ovalbumin sensitization and challenge. Based on these findings, OPG knockout mice were protected against methacholine-induced airway hyperresponsiveness. OPG expression is thought to be essential for induction of the allergic immune response in asthma., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to investigate the effectiveness of Diamour®, a newly developed vitrification device, for the ultra-rapid frozen storage of human blastocysts., Materials and Methods: Surplus blastocysts obtained using assisted reproductive technology at our clinic during a 2-year period (2018-2019) were assigned for vitrification with the Diamour® device in 2019 or a comparator device in 2018. We retrospectively compared outcomes (clinical pregnancy rate, abortion rate, live birth rate, and perinatal outcomes) between the two vitrification devices., Results: We obtained 228 blastocysts from 178 patients, and 118 blastocysts were cryopreserved using the Diamour® vitrification device and the other 110 were cryopreserved using a Cryotop®, the comparator device. We found no significant difference between the Diamour®-vitrified and comparator-vitrified blastocysts in clinical pregnancy rate (32.2% vs. 30.9%; p = 0.83), abortion rate (17.0% vs. 9.1%; p = 0.08), and live birth rate (25.4% vs. 26.4%; p = 0.87). The Diamour®-vitrified blastocysts yielded 30 live births, and the comparator-vitrified blastocysts 29. The two devices yielded no significant difference in birth weight (Diamour®: 3049 ± 337 g, comparator: 3008 ± 340 g; p = 0.65) and congenital abnormalities, with just 1 case (cleft lip) noted with Diamour® vitrification (p = 0.33). The devices also showed no significant differences in the incidence of gestational diabetes mellitus, hypertensive disorders of pregnancy, placenta previa, preterm birth, macrosomia, low birth weight, and delivery method., Conclusion: The Diamour® device achieves outcomes similar to those of the currently widely used Cryotop® device for clinical pregnancy with frozen-thawed human blastocysts., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: This retrospective analysis of patients treated with endoscopic endonasal transsphenoidal surgery (ETSS) alone or simultaneous combined surgery investigated imaging features suitable for surgical methods and pitfalls in simultaneous combined surgery for giant pituitary adenoma., Patients and Methods: Ten patients with giant pituitary adenoma treated by ETSS alone or simultaneous combined endoscopic endonasal and transcranial surgery were enrolled. By analyzing tumor imaging features on magnetic resonance imaging (MRI), operative findings and clinical outcomes, we examined types of imaging features suitable for each surgical method., Results: Four patients received ETSS alone and six patients underwent simultaneous combined endonasal and transcranial surgery. Four patients treated by ETSS alone and three patients treated by combined surgery had high resection rates and good outcomes. The remaining three patients with combined surgery achieved partial resection and visual deterioration in one patient. MRI features suitable for ETSS included an enlarged sella, upward tumor extension, and round surface, whereas those for combined surgery included normal/enlarged sella, anterior and/or unilateral tumor extension, and a multilobulated surface. Tumors extending extensively bilaterally or upward and encasing neurovascular structures could not be effectively resected even under combined surgery., Conclusion: Both ETSS alone and simultaneous combined endonasal and transcranial surgery showed good results for giant pituitary adenoma when the surgical methods matched suitable imaging features. Tumors with unilateral or anterior extension and a multilobulated surface were maximally resected without neurological deficit by combined surgery, but tumors showing extensive multi-directional extension and full encasement of neurovascular structures were not effectively resected even with combined surgery., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: We have shown that "Click-to-sense" (CTS) assay based on the visualization of cancer cells by fluorescence probe targeted for acrolein is useful for differentiating between the malignant and benign lesions of the breast. In the present study, we aimed to apply CTS assay to the examination of the simulated surgical margins, being compared with frozen section (FS) analysis., Experimental Design: The simulated surgical margin samples (n = 300) were obtained from 1 to 2 cm distant sites from the tumor margin in the mastectomy specimens of breast cancer patients, and divided into the training (n = 150) and validation (n = 150) set. The samples were subjected to CTS assay, subsequently to FS analysis and finally to permanent section (PS) analysis., Results: Diagnostic accuracy of the CTS assay and FS analysis was evaluated in the examination of the simulated surgical margin status finally determined by the PS analysis. In the training set, sensitivity, specificity, and accuracy was 89.3%, 98.4%, and 96.7% for the CTS assay and 89.3%, 98.4%, and 96.7% for the FS analysis. In the validation set, sensitivity, specificity, and accuracy was 93.3%, 98.3%, and 97.3% for the CTS assay, and 93.3%, 99.2%, and 98.0% for the FS analysis., Conclusions: The CTS assay is as accurate as the FS analysis in the examination of the simulated surgical margins in breast cancer patients, and it seems to have a potential to replace the FS analysis for the intra-operative examination of surgical margins in breast-conserving surgery since it is less labor-intensive and more time-saving than the FS analysis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This research aimed to determine whether patterns of temporal changes in activity levels can indicate postoperative complications following hepatectomy., Methods: Between December 2016 and December 2019, 147 patients wore an accelerometer to measure their physical activity levels after hepatectomy until postoperative day 7. Patterns of changes in activity levels were categorized as follows: upward slope type (n = 88), wherein activity levels gradually increased; bell curve type (n = 13), wherein activity levels initially increased but subsequently decreased; and flat type (n = 46), wherein there was no apparent increase in activity levels. Patient characteristics and postoperative complications were compared for each group., Results: Postoperative complications occurred in 4.5% of patients in the upward slope group, in 76.9% in the bell curve group, and in 65.2% in the flat group (p < 0.001). Surgical site infections (SSI), refractory pleural effusion, and ascites were more common in the bell curve group, while pneumonia was only observed in the flat group., Conclusion: SSI, pleural effusion, and ascites should be considered when previously increasing activity levels decline during the postoperative period. In addition, there is a high risk of SSI and pneumonia when activity levels do not increase at all after surgery., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Cancer cells in intraoperative peritoneal washings (PW) indicate increased peritoneal recurrence. Detection of CEA or CK20 genes indicates poor prognosis. We assessed long-term prognosis of patients with amplification of cancer-related genes in PW obtained intraoperatively during curative gastric cancer surgery., Methods: PW was collected before and immediately after curative gastrectomy. CEA, CK20, TFF1, MUC2, and FABP1-mRNA were selected as marker genes for reverse transcription polymerase chain reaction. Peritoneal recurrence-free survival (PRFS) and overall survival (OS) after >7-year follow-up were examined using the Kaplan-Meier method., Results: Of 138 patients who underwent gastrectomy with negative cytological findings at laparotomy, 80 patients showed negative cancer-related gene amplification in preoperative PW. Fifty-eight patients were excluded due to positive gene amplification, which suggested presence of preoperative peritoneal cancer cells. The 80 patients had mRNA amplification in PW after surgery. Amplification of multiple and single cancer-related marker genes was observed in 38 and 21 patients; 21 cases had marker-negative results. Five-year PRFS was 69.1%, 95.2%, and 100% in multi-marker-positive, single marker-positive, and marker-negative cases, respectively. Multi-marker-positive patients had significantly worse PRFS than the other groups (p < 0.05). Multivariate analysis in the Cox proportional hazards model identified multi-marker-positivity as an independent prognostic factor for PRFS (hazard ratio, 7.6; 95% confidence interval, 1.07-62.63; p = 0.046), and multi-marker-positive patients had significantly worse OS than other groups (p < 0.01)., Conclusion: Multi-marker cancer-related gene amplification in PW is associated with worse prognosis in PRFS and OS even after a long follow-up; PRFS can be stratified by the number of genes amplified., Competing Interests: Declaration of competing interest The authors have no commercial conflicts of interest related to this study., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Rutin is a natural flavonoid glycoside found in several vegetables and fruits such as buckwheat and onion. Rutin has a range of pharmacological effects that include anti-oxidant, anti-inflammation, anti-bacterial, and anti-cancer activities. α-glucosyl-rutin (AGR) is a derivative of rutin with increased water solubility that is used in cosmetics and foods. However, the effects of AGR on cellular responses have not been clarified, especially in stem cells. Induced pluripotent stem cells (iPSCs) show high proliferative activity and pluripotency; however, regulation of molecular machinery such as cell cycle, metabolism, and DNA repair differs between iPSCs and somatic cells. Here, we compared the effects of AGR on iPSCs and differentiated cells (fibroblasts and skin keratinocytes). AGR-treated iPSCs exhibited increased cell viability. RNA sequencing and reverse transcriptase PCR analysis revealed that AGR induced expression of immediate early genes (IEGs) and differentiation-related genes in iPSCs. Our results suggest that AGR may activate differentiation signals mediated by IEG responses in iPSCs, resulting in altered metabolic activity and increased cell viability., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P < 0.05). Serum interleukin-1β was increased but to a lesser extent in response to LPS injection in rAT-treated mice than in control mice. Lectin staining and ultrastructural studies showed a notable attenuation of injury to the endothelial glycocalyx after rAT treatment. Microarray analysis further showed an up-regulation of gene sets corresponding to DNA repair, such as genes involved in DNA helicase activity, regulation of telomere maintenance, DNA-dependent ATPase activity, and ciliary plasm, after rAT treatment. Thus, rAT treatment may promote DNA repair, attenuate inflammation, and promote ciliogenesis, thereby attenuating the acute respiratory distress syndrome caused by endothelial injury., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

We aimed to validate the cosmetic utility of addition of nipple-areola recentralization (NAR) to rotation flap according to nipple tumor distance (NTD) as a volume displacement technique after breast conserving surgery (BCS) for lower-outer and upper-inner breast cancers. Twenty breast cancer patients who had been treated with rotation flap with (Group 1; n = 6) or without (Group 2; n = 14) NAR after BCS for lower-outer or upper-inner located tumors, and those who had undergone BCS without oncoplastic surgical technique for tumors in the same area (Control group; n = 43), were retrospectively investigated. Cosmetic outcome was evaluated using Harvard scale and/or BCCT.core. As a result, the ratio of patients categorized as excellent/good was 83% in Group 1 and 93% in Group 2, respectively, and there was no significant difference between them (P = 0.521). In addition, Group 1 + 2 showed a significantly higher ratio of patients classified as excellent/good than the control group (90% vs. 56%; P = 0.009). After adjustment of clinical background parameters using propensity score matching analysis between Group 1 + 2 and the control group, 12 pairs with similar background factors were matched. Among them, Group 1 + 2 showed a higher ratio of patients categorized as excellent/good than the control group (92% vs. 42%; P = 0.034). In conclusion, addition of NAR to rotation technique according to NTD may enable us to perform a volume displacement after BCS for lower-outer or upper-inner located tumors irrespective of NTD without sacrificing postoperative breast appearance., Competing Interests: Declaration of Competing Interest KM received research funding from Meito Sangyo for work performed outside of the current study; other authors declare no conflicts of interest associated with this manuscript., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Nonalcoholic fatty liver disease (NAFLD) is a late complication of pancreaticoduodenectomy (PD). However, this complication is difficult to predict preoperatively. This study aimed to assess the association between NAFLD and preoperative computed tomography (CT) findings., Methods: Medical records of 112 patients who had undergone PD and had CT scans preoperatively and 6 months postoperatively were retrospectively reviewed. We evaluated several CT findings, including the CT attenuation value of the remnant pancreas, remnant pancreatic volume (RPV), and the estimated functional remnant pancreatic volume (eFRPV) on preoperative CT. The variables, including the CT findings and histopathological findings, were compared between the patients with and without NAFLD after PD., Results: The NAFLD group included 21 patients (18.8%). The CT attenuation value of the remnant pancreas was correlated with the pancreatic acinar cell density (r = 0.537), and was lower in the NAFLD group than in the non-NAFLD group (p = 0.007). The eFRPV was lower in the NAFLD group than in the non-NAFLD group (p = 0.002). An eFRPV ≤47 mL·HU was an independent predictive factor for NAFLD (p = 0.007; odds ratio: 6.73; 95% confidence interval: 1.70-26.70)., Conclusion: The eFRPV can be used to preoperatively predict NAFLD after PD., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Podocytes are highly specialized cells within the glomerulus that are essential for ultrafiltration. The slit diaphragm between the foot processes of podocytes functions as a final filtration barrier to prevent serum protein leakage into urine. The slit-diaphragm consists mainly of Nephrin and Neph1, and localization of these backbone proteins is essential to maintaining the integrity of the glomerular filtration barrier. However, the mechanisms that regulate the localization of these backbone proteins have remained elusive. Here, we focused on the role of membrane-associated guanylate kinase inverted 2 (MAGI-2) in order to investigate mechanisms that orchestrate localization of slit-diaphragm backbone proteins. MAGI-2 downregulation coincided with a reduced expression of slit-diaphragm backbone proteins in human kidneys glomerular disease such as focal segmental glomerulosclerosis or IgA nephropathy. Podocyte-specific deficiency of MAGI-2 in mice abrogated localization of Nephrin and Neph1 independently of other scaffold proteins. Although a deficiency of zonula occuldens-1 downregulated the endogenous Neph1 expression, MAGI-2 recovered Neph1 expression at the cellular edge in cultured podocytes. Additionally, overexpression of MAGI-2 preserved Nephrin localization to intercellular junctions. Co-immunoprecipitation and pull-down assays also revealed the importance of the PDZ domains of MAGI-2 for the interaction between MAGI-2 and slit diaphragm backbone proteins in podocytes. Thus, localization and stabilization of Nephrin and Neph1 in intercellular junctions is regulated mainly via the PDZ domains of MAGI-2 together with other slit-diaphragm scaffold proteins. Hence, these findings may elucidate a mechanism by which the backbone proteins are maintained., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the accuracy of pre-percutaneous coronary intervention (PCI) predicted nonhyperemic pressure ratios (NHPRs) with actual post-PCI NHPRs and to assess the efficacy of PCI strategy using pre-PCI NHPR pullback., Background: Predicting the functional results of PCI is feasible using pre-PCI longitudinal vessel interrogation with the instantaneous wave-free ratio (iFR), a pressure-based, adenosine-free NHPR. However, the reliability of novel NHPRs (resting full-cycle ratio [RFR] and diastolic pressure ratio [dPR]) for this purpose remains uncertain., Methods: In this prospective, multicenter, randomized controlled trial, vessels were randomly assigned to receive pre-PCI iFR, RFR, or dPR pullback (50 vessels each). The pre-PCI predicted NHPRs were compared with actual NHPRs after contemporary PCI using intravascular imaging. The number and the total length of treated lesions were compared between NHPR pullback-guided and angiography-guided strategies., Results: The predicted NHPRs were strongly correlated with actual NHPRs: iFR, r = 0.83 (95% confidence interval: 0.72 to 0.90; p < 0.001); RFR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001), and dPR, r = 0.84 (95% confidence interval: 0.73 to 0.91; p < 0.001). The number and the total length of treated lesions were lower with the NHPR pullback strategy than with the angiography-guided strategy, leading to physiological improvement., Conclusions: Predicting functional PCI results on the basis of pre-procedural RFR and dPR pullbacks yields similar results to iFR. Compared with an angiography-guided strategy, a pullback-guided PCI strategy with any of the 3 NHPRs reduced the number and the total length of treated lesions. (Study to Examine Correlation Between Predictive Value and Post PCI Value of iFR, RFR and dPR; UMIN000033534)., Competing Interests: Author Relationship With Industry Dr. Escaned has provided consulting and speaking services at educational events for Abbott, Boston Scientific, and Philips Healthcare. Dr. Mizukami has received consulting fees from HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020. Published by Elsevier Inc.)

Background and Aims: Lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor. However, Lp(a) levels are lower in patients with chronic liver disease than in healthy subjects. Furthermore, Lp(a) levels decrease as residual liver function declines. Although non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), increases the risk of cardiovascular diseases, the relationship between serum Lp(a) level and NASH is unknown. Thus, we examined the relationship between serum Lp(a) levels and biopsy-proved NAFLD and clarified the significance of Lp(a) measurements for cardiovascular disease screening in patients with NAFLD., Methods: A total of 176 patients with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. The relationship between serum Lp(a) levels and NAFLD was analyzed., Results: Serum Lp(a) levels in advanced fibrosis (stage 3-4) were lower than those in non-advanced fibrosis (stage 0-2) (p < 0.05). After adjustment for age, sex, body mass index, alanine aminotransferase (ALT), creatinine (Cre), HbA 1c level, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the use of lipid-lowering agents, the significant inverse association between advanced fibrosis and serum Lp(a) levels remained (p < 0.01). Although the Lp(a) level was inversely associated with an NAFLD Activity Score (NAS) of 5-8, there was no significant association between Lp(a) levels and NAS adjusted for age, sex, body mass index, ALT, Cre, HbA 1c level, HDL-C, LDL-C, TG, and the use of lipid-lowering agents., Conclusions: Advanced NASH is associated with low serum Lp(a) levels; therefore, Lp(a) levels may not be useful in evaluating cardiovascular risk., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) causes hospital- and community-acquired infections. It is not clear whether genetic characteristics of the bacteria contribute to disease pathogenesis in MRSA infection. We hypothesized that whole genome analysis of MRSA strains could reveal the key gene loci and/or the gene mutations that affect clinical manifestations of MRSA infection., Methods: Whole genome sequences (WGS) of MRSA of 154 strains were analyzed with respect to clinical manifestations and data. Further, we evaluated the association between clinical manifestations in MRSA infection and genomic information., Results: WGS revealed gene mutations that correlated with clinical manifestations of MRSA infection. Moreover, 12 mutations were selected as important mutations by Random Forest analysis. Cluster analysis revealed strains associated with a high frequency of bloodstream infection (BSI). Twenty seven out of 34 strains in this cluster caused BSI. These strains were all positive for collagen adhesion gene (cna) and have mutations in the locus, those were selected by Random Forest analysis. Univariate and multivariate analysis revealed that these gene mutations were the predictor for the incidence of BSI. Interestingly, mutant CNA protein showed lower attachment ability to collagen, suggesting that the mutant protein might contribute to the dissemination of bacteria., Conclusions: These findings suggest that the bacterial genotype affects the clinical characteristics of MRSA infection., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Although we previously reported the fasting 13 C-glucose breath test (FGBT) was useful for the diagnosis of hepatic insulin resistance (IR), there has been no report in an actual clinical setting. We therefore performed the FGBT in patients with heart disease to assess the difference in the diagnostic ability of HIR between the FGBT and HOMA-IR; we also assessed the relationship between the FGBT and known cardiovascular risk factors., Methods: Two hundred patients (100 with ischemic heart disease [IHD], 50 with non-ischemic heart disease [NIHD], and 50 with non-cardiac lifestyle-related disease [NCD]) participated in this study. The data of 40 healthy volunteers [HV] was obtained in our previous study. We evaluated the 13 C excretion rate at 120 min (C 120 ) as the indicator of hepatic IR in the FGBT., Results: The value of C 120 in each disease group was significantly lower than in HV, but the HOMA-IR in the IHD and NCD groups was not significantly different from that in HV. The value of C 120 significantly correlated with known cardiovascular risk factors., Conclusions: These results indicated the FGBT is more sensitive than HOMA-IR for evaluating hepatic IR as a cardiovascular risk factor and is likely useful for managing patients to prevent cardiovascular disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Although standard treatment for heart failure (HF) has been established, it remains difficult to relieve HF-associated symptoms in some patients. Kampo medicines have been used to treat various diseases; however, it remains unclear whether they are effective in HF patients. We therefore performed a prospective, randomized, controlled trial to investigate whether Mokuboito, a Kampo medicine, affected symptoms and other parameters in hospitalized patients with acute decompensated HF (ADHF), as compared to standard therapy alone., Methods: Forty patients were allocated randomly to Group S (standard therapy alone) or Group M (oral administration of Mokuboito plus standard therapy). The primary outcome was changes in global clinical status based on a visual analog scale (VAS) from baseline at day 10 or discharge if earlier., Results: The decrease in VAS score was significantly greater in Group M than Group S (p=0.001). Although there were no differences between the groups in changes in the secondary endpoints of body weight, peripheral edema, biochemical and echocardiographic parameters, left ventricular end-diastolic diameter, and serum total bilirubin levels were significantly reduced in Group M (p=0.038; 0.002, respectively) but not in Group S, implying that Mokuboito might attenuate organ congestion and cardiac preload., Conclusions: Oral administration of Mokuboito significantly improved ADHF-related symptoms. Our observations might provide the basis for a novel therapeutic strategy in hospitalized patients with ADHF., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Serine proteases have important roles in skin barrier function and desquamation, and the aberrant expression or the dysfunction of serine proteases is associated with the pathogenesis of skin diseases. Serine protease activities are tightly regulated by serine proteases such as kallikrein-related peptidases (KLKs) and serine protease inhibitors such as lympho-epithelial Kazal-type related inhibitor (LEKTI). For a better understating of diseases' pathogenesis, the regulation mechanism of serine proteases and the inhibitors' expression in epidermal keratinocytes must be clarified., Objectives: To investigate the effects of the cytokines on the expression of LEKTI in epidermal keratinocytes., Methods: Normal human epidermal keratinocytes (NHEKs) were stimulated with panels of inflammatory cytokines. The expression of serine protease inhibitors was analyzed using quantitative real-time PCR and ELISA. LEKTI expression in normal human skin and lesions from psoriasis or atopic dermatitis (AD) were analyzed by immunohistochemically and tape-stripping. Trypsin- and chymotrypsin-like serine protease activities in culture supernatants were measured by using specific substrates., Results: TNF-α and IL-17A significantly induced the expression of LEKTI in NHEKs. The immunohistochemical and tape-stripping analysis revealed that psoriatic skin lesions had higher LEKTI expression compared to normal skin and AD lesions. Trypsin- and chymotrypsin-like protease activities in the culture media were upregulated 3-5 days later but attenuated 6-7 days later period by these cytokines., Conclusions: In epidermal keratinocytes, the Th1&Th17 cytokines TNF-α and IL-17A induce the expression of serine protease inhibitor LEKTI, and it might occur to suppress the increase in the serine protease activities under inflammation., (Copyright © 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Acetabular dysplasia of the hip following open reduction can complicate the treatment of developmental dysplasia of the hip (DDH). The purposes of this retrospective study were to investigate the long-term results of open reduction performed via an extensive anterolateral approach for DDH after walking age and to predict acetabular development using postoperative radiographs and arthrograms., Methods: From 1973 to 2001, we performed open reduction for 131 hips in 119 pediatric patients with DDH after failed closed reduction. Of these, 85 hips of 73 patients who underwent arthrography at 5 years old were followed-up radiologically until skeletal maturity. Mean age at the time of surgery was 17 ± 4.6 months (range, 10-33 months), and mean age at final survey was 19 ± 5.7 years (range, 14-33 years). Mean follow-up time was 17.7 ± 5.8 years (range, 13-32 years). Groups with satisfactory outcomes (66 hips) and unsatisfactory outcomes (19 hips) according to the Severin classification were compared. Factors predicting acetabular development were identified using univariate and multiple logistic analyses., Results: Univariate analysis showed a significant between-group difference in acetabular index (AI) at 2 months postoperatively, and in center-edge (CE) angle, cartilaginous AI (CAI), and cartilaginous CE angle at 5 years old (p < 0.05 each). In multiple logistic regression analysis, CAI at 5 years old represented a predictor of acetabular development after open reduction for DDH (odds ratio, 1.81; 95% confidence interval (CI), 1.04-3.13; p < 0.05). Area under the receiver operating characteristic curve for CAI at 5 years old was 0.93 (95%CI, 0.85-1.0), and the optimal cut-off was 10° (81.8% sensitivity, 92% specificity)., Conclusions: A CAI ≥10° on hip arthrograms at 5 years old may offer a useful indicator of the need for corrective surgery following open reduction after walking age., (Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Introduction: New treatments to inhibit neointimal formation after percutaneous transluminal angioplasty (PTA) are needed for patients undergoing chronic hemodialysis (HD). We compared the efficacy and safety of AMG0102, a balloon catheter containing nuclear factor κB (NF-κB) decoy oligodeoxynucleotide (ODN) with the PTA balloon catheter (control group) for arteriovenous fistula (AVF) stenosis., Methods: In total, 175 patients (age ≥20 years, undergoing HD, with venous stenosis at the anastomotic region) were registered in this prospective open-label, randomized study. Patients were followed postoperatively for 36 weeks. The duration of primary patency on the targeted venous stenosis site (primary endpoint) was estimated by the Kaplan-Meier method., Results: A lower restenosis risk was observed for the AMG0102 group, but it was not statistically significant (stratified log-rank test P  = 0.250, hazard ratio [HR] 0.774; 95% confidence interval [CI]: 0.500-1.198). The median duration of primary patency was 245 days and 172 days in the AMG0102 and control groups, respectively. After stratification based on the status of diabetes complications, the HR was 0.666 (95% CI: 0.366-1.212; P  = 0.183) and the median duration of primary patency was prolonged by 108 days in the AMG0102 group with diabetes complications (245 days) compared with the control group (137 days). Adverse event (AE) incidence up to 36 postoperative weeks did not differ between groups. Four device failures occurred in 3 patients (AMG0102 group), but none resulted in AEs., Conclusion: Further modifications to enhance NF-κB decoy ODN uptake and efficacy are necessary to show its clinical utility for AVF stenosis in chronic HD.

Background: The efficacy of physical therapy for patients with lumbar spinal stenosis (LSS) has been reported only for the short term, and few reports have compared outcomes of surgical treatment with nonsurgical treatment after physical therapy. The purpose of this study was to assess 2-year outcomes of LSS patients treated with surgery or under follow-up observation after physical therapy for 6 weeks., Methods: Patients presenting with neurogenic claudication, radiologically-confirmed central LSS affecting both legs and refractory symptoms to pharmacotherapy of more than 3 months were enrolled. Patients were treated with manual therapy, stretching and strengthening exercises, and body weight-supported treadmill walking once a week for 6 weeks. Clinical outcomes were measured using the Zurich Claudication Questionnaire (ZCQ), visual analog scale of low back pain, leg pain, and numbness, the Japanese Orthopedic Association Back Pain Evaluation Questionnaire and the SF-36. Two years after physical therapy, patients were classified into the observation group (Group I) or the surgery group (Group II), whose patients failed to respond to physical therapy and wanted to undergo surgery., Results: Thirty-eight patients were enrolled; 28 had complete data at 2 years: 21 and 7 in Groups I and II, respectively. Group II had a higher body mass index (BMI) than Group I. There were no significant differences in clinical outcomes at baseline. Six weeks after physical therapy, Group I had significantly better outcomes for symptom severity and physical function on the ZCQ subscales, physical functioning and bodily pain on the SF-36 subscales. These outcomes in Group I were maintained or improved and did not differ significantly between groups at 2-years. However, the physical function on the ZCQ subscales was improved in Group II more than those in Group I (mean difference -0.6; 95% CI: -1.2 to -0.03, P < 0.05) at 2 years., Conclusions: At 2 years, the outcomes except for the change in physical function score in the ZCQ subscale did not differ significantly between patients who had undergone surgery and those who avoided surgery., (Copyright © 2018. Published by Elsevier B.V.)

The pathologic feature of intraductal papillomas is defined as a papillary structure composed of a fibrovascular stromal core lined by luminal epithelial cells and myoepithelial cells. We used droplet digital PCR for the mutational analysis of AKT1 (E17K) and PIK3CA (H1047R, E542K, and E545K) in 60 papillomas. AKT1 and PIK3CA mutations were detected in 12 (20%) and 17 (28%) of the papillomas, respectively. In five tumors harboring mutations, mutational analysis of AKT1 or PIK3CA was performed separately using luminal epithelial cells and myoepithelial cells sorted using anti-cytokeratin 19 antibody and anti-α smooth muscle actin antibody. The two types of cells from a given papilloma had the identical mutation. Three patients with the PIK3CA mutation-positive papilloma developed breast cancers at the resection site of the papilloma, but none of these subsequent breast cancers had the PIK3CA mutation. These results indicate that a papilloma stems from a bipotent progenitor cell that contains the AKT1 or PIK3CA mutation and proliferates and differentiates to form the papilloma. Papilloma can be a risk factor for developing breast cancer but is unlikely to be its obligate precursor., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Recent studies suggest that trimethylamine N-oxide (TMAO) is associated with the development of chronic kidney disease and heart failure. In this study, we investigated the importance of organic cation transporters (OCTs) in the clearance and tissue distribution of TMAO. The low-affinity and high-capacity transport of TMAO by mouse and human OCT1 and OCT2 was observed. Uptake and efflux of TMAO by the mouse hepatocytes as well as TMAO uptake into mouse kidney slices were significantly decreased by the addition of tetraethylammonium or Oct1/2 double knockout (dKO). Plasma concentrations of endogenous TMAO and TMAO-d9 given by intravenous infusion was 2-fold higher in Oct1/2 dKO than in wild-type mice due to significant decrease in its renal clearance. These results indicate that OCTs have a crucial role in the kinetics of TMAO in mice. In human, however, the OCT2-mediated tubular secretion in the urinary excretion of TMAO was insignificant because the renal clearance of TMAO was similar to that of creatinine in both young and elderly subjects, suggesting the species difference in the urinary excretion mechanisms of TMAO between mouse and human., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The sodium taurocholate co-transporting polypeptide (NTCP) is the main target of most hepatitis B virus (HBV) specific entry inhibitors. Unfortunately, these agents also block NTCP transport of bile acids into hepatocytes, and thus have the potential to cause adverse effects. We aimed to identify small molecules that inhibit HBV entry while maintaining NTCP transporter function., Methods: We characterized a series of cyclosporine (CsA) derivatives for their anti-HBV activity and NTCP binding specificity using HepG2 cells overexpressing NTCP and primary human hepatocytes. The four most potent derivatives were tested for their capacity to prevent HBV entry, but maintain NTCP transporter function. Their antiviral activity against different HBV genotypes was analysed., Results: We identified several CsA derivatives that inhibited HBV infection with a sub-micromolar IC 50 . Among them, SCY446 and SCY450 showed low activity against calcineurin (CN) and cyclophilins (CyPs), two major CsA cellular targets. This suggested that instead, these compounds interacted directly with NTCP to inhibit viral attachment to host cells, and have no immunosuppressive function. Importantly, we found that SCY450 and SCY995 did not impair the NTCP-dependent uptake of bile acids, and inhibited multiple HBV genotypes including a clinically relevant nucleoside analog-resistant HBV isolate., Conclusions: This is the first example of small molecule selective inhibition of HBV entry with no decrease in NTCP transporter activity. It suggests that the anti-HBV activity can be functionally separated from bile acid transport. These broadly active anti-HBV molecules are potential candidates for developing new drugs with fewer adverse effects., Lay Summary: In this study, we identified new compounds that selectively inhibited hepatitis B virus (HBV) entry, and did not impair bile acid uptake. Our evidence offers a new strategy for developing anti-HBV drugs with fewer side effects., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Treatment of hip dislocation diagnosed after walking age is often difficult. We report the surgical treatment of these patients by open reduction with a soft tissue surgical procedure without osteotomy., Methods: Thirty-eight children (43 hips) diagnosed with complete dislocation of the hip after walking age were included in this study. We radiographically analysed postoperative hip joint development up to 6 years of age. To assess the predictors of acetabular development, we evaluated the radiographs, using an acetabular index of ≤35° and a centre-edge angle of >5° at 6 years of age as satisfactory outcomes, and evaluated the advance of acetabular development over time., Results: AI on the affected side was improved with time after open reduction. The diameter of the capital femoral ossific nucleus on the affected side was almost equivalent to that on the unaffected side at 6-12 months after surgery, after which the centre-edge angle improved gradually from one year after surgery. We compared hips classified as satisfactory to unsatisfactory at 6 years of age, and found that the centre-edge angle at one year after open reduction was significantly associated with acetabular development (P = 0.044). The cut-off value was -2° with sensitivity of 0.909 and specificity of 0.677., Conclusions: The results of the current study suggest that initial development of the capital femoral ossific nucleus after open reduction would be followed by improved joint congruity, and that this would facilitate acetabular development. The centre-edge angle at one year after surgery could be regarded as a potential predictor of acetabular development in open reduction surgery for late-diagnosed developmental dysplasia of the hip cases., (Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma., Patients and Methods: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes., Results: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001)., Conclusion: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Epstein-Barr virus (EBV)-associated T/natural killer (NK)-lymphoproliferative disorders (LPDs) include hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). The pathomechanisms of these diseases are still unclear., Objective: To understand the inflammatory process, we examined EBV reactivation markers, BZLF1 and BDRF1 mRNA in the tissue and blood from patients with EBV-associated T/NK-LPDs., Methods: Sixty-four patients with EBV-associated LPDs and epithelial neoplasms, and EBV+ cell line cells were studied. DNase-treated and resistant EBV DNA load in blood and cell culture supernatants were calculated. An EBV reactivation signal was analyzed in the tissue, blood and cell line cells., Results: In the tissue, BZLF1 mRNA was detected in 5 of 6 (83%) samples of EBV+ epithelial neoplasms, 16 of 21 (76%) of EBV+ lymphomas, and 5 of 15 (33%) of systemic HV and/or HMB, but negative in all 15 patients with classical HV. In the blood, BZLF1 mRNA was detected in only one of 19 (5.3%) samples of EBV-associated T/NK-LPDs. A down-stream reactivation signal, BDRF1 mRNA was expressed in all 6 samples of EBV+ epithelial neoplasms, but it was positive in only one of 15 (6.7%) samples from systemic HV and HMB in the tissue. EBV+ T/NK-cell line cells treated with phorbol 12-myristate 13-acetate produced BZLF1 and BDRF1 mRNA, and encapsidated EBV DNA was detected in the culture supernatants of cell line cells., Conclusion: Stimulation-induced EBV reactivation occurred both in vivo and in vitro, but it was almost abortive in vivo. Reactivation-related EBV antigens might be responsible for induction of systemic HV and HMB., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Echocardiographic parameters to predict pulmonary capillary wedge pressure (PCWP) in mitral regurgitation (MR) are not yet elucidated. We reported that PCWP could be accurately estimated by novel KT index which is defined as log10[left atrial (LA) emptying function (EF)/LA volume]. We examined the usefulness of the KT index as a predictor of PCWP in primary and secondary MR with sinus rhythm and also MR with atrial fibrillation., Methods: LA dimension, strain, volume, EF, and E/e' were measured in moderate to severe MR with sinus rhythm (n=58, age: 67±8 years) and MR with atrial fibrillation (n=24, age: 69±11 years) just before catheterization and in normal subjects (n=26, age: 67±11 years) using speckle tracking echocardiography. MR with sinus rhythm was divided into primary MR (n=27) and secondary MR (n=31). The estimated PCWP (ePCWP) was calculated as 10.8-12.4×KT index., Results: There was a correlation between PCWP and LA dimension, E/e', minimum LA volume index, active LAEF, total LAEF, or LA strain (r=0.32, r=0.31, r=0.55, r=-0.61, r=-0.51, and r=-0.50, respectively, p<0.05). The better correlation was found between PCWP and ePCWP in MR including both primary and secondary MR and also MR with atrial fibrillation (r=0.70, r=0.67, and r=0.58, respectively, p<0.01). Multiple regression analysis revealed that ePCWP was an independent predictor of PCWP in MR. The ePCWP demonstrated good diagnostic accuracy (area under the curve of 0.86) and sensitivity (81%) and specificity (71%) to predict elevated PCWP >15mmHg using a cut-off of 16mmHg., Conclusion: The ePCWP was the reliable echocardiographic parameter to predict PCWP in primary and secondary MR and might also be useful in MR with atrial fibrillation. The ePCWP may have an incremental value in a clinical setting., (Copyright © 2015. Published by Elsevier Ltd.)