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Background: Menopause, a dramatical estrogen-deficient condition, is considered the most significant milestone in women’s health. Purpose: To investigate the metabolite changes attributed to estrogen deficiency using random forest (RF)-based machine learning (ML) modeling strategy in ovariectomized (OVX) mice as well as determine the clinical relevance of selected metabolites in older women. Methods and results: Untargeted and targeted metabolomic analyses revealed that metabolites related to TCA cycle, sphingolipids, phospholipids, fatty acids, and amino acids, were significantly changed in the plasma and/or muscle of OVX mice. Subsequent ML classifiers based on RF algorithm selected alpha-ketoglutarate (AKG), arginine, carnosine, ceramide C24, phosphatidylcholine (PC) aa C36:6, and PC ae C42:3 in plasma as well as PC aa 34:1, PC aa C34:3, PC aa C36:5, PC aa C32:1, PC aa C36:2, and sphingosine in muscle as top featured metabolites that differentiate the OVX mice from the sham-operated group. When circulating levels of AKG, arginine, and carnosine, which showed the most significant changes in OVX mice blood, were measured in postmenopausal women, higher plasma AKG levels were associated with lower bone mass, weak grip strength, poor physical performance, and increased frailty risk. Conclusions: Metabolomics- and ML-based methods identified the key metabolites of blood and muscle that were significantly changed after ovariectomy in mice, and the clinical implication of several metabolites was investigated by looking at their correlation with body composition and frailty-related parameters in postmenopausal women. These findings provide crucial context for understanding the diverse physiological alterations caused by estrogen deficiency in women.

AbstractThe eBlock37 is a subscale electrically heated and heat-pipe-cooled prototype of a fast spectrum microreactor that is under development at Los Alamos National Laboratory. The prototype consists of an electrically heated core and gas-cooled heat exchanger. These subassemblies, both built from 316 L stainless steel, are thermally linked by an array of 37 sodium heat pipes that transfer a nominal 100 kW from the core at 700°C. An overarching objective of this effort is to overcome challenges associated with core block and heat exchanger manufacture and integration of high-temperature heat pipes into the assembly. Components that would be safety critical in an actual reactor, such as the heat pipe wicks, are being built under a Nuclear Quality Assurance 1 quality program. The completed assembly is intended for non-nuclear electrically heated testing, which will be conducted at a demonstration facility at Idaho National Laboratory. This paper provides a top-level summary of the efforts to date.

Metastatic breast cancer is an extremely complex disease with limited treatment options due to the lack of information about the major characteristics of metastatic disease. There is an urgent need, therefore, to understand the changes in cellular complexity and dynamics that occur during metastatic progression. In the current study, we analyzed the cellular and molecular differences between primary tumors and paired lung metastases using a syngeneic p53-null mammary tumor model of basal-like breast cancer. Distinct subpopulations driven by the Wnt- and/or STAT3 signaling pathways were detected in vivo using a lentiviral Wnt- and STAT3 signaling reporter system. A significant increase in the overlapping populations driven by both the Wnt- and STAT3 signaling pathways was observed in the lung metastases as compared to the primary tumors. Furthermore, the overlapping populations showed a higher metastatic potential relative to the other populations and pharmacological inhibition of both signaling pathways was shown to markedly reduce the metastatic lesions in established lung metastases. An analysis of the unique molecular features of the lung metastases revealed a significant association with immune response signatures. Specifically, Foxp3 gene expression was markedly increased and elevated levels of Foxp3?+?Treg cells were detected in close proximity to lung metastases. Collectively, these studies illustrate the importance of analyzing intratumoral heterogeneity, changes in population dynamics, and the immune microenvironment during metastatic progression.

Background and Aims: This study was designed to analyze the feasibility of laparoscopic right posterior sectionectomy compared to laparoscopic right hemihepatectomy in patients with hepatocellular carcinoma located in the posterior segments.Material and Methods: The study included patients who underwent either laparoscopic right posterior sectionectomy or laparoscopic right hemihepatectomy for hepatocellular carcinoma located in segment 6 or 7 from January 2009 to December 2016 at Samsung Medical Center. After 1:1 propensity score matching, patient baseline characteristics and operative and postoperative outcomes were compared between the two groups. Disease-free survival and overall survival were compared using Kaplan–Meier log-rank test.Results: Among 61 patients with laparoscopic right posterior sectionectomy and 37 patients with laparoscopic right hemihepatectomy, 30 patients from each group were analyzed after propensity score matching. After matching, baseline characteristics of the two groups were similar including tumor size (3.4 ± 1.2 cm in laparoscopic right posterior sectionectomy vs 3.7 ± 2.1 cm in laparoscopic right hemihepatectomy, P = 0.483); differences were significant before matching (3.1 ± 1.3 cm in laparoscopic right posterior sectionectomy vs 4.3 ± 2.7 cm in laparoscopic right hemihepatectomy, P = 0.035). No significant differences were observed in operative and postoperative data except for free margin size (1.04 ± 0.71 cm in laparoscopic right posterior sectionectomy vs 2.95 ± 1.75 cm in laparoscopic right hemihepatectomy, P < 0.001). Disease-free survival (5-year survival: 38.0% in laparoscopic right posterior sectionectomy vs 47.0% in laparoscopic right hemihepatectomy, P = 0.510) and overall survival (5-year survival: 92.7% in laparoscopic right posterior sectionectomy vs 89.6% in laparoscopic right hemihepatectomy, P = 0.593) did not differ between the groups based on Kaplan–Meier log-rank test.Conclusion: For hepatocellular carcinoma in the posterior segments, laparoscopic right posterior sectionectomy was feasible compared to laparoscopic right hemihepatectomy when performed by experienced laparoscopic surgeons.

The incidence of acute kidney injury (AKI) and its impact on chronic kidney disease (CKD) following pediatric nonkidney solid organ transplantation is unknown. We aimed to determine the incidence of AKIand CKDand examine their relationship among children who received a heart, lung, liver, or multiorgan transplant at the Hospital for Sick Children between 2002 and 2011. AKIwas assessed in the first year posttransplant. Among 303 children, perioperative AKI(within the first week) occurred in 67% of children, and AKIafter the first week occurred in 36%, with the highest incidence among lung and multiorgan recipients. Twenty‐three children (8%) developed CKDafter a median follow‐up of 3.4 years. Less than 5 children developed end‐stage renal disease, all within 65 days posttransplant. Those with 1 AKIepisode by 3 months posttransplant had significantly greater risk for developing CKDafter adjusting for age, sex, and estimated glomerular filtration rate at transplant (hazard ratio: 2.77, 95% confidence interval, 1.13‐6.80, Ptrend = .008). AKIis common in the first year posttransplant and associated with significantly greater risk of developing CKD. Close monitoring for kidney disease may allow for earlier implementation of kidney‐sparing strategies to decrease risk for progression to CKD. In an observational cohort study of 303 children after heart, lung, liver, or multiorgan transplantation, acute kidney injury occurs in approximately one‐third of children in the first year posttransplant and is associated with significantly greater risk of developing chronic kidney disease.

Manic episodes are one of the major diagnostic symptoms in a spectrum of neuropsychiatric disorders that include schizophrenia, obsessive-compulsive disorder and bipolar disorder (BD). Despite a possible association between BD and the gene encoding phospholipase Cγ1 (PLCG1), its etiological basis remains unclear. Here, we report that mice lacking phospholipase Cγ1 (PLCγ1) in the forebrain (Plcg1f/f; CaMKII) exhibit hyperactivity, decreased anxiety-like behavior, reduced depressive-related behavior, hyperhedonia, hyperphagia, impaired learning and memory and exaggerated startle responses. Inhibitory transmission in hippocampal pyramidal neurons and striatal dopamine receptor D1-expressing neurons of Plcg1-deficient mice was significantly reduced. The decrease in inhibitory transmission is likely due to a reduced number of γ-aminobutyric acid (GABA)-ergic boutons, which may result from impaired localization and/or stabilization of postsynaptic CaMKII (Ca2+/calmodulin-dependent protein kinase II) at inhibitory synapses. Moreover, mutant mice display impaired brain-derived neurotrophic factor-tropomyosin receptor kinase B-dependent synaptic plasticity in the hippocampus, which could account for deficits of spatial memory. Lithium and valproate, the drugs presently used to treat mania associated with BD, rescued the hyperactive phenotypes of Plcg1f/f; CaMKIImice. These findings provide evidence that PLCγ1 is critical for synaptic function and plasticity and that the loss of PLCγ1 from the forebrain results in manic-like behavior.

Population‐based cancer screening recommendations are also suggested for solid organ transplant recipients (SOTR); however, recommendation adherence is unknown. In a population‐based cohort of SOTRin Ontario between 1997 and 2010, we determined the uptake of breast, cervical, and colorectal cancer screening tests and identified factors associated with up‐to‐date screening using recurrent event analysis. We identified 4436 SOTReligible for colorectal, 2252 for cervical, and 1551 for breast cancer screening. Of those, 3437 (77.5%), 1572 (69.8%), and 1417 (91.4%), respectively, were not up‐to‐date for cancer screening tests during the observation period. However, these rates are likely an overestimate due to the inability to differentiate between tests done for screening or for diagnosis. SOTRwith fewer comorbidities had higher rates of becoming screen up‐to‐date. Assessment by a primary care provider (PCP) was associated with becoming up‐to‐date with cancer screening (breast relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.12–1.76, cervical RR= 1.29, 95% CI: 1.06–1.57, colorectal RR= 1.30, 95% CI: 1.15–1.48). Similar results were observed for continuity of care by transplant specialist at a transplant center. In conclusion, cancer screening for most SOTRdoes not adhere to standard recommendations. Involvement of PCPs in posttransplant care and continuity of care at a transplant center may improve the uptake of screening. This population‐based study finds that cancer screening for most solid organ transplant recipients does not adhere to standard recommendations.

In the United States, kidney transplant rates vary significantly across end‐stage renal disease (ESRD) networks. We conducted a population‐based cohort study to determine whether there was variability in kidney transplant rates across renal programs in a health care system distinct from the United States. We included incident chronic dialysis patients in Ontario, Canada, from 2003 to 2013 and determined the 1‐, 5‐, and 10‐year cumulative incidence of kidney transplantation in 27 regional renal programs (similar to U.S. ESRDnetworks). We also assessed the cumulative incidence of kidney transplant for “healthy” dialysis patients (aged 18–50 years without diabetes, coronary disease, or malignancy). We calculated standardized transplant ratios (STRs) using a Cox proportional hazards model, adjusting for patient characteristics (maximum possible follow‐up of 11 years). Among 23 022 chronic dialysis patients, the 10‐year cumulative incidence of kidney transplantation ranged from 7.4% (95% confidence interval [CI] 4.8–10.7%) to 31.4% (95% CI16.5–47.5%) across renal programs. Similar variability was observed in our healthy cohort. STRs ranged from 0.3 (95% CI0.2–0.5) to 1.5 (95% CI1.4–1.7) across renal programs. There was significant variation in kidney transplant rates across Ontario renal programs despite patients having access to the same publicly funded health care system. A population‐based cohort study finds significant variation in kidney transplant rates across Ontario, Canada, renal programs despite patients having access to the same publicly funded healthcare system.

We performed a retrospective study of 1868 consecutive unrelated donors to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs) and intention of a second donation in hematopoietic stem cell (HSC) donation. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0–10) and donor’s intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 h after HSC collection and at 1 week, 4 weeks, and 4 months thereafter. Predictors of general discomfort included female sex (P<0.0001), bone marrow (BM) collection (P<0.0001) or PBSC collection through a central line (CL; P=0.0349), 2-day collection (P=0.0150) and negative or undetermined intention of a second donation on day 1 (P<0.0001). Predictors of limitations in ADLs included age group of 30–39 years (P=0.0046), female sex (P<0.0001), BM collection (P<0.0001) or PBSC collection through a CL (P<0.0001) and negative or undetermined intention of a second donation on day 1 (P<0.0001). The only predictor of positive intention of a second donation was male sex (P=0.0007). Age, sex and collection method and period should be considered risk factors when unrelated HSC donation is performed.

Hydrogen permeation of two kinds of ferritic steel with different level of 2nd phase particles are compared utilising electrochemical permeation technique evaluated under various loads. This study indicates that tensile stress in plastic domain induces expansion of the interface between the 2nd phase particles and steel matrix, and formation of blister crack. Such microstructural-discontinuity provides additional hydrogen traps, resulting in slower diffusion and lower steady-state permeation flux. These phenomena appear predominantly in steel containing coarse-sized inclusion and precipitate having sharp extremities. The numerical analysis also supports that the steel containing coarse-sized 2nd phase particles with sharp extremities exhibits higher parameters of hydrogen capture rate per irreversible traps and blister crack formation rate than the steel containing fine-sized ones with spherical shape.

Solid organ transplant recipients (SOTRs) are at increased risk of developing and dying from cancer. However, controversies exist around cancer screening in this population owing to reduced life expectancy and competing causes of death. This systematic review assesses the availability, quality and consistency of cancer screening recommendations in clinical practice guidelines (CPGs). We systematically searched bibliographic databases and gray literature to identify CPGs and assessed their quality using AGREE II. Recommendations were extracted along with their supporting evidence. Thirteen guidelines were included in the review. CPGs for kidney recipients were the most frequent source of screening recommendations, and recommendations for skin cancer screening were most frequently presented. Some screening recommendations differed from those for the general population, based on literature demonstrating higher cancer incidence among SOTRs versus direct evidence of screening effectiveness. Relevant stakeholders such as oncology specialists, primary care providers and public health experts were not involved in the formulation of the screening recommendations. In conclusion, although several guidelines make recommendations for cancer screening in SOTRs, the availability of cancer screening recommendations varied considerably by transplanted organ. More studies are required to inform cancer screening recommendations in SOTRs, and guideline development should involve transplant patients, oncologists and cancer screening specialists. This systematic review assesses cancer screening recommendations in posttransplant care clinical practice guidelines and finds that although 13 guidelines make recommendations for cancer screening in transplant recipients, the availability of recommendations varies considerably by transplanted organ and that relevant stakeholders were not involved in the formulation of screening recommendations. See Blosser's editorial on page 9.

Hydrogen permeation of two kinds of ferritic steel with different level of 2nd phase particles are compared utilising electrochemical permeation technique evaluated under various loads. This study indicates that tensile stress in plastic domain induces expansion of the interface between the 2nd phase particles and steel matrix, and formation of blister crack. Such microstructural-discontinuity provides additional hydrogen traps, resulting in slower diffusion and lower steady-state permeation flux. These phenomena appear predominantly in steel containing coarse-sized inclusion and precipitate having sharp extremities. The numerical analysis also supports that the steel containing coarse-sized 2nd phase particles with sharp extremities exhibits higher parameters of hydrogen capture rate per irreversible traps and blister crack formation rate than the steel containing fine-sized ones with spherical shape.

AimsThe aim of the study was to develop a quantitative scoring system to predict whether a large-to-massive rotator cuff tear was arthroscopically reparable prior to surgery.Patients and MethodsWe conducted a retrospective review of the pre-operative MR imaging and surgical records of 87 patients (87 shoulders) who underwent arthroscopic repair of a large-to-massive rotator cuff tear. Patients were divided into two groups, based on the surgical outcome of the repair. Of the 87 patients, 53 underwent complete repair (Group I) and 34 an incomplete repair (Group II). Pre-operative MR images were reviewed to quantify several variables. Between-group differences were evaluated and multiple logistic regression analysis was used to calculate the predictive value of significant variables. The reparability index (RI) was constructed using the odds ratios of significant variables and a receiver operating characteristic curve analysis performed to identify the optimal RI cutoff to differentiate between the two groups.ResultsThe following variables were identified as independent predictors of arthroscopic reparability: the size of the defect with medial-lateral diameter (cutoff, 4.2 cm) and anterior-posterior diameter (cutoff, 3.7cm); Patte’s grade of muscle atrophy (cutoff, grade 3) and Goutallier grade of fatty degeneration (cutoff, grade 3). An RI cutoff value of 2.5 provided the highest differentiation between groups I and II, with an area under the curve of 0.964, and a sensitivity of 73.5% and specificity of 96.2%.ConclusionThe RI developed in our study may prove to be an efficient clinical scoring system to predict whether a large-to-massive rotator cuff tear is arthroscopically reparable.Cite this article: Bone Joint J2016;98-B:1656–61.

Objectives:: The aim of this study was to explore the phenotypic differences underpinning obesity susceptibility or resistance based on the metabolic and transcriptional profiling of C57BL/6J mice fed a high-fat diet (HFD). Methods:: The mice were fed either a normal diet or HFD for 12 weeks. After 6 weeks, the mice on HFD were classified as either obesity-prone (OP) or obesity-resistant (OR) depending on the body weight gain. Results:: Lipid profiles from plasma and liver significantly improved in OR mice relative to the OP group. Energy expenditure was greater in OR mice than in OP mice, with a simultaneous decrease in body fat mass. Epididymal white adipose tissue (eWAT) and liver were enlarged in OP mice (with visible immune-cell infiltration), but these effects were attenuated in OR mice compared with OP mice. Overall glucose metabolism was enhanced in OR mice compared with OP mice, including homeostasis model assessment for insulin resistance, plasma glucose and insulin concentrations, glucokinase activity and hepatic glycogen. Plasma adipokines and proinflammatory cytokines were upregulated in OP mice, and these changes were attenuated in OR mice. Transcriptomic profiles of eWAT and liver revealed common and divergent patterns of transcriptional changes in OP and OR mice, and pointed to differential metabolic phenotypes of OP and OR mice. There were substantial differences between OP and OR mice in molecular pathways, including atherosclerosis signaling, sperm motility, cAMP-mediated signaling in eWAT; and fibrosis, agranulocyte adhesion and diapedesis, and atherosclerosis signaling in liver. Conclusions:: Taken altogether, the results provide robust evidence of major divergence in the transcriptomes, phenotypes and metabolic processes between obesity susceptibility and obesity resistance in the HFD-fed C57BL/6J mice.

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long‐term mortality. In a typical analysis of time‐to‐event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of “independent censoring,” which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause‐specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation. The authors review the principles of competing risk analysis, provide a summary of the transplant literature where competing risk methods have been applied, and use data from the Scientific Registry of Transplant Recipients to compare the risk of mortality in sensitized waitlisted kidney transplant candidates using standard survival analysis models versus subdistribution hazards models.

As the criteria for liver donation have been extended to include marginal donors, liver grafts are becoming particularly vulnerable to hepatic ischemia–reperfusion injury (IRI). However, no specific measures have been validated to ameliorate hepatic IRI. In this article, we explored whether everolimus has protective effects against hepatic IRIin relation with autophagy. The effects of everolimus were investigated in both in vitroand in vivohepatic IRImodels. Mouse hepatocyte AML12 cells and BALB/c mice were utilized for the establishment of each model. In the IRI‐induced AML12 cells, everolimus treatment increased the expressions of autophagic markers (microtubule‐associated protein 1 light chain 3 and p62) and decreased pro‐apoptotic proteins (cleaved caspase 3 and cleaved poly‐ADP ribose polymerase). The blockage of autophagy, using either bafilomycin A1 or si‐autophagy‐related protein 5, abrogated these anti‐apoptosis effects of everolimus. Subsequently, everolimus administration to the hepatic IRI‐induced mice provided hepatoprotective effects in terms of (1) decreasing the expressions of pro‐apoptotic proteins, (2) inhibiting the release of pro‐inflammatory cytokines (IL‐6 and tumor necrosis factor‐α), (3) reducing elevated liver enzymes (aspartate transaminase, alanine transaminase, and ammonia), and (4) restoring liver histopathology. These findings suggest that everolimus protects the liver against hepatic IRIby way of activating autophagy, and thus could be a potential therapeutic agent for hepatic IRI. This experimental study suggests that everolimus protects the liver against hepatic ischemia–reperfusion injury by way of activating autophagy, and thus could be a potential therapeutic agent.

High-dose chemotherapy and autologous stem cell transplantation (ASCT) for extranodal natural killer/T-cell lymphoma (ENKTL) is a reasonable option for a subset of patients. The impact of response status, according to positron emission tomography/computed tomography (PET/CT) results and/or presence of circulating EBV DNA prior to ASCT, has not yet been established. We analyzed 27 ENKTL patients with pre-ASCT circulating EBV DNA who had undergone pre-ASCT PET/CT between 2009 and 2014. We classified patients into two groups based on the result of pretransplantation assessment: a favorable risk group (pretransplant five-point Deauville score (DS) of 1–2 based on PET/CT and no detectable EBV DNA) and an unfavorable risk group (DS 1–2 with detectable EBV DNA, DS 3–5 with or without detectable EBV DNA). After a median follow-up of 37 months, overall survival and PFS were significantly different between the two groups (median OS: not reached for favorable risk group vs 7.0 months for unfavorable risk group, P=0.017; median PFS: 16.0 vs 5.0 months, P=0.019). Multivariate analysis revealed that pre-ASCT DS and EBV DNA was the only independent prognostic factor considering stage, IPI and NKPI. Precise assessment of the status of disease before transplantation may provide more benefit from ASCT to ENKTL patients.

The Korea Atomic Energy Research Institute (KAERI) has been developing the 150 MWe Prototype Generation-IV Sodium-cooled Fast Reactor (PGSFR). The design concept is highly based on passive safety mechanisms, minimizing the need for engineered safety systems. Presently, it is of primary importance to assure the reactor dynamics and stability against small reactivity disturbances under power operating conditions. KAERI has therefore developed the NuSTAB code for stability analysis of the PGSFR. In NuSTAB, the neutron-kinetic and thermal-hydraulic coupling equations are linearized to form the characteristic equation, which is solved as a generalized eigenvalue problem for determining the decay ratio, an indicator of the system stability. In this paper, the stability of the PGSFR was analyzed by applying the point kinetic and spatial kinetic options in the NuSTAB code. System responses to temperature feedbacks including the Doppler effect, thermal expansion, coolant density change, and overall feedback were studied. The results indicate that the initial U and final TRU cores of the PGSFR are both inherently stable thanks to the temperature feedbacks.

Background:: It is well known that high-fat diet (HFD) can cause immune system-related pathological alterations after a significant body weight gain. The mechanisms of the delayed pathological alterations during the development of diet-induced obesity (DIO) are not fully understood. Methods:: To elucidate the mechanisms underlying DIO development, we analyzed time-course microarray data obtained from a previous study. First, differentially expressed genes (DEGs) were identified at each time point by comparing the hepatic transcriptome of mice fed HFD with that of mice fed normal diet. Next, we clustered the union of DEGs and identified annotations related to each cluster. Finally, we constructed an ‘integrated obesity-associated gene regulatory network (GRN) in murine liver’. We analyzed the epididymal white adipose tissue (eWAT) transcriptome usig the same procedure. Results:: Based on time-course microarray data, we found that the genes associated with immune responses were upregulated with an oscillating expression pattern between weeks 2 and 8, relatively downregulated between weeks 12 and 16, and eventually upregulated after week 20 in the liver of the mice fed HFD. The genes associated with immune responses were also upregulated at late stage, in the eWAT of the mice fed HFD. These results suggested that a critical transition occurred in the immune system-related transcriptomes of the liver and eWAT around week 16 of the DIO development, and this may be associated with the delayed pathological alterations. The GRN analysis suggested that Maff may be a key transcription factor for the immune system-related critical transition thatoccurred at week 16. We found that transcription factors associated with immune responses were centrally located in the integrated obesity-associated GRN in the liver. Conclusions:: In this study, systems analysis identified regulatory network modules underlying the delayed immune system-related pathological changes during the development of DIO and could suggest possible therapeutic targets.

Recipients of pancreas transplant alone (PTA) may be at increased risk for developing end‐stage renal disease (ESRD). The survival experience of PTA recipients developing ESRD has not been described. Furthermore, the relative survival of these patients as compared to diabetics on chronic dialysis is unknown. We studied all adult PTA recipients from January 1, 1990 to September 1, 2008 using the Scientific Registry of Transplant Recipients. Each PTA recipient developing ESRD was matched to 10 diabetics on chronic dialysis from the United States Renal Data System. Cox proportional hazards models were fitted to determine the relation between ESRD and mortality among PTA recipients, and the relation between PTA and mortality among diabetics on chronic dialysis. There were 1597 PTA recipients in the study, of which 207 developed ESRD. Those with ESRD had a threefold increase in mortality versus those without (adjusted hazard ratio 3.28 [95% confidence interval: 2.27, 4.76]). There was no significant difference in the risk of death among PTA recipients with ESRD versus diabetics on dialysis. PTA recipients developing ESRD are three times more likely to die than PTA recipients without ESRD; however, the risk of death in these patients was similar to diabetics on chronic dialysis without PTA.

Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.

Apoptosis during engraftment and inflammation induce poor islet xenograft survival. We aimed to determine whether overexpression of human heme oxygenase‐1 (HO‐1) or soluble tumor necrosis factor‐α receptor type I with human IgG1Fc (sTNF‐αR‐Fc) in porcine islets could improve islet xenograft survival. Adult porcine islets were transduced with adenovirus containing human HO‐1, sTNF‐αR‐Fc, sTNF‐αR‐Fc/HO‐1 or green fluorescent protein (control). Humanized mice were generated by injecting human cord blood–derived CD34+stem cells into NOD‐scid‐IL‐2Rγnullmice. Both HO‐1 and sTNF‐αR‐Fc reduced islet apoptosis under in vitrohypoxia or cytokine stimuli and suppressed RANTES induction without compromising insulin secretion. Introduction of either gene into islets prolonged islet xenograft survival in pig‐to‐humanized mice transplantation. The sTNF‐αR‐Fc/HO‐1 group showed the best glucose tolerance. Target genes were successfully expressed in islet xenografts. Perigraft infiltration of macrophages and T cells was suppressed with decreased expression of RANTES, tumor necrosis factor‐α and IL‐6 in treatment groups; however, frequency of pig‐specific interferon‐γ–producing T cells was not decreased, and humoral response was not significant in any group. Early apoptosis of islet cells was suppressed in the treatment groups. In conclusion, overexpression of HO‐1 or sTNF‐αR‐Fc in porcine islets improved islet xenograft survival by suppressing both apoptosis and inflammation. HO‐1 or sTNF‐αR‐Fc transgenic pigs have potential for islet xenotransplantation. In an adult pig islet to humanized mouse transplantation model, overexpression of human HO–1 or sTNF–α–Fc in porcine islets improves islet xenograft survival by suppressing both early apoptosis of islet cells and inflammation.

We compared the ceiling effects of two patient-rating scores, the Disability of the Arm, Shoulder and Hand (DASH) and Patient-Rated Wrist Evaluation (PRWE), and a physician-rating score, the Modified Mayo Wrist Score (MMWS) in assessing the outcome of surgical treatment of an unstable distal radial fracture. A total of 77 women with a mean age of 64.2 years (50 to 88) who underwent fixation using a volar locking plate for an unstable distal radial fracture between 2011 and 2013 were enrolled in this study. All completed the DASH and PRWE questionnaires one year post-operatively and were assessed using the MMWS by the senior author. The ceiling effects in the outcome data assessed for each score were estimated.The data assessed with both patient-rating scores, the DASH and PRWE, showed substantial ceiling effects, whereas the data assessed with MMWS showed no ceiling effect.Researchers should be aware of a possible ceiling effect in the assessment of the outcome of the surgical treatment of distal radial fractures using patient-rating scores. It could also increase the likelihood of a type II error.Cite this article: Bone Joint J2015;97-B:1651–6.

Pig islets are an alternative source for islet transplantation to treat type 1 diabetes (T1D), but reproducible curative potential in the pig‐to‐nonhuman primate (NHP) model has not been demonstrated. Here, we report that pig islet grafts survived and maintained normoglycemia for >6 months in four of five consecutive immunosuppressed NHPs. Pig islets were isolated from designated pathogen‐free (DPF) miniature pigs and infused intraportally into streptozotocin‐induced diabetic rhesus monkeys under pretreatment with cobra venom factor (CVF), anti‐thymocyte globulin (ATG) induction and maintenance with anti‐CD154 monoclonal antibody and low‐dose sirolimus. Ex vivoexpanded autologous regulatory T cells were adoptively transferred in three recipients. Blood glucose levels were promptly normalized in all five monkeys and normoglycemia (90–110 mg/dL) was maintained for >6 months in four cases, the longest currently up to 603 days. Intravenous glucose tolerance tests during the follow‐up period showed excellent glucose disposal capacity and porcine C‐peptide responses. Adoptive transfer of autologous regulatory T cells was likely to be associated with more stable and durable normoglycemia. Importantly, the recipients showed no serious adverse effects. Taken together, our results confirm the clinical feasibility of pig islet transplantation to treat T1D patients without the need for excessive immunosuppressive therapy. The authors report control of diabetes for longer than six months in four consecutive nonhuman primates by the transplantation of adult pig islets using a modest immunosuppressive regimen with an acceptable adverse effect profile.

The authors describe their experience of one heart recipient and two kidney recipients with fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly drowned victim of a suicide attempt.

Scedosporiumspp. is the most common mold infection in pneumonia resulting from near-drowning. Three fatal scedosporiosis cases developed after solid organ transplantation, probably transmitted from the nearly-drowned donor. One heart transplant recipient and two kidney transplant recipients developed fatal scedosporiosis following deceased donor transplantation from the same donor, a nearly-drowned victim of a suicide attempt. Genotypically, indistinguishable strains of Scedosporium auratiacumwere recovered from the three recipients. Two liver transplant recipients from the same donor received prophylactic voriconazole without any subsequent signs of infection. To determine the safety of donation from nearly-drowned donors, a national traceback investigation was also performed of the causes of deaths in all transplant recipients who received organs from drowned donors between 2001 and 2013. Over 13 years, 2600 deceased donor transplants were performed in Korea. Among these 2600 deceased donor transplants, 27 (1%) victims of drowning donated their organs. From these 27 donors, 84 patients received organ transplants and 18 died, including the above three. We found no microbiologic evidence of invasive mold transmission from the nearly-drowned donors to the other 15 recipients. Although disseminated infection in the donor could not be demonstrated by culture, undiagnosed disseminated donor infection and transmission of Scedosporiumspp. should be considered in near-drowning events.

This single‐center, retrospective cohort study of 1,170 incident kidney transplant recipients shows that the association of serum uric acid level and graft failure is dependent on the analytical method used to account for time‐varying levels of both uric acid and graft function.

TiO2photocatalyst beads were synthesised using the circulating fluidised bed–chemical vapour deposition (CFB-CVD) method. Their photocatalytic activity was compared with the TiO2photocatalyst balls synthesised using the conventional CVD (C-CVD) method. The TiO2film synthesized by CFB-CVD showed (110) oriented anatase crystal structure. Compared to the film synthesised by C-CVD, the CFB-CVD synthesised film had much less dense crystal structure owing to TiO2powders precipitated during the film growth. When the CFB-CVD synthesised TiO2beads were used in the photocatalytic decomposition of RhB in a fluidised bed reactor, the decomposition rate increased with increasing UV intensity and circulating flowrate and with decreasing initial RhB concentration. One important shortcoming of the TiO2photocatalyst beads synthesised by CFB-CVD turned out to be that the photocatalytic activity was decreased significantly by repeated reuse, calling for further investigation to improve the durability.