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Background: Deficits of executive function (EF) have been proposed as all or part of the underlying mechanisms of language impairment in at least some types of aphasia. Executive functions also play a role in the recovery process. There is evidence that bilingual persons have some executive functioning advantages compared to monolingual persons. In this paper we combine two lines of recent investigation in order to explore the relationship between executive function and conversational strategies in bilingual aphasia. Aims: The aim of this preliminary research was to compare the executive functioning profiles of bilingual individuals to those of monolingual participants with aphasia. A further aim was to examine evidence in the conversational samples of the participants in relation to the application of a range of executive skills and to link cognitive and conversational profiles using Barkley's (1997) model of executive functions. Methods & Procedures: The performance of two bilingual individuals with aphasia on a test battery of executive function tests was compared with that of eight monolingual persons (seven with aphasia and one with right hemisphere damage). The test battery included measures of behavioural inhibition, working memory, problem solving, and reconstitution. The presence or absence of executive features in the conversational samples of the participants was judged by four raters using conversational analysis methods. Outcomes & Results: Significant differences were found between the scores of the bilingual participants and those of the monolingual participants on measures of behavioural inhibition, working memory, planning and problem solving, and reconstitution. The bilingual participants' scores were mostly within normal limits and suggested well-retained executive functions. Conversation analysis showed evidence of differential application of these executive functions to conversational management. Regardless of severity or type of aphasia, the bilingual participants showed evidence of good topic management, repair, and flexibility compared to the monolingual participants. Conclusions: The results are interpreted in relation to current issues in bilingualism. Our preliminary findings shed light on differential approaches to assessment, therapy, and choice of language for bilingual aphasia. [ABSTRACT FROM AUTHOR]

We validated doubly-labelled water (DLW) by comparison to indirect calorimetry and food intake–mass balance in eight Labrador dogs (24–32 kg) over 4 d. We used several alternative equations for calculating CO2 production, based on the single- and two-pool models and used two alternative methods for evaluating the elimination constants: two-sample and multiple-sampling. In all cases the DLW technique overestimated the direct estimate of CO2 production. The greatest overestimates occurred with the single-pool model. Using two samples, rather than multiple samples, to derive the elimination constants produced slightly more discrepant results. Discrepancies greatly exceeded the measured analytical precision of the DLW estimates. The higher values with DLW probably occurred because the dogs were extremely active during the 1 h in each 24 spent outside the chamber. Estimates of CO2 production from food intake–mass balance, which include this activity, produced a much closer comparison to DLW (lowest mean discrepancy 0·3 % using the observed group mean dilution space ratio and an assumption that the mass changes reflected changes in hydration for all except one animal). We recommend an equilibration time of 6 h and use of the two-pool model based on the observed population dilution space for future studies of energy demands in dogs of this body mass. [ABSTRACT FROM PUBLISHER]

Discusses the work of the former Hungarian Prime Minister, Count Istvan Bethlen, who believed that only a rearrangement in European relations could assist in realizing the revisionist aspirations of Hungary. How Count Bethlen set out to restore the integrity of `historical' Hungary; Reviews the pamphlet, `Treaty Revision and the Hungarian Frontiers,' by R.W. Seton-Watson; More.

Recent studies suggest that hypercalcemia of sarcoidosis is due to high blood concentrations of calcitriol and that this compound may be synthesized at an extra-renal site. We report that sarcoid lymph node homogenate metabolized calcifediol to a substance indistinguishable from calcitriol, whereas six nonsarcoid lymph nodes failed to produce this compound. [ABSTRACT FROM AUTHOR]

The article cites the practicalities of measuring and interpreting field metabolic rate in dogs. Separation of energy expenditure of a dog for work from its daily energy expenditure when not working is considered necessary for the measurements of field metabolic rate using the doubly-labeled water technique to be correctly interpreted and used to determine energy requirements of working dogs. Total energy expenditure can be separated into components for maintenance, standing and other activities. Time- or energy-budget analysis is also said to be necessary to estimate average daily energy expenditure.

Background -- Rainbow lorikeets are nectarivorous birds whose natural diet is low in protein and relatively high in free amino acids. Protein metabolisability (PM) of egg white (EW) protein is lower in rainbow lorikeets (6.9%) than whole egg protein in white leghorn roosters (13.9%). Objective -- (1) To determine whether PM of other sources of protein fed to lorikeets is higher than that of EW. (2) To compare the general proteolytic activity (GPA) (pepsin) of the proventriculus of the rainbow lorikeet and a granivorous bird, the domestic chicken, Gallus gallus domesticus L. Design -- (1) Five lorikeets were fed one of three diets, an EW diet, an EW and casein hydrolysate (CH) diet and a commercial "lorikeet and honeyeater" (L/H) feed (Wombaroo Food Products, Glen Osmond, SA). Lorikeets were kept in metabolism cages for 3d for feed intake measurements and excreta collection. Samples were freeze dried and analysed for nitrogen. (2) The GPA of the proventriculus of three lorikeets and three chickens was measured using haemoglobin as a substrate. Outcomes -- (1) The PM (mean ± SD, n = 5) was 4.3 ± 2.6% for the EW diet, 5.6 ± 2.5% for the EW/CH diet and 7.3 ± 3.2% for the L/H feed. The PM for the EW diet was not significantly different from the EW/CH diet and L/H feed (P>0.05). (2) The GPA of the proventriculus of lorikeets at pH 1.0 was significantly lower (P<0.01) than that of the chicken at each incubation period. Conclusions -- (1) The results of the feeding experiments with lorikeets confirm that PM of artificial protein sources is low. (2) The GPA of the proventriculus of lorikeets is lower than that of the chicken. This may contribute to the low PM by lorikeets. [ABSTRACT FROM AUTHOR]

Background - In Australia, about 40% of pet dogs are overweight (1). High fat diets and obesity affect heart function of dogs (2). In people, exercise has been shown to improve heart function. There is no information on body condition and level of exercise on heart rate in pet dogs. Objective - To determine the effects of body condition and level of exercise on heart rate (HR) of pet dogs carrying out a three-stage exercise test. Design - Owners of dogs in the Melbourne metropolitan area volunteered their pets for the study. The exercise test, carried out over a 21 m circuit of four ramps, consisted of three periods of 2 min exercise followed by 2 min rest. Circuit speeds varied with size: dogs less than 47 cm in height ran at 3, 4 and 5 km/h, those above 47 cm ran at 4, 6 and 8 km/h. A Polar heart rate monitor (Kempele, Finland) was used to record HR at rest, during exercise and during recovery. Body condition was assessed using the Purina body condition system (3). Outcomes - Resting HR of smaller dogs (n=16) was significantly (P<0.05) greater, 135.4 ± 25.7 beats/min (bpm), that of larger dogs, 103.3 ± 20.3 bpm (n=32). Although overweight large dogs (n=20) had a significantly (P<0.05) greater HR (111.8 ± 20.3 bpm) than lean dogs (96.4 ± 18.2, n=28), recovery HR (average HR during recovery as a percentage of HR during exercise) of overweight dogs exercised every day was faster that of lean dogs with limited exercise. Conclusions -- Heart function of pet dogs can be affected by body condition and exercise. [ABSTRACT FROM AUTHOR]

Background: Undifferentiated carcinoma (UC) is a rare subtype of pancreatic cancer distinguished from UC with osteoclast-like giant cells (UC-OGC) in 2019, affecting interpretation of literature that does not distinguish these subtypes. We sought to identify translationally relevant differences between these 2 variants and compared with pancreatic ductal adenocarcinoma., Methods: We characterized clinical and multiomic differences between UC (n = 32) and UC-OGC (n = 15) using DNA sequencing, RNA sequencing, and multiplex immunofluorescence and compared these findings with pancreatic ductal adenocarcinoma., Results: Characteristics at diagnosis were similar between UC and UC-OGC, though the latter was more resectable (P = .009). Across all stages, median overall survival was shorter for UC than for UC-OGC (0.4 years vs 10.8 years, respectively; P = .003). This shorter survival was retained after stratification by resection, albeit without statistical significance (1.8 years vs 11.9 years, respectively; P = .08). In a subset of patients with available tissue, the genomic landscape was similar among UC (n = 9), UC-OGC (n = 5), and pancreatic ductal adenocarcinoma (n = 159). Bulk RNA sequencing was deconvoluted and, along with multiplex immunofluorescence in UC (n = 13), UC-OGC (n = 5), and pancreatic ductal adenocarcinoma (n = 16), demonstrated statistically significantly increased antigen-presenting cells, including M2 macrophages and natural killer cells, and decreased cytotoxic and regulatory T cells in UC and UC-OGC vs pancreatic ductal adenocarcinoma. Findings were similar between UC and UC-OGC , except for decreased regulatory T cells in UC-OGC (P = .04)., Conclusions: In this series, UC was more aggressive than UC-OGC, with these variants having more antigen-presenting cells and fewer regulatory T cells than pancreatic ductal adenocarcinoma, suggesting potential for immune-modulating therapies in the treatment of these pancreatic cancer subtypes., (© The Author(s) 2024. Published by Oxford University Press.)

Pancreatic ductal adenocarcinoma has a unique tumor microbiome and the systemic depletion of bacteria or fungi using antibiotic/antifungal cocktails leads to a decrease in pancreatic tumor burden in mice. However, functional studies remain rare due to the limited availability of clinically relevant microbiota. Here, we describe in detail the isolation of bacteria and fungi from the small intestine and tumor of pancreatic cancer patients at the Rogel Cancer Center. We then further characterized the impact of a newly isolated Klebsiella oxytoca strain ( UMKO1 ) on the pancreatic tumor microenvironment using bacterial genome sequencing, untargeted and targeted metabolomics, as well as an ex vivo tumor transplant system. We found that UMKO1 possesses a gene for the long form of cytidine deaminase, which can inactivate the standard PDAC chemotherapeutic agent gemcitabine. In addition, we found that UMKO1 can produce several indoles when grown in tumor-like conditions, metabolites that can lead to an immune suppressive environment and interfere with therapy outcome. To test this in detail, we assessed changes in immune populations in pancreatic tumor explants upon exposure to the supernatant of UMKO1 and other isolated bacteria grown in tumor Interstitial fluid media (TIFM). We found that while none of the bacterial supernatants changed the abundance of CD8 T cells, granzyme B positive CD8 T cells were the lowest in tumor explants exposed to UMKO1 , and not other isolated Klebsiella species or the non-pathogenic laboratory strain E. coli K12 . In summary, the isolated collection of bacteria and fungi from this study are a valuable toolbox to study the impact of microbiota on pancreatic cancer.

Background & Aims: The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRAS G12D ). One of the most commonly used models involves targeted insertion of a cre-recombinase into the Ptf1a gene. However, this approach disrupts the Ptf1a gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRAS G12D ). This study aims to determine if Ptf1a haploinsufficiency affected the acinar cell response to KRAS G12D before and after induction of pancreatic injury., Methods: We performed morphological and molecular analysis of 3 genetically engineered mouse models that express a tamoxifen-inducible cre-recombinase to activate Kras G12D in acinar cells of the pancreas. The cre-recombinase was targeted to the acinar-specific transcription factor genes, Ptf1a or Mist1/Bhlha15, or expressed within a BAC-derived Elastase transgene. Histological and RNA-seq analyses were used to delineate differences between the models., Results: Up to 2 months after tamoxifen induction of KRAS G12D , morphological changes were negligible. However, induction of pancreatic injury by cerulein resulted in widespread PanIN lesions in Ptf1a creERT pancreata within 7 days and maintained for at least 5 weeks post-injury, which was not seen in the models with 2 functional Ptf1a alleles. RNA-sequencing analysis prior to injury induction suggested Ptf1a creERT and Mist1 creERT mice have unique profiles of gene expression that predict a differential response to injury. Multiplex analysis of pancreatic tissue confirmed different inflammatory responses between the models., Conclusions: These findings suggest Ptf1a haploinsufficiency in Ptf1a creERT mouse models promotes KRAS G12D priming of genes for promotion of pancreatic ductal adenocarcinoma., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Trace metal contamination is a widespread issue due to its many natural and anthropogenic sources and known carcinogenic, teratogenic, and reproductive effects. As previous invertebrate trace metal research has primarily focused on model species (Daphnia magna, Chironomidae, etc.), our understanding of effects on non-model invertebrate species remains relatively poor. As such, this study assessed the exposure effects of cadmium, arsenic, and lead on viability, locomotor behavior, and embryonic development of the Seminole ramshorn snail (Planorbella duryi). Exposure treatments of CdCl 2 , Na 2 HAsO 4 • 7H 2 O, or Pb (NO 3 ) 2 were prepared at concentrations of 0, 0.01, 0.1, 1, and 10 mg/L and confirmed using inductively coupled plasma optical emission spectroscopy (ICP-OES). Individual adult P. duryi were exposed for 7 days with viability assessed every 24 h, and locomotor behavior was accessed on Days 1 and 7 using ToxTrac v2.97 automated behavior software. Individual embryos from newly laid (<6 h old) embryonic clutches were exposed for 10 days, during which embryonic development stage was documented every 24 h. Based on our results, an additional follow-up study for cadmium was conducted using a lower range of 0-0.1 mg/L to allow for the observation of sublethal endpoints. Adult lead and cadmium exposure resulted in significant mortality in the highest treatments (1 and 10 mg/L), dose-dependent behavioral effects, and delayed embryonic development. Arsenic exposures resulted in little to no impacts for all assessed endpoints. Our results provide new insight into the sublethal impacts of these contaminants and highlight potential for behavior and embryonic development as useful tools for risk assessment. PRACTITIONER POINTS: The exposure effects of lead, cadmium, and arsenic on the viability, embryonic development, and locomotor behavior of a common freshwater snail species was investigated using environmentally relevant concentrations. The severity of impact differed for each trace metal, with cadmium being the most toxic and arsenic the least toxic at concentrations ranging from 0 to 10 mg/L. Embryonic development appeared to be the most sensitive endpoint of those tested in this study, suggesting that exposure may have prolonged effects that extend to population and community levels. The Seminole ramshorn snail serves as a sensitive alternative model species that can be used to assess the impacts of contaminants on freshwater invertebrates in future studies., (© 2024 The Authors. Water Environment Research published by Wiley Periodicals LLC on behalf of Water Environment Federation.)

Coal ash (CA) is an industrial waste product that has been shown to contain several neurotoxic constituents such as cadmium, selenium, mercury, lead, and arsenic. Contaminant-laced leachates enter the environment via seepage, runoff, permitted discharge, or accidental spills from CA storage ponds or landfills which may pose a risk to wildlife residing in receiving waterways. In this study, we assessed 1) the presence and concentration of thirteen trace elements (Al, Ca, Mg, Cr, Cd, As, Se, Pb, Cu, Zn, Mn, Fe, B) in surface water and sediment grab samples using ICP-OES, 2) the temporal variability of trace elements using Pb-210 dated sediment core samples, 3) differences in species diversity using environmental DNA (eDNA) analyses, and 4) the presence and concentration of trace metals in banded killifish (Fundulus diaphanus) epaxial muscle tissue collected from waterways surrounding the Possum Point Power Station (Stafford, VA). Results showed the highest concentrations of As, Cd, Cr, Cu, Fe, Mg, Se, Zn, and B in Quantico Creek (QC) adjacent to the coal ash ponds and elevated average cadmium and zinc concentrations compared to both upstream and downstream locations along the Potomac River. Sediment core profiles and Pb-210 analyses showed historical enrichment of several trace elements in QC beginning after the commissioning of the power plant in 1948. When compared to upstream and downstream sites, species diversity was drastically reduced in Quantico Creek based on eDNA identification. Muscle tissues of banded killifish collected in Quantico Creek displayed increased Al, Cd, and Zn concentrations compared to upstream and downstream sites. Collectively, our results demonstrate the potential impacts of coal ash landfills on aquatic ecosystems and suggest that further research is needed to fully inform risk assessment and remediation efforts., 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 © 2023 Elsevier Ltd. All rights reserved.)

Coal fly ash is an industrial waste product generated by coal fired powerplants which has been shown to contain elevated concentrations of several toxic trace metals. When stored in landfills or other repositories, these trace metals can enter nearby surface waters via a number of routes including leaching or runoff. Our study examined 1) the presence and concentration of eleven trace elements in a range of lab-created coal ash leachate solutions at neutral pH using ICP-OES, 2) the physiological effects of these leachate solutions on a freshwater gastropod (Planorbella duryi), and 3) the ability of these trace metals to bioaccumulate in the tissues of exposed individuals. As, Cd, Cu, Mg, Mn, and Pb were detected in solutions at increasing concentrations concurrent with ash concentration. Exposure to leachates caused significant delays in embryonic development, reduced juvenile shell growth, decreases in egg and clutch production, and the display of avoidance behaviors. Tissues of exposed snails contained elevated concentrations of As, Cd, Cu, and Cr, with bioconcentration factors 177,550 times higher in cadmium and 85,468 times higher in arsenic in the highest treatment compared to control organisms. Our results highlight the potential harmful effects of coal ash leachates on a novel freshwater invertebrate species using several unique methodologies, providing key information regarding their potential impacts on surrounding aquatic ecosystems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Tyler Edward Frankel reports financial support was provided by Morris Animal Foundation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Early detection of Pancreatic Ductal Adenocarcinoma (PDAC), one of the most aggressive malignancies of the pancreas, is crucial to avoid metastatic spread to other body regions. Detection of pancreatic cancer is typically carried out by assessing the distribution and arrangement of tumor and immune cells in histology images. This is further complicated due to morphological similarities with chronic pancreatitis (CP), and the co-occurrence of precursor lesions in the same tissue. Most of the current automated methods for grading pancreatic cancers rely on extensive feature engineering involving accurate identification of cell features or utilising single number spatially informed indices for grading purposes. Moreover, sophisticated methods involving black-box approaches, such as neural networks, do not offer insights into the model's ability to accurately identify the correct disease grade. In this paper, we develop a novel cell-graph based Cell-Graph Attention (CGAT) network for the precise classification of pancreatic cancer and its precursors from multiplexed immunofluorescence histology images into the six different types of pancreatic diseases. The issue of class imbalance is addressed through bootstrapping multiple CGAT-nets, while the self-attention mechanism facilitates visualization of cell-cell features that are likely responsible for the predictive capabilities of the model. It is also shown that the model significantly outperforms the decision tree classifiers built using spatially informed metric, such as the Morisita-Horn (MH) indices., Competing Interests: AR has a consulting agreement with Voxel analytics LLC and consults for Genophyll, LLC. MB is currently employed with the Division of Data and Decision Sciences, Tata Consultancy Services, India. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funders were not involved in the study design, collection, analysis, and interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2021 Baranwal, Krishnan, Oneka, Frankel and Rao.)

Purpose : Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell immune responses in various cancers including pancreas. This has led us to our objective that was to develop a clinically relevant in vitro organoid model to specifically target mechanisms that deplete MDSCs as a therapeutic strategy for PDAC. Method : Murine and human pancreatic ductal adenocarcinoma (PDAC) autologous organoid/immune cell co-cultures were used to test whether PDAC can be effectively treated with combinatorial therapy involving PD-1 inhibition and MDSC depletion. Results : Murine in vivo orthotopic and in vitro organoid/immune cell co-culture models demonstrated that polymorphonuclear (PMN)-MDSCs promoted tumor growth and suppressed cytotoxic T lymphocyte (CTL) proliferation, leading to diminished efficacy of checkpoint inhibition. Mouse- and human-derived organoid/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of arginase 1-expressing PMN-MDSCs within these co-cultures rendered the organoids susceptible to anti-PD-1/PD-L1-induced cancer cell death. Conclusions : Here we use mouse- and human-derived autologous pancreatic cancer organoid/immune cell co-cultures to demonstrate that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition. We present a pre-clinical model that may predict the efficacy of targeted therapies to improve the outcome of patients with this aggressive and otherwise unpredictable malignancy.

Pancreatic Cancer (PDA) is an aggressive malignancy characterized by early spread and a high mortality. Current studies suggest that a subpopulation of cells exist within tumors, cancer stem cell (CSC), which are capable of self-renewal and give rise to unique progeny which form the major neoplastic cellular component of tumors. While CSCs constitute a small cellular subpopulation within the tumor, their resistance to chemotherapy and radiation make them an important therapeutic target for eradication. Along with distinctive phenotypic properties, CSCs possess a unique metabolic plasticity allowing them to rapidly respond and adapt to environmental changes. These cells and their progeny also display a significantly altered epigenetic state with distinctive patterns of DNA methylation. Several mechanisms of cross-talk between epigenetic and metabolic pathways in PDA exist which ultimately contribute to the observed cellular plasticity and enhanced tumorigenesis. In this review we discuss various examples of this metabolic-epigenetic interplay and how it may constitute a new avenue for therapy specifically targeting CSCs in PDA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Microenvironment evaluation of intact tissue for analysis of cell infiltration and spatial organization are essential in understanding the complexity of disease processes. The principle techniques used in the past include immunohistochemistry (IHC) and immunofluorescence (IF) which enable visualization of cells as a snapshot in time using between 1 and 4 markers. Both techniques have shortcomings including difficulty staining poorly antigenic targets and limitations related to cross-species reactivity. IHC is reliable and reproducible, but the nature of the chemistry and reliance on the visible light spectrum allows for only a few markers to be used and makes co-localization challenging. Use of IF broadens potential markers but typically relies on frozen tissue due to the extensive tissue autofluorescence following formalin fixation. Flow cytometry, a technique that enables simultaneous labeling of multiple epitopes, abrogates many of the deficiencies of IF and IHC, however, the need to examine cells as a single cell suspension loses the spatial context of cells discarding important biologic relationships. Multiplex fluorescent immunohistochemistry (mfIHC) bridges these technologies allowing for multi-epitope cellular phenotyping in formalin fixed paraffin embedded (FFPE) tissue while preserving the overall microenvironment architecture and spatial relationship of cells within intact undisrupted tissue. High fluorescent intensity fluorophores that covalently bond to the tissue epitope enables multiple applications of primary antibodies without worry of species specific cross-reactivity by secondary antibodies. Although this technology has been proven to produce reliable and accurate images for the study of disease, the process of creating a useful mfIHC staining strategy can be time consuming and exacting due to extensive optimization and design. In order to make robust images that represent accurate cellular interactions in-situ and to mitigate the optimization period for manual analysis, presented here are methods for slide preparation, optimizing antibodies, multiplex design as well as errors commonly encountered during the staining process.

Progestins are utilized as a component of human contraceptives, and commonly enter the environment via wastewater treatment plant effluent. Certain progestins activate fish androgen receptors and cause decreases in fecundity and masculinization of females. We used a nest acquisition assay and computer-assisted sperm analysis to examine the effects of levonorgestrel on male fathead minnow (Pimephales promelas) reproductive fitness. Males were exposed to 0, 10, or 100 ng/L levonorgestrel for 14 d. Combinations of a control male and a male from one of the treatments were placed into a competitive nesting assay, and the time each male spent holding the nest and time spent exhibiting aggressive behaviors were analyzed at 48 h postexposure. Semen samples were analyzed for total motility, straight-line velocity, curvilinear velocity, average path velocity, linearity, beat cross frequency, and wobble at 0, 30, 60, 90, and 120 s postactivation. Males exposed to either 10 or 100 ng/L of levonorgestrel exhibited increased nest acquisition success and lower levels of aggression compared with control-control pairings, as well as decreases in multiple sperm motion characteristics. Our results suggest that further research is required to ascertain the effects of levonorgestrel on male gamete quality and reproductive behaviors. Environ Toxicol Chem 2018;37:1131-1137. © 2017 SETAC., (© 2017 SETAC.)

The synthetic progestin levonorgestrel is commonly utilized in human oral contraceptives. It enters the environment as a component of wastewater treatment plant effluent, and has been measured at low ng/L concentrations in surface waters. It has been shown to activate fish androgen receptors, causing the physical masculinization of females, changes in reproductive behavior, and decreases in fecundity. In the present study, the effects of levonorgestrel exposure on early-stage oogenesis in the fathead minnow (Pimephales promelas) was examined. Adult females were exposed to 0, 10, or 100 ng/L levonorgestrel for 14 d using a flow-through exposure system. The ovaries from each female were then removed via dissection and weighed for gonadosomatic index (GSI) calculations, and oocytes from one lobe preserved in Serra's fixative. Total numbers of late-stage vitellogenic oocytes exhibiting a germinal vesicle were then quantified. In a second exposure, blood plasma samples were collected from adult females and analyzed for vitellogenin concentrations using enzyme-linked immunosorbent assay. Females exposed to both concentrations of levonorgestrel developed male secondary sexual characteristics in a dose-dependent manner, and ovaries contained significantly fewer late stage oocytes. Exposure to 100 ng/L of levonorgestrel resulted in decreased GSI and blood plasma vitellogenin concentrations. The results suggest that female exposure to levonorgestrel alone may have profound effects on reproduction in progestin-contaminated environments. Environ Toxicol Chem 2017;36:3299-3304. © 2017 SETAC., (© 2017 SETAC.)

The field of tumor immunology and immunotherapy has undergone a renaissance in the past decade do in large part to a better understanding of the tumor immune microenvironment. After suffering countless successes and setbacks in the twentieth century, immunotherapy has now come to the forefront of cancer research and is recognized as an important tool in the anti-tumor armamentarium. The goal of therapy is to aid the immune system in recognition and destruction of tumor cells by enhancing its ability to react to tumor antigens. This traditionally has been accomplished by induction of adaptive immunity through vaccination or through passive delivery of immunologic effectors as in the case of adoptive cell transfer. The recent discovery of immune "checkpoints" whose purpose is to suppress immune activity and prevent auto-immunity has created a new angle by which reactivity to tumors can be enhanced. Blockers of these checkpoints have yielded impressive clinical results and have recently been approved for use in a wide variety of malignancies. With data showing increasing rates of not only treatment response, but complete remissions, immunotherapy is poised to become an increasingly utilized therapy in the treatment of cancer.

Background and Objectives: Hirschsprung's disease (HD) must always be considered in very early-onset constipation. Although HD has a well-described clinical course, little is known about those neonates in whom HD was excluded. We aimed to describe the long-term clinical outcomes of neonates with a clinical suspicion of HD that was excluded by rectal suction biopsy., Methods: This is a single-center double-cohort comparative study. Neonates who underwent rectal mucosa biopsy for suspected HD were age and sex matched with healthy controls. A survey on clinical outcomes, stooling patterns, and other gastrointestinal (GI)-related conditions was sent to parents. Pathology slides were re-reported by an experienced histopathologist blinded to the clinical data., Results: A total of 51 neonates were included [25 cases, 26 controls; 41% males, median time of follow-up 4.25 years (interquartile range 2.7-6.9)]. Nine (36%) of patients in the case group required prolonged laxative use for constipation during the first year of life compared with 0 (0%) controls (P<0.001). This difference was maintained at the end of follow-up, with 5 (20%) versus 0 (0%), respectively (P=0.02). Case neonates were significantly more likely to be hospitalized or to be diagnosed with a chronic GI-related condition than the controls (33 vs. 12%, P=0.01; and 19 vs. 8%, P=0.04, respectively)., Conclusion: Neonatal constipation is associated with long-term GI-related disorders and should be considered clinically significant even when the diagnosis of HD is excluded. Neonates with early-onset abnormal stooling patterns should be monitored with adequate pediatrician or pediatric gastroenterologist follow-up.

Interleukin (IL)-22, a member of the IL-10 family, is a cytokine secreted by several types of immune cells including IL-22(+)CD4(+) T cells (Th22) and IL-22 expressing innate leukocytes (ILC22). Recent studies have demonstrated that IL-22 is a key component in mucosal barrier defense, tissue repair, epithelial cell survival, and proliferation. Furthermore, accumulating evidence has defined both protective and pathogenic properties of IL-22 in a number of conditions including autoimmune disease, infection, and malignancy. In this review, we summarize the expression and signaling pathway and functional characteristics of the IL-22 and IL-22 receptor axis in physiological and pathological scenarios and discuss the potential to target IL-22 signaling to treat human diseases.

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell-mediated immunity at the tumor site., (©2015 American Association for Cancer Research.)

Several studies have been conducted in an attempt to determine the optimal freezing rate for cryopreservation of striped bass (Morone saxatilis) sperm. In this study, the effects of freezing rate (-10 °C, -15 °C, -20 °C, and -40 °C/min) on gamete quality was examined, using Sybr-14 and propidium iodide to determine viability (sperm cell membrane integrity), ATP concentration using a luciferin-luciferase bioluminescence assay, and a CEROS computer-assisted sperm analysis system to characterize striped bass sperm motion. Adult male striped bass (N = 12) were sampled once a week for 5 weeks. Collected samples were extended, cryoprotected using a 7.5% (vol/vol) dimethyl sulfoxide final concentration solution, and frozen using a Planer Kryosave controlled-rate freezer. Samples were stored in liquid nitrogen for 49 days, and sperm quality was re-evaluated after thaw (same methods). Sperm cryopreserved at -40 °C/min resulted in means for total motility (10.06%), progressive motility (7.14%), ATP concentration (0.86 pmol/10(6) cells), and sperm viability (56.5%) that were greater (P < 0.05) than those for slower cooling rates. Therefore, -40 °C/min was the optimal freezing rate (among those tested) for cryopreservation of striped bass sperm., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Identification and measurement of adverse medical events is central to patient safety, forming a foundation for accountability, prioritizing problems to work on, generating ideas for safer care, and testing which interventions work. We compared three methods to detect adverse events in hospitalized patients, using the same patient sample set from three leading hospitals. We found that the adverse event detection methods commonly used to track patient safety in the United States today-voluntary reporting and the Agency for Healthcare Research and Quality's Patient Safety Indicators-fared very poorly compared to other methods and missed 90 percent of the adverse events. The Institute for Healthcare Improvement's Global Trigger Tool found at least ten times more confirmed, serious events than these other methods. Overall, adverse events occurred in one-third of hospital admissions. Reliance on voluntary reporting and the Patient Safety Indicators could produce misleading conclusions about the current safety of care in the US health care system and misdirect efforts to improve patient safety.

Background: Regardless of the indication, tricuspid valve replacement (TVR) has historically been associated with high mortality and morbidity. We report the results of our experience in a high-risk patient population with an emphasis on operative mortality, long-term survival, and valve related events according to the type of prosthesis., Methods: Between 1985 and 1999 TVR was performed in 81 patients (isolated n = 25, combined with valve surgery n = 44, combined with CABG or other n = 12). The mean age was 61 years old (range 19-83 years old). Risk factors included New York Heart Association functional class III/IV (n = 73, 90%), reoperation (n = 58, 72%), urgent/emergent indication (n = 62, 76%), and hepatic dysfunction (n = 13, 16%). Mean pulmonary artery pressure was 34 mmHg. Etiology of tricuspid regurgitation was classified as functional (n = 18, 22%) or organic (n = 52, 64%), or failed previous tricuspid valve surgery (n = 11, 14%)., Results: Tricuspid valve replacement was performed with either a bioprosthetic (n = 34, 42%) or mechanical valve (n = 47, 58%). The overall operative mortality was 22% (n = 18). Risk factors for mortality included urgent/emergent status, age greater than 50 years old, functional etiology, and elevated pulmonary artery pressure. Of the 60 survivors, 26 (43%) died during follow up. After univariate analysis, organic etiology was the only predictor of late death (p = 0.01). Kaplan-Meier survival at 2.5, 5, and 10 years was 80%, 60%, and 45% for bioprosthetic, and 84%, 69%, and 59% for mechanical valves, respectively., Conclusions: Patients requiring TVR are typically high-risk with a high-percentage of reoperations, concomitant cardiac procedures, and end-stage functional class. Operative and overall mortality remains high. Heart failure was the predominant cause of early and late deaths, emphasizing importance of timely referral before the development of end-stage cardiac impairment.

Radiation dose prescription, interpretation, and planning can be problematic for brachytherapy due to high spatial heterogeneity, varying and various dose rates, absence of superimposed calculated isodose distributions onto affected tissues, and lack of dose volume histograms. A new treatment planner has been developed to reduce these limitations in brachytherapy planning. The PC-based planning system uses a CT-simulator to sequentially scan the patient to generate orthogonal images (to localize seed positions) and subsequently axially scan the patient. This sequential scanning procedure avoids using multiple independent patient scans, templates, external frames, or fiducial markers to register the reconstructed seed positions with patient contours. Dose is computed after assigning activity to (low dose rate) Ir192, linear Cs137, or I125 seeds or dwell times (high dose rate) to the Ir192 source. The planar isodose distribution is superimposed onto axial, coronal, or sagittal views of the tissues following image reconstruction. The treatment plan computes (1) direct and cumulative volume dose histograms for individual tissues, (2) the average, standard deviation, and coefficient of skewness of the dose distribution within individual tissues, (3) an average (over all tissue pixels) survival probability (S) and average survival dose DASD for a given radiation treatment, (4) normal tissue complication probability (NTCP) delivered to a given tissue. All four computed quantities account for dose heterogeneity. These estimates of the biological response to radiation from laboratory-based studies may help guide the evaluation of the prescribed low- or high-dose rate therapy in retrospective and prospective clinical studies at a number of treatment sites.

Two experiments were conducted in broiler chicks to determine whether dietary imbalances of sulfur amino acids (SAA), vitamin A, or interactions between the two nutrients could influence organic bone matrix metabolism measured with L-[35S]-methionine. In the first experiment, in vivo incorporation of 35S into the tibiotarsal bone matrix of 2-wk-old birds was unaffected by vitamin A treatment of 10 and 100 times the requirement when compared with that of birds receiving recommended amounts of vitamin A. However, 35S incorporation was significantly reduced by increasing the SAA concentration of the diet to 1.5 times the requirement relative to lysine. In the second experiment, in vitro incorporation of 35S, derived from L-[35S]-methionine, into bone matrix was reduced in birds consuming a diet containing 1.5 times the methionine requirement relative to lysine (Diet HS) when compared with those receiving .75 (Diet LS), 1.0 (Diet NS), or 1.25 (Diet MS) times the requirement. Birds consuming Diet LS incorporated significantly more 35S into organic bone matrix than birds consuming the other three diets. Although the ratio of SAA to lysine was that recommended (.76:1), on a weight basis the concentration of SAA in diet NS was relatively high (11.48 g/kg diet) compared with the NRC (1984) recommendation of 9.3 g/kg diet. The results show that excess SAA can affect organic bone matrix metabolism and suggest that SAA may play a role in the etiology of tibial dyschondroplasia. They also indicate the importance of distinguishing between nutrient content of the diet expressed as a ratio and that expressed on a weight basis.

Results are presented for SPECT computations of liver volumes and 111In-labeled antibody activities in the livers of eight normal beagle dogs. Administered activities ranged from 1 to 2 mCi. SPECT studies were acquired 1 day postinjection using a rotating gamma camera system with elliptical orbits in a 360-degree rotation (128 views, 15 sec/view, 64 x 64 matrices). Uniformity-corrected images were reconstructed by use of the circular harmonic transform algorithm with computer software developed in-house. Liver volumes and activities were computed from transverse slices, 1 pixel (6.25 mm) in thickness. Comparison of SPECT and autopsy data demonstrated that absolute values of percent differences between measured and computed liver volumes ranged from 1.0% to 7.2%. Absolute values of percent differences between autopsy data and computed 111In activities in the liver ranged from 2.3% to 7.5%. These results suggest that quantitative SPECT has the potential of becoming an important tool in clinical trials for determining activities and localization volumes of radiolabeled antibodies directly from radionuclide images.

Language-disordered children's use of two devices through which utterances are related to ongoing discourse, focus and substitution operations, were observed. Focus operations merely repeat, while substitutions repeat part but also alter a previous utterance in some way. Previous research with normal-language children shows that the predominant device a child uses changes developmentally, with focus operations more frequently used early and substitution operations emphasized later. The use of these devices was observed in the spontaneous conversations of three language-disordered children. Two were at a lower linguistic level (MLU's of 1.8 and 2.2) than the third (MLU 3.2). A developmental trend reflecting that of the normally developing children emerged. These results indicate that language-disordered children are not qualitatively different from normally developing children in their ability to use these particular devices for learning to participate in conversations.

1. The syndrome induced by depriving cats of animal lipid is partially cured by feeding 18:3omega6. This is associated with an increase in levels of 20:3omega6, but not 20:4omega6, in plasma phospholipids. 2. It is concluded that the cat lacks delta5 desaturase activity and has a dietary requirement for 18:3omega6 and possible 20:4omega6.

Bioactive PTH was measured in Wistar rats under a variety of experimental conditions. The mean activity in normal rat sera was 0.17 +/- 0.12 ng/ml (expressed in terms of bovine PTH 1-34). Sera from animals reared on a vitamin D deficient diet showed a mean value of 0.46 +/- 0.24 ng/ml (P less than 0.01), whereas sera from animals with 1,25-dihydroxyvitamin D (1,25(OH)2D) deficiency had a mean activity of 0.62 +/- 0.23 ng/ml (P less than 0.01). Dietary calcium deficiency also resulted in high serum PTH levels (0.71 +/- 0.34 ng/ml, P less than 0.01) in spite of marked elevations of serum 1,25(OH)2D concentrations in these animals. A significant negative correlation was noted between serum calcium and bioactive PTH. Calcium infusions into hypocalcemic, vitamin D-deficient rats caused a fall in serum bioactive PTH concentrations to a mean of 13% of control values within 10 min. Intraperitoneal administration of 1,25(OH)2D3 to hypocalcemic, 1,25(OH)2D-deficient rats did not suppress serum bioactive PTH concentrations after 30 or 60 min even though serum 1,25(OH)2D concentrations were greater than 900 pmol/liter in each animal at these time points. To our knowledge, this is the first study using PTH bioassays for physiological experiments in rats.

The effect of vitamin A on calcium-regulating hormones was studied in rats. A single oral dose of 30 mg retinol equivalents (RE) given to adult rats caused no change to serum biologically active parathyroid hormone (bioactive-PTH) concentrations. Bioactive-PTH secretion from rat thyroparathyroid gland complexes was not significantly altered after in vitro incubation with 1.18 X 10(-6) M retinol. Chronically intoxicated rats given 15 mg RE 3 times a week for 6 wk, showed higher osteoclast numbers and lower osteoid than controls. Serum bioactive-PTH was not detectable and serum 25-hydroxyvitamin D (25-OHD) (25.2 +/- 12.5 nmol/L) was significantly (P less than 0.03) lower than controls (43.3 +/- 3.1). In acutely intoxicated rats (60 mg RE/d for 2 d), serum bioactive-PTH levels were significantly lower (0.02 +/- 0.05 ng/ml, P less than 0.03) than in control animals (0.14 +/- 0.08). Lower doses of vitamin A, 7.5 mg RE 3 times a week for 3 wk, suppressed serum bioactive-PTH to undetectable levels but had no significant effect on serum 25-OHD. Serum calcium and 25-OHD levels were significantly lower in vitamin D-intoxicated rats given 7.5 mg RE 3 times a week (ca. 3.16 +/- 0.19 mmol/L; 25-OHD 599.7 +/- 110.6 nmol/L) than vitamin D-intoxicated controls (3.42 +/- 0.17; 789.3 +/- 17.7). These results suggest that hypervitaminosis A can alter the metabolism of calcium-regulating hormones.