549 research outputs found

    Impact of alpha-tocopherol deficiency and supplementation on sacrocaudalis and gluteal muscle fiber histopathology and morphology in horses.

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    BackgroundA subset of horses deficient in alpha-tocopherol (α-TP) develop muscle atrophy and vitamin E-responsive myopathy (VEM) characterized by mitochondrial alterations in the sacrocaudalis dorsalis medialis muscle (SC).ObjectivesTo quantify muscle histopathologic abnormalities in subclinical α-TP deficient horses before and after α-TP supplementation and compare with retrospective (r)VEM cases.AnimalsProspective study; 16 healthy α-TP-deficient Quarter Horses. Retrospective study; 10 retrospective vitamin E-responsive myopathy (rVEM) cases .MethodsBlood, SC, and gluteus medius (GM) biopsy specimens were obtained before (day 0) and 56 days after 5000 IU/450 kg horse/day PO water dispersible liquid α-TP (n = 8) or control (n = 8). Muscle fiber morphology and mitochondrial alterations were compared in samples from days 0 and 56 and in rVEM cases.ResultsMitochondrial alterations more common than our reference range (<2.5% affected fibers) were present in 3/8 control and 4/8 treatment horses on day 0 in SC but not in GM (mean, 2.2; range, 0%-10% of fibers). Supplementation with α-TP for 56 days did not change the percentage of fibers with mitochondrial alterations or anguloid atrophy, or fiber size in GM or SC. Clinical rVEM horses had significantly more mitochondrial alterations (rVEM SC, 13% ± 7%; GM, 3% ± 2%) and anguloid atrophy compared to subclinical day 0 horses.Conclusions and clinical importanceClinically normal α-TP-deficient horses can have mitochondrial alterations in the SC that are less severe than in atrophied VEM cases and do not resolve after 56 days of α-TP supplementation. Preventing α-TP deficiency may be of long-term importance for mitochondrial viability

    Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

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    BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST

    In children, the microbiota of the nasopharynx and bronchoalveolar lavage fluid are both similar and different

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    RATIONALE: Sputum and bronchoalveolar lavage fluid (BALF) are often obtained to elucidate the lower airway microbiota in adults. Acquiring sputum samples from children is difficult and obtaining samples via bronchoscopy in children proves challenging due to the need for anesthesia and specialized procedural expertise; therefore nasopharyngeal (NP) swabs are often used as surrogates when investigating the pediatric airway microbiota. In adults, the airway microbiota differs significantly between NP and BALF samples however, minimal data exist in children. OBJECTIVES: To compare NP and BALF samples in children undergoing clinically indicated bronchoscopy. METHODS: NP and BALF samples were collected during clinically indicated bronchoscopy. Bacterial DNA was extracted from 72 samples (36 NP/BALF pairs); the bacterial V1-V3 region of the 16S rRNA gene was amplified and sequenced on the Illumina Miseq platform. Analysis was performed using mothur software. RESULTS: Compared to NP samples, BALF had increased richness and diversity. Similarity between paired NP and BALF (intra-subject) samples was greater than inter-subject samples (P = 0.0006). NP samples contained more Actinobacteria (2.2% vs 21%; adjusted P = 1.4 × 10-6 ), while BALF contained more Bacteroidetes (29.5% vs 3.2%; adjusted P = 1.2 × 10-9 ). At the genus level several differences existed, however Streptococcus abundance was similar in both sample types (NP 37.3% vs BAL 36.1%; adjusted P = 0.8). CONCLUSION: Our results provide evidence that NP samples can be used to distinguish differences between children, but the relative abundance of organisms may differ between the nasopharynx and lower airway in pediatric patients. Studies utilizing NP samples as surrogates for the lower airway should be interpreted with caution

    Dietary Isoflavones Alter Gut Microbiota and Lipopolysaccharide Biosynthesis to Reduce Inflammation

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    The etiopathogenesis of multiple sclerosis (MS) is strongly affected by environmental factors such as diet and the gut microbiota. An isoflavone-rich (ISO) diet was previously shown to reduce the severity of MS in the animal model experimental autoimmune encephalomyelitis (EAE). Translation of this concept to clinical trial where dietary isoflavones may be recommended for MS patients will require preliminary evidence that providing the isoflavone-rich diet to people with MS (PwMS) who lack phytoestrogen-metabolizing bacteria has beneficial effects. We have previously shown that the gut microbiota of PwMS resembles the gut microbiota of mice raised under a phytoestrogen-free (phyto-free) diet in that it lacks phytoestrogen-metabolizing bacteria. To investigate the effects of phytoestrogens on the microbiota inflammatory response and EAE disease severity we switched the diet of mice raised under a phyto-free (PF) diet to an isoflavone-rich diet. Microbiota analysis showed that the change in diet from one that is ISO to one that is PF reduces beneficial bacteria such as Bifidobacterium species. In addition we observed functional differences in lipopolysaccharide (LPS) biosynthesis pathways. Moreover LPS extracted from feces of mice fed an ISO diet induced increased production of anti-inflammatory cytokines from bone marrow-derived macrophages relative to fecal-LPS isolated from mice fed a PF diet. Eventually mice whose diet was switched from a PF diet to an ISO diet trended toward reduced EAE severity and mortality. Overall we show that an isoflavone-rich diet specifically modulates LPS biosynthesis of the gut microbiota imparts an anti-inflammatory response and decreases disease severity

    Evidence for Black Hole Growth in Local Analogs to Lyman Break Galaxies

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    We have used XMM-Newton to observe six Lyman Break Analogs (LBAs): members of the rare population of local galaxies that have properties that are very similar to distant Lyman Break Galaxies. Our six targets were specifically selected because they have optical emission-line properties that are intermediate between starbursts and Type 2 (obscured) AGN. Our new X-ray data provide an important diagnostic of the presence of an AGN. We find X-ray luminosities of order 10^{42} erg/s and ratios of X-ray to far-IR luminosities that are higher than values in pure starburst galaxies by factors ranging from ~ 3 to 30. This strongly suggests the presence of an AGN in at least some of the galaxies. The ratios of the luminosities of the hard (2-10 keV) X-ray to [O III]\lambda 5007 emission-line are low by about an order-of-magnitude compared to Type 1 AGN, but are consistent with the broad range seen in Type 2 AGN. Either the AGN hard X-rays are significantly obscured or the [O III] emission is dominated by the starburst. We searched for an iron emission line at ~ 6.4 keV, which is a key feature of obscured AGN, but only detected emission at the ~ 2\sigma level. Finally, we find that the ratios of the mid-infrared (24\mu m) continuum to [O III]\lambda 5007 luminosities in these LBAs are higher than the values for Type 2 AGN by an average of 0.8 dex. Combining all these clues, we conclude that an AGN is likely to be present, but that the bolometric luminosity is produced primarily by an intense starburst. If these black holes are radiating at the Eddington limit, their masses would lie in the range of 10^5 to 10^6 M_{sun}. These objects may offer ideal local laboratories to investigate the processes by which black holes grew in the early universe.Comment: Accepted for publication in Ap

    Pharmacists' Perspectives on the Use of My Health Record

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    Background: My Health Record (MHR) is a relatively new nationwide Australian digitalhealth record system accessible by patients and a range of healthcare professionals. Pharmacists willbe key contributors and users of the MHR system, yet little is known about the perceived barriers andbenefits of use. (2) Objective: To explore pharmacists’ perspectives related to potential benefits andbarriers associated with use of MHR. (3) Methods: An online survey was developed and face-validated.The survey was advertised to Australian pharmacists on pharmacy professional bodies’ websites. Thiswas a cross-sectional study using an anonymous questionnaire. Descriptive statistics were used todescribe the distribution of the data. Chi-square, Kendall’s tau coefficient (tau-c) and Kruskal–Wallistests were used to examine the relationships where appropriate. (4) Results: A total of 63 pharmacistscompleted the survey. The majority of respondents worked in a metropolitan area (74%), and themost common workplace setting was community pharmacy (65%). Perceived benefits identifiedby responders include that the use of MHR would help with continuity of care (90%), and that itwould improve the safety (71%) and quality (75%) of care they provided. Importantly, more thanhalf of pharmacists surveyed agreed that MHR could reduce medication errors during dispensing(57%) and could improve professional relationships with patients (57%) and general practitioners(59%). Potential barriers identified by pharmacists included patients’ concerns about privacy (81%),pharmacists’ own concern about privacy (46%), lack of training, access to and confidence in using thesystem. Sixty six percent of respondents had concerns about the accuracy of information containedwithin MHR, particularly among hospital and general practice pharmacists (p = 0.016) and almosthalf (44%) had concerns about the security of information in the system, mainly pharmacists workingat general practice and providing medication review services (p= 0.007). Overall satisfaction withMHR varied, with 48% satisfied, 33% neither satisfied nor dissatisfied, and 19% dissatisfied, witha higher satisfaction rate among younger pharmacists (p = 0.032). (5) Conclusions: Pharmacistsconsidered that the MHR offered key potential benefits, notably improving the safety and quality ofcare provided. To optimize the use of MHR, there is a need to improve privacy and data securitymeasures, and to ensure adequate provision of user support and education surrounding the ability tointegrate use of MHR with existing workflows and software

    Dissecting the structural basis of MEIG1 interaction with PACRG

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    The product of the meiosis-expressed gene 1 (MEIG1) is found in the cell bodies of spermatocytes and recruited to the manchette, a structure unique to elongating spermatids, by Parkin co-regulated gene (PACRG). This complex is essential for targeting cargo to the manchette during sperm flagellum assembly. Here we show that MEIG1 adopts a unique fold that provides a large surface for interacting with other proteins. We mutated 12 exposed and conserved amino acids and show that four of these mutations (W50A, K57E, F66A, Y68A) dramatically reduce binding to PACRG. These four amino acids form a contiguous hydrophobic patch on one end of the protein. Furthermore, each of these four mutations diminishes the ability of MEIG1 to stabilize PACRG when expressed in bacteria. Together these studies establish the unique structure and key interaction surface of MEIG1 and provide a framework to explore how MEIG1 recruits proteins to build the sperm tail

    Annotated Bibliography of Research in the Teaching of English

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    Since 2003, RTE has published the annual “Annotated Bibliography of Research in the Teaching of English,” a list of curated and annotated works reviewed and selected by a large group of dedicated educator-scholars in our field. The goal of the annual bibliography is to offer a synthesis of the research published in the area of English language arts within the past year for RTE readers’ consideration. Abstracted citations and those featured in the “Other Related Research” sections were published, either in print or online, between June 2020 and June 2021. The bibliography is divided into nine sections, with some changes to the categories this year in response to the ever-evolving nature of research in the field. Small teams of scholars with diverse research interests and background experiences in preK–16 educational settings reviewed and selected the manuscripts for each section using library databases and leading scholarly journals. Each team abstracted significant contributions to the body of peer-reviewed studies that addressed the current research questions and concerns in their topic area

    CYberinfrastructure for COmparative effectiveness REsearch (CYCORE): improving data from cancer clinical trials

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    Improved approaches and methodologies are needed to conduct comparative effectiveness research (CER) in oncology. While cancer therapies continue to emerge at a rapid pace, the review, synthesis, and dissemination of evidence-based interventions across clinical trials lag in comparison. Rigorous and systematic testing of competing therapies has been clouded by age-old problems: poor patient adherence, inability to objectively measure the environmental influences on health, lack of knowledge about patients’ lifestyle behaviors that may affect cancer’s progression and recurrence, and limited ability to compile and interpret the wide range of variables that must be considered in the cancer treatment. This lack of data integration limits the potential for patients and clinicians to engage in fully informed decision-making regarding cancer prevention, treatment, and survivorship care, and the translation of research results into mainstream medical care. Particularly important, as noted in a 2009 report on CER to the President and Congress, the limited focus on health behavior-change interventions was a major hindrance in this research landscape (DHHS 2009). This paper describes an initiative to improve CER for cancer by addressing several of these limitations. The Cyberinfrastructure for Comparative Effectiveness Research (CYCORE) project, informed by the National Science Foundation’s 2007 report “Cyberinfrastructure Vision for 21st Century Discovery” has, as its central aim, the creation of a prototype for a user-friendly, open-source cyberinfrastructure (CI) that supports acquisition, storage, visualization, analysis, and sharing of data important for cancer-related CER. Although still under development, the process of gathering requirements for CYCORE has revealed new ways in which CI design can significantly improve the collection and analysis of a wide variety of data types, and has resulted in new and important partnerships among cancer researchers engaged in advancing health-related CI
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