160 results on '"C. Holder"'
Search Results
2. Neurodevelopment outcomes based on timing of transcatheter PDA closure in extremely low birth weight infants
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R Philip, C Sentilles, C Holder, A Bejnood, SK Chilakala, L Apalodimas, J Johnson, and S Sathanandam
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General Medicine - Published
- 2023
3. COMPARISON OF RATES OF ASEPTIC LOOSENING IN HIGH OFFSET VERSUS STANDARD OFFSET CEMENTLESS FEMORAL STEMS
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A. Faveere, L. Milne, C. Holder, and S.E. Graves
- Abstract
Increasing femoral offset in total hip replacement (THR) has several benefits including improved hip abductor strength and enhanced range of motion. Biomechanical studies have suggested that this may negatively impact on stem stability. However, it is unclear whether this has a clinical impact. Using data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), the aim of this study was to determine the impact of stem offset and stem size for the three most common cementless THR prostheses revised for aseptic loosening.The study period was September 1999 to December 2020. The study population included all primary procedures for osteoarthritis with a cementless THR using the Corail, Quadra-H and Polarstem. Procedures were divided into small and large stem sizes and by standard and high stem offset for each stem system. Hazard ratios (HR) from Cox proportional hazards models, adjusting for age and gender, were performed to compare revision for aseptic loosening for offset and stem size for each of the three femoral stems.There were 55,194 Corail stems, 13,642 Quadra-H stem, and 13,736 Polarstem prostheses included in this study. For the Corail stem, offset had an impact only when small stems were used (sizes 8-11). Revision for aseptic loosening was increased for the high offset stem (HR=1.90;95% CI 1.53–2.37;pThere was also a higher revision risk for aseptic loosening for high offset small size Quadra-H stems (sizes 0-3). Similar to the Corail stem, offset did not impact on the revision risk for larger stems (Corail sizes 12-20, Quadra-H sizes 4-7). The Polarstem did not show any difference in aseptic loosening revision risk when high and standard offset stems were compared, and this was irrespective of stem size.High offset may be associated with increased revision for aseptic loosening, but this is both stem size and prosthesis specific.
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- 2023
4. EARLY REVISION RATES OF TOTAL HIP ARTHROPLASTY USING INTELLIJOINT HIP® COMPUTER NAVIGATION SYSTEM: A STUDY FROM THE AUSTRALIAN NATIONAL JOINT REPLACEMENT REGISTRY OF 1,911 PROCEDURES
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E.C. Lourens, A.P. Kurmis, C. Holder, and R. N. de Steiger
- Abstract
Total hip arthroplasty (THA) is an effective treatment for symptomatic hip osteoarthritis (OA). Computer-navigation technologies in total knee arthroplasty show evidence-supported survivorship advantages and are used widely. The aim of this study was to determine the revision outcome of hip commercially available navigation technologies.Data from the Australian Orthopaedic Association National Joint Replacement Registry from January 2016 to December 2020 included all primary THA procedures performed for osteoarthritis (OA). Procedures using the Intellijoint HIP® navigation were identified and compared to procedures inserted using ‘other’ computer navigation systems and to all non-navigated procedures. The cumulative percent revision (CPR) was compared between the three groups using Kaplan-Meier estimates of survivorship and hazard ratios (HR) from Cox proportional hazards models, adjusted for age and gender. A prosthesis specific analysis was also performed.There were 1911 procedures that used the Intellijoint® system, 4081 used ‘other’ computer navigation, and 160,661 were non-navigated. The all-cause 2-year CPR rate for the Intellijoint HIP® system was 1.8% (95% CI 1.2, 2.6), compared to 2.2% (95% CI 1.8, 2.8) for other navigated and 2.2% (95% CI 2.1, 2.3) for non-navigated cases. A prosthesis specific analysis identified the Paragon/Acetabular Shell THAs combined with the Intellijoint HIP® system as having a higher (3.4%) rate of revision than non-navigated THAs (HR = 2.00 (1.01, 4.00), p=0.048).When this outlier combination was excluded, the Intellijoint® system group demonstrated a two-year CPR of 1.3%. There was no statistical difference in the CPR between the three groups before or after excluding Paragon/Acetabular Shell system.The preliminary data presented demonstrate no statistical difference in all cause revision rates when comparing the Intellijoint HIP® THA navigation system with ‘other’ navigation systems and ‘non-navigated’ approaches for primary THAs performed for OA. The current sample size remains too small to permit meaningful subgroup statistical comparisons.
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- 2023
5. In Vivo Evaluation of Three-Dimensional Printed, Keratin-Based Hydrogels in a Porcine Thermal Burn Model
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John P. Fisher, Javier Navarro, Alexis R. Gabard, Gregory J. Herendeen, Luke Burnett, Robert C Holder, Robert J. Christy, and Ryan M. Clohessy
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chemistry.chemical_classification ,integumentary system ,Halofuginone ,Biomedical Engineering ,Biomaterial ,Bioengineering ,Original Articles ,macromolecular substances ,medicine.disease ,Biochemistry ,Thermal burn ,Biomaterials ,chemistry ,Fibrosis ,In vivo ,Keratin ,Self-healing hydrogels ,medicine ,Wound healing ,Biomedical engineering ,medicine.drug - Abstract
Keratin is a natural material that can be derived from the cortex of human hair. Our group had previously presented a method for the printed, sequential production of three-dimensional (3D) keratin scaffolds. Using a riboflavin–sodium persulfate–hydroquinone (initiator–catalyst–inhibitor) photosensitive solution, we produced 3D keratin-based constructs through ultraviolet crosslinking in a lithography-based 3D printer. In this study, we have used this bioink to produce a keratin-based construct that is capable of delivering small molecules, providing an environment conducive to healing of dermal burn wounds in vivo, and maintaining stability in customized packaging. We characterized the effects of manufacturing steps, such as lyophilization and gamma irradiation sterilization on the properties of 3D printed keratin scaffolds prepared for in vivo testing. Keratin hydrogels are viable for the uptake and release of contracture-inhibiting Halofuginone, a collagen synthesis inhibitor that has been shown to decrease collagen synthesis in fibrosis cases. This small-molecule delivery provides a mechanism to reduce scarring of severe burn wounds in vitro. In vivo data show that the Halofuginone-laden printed keratin is noninferior to other similar approaches reported in literature. This is indicative that the use of 3D printed keratin is not inhibiting the healing processes, and the inclusion of Halofuginone induces a more organized dermal healing after a burn; in other words, this treatment is slower but improves healing. These studies are indicative of the potential of Halofuginone-laden keratin dressings in dermal wound healing. We aim to keep increasing the complexity of the 3D printed constructs toward the production of complex scaffolds for the treatment and topographical reconstruction of severe burn wounds to the face. IMPACT STATEMENT: Keratin-based photosensitive bioink can be used to three-dimensionally (3D) print complex scaffolds for the topical treatment of dermal burn wounds. We have developed reproducible protocols that allow us to 3D print large volumes of keratin-based hydrogels, and we now have a better understanding of how 3D printed geometrical features, crosslinking properties, or mass are altered due to the manufacturing processes. The printed hydrogels improved healing parameters in vivo on a porcine thermal burn model, indicative of the potential of the scaffolds for the regeneration of complex dermal wounds. Overall, our approach elucidates on physiological and topographical 3D healing of burn wounds.
- Published
- 2020
6. A Multicatalytic Approach to the Hydroaminomethylation of α‐Olefins
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Jeffrey C. Holder, John F. Hartwig, and Steven Hanna
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Formates ,chemistry.chemical_element ,Alkenes ,Iridium ,010402 general chemistry ,Transfer hydrogenation ,Methylation ,01 natural sciences ,Reductive amination ,Article ,Catalysis ,Rhodium ,chemistry.chemical_compound ,Coordination Complexes ,Amines ,Alkyl ,Amination ,chemistry.chemical_classification ,Sulfonamides ,Molecular Structure ,010405 organic chemistry ,Sodium formate ,Aryl ,General Chemistry ,General Medicine ,Combinatorial chemistry ,0104 chemical sciences ,chemistry ,Hydrogenation ,Hydroformylation - Abstract
We report an approach to conducting the hydroaminomethylation of diverse α-olefins with a wide range of alkyl, aryl, and heteroarylamines at low temperatures (70–80 °C) and pressures (1.0–3.4 bar) of synthesis gas. This approach is based on simultaneously using two distinct catalysts that are mutually compatible. The hydroformylation step is catalyzed by a rhodium diphosphine complex, and the reductive amination step, which is conducted as a transfer hydrogenation with aqueous, buffered sodium formate as the reducing agent, is catalyzed by a cyclometallated iridium complex. By adjusting the ratio of CO to H(2), we conducted the reaction at one atmosphere of gas with little change in yield. A diverse array of olefins and amines, including hetreroarylamines that do not react under more conventional conditions with a single catalyst, underwent hydroaminomethylation with this new system, and the pharmaceutical ibutilide was prepared in higher yield and under milder conditions than those reported with a single catalyst.
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- 2019
7. Transcriptomic characterization of microglia activation in a rat model of ischemic stroke
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Emiri T. Mandeville, Wenlu Li, Wenjun Deng, MingMing Ning, Eng H. Lo, Ken Arai, Aaron Tt Chuang, Julie C. Holder, Yasukazu Terasaki, and Changhong Xing
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Male ,Inflammatory response ,Rat model ,Brain Ischemia ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Animals ,Stroke ,030304 developmental biology ,0303 health sciences ,Microglia ,business.industry ,Original Articles ,medicine.disease ,Phenotype ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Neurology ,Ischemic stroke ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Microglia are key regulators of inflammatory response after stroke and brain injury. To better understand activation of microglia as well as their phenotypic diversity after ischemic stroke, we profiled the transcriptome of microglia after 75 min transient focal cerebral ischemia in 3-month- and 12-month-old male spontaneously hypertensive rats. Microglia were isolated from the brains by FACS sorting on days 3 and 14 after cerebral ischemia. GeneChip Rat 1.0ST microarray was used to profile the whole transcriptome of sorted microglia. We identified an evolving and complex pattern of activation from 3 to 14 days after stroke onset. M2-like patterns were extensively and persistently upregulated over time. M1-like patterns were only mildly upregulated, mostly at day 14. Younger 3-month-old brains showed a larger microglial response in both pro- and anti-inflammatory pathways, compared to older 12-month-old brains. Importantly, our data revealed that after stroke, most microglia are activated towards a wide spectrum of novel polarization states beyond the standard M1/M2 dichotomy, especially in pathways related to TLR2 and dietary fatty acid signaling. Finally, classes of transcription factors that might potentially regulate microglial activation were identified. These findings should provide a comprehensive database for dissecting microglial mechanisms and pursuing neuroinflammation targets for acute ischemic stroke.
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- 2020
8. Pediatrics - 2 Childhood Primary CNS Vasculitis: A Series of Case Studies
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N Shay and C Holder
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Psychiatry and Mental health ,Clinical Psychology ,Pediatrics ,medicine.medical_specialty ,Neuropsychology and Physiological Psychology ,business.industry ,medicine ,Primary CNS Vasculitis ,General Medicine ,business - Published
- 2018
9. Pediatrics-2Validation of the MVP in an Epileptic Population
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C Holder and N Shay
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Pediatrics ,medicine.medical_specialty ,education.field_of_study ,business.industry ,05 social sciences ,Population ,General Medicine ,03 medical and health sciences ,Psychiatry and Mental health ,Clinical Psychology ,0302 clinical medicine ,Neuropsychology and Physiological Psychology ,medicine ,0501 psychology and cognitive sciences ,business ,education ,030217 neurology & neurosurgery ,050104 developmental & child psychology - Published
- 2017
10. Efficacy of a mouthrinse based on hydroxyapatite to reduce initial bacterial colonisation in situ
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N Tahan, C Holder, Matthias Hannig, Anna Kensche, Sabine Basche, and Christian Hannig
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Adult ,In situ ,Mouthwashes ,Dental pellicle ,02 engineering and technology ,Bacterial Adhesion ,Microbiology ,Streptococcus mutans ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Dental Pellicle ,Dental Enamel ,Saliva ,General Dentistry ,Microbial Viability ,biology ,Enamel paint ,Chemistry ,Chlorhexidine ,Biofilm ,Tooth surface ,030206 dentistry ,Cell Biology ,General Medicine ,Adhesion ,Middle Aged ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Microscopy, Electron ,Durapatite ,Microscopy, Fluorescence ,Otorhinolaryngology ,Biofilms ,visual_art ,visual_art.visual_art_medium ,Cattle ,0210 nano-technology ,Nuclear chemistry ,medicine.drug - Abstract
Objective The present in situ - investigation aimed to specify the impact of pure hydroxyapatite microclusters on initial bioadhesion and bacterial colonization at the tooth surface. Design Pellicle formation was carried out in situ on bovine enamel slabs (9 subjects). After 1 min of pellicle formation rinses with 8 ml of hydroxyapatite (HA) microclusters (5%) in bidestilled water or chlorhexidine 0.2% were performed. As negative control no rinse was adopted. In situ biofilm formation was promoted by the intraoral slab exposure for 8 h overnight. Afterwards initial bacterial adhesion was quantified by DAPI staining and bacterial viability was determined in vivo/in vitro by live/dead-staining (BacLight). SEM analysis evaluated the efficacy of the mouthrinse to accumulate hydroxyapatite microclusters at the specimens’ surface and spit-out samples of the testsolution were investigated by TEM. Results Compared to the control (2.36 × 106 ± 2.01 × 106 bacteria/cm2), significantly reduced amounts of adherent bacteria were detected on specimens rinsed with chlorhexidine 0.2% (8.73 × 104 ± 1.37 × 105 bacteria/cm2) and likewise after rinses with the hydroxyapatite testsolution (2.08 × 105 ± 2.85 × 105 bacteria/cm2, p Conclusion Hydroxyapatite microclusters reduced initial bacterial adhesion to enamel in situ considerably and could therefore sensibly supplement current approaches in dental prophylaxis.
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- 2017
11. 'Wasserspiele' im öffentlichen Raum – Herausforderung für die Wasserhygiene?
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B Knorr, S Brockmann, A Karras, and C Holder
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Public Health, Environmental and Occupational Health - Published
- 2017
12. Begehung von invasiven Heilpraktikerpraxen offenbart Hygienemängel
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S Brockmann, J Fritz, C Holder, Martin Eichner, and V Brocke
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Public Health, Environmental and Occupational Health - Published
- 2017
13. Family PArtners in Lifestyle Support (PALS): Family-based weight loss for African American adults with type 2 diabetes
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Gwendolyn Davis, Shiriki K. Kumanyika, Laura P. Svetkey, Judith C. Holder-Cooper, Sonia P. Steele, Thomas C. Keyserling, Carmen D. Samuel-Hodge, Ziya Gizlice, and Phillip J. Brantley
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Gerontology ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Type 2 diabetes ,Overweight ,law.invention ,03 medical and health sciences ,Social support ,0302 clinical medicine ,Endocrinology ,Randomized controlled trial ,Weight loss ,law ,Diabetes mellitus ,Intervention (counseling) ,medicine ,030212 general & internal medicine ,Nutrition and Dietetics ,business.industry ,16. Peace & justice ,medicine.disease ,Obesity ,3. Good health ,medicine.symptom ,business ,Demography - Abstract
Objective To develop and test a family-centered behavioral weight loss intervention for African American adults with type 2 diabetes. Methods In this randomized trial, dyads consisting of an African American adult with overweight or obesity and type 2 diabetes (index participant) paired with a family partner with overweight or obesity but not diagnosed with diabetes were assigned in a 2:1 ratio to a 20-week special intervention (SI) or delayed intervention (DI) control group. The primary outcome was weight loss among index participants at the 20-week follow-up. Results One hundred eight participants (54 dyads—36 (SI) and 18 (DI) dyads) were enrolled: 81% females; mean age, 51 years; mean weight,103 kg; and mean BMI, 37 kg/m2. At post-intervention, 96 participants (89%) returned for follow-up measures. Among index participants, mean difference in weight loss between groups was −5.0 kg, P
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- 2016
14. Preparation of (
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Jeffrey C, Holder, Samantha E, Shockley, Mario P, Wiesenfeldt, Hideki, Shimizu, and Brian M, Stoltz
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- 2019
15. A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity
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Mohamed Elmasry, Cerys A. Lovatt, Julie C. Holder, Christopher E. Goldring, Hélène Aerts, Christopher A. Schofield, Helga H.J. Gerets, Delphine Hoët, Richard J. Weaver, Eliane Alexandre, Lysiane Richert, Gilles Labbe, Esther Johann, Sébastien Anthérieu, Martina Dorau, Magnus Ingelman-Sundberg, B. Kevin Park, Neil R. Kitteringham, Robert P. Jones, Simone H. Stahl, Philip G. Hewitt, Rowena Sison-Young, and Volker M. Lauschke
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0301 basic medicine ,Drug ,Cytotoxicity ,Health, Toxicology and Mutagenesis ,media_common.quotation_subject ,Cell ,Acute ,Pharmacology ,Toxicology ,030226 pharmacology & pharmacy ,Organ Toxicity and Mechanisms ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,Predictive toxicology ,Toxicity Tests, Acute ,Humans ,Medicine ,Cells, Cultured ,media_common ,Cryopreservation ,Liver injury ,Toxicity ,business.industry ,Reproducibility of Results ,Hep G2 Cells ,General Medicine ,medicine.disease ,In vitro ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Hepatocytes ,Hepatic stellate cell ,Pharmaceuticals ,Chemical and Drug Induced Liver Injury ,business - Abstract
Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and four non-DILI implicated in man) were selected for our study, which was conducted, for the first time, across multiple laboratories. None of the cell models could distinguish faithfully between DILI and non-DILI compounds. Only when nominal in vitro concentrations were adjusted for in vivo exposure levels were primary human hepatocytes (PHH) found to be the most accurate cell model, closely followed by HepG2. From a practical perspective, this study revealed significant inter-laboratory variation in the response of PHH, HepG2 and Upcyte cells, but not HepaRG cells. This variation was also observed to be compound dependent. Interestingly, differences between donors (hepatocytes), clones (HepG2) and the effect of cryopreservation (HepaRG and hepatocytes) were less important than differences between the cell models per se. In summary, these results demonstrate that basic cell health endpoints will not predict hepatotoxic risk in simple hepatic cells in the absence of pharmacokinetic data and that a multicenter assessment of more sophisticated signals of molecular initiating events is required to determine whether these cells can be incorporated in early safety assessment. Electronic supplementary material The online version of this article (doi:10.1007/s00204-016-1745-4) contains supplementary material, which is available to authorized users.
- Published
- 2016
16. Erwartungen in himmelblau und rosarot: Erklärung für Geschlechterdifferenzen im lebenslangen Lernen
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Markus Dresel, Natalie Fischer, Barbara Schober, Albert Ziegler, Ruth Rustemeyer, Peter H. Ludwig, Martin C. Holder, and Monika Finsterwald
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Befunde der padagogischen Geschlechterforschung der letzten Jahre zeigen, dass Schulerinnen und Schuler teils ausgepragte Differenzen in selbstbezogenen Kognitionen aufweisen. Auch ihre Eltern und Lehrkrafte unterscheiden in ihren zukunftsbezogenen Uberzeugungen deutlich zwischen weiblichen und mannlichen Lernenden. Zu solchen Erwartungskonstrukten zahlen die Erfolgszuversicht hinsichtlich der Leistungsfahigkeit, das allgemein-schulische und domanenspezifische Selbstvertrauen bzw. das Fahigkeitsselbstkonzept sowie das Bild von der eigenen Begabung. Mit diesen gleichzustellende erwartungsnahe bzw. formende mentale Konzepte sind geschlechtsdifferente Stereotypen, Vorurteile und Kausalattribuierungen des Lernerfolgs sowie das Selbstwertgefuhl (Ludwig 1991).
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- 2018
17. AB1423-HPR Impact of osteoarthritis on work participation: a systematic review
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C. Holder, S Secchi, and Yeliz Prior
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Biopsychosocial model ,Gerontology ,business.industry ,Presenteeism ,Psychological intervention ,Absenteeism ,Medicine ,Observational study ,Scientific literature ,business ,Medical literature ,Qualitative research - Abstract
Background Osteoarthritis (OA) is a common musculoskeletal condition in working age adults and linked to substantial reduction is work productivity and increased risk of work loss.1,2 Objectives This systematic review aimed to investigate the impact of OA on the individual’s work participation to identify targets for interventions and reduce the risk of future work loss. Methods Database searches included the Cochrane Library, Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health literature, King’s Fund, Allied and Alternative Medicine, Psychological Information Database, Applied Social Sciences Index and Abstracts, Ageline, Social Services Abstracts and British Nursing Index from earliest to November 2017. The PRISMA statement was used to guide the process. Observational, interventional and qualitative studies were included in the review and their methodological quality was assessed by two researchers using the Johanna Brigg Institute Checklists. Results Twenty-two studies, which were published in 2007 to 2016 (12 cross sectional; 5 cohort; and 5 qualitative) were included. Measurement of workplace limitation varied largely amongst the studies. High pain intensity, decreased physical functioning, physically demanding jobs, lack of opportunities to re-train, and lack of co-worker support were identified as important workplace factors associated with loss of productivity, and both presenteeism and absenteeism were predictive of job disruption and premature work loss. Function was identified as an important mediator of the impact of pain on work productivity, with physiotherapy and exercise classes that target pain and physical function3 and maximising work place support4 being recommended to prevent or reduce loss of work productivity. Qualitative studies emphasised the significance of physical environments, and social networks and support, recommending interventions to target individual needs to prevent future work loss.5 Conclusions There is a wide range of scientific literature to suggest working people with OA are experiencing work instability due to pain, reduced physical functioning, activity limitation, and lack of co-worker and workplace support, placing them at increased risk of work disability. However, the measurement of workplace limitation varies greatly in this literature, making it hard to conduct empirical comparisons. Due to the temporal and biopsychosocial nature of work disability, there is a need for longitudinal studies to investigate the links between workplace factors and the onset and persistence of work instability in people with OA. Additionally, future qualitative studies should explore the role of personal and psychological factors, such as an individual’s self-efficacy and coping skills, and the employer’s perspectives on the provision of workplace support, to establish whether these potentially modifiable factors could influence work outcomes in people with OA. References [1] Kingsbury, et al. Rheumatology2014;53:937–947 [2] Sharif, et al. Rheumatology2016;55:861–868 [3] Wlikie, et al. PlosOne2015;10(4):e0120042. [4] Wilkie, et al. Rhuematology2014;53:459–469 [5] Bromann, et al. Dis & Rehab2014;36:19 Acknowledgements This project was funded by the National Centre of Excellence for Musculoskeletal Health and Work (CMHW); a multidisciplinary collaboration funded by Arthritis Research UK and the Medical Research Council (MRC). Disclosure of Interest None declared
- Published
- 2018
18. A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H
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Brian M. Stoltz, Jeffrey C. Holder, and Samantha E. Shockley
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Letter ,Molecular Structure ,Bicyclic molecule ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Enantioselective synthesis ,Rational design ,chemistry.chemical_element ,Stereoisomerism ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Stereocenter ,Diterpenes ,Physical and Theoretical Chemistry ,Palladium ,Conjugate - Abstract
A catalytic, enantioselective formal synthesis of (+)-dichroanone and (+)-taiwaniaquinone H is reported. The all-carbon quaternary stereocenter was constructed by asymmetric conjugate addition catalyzed by a palladium(II) (S)-tert-butylpyridinooxazoline complex. The unexpected formation of a [3.2.1] bicyclic intermediate required the identification of a new route. Analysis of the Hammett constants for para-substituted arenes enabled the rational design of a highly enantioselective conjugate addition substrate that led to the completion of the formal synthesis.
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- 2014
19. Role of IscX in Iron–Sulfur Cluster Biogenesis in Escherichia coli
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Jameson R. Bothe, Ronnie O. Frederick, Jin Hae Kim, John L. Markley, and Johneisa C. Holder
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inorganic chemicals ,Stereochemistry ,Iron ,Iron–sulfur cluster ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,03 medical and health sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Iron-Binding Proteins ,Escherichia coli ,medicine ,Ternary complex ,030304 developmental biology ,0303 health sciences ,Binding Sites ,biology ,Cysteine desulfurase ,Escherichia coli Proteins ,fungi ,Small acidic protein ,General Chemistry ,0104 chemical sciences ,Carbon-Sulfur Lyases ,Cross-Linking Reagents ,chemistry ,Cysteine desulfurase activity ,biology.protein ,Ferric ,ISCU ,Sulfur ,medicine.drug ,Cysteine - Abstract
The Escherichia coli isc operon encodes key proteins involved in the biosynthesis of iron–sulfur (Fe–S) clusters. Whereas extensive studies of most ISC proteins have revealed their functional properties, the role of IscX (also dubbed YfhJ), a small acidic protein encoded by the last gene in the operon, has remained in question. Previous studies showed that IscX binds iron ions and interacts with the cysteine desulfurase (IscS) and the scaffold protein for cluster assembly (IscU), and it has been proposed that IscX functions either as an iron supplier or a regulator of Fe–S cluster biogenesis. We have used a combination of NMR spectroscopy, small-angle X-ray scattering (SAXS), chemical cross-linking, and enzymatic assays to enlarge our understanding of the interactions of IscX with iron ions, IscU, and IscS. We used chemical shift perturbation to identify the binding interfaces of IscX and IscU in their complex. NMR studies showed that Fe2+ from added ferrous ammonium sulfate binds IscX much more avidly than does Fe3+ from added ferric ammonium citrate and that Fe2+ strengthens the interaction between IscX and IscU. We found that the addition of IscX to the IscU–IscS binary complex led to the formation of a ternary complex with reduced cysteine desulfurasemore » activity, and we determined a low-resolution model for that complex from a combination of NMR and SAXS data. We postulate that the inhibition of cysteine desulfurase activity by IscX serves to reduce unproductive conversion of cysteine to alanine. By incorporating these new findings with results from prior studies, we propose a detailed mechanism for Fe–S cluster assembly in which IscX serves both as a donor of Fe2+ and as a regulator of cysteine desulfurase activity.« less
- Published
- 2014
20. OMICS AND PROGNSTIC MARKERS
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K. Adachi, H. Sasaki, S. Nagahisa, K. Yoshida, N. Hattori, Y. Nishiyama, T. Kawase, M. Hasegawa, M. Abe, Y. Hirose, A. Alentorn, Y. Marie, S. Poggioli, H. Alshehhi, B. Boisselier, C. Carpentier, K. Mokhtari, L. Capelle, D. Figarella-Branger, K. Hoang-Xuan, M. Sanson, J.-Y. Delattre, A. Idbaih, S. Yust-Katz, M. Anderson, A. Olar, A. Eterovic, N. Ezzeddine, K. Chen, H. Zhao, G. Fuller, K. Aldape, J. de Groot, N. Andor, J. Harness, S. G. Lopez, T. L. Fung, H. W. Mewes, C. Petritsch, A. Arivazhagan, K. Somasundaram, K. Thennarasu, P. Pandey, B. Anandh, V. Santosh, B. Chandramouli, A. Hegde, P. Kondaiah, M. Rao, R. Bell, R. Kang, C. Hong, J. Song, J. Costello, R. Nagarajan, B. Zhang, A. Diaz, T. Wang, L. Bie, Y. Li, H. Liu, W. F. C. Luyo, M. H. Carnero, M. E. P. Iruegas, A. R. Morell, M. C. Figueiras, R. L. Lopez, C. F. Valverde, A. K.-Y. Chan, J. C.-S. Pang, N. Y.-F. Chung, K. K.-W. Li, W. S. Poon, D. T.-M. Chan, Y. Wang, H.-a. K. Ng, M. Chaumeil, P. Larson, H. Yoshihara, D. Vigneron, S. Nelson, R. Pieper, J. Phillips, S. Ronen, V. Clark, Z. E. Omay, A. Serin, J. Gunel, B. Omay, C. Grady, M. Youngblood, K. Bilguvar, J. Baehring, J. Piepmeier, P. Gutin, A. Vortmeyer, C. Brennan, M. N. Pamir, T. Kilic, B. Krischek, M. Simon, K. Yasuno, M. Gunel, A. L. Cohen, M. Sato, K. D. Aldape, C. Mason, K. Diefes, L. Heathcock, L. Abegglen, D. Shrieve, W. Couldwell, J. D. Schiffman, H. Colman, Q. G. D'Alessandris, T. Cenci, M. Martini, L. Ricci-Vitiani, R. De Maria, L. M. Larocca, R. Pallini, B. Theeler, F. Lang, G. Rao, M. Gilbert, E. Sulman, R. Luthra, K. Eterovic, M. Routbort, R. Verhaak, G. Mills, J. Mendelsohn, F. Meric-Bernstam, A. Yung, K. MacArthur, S. Hahn, G. Kao, R. Lustig, M. Alonso-Basanta, S. Chandrasekaran, E. P. Wileyto, E. Reyes, J. Dorsey, K. Fujii, K. Kurozumi, T. Ichikawa, M. Onishi, J. Ishida, Y. Shimazu, B. Kaur, E. A. Chiocca, I. Date, C. Geisenberger, A. Mock, R. Warta, C. Schwager, C. Hartmann, A. von Deimling, A. Abdollahi, C. Herold-Mende, O. Gevaert, A. Achrol, S. Gholamin, S. Mitra, E. Westbroek, J. Loya, L. Mitchell, S. Chang, G. Steinberg, S. Plevritis, S. Cheshier, J. Xu, S. Napel, G. Zaharchuk, G. Harsh, D. Gutman, C. Holder, R. Colen, W. Dunn, R. Jain, L. Cooper, S. Hwang, A. Flanders, D. Brat, J. Hayes, A. Droop, H. Thygesen, M. Boissinot, D. Westhead, S. Short, S. Lawler, P. Bady, S. Kurscheid, M. Delorenzi, M. E. Hegi, C. Crosby, C. Faulkner, T. Smye-Rumsby, K. Kurian, M. Williams, K. Hopkins, A. Palmer, H. Williams, C. Wragg, H. R. Haynes, K. M. Kurian, P. White, T. Oka, L. Jalbert, A. Elkhaled, R. Jensen, K. Salzman, M. Schabel, D. Gillespie, M. Mumert, B. Johnson, T. Mazor, M. Barnes, S. Yamamoto, H. Ueda, K. Tatsuno, K. Aihara, A. Bollen, M. Hirst, M. Marra, A. Mukasa, N. Saito, H. Aburatani, M. Berger, B. Taylor, S. Popov, A. Mackay, W. Ingram, A. Burford, A. Jury, M. Vinci, C. Jones, D. T. W. Jones, V. Hovestadt, S. Picelli, W. Wang, P. A. Northcott, M. Kool, G. Reifenberger, T. Pietsch, M. Sultan, H. Lehrach, M.-L. Yaspo, A. Borkhardt, P. Landgraf, R. Eils, A. Korshunov, M. Zapatka, B. Radlwimmer, S. M. Pfister, P. Lichter, A. Joy, I. Smirnov, M. Reiser, W. Shapiro, S. Kim, B. Feuerstein, C. Jungk, S. Friauf, A. Unterberg, T. A. Juratli, J. McElroy, W. Meng, A. Huebner, K. D. Geiger, D. Krex, G. Schackert, A. Chakravarti, T. Lautenschlaeger, B. Y. Kim, W. Jiang, J. Beiko, S. Prabhu, F. DeMonte, R. Sawaya, D. Cahill, I. McCutcheon, C. Lau, L. Wang, K. Terashima, S. Yamaguchi, M. Burstein, J. Sun, T. Suzuki, R. Nishikawa, H. Nakamura, A. Natsume, S. Terasaka, H.-K. Ng, D. Muzny, R. Gibbs, D. Wheeler, X.-q. Zhang, S. Sun, K.-f. Lam, K. M. Y. Kiang, J. K. S. Pu, A. S. W. Ho, G. K. K. Leung, F. Loebel, W. T. Curry, F. G. Barker, N. Lelic, A. S. Chi, D. P. Cahill, D. Lu, J. Yin, C. Teo, K. McDonald, A. Madhankumar, C. Weston, B. Slagle-Webb, J. Sheehan, A. Patel, M. Glantz, J. Connor, C. Maire, J. Francis, C.-Z. Zhang, J. Jung, V. Manzo, V. Adalsteinsson, H. Homer, B. Blumenstiel, C. S. Pedamallu, E. Nickerson, A. Ligon, C. Love, M. Meyerson, K. Ligon, L. E. Jalbert, S. J. Nelson, A. W. Bollen, I. V. Smirnov, J. S. Song, A. B. Olshen, M. S. Berger, S. M. Chang, B. S. Taylor, J. F. Costello, S. Mehta, B. Armstrong, S. Peng, A. Bapat, M. Berens, B. Melendez, M. Mollejo, P. Mur, T. Hernandez-Iglesias, C. Fiano, J. Ruiz, J. A. Rey, V. Stadler, A. Schulte, K. Lamszus, C. Schichor, M. Westphal, J.-C. Tonn, O. Morozova, S. Katzman, M. Grifford, S. Salama, D. Haussler, A. Olshen, S. Fouse, S. Nakamizo, T. Sasayama, H. Tanaka, K. Tanaka, K. Mizukawa, M. Yoshida, E. Kohmura, P. Northcott, D. Jones, S. Pfister, R. Otani, S. Takayanagi, K. Saito, S. Tanaka, M. Shin, T. Ozawa, M. Riester, Y.-K. Cheng, J. Huse, K. Helmy, N. Charles, M. Squatrito, F. Michor, E. Holland, M. Perrech, L. Dreher, G. Rohn, R. Goldbrunner, M. Timmer, B. Pollo, V. Palumbo, C. Calatozzolo, M. Patane, R. Nunziata, M. Farinotti, A. Silvani, S. Lodrini, G. Finocchiaro, E. Lopez, A. Rioscovian, R. Ruiz, G. Siordia, A. P. de Leon, C. Rostomily, R. Rostomily, D. Silbergeld, D. Kolstoe, M. Chamberlain, J. Silber, P. Roth, A. Keller, J. Hoheisel, P. Codo, A. Bauer, C. Backes, P. Leidinger, E. Meese, E. Thiel, A. Korfel, M. Weller, G. Nagae, M. Nagane, J. Z. Sanborn, T. Mikkelsen, S. Jhanwar, L. Chin, M. Nishihara, M. Schliesser, C. Grimm, E. Weiss, R. Claus, D. Weichenhan, M. Weiler, T. Hielscher, F. Sahm, B. Wiestler, A.-C. Klein, J. Blaes, C. Plass, W. Wick, G. Stragliotto, A. Rahbar, C. Soderberg-Naucler, M. Won, R. Ezhilarasan, P. Sun, D. Blumenthal, M. Vogelbaum, R. Jenkins, R. Jeraj, P. Brown, K. Jaeckle, D. Schiff, J. Dignam, J. Atkins, D. Brachman, M. Werner-Wasik, M. Mehta, J. Shen, J. Luan, A. Yu, M. Matsutani, Y. Liang, T.-K. Man, A. Trister, M. Tokita, S. Mikheeva, A. Mikheev, S. Friend, M. van den Bent, L. Erdem, T. Gorlia, M. Taphoorn, J. Kros, P. Wesseling, H. Dubbink, A. Ibdaih, P. French, H. van Thuijl, J. Heimans, B. Ylstra, J. Reijneveld, A. Prabowo, I. Scheinin, H. van Essen, W. Spliet, C. Ferrier, P. van Rijen, T. Veersema, M. Thom, A. S.-v. Meeteren, E. Aronica, H. Kim, S. Zheng, D. J. Brat, S. Virk, S. Amini, C. Sougnez, J. Barnholtz-Sloan, R. G. W. Verhaak, C. Watts, A. Sottoriva, I. Spiteri, S. Piccirillo, A. Touloumis, P. Collins, J. Marioni, C. Curtis, S. Tavare, B. Tews, T. P. C. Yeung, B. Al-Khazraji, L. Morrison, L. Hoffman, D. Jackson, T.-Y. Lee, S. Yartsev, G. Bauman, J. Fu, R. Vegesna, Y. Mao, L. E. Heathcock, W. Torres-Garcia, S. Wang, A. McKenna, C. W. Brennan, W. K. A. Yung, J. N. Weinstein, E. P. Sulman, and D. Koul
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Abstracts ,Cancer Research ,Text mining ,Oncology ,business.industry ,Neurology (clinical) ,Computational biology ,Biology ,Omics ,business - Published
- 2013
21. Mechanism and Enantioselectivity in Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to β-Substituted Cyclic Enones: Insights from Computation and Experiment
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Kotaro Kikushima, Alexander N. Marziale, Lufeng Zou, Michele Gatti, Yu Lan, Kendall N. Houk, Brian M. Stoltz, Peng Liu, and Jeffrey C. Holder
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Models, Molecular ,inorganic chemicals ,Steric effects ,Molecular Conformation ,chemistry.chemical_element ,Biochemistry ,Article ,Catalysis ,Substrate Specificity ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Models ,Organic chemistry ,Olefin fiber ,Chemistry ,Ligand ,Chiral ligand ,Enantioselective synthesis ,Water ,Molecular ,Stereoisomerism ,General Chemistry ,Ketones ,Boronic Acids ,Combinatorial chemistry ,Kinetics ,Chemical Sciences ,Salts ,Enone ,Palladium - Abstract
Enantioselective conjugate additions of arylboronic acids to β-substituted cyclic enones have been previously reported from our laboratories. Air- and moisture-tolerant conditions were achieved with a catalyst derived in situ from palladium(II) trifluoroacetate and the chiral ligand (S)-t-BuPyOx. We now report a combined experimental and computational investigation on the mechanism, the nature of the active catalyst, the origins of the enantioselectivity, and the stereoelectronic effects of the ligand and the substrates of this transformation. Enantioselectivity is controlled primarily by steric repulsions between the t-Bu group of the chiral ligand and the α-methylene hydrogens of the enone substrate in the enantiodetermining carbopalladation step. Computations indicate that the reaction occurs via formation of a cationic arylpalladium(II) species, and subsequent carbopalladation of the enone olefin forms the key carbon–carbon bond. Studies of nonlinear effects and stoichiometric and catalytic reactions of isolated (PyOx)Pd(Ph)I complexes show that a monomeric arylpalladium–ligand complex is the active species in the selectivity-determining step. The addition of water and ammonium hexafluorophosphate synergistically increases the rate of the reaction, corroborating the hypothesis that a cationic palladium species is involved in the reaction pathway. These additives also allow the reaction to be performed at 40 °C and facilitate an expanded substrate scope.
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- 2013
22. POSTER SESSIONS SCHEDULE
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C Hinkin, M Cuevas, A Rauscher, W Kim, T Fogel, G Walls, M Heran, L Drag, S Akeson, K An, Mark T. Barisa, J Cantor, R Pella, C Ward, D Terry, E Parke, I Grant, K Blackstone, David B. Salisbury, P Davidson, G McDonald, C Strongin, Sudhin A. Shah, R Kim, A Miele, K Carlson, N Cadavid, J Donders, S Mahal, T Feaster, K Griffits, J Mayfield, T Brand, A Vernon, Scott R. Miller, C Price, C Vickery, L Carrion, J Beaute, L Weigand, G Crucian, A Tan, M Shuman, Talin Babikian, T Van Vleet, D La, I Thiruselvam, N Nemanim, L Baum, L Loneman, A Schmitt, R Hoadley, J Keller, J Kim, Bonnie M. Scott, M Edwards, M Rohling, B Palmer, G Godoy-Garcete, Ana Rosario, M Taylor, S Letendre, I Sanchez, A Harmell, David L. McArthur, S Greco, M O'Neil, H Yoshida, Jerome H. Carter, Marie N. Dahdah, E Jeffay, L McCutcheon, E Stambrook, A Rach, A Minassian, S Vinogradov, R Akarakian, S Khen, D Schiehser, M Young-Bernier, B Roberg, P Marchetti, L Kenworthy, P Ross, N Didehbani, M Lally, T Brickell, G Vasilev, D Kansagara, Glen A. Palmer, Amanda R. Rabinowitz, A Bedard, Desiree Byrd, K daCruz, A Torstrick, T Nguyen, M Solomon, E Hanson, S Turecka, J Moskowitz, Catherine Stasio, J Kenton, E Call, J McLeod, H Rossetti, Paula I. Martin, J Wasisco, C Depp, Sunni A. Barnes, R Lange, T Lotze, S Erikson, Samantha E. John, K Gulliver, Daniel N. Allen, M Schoenberg, M Joan, S Hass, D Munic-Miller, N Grant, M Weiner, S. DeBoard Marion, C Waksmunski, H Muetze, K Brady, P Roskos, Cynthia Dunklin, N Puente, K Russler, M Salzberg, I Neeland, J McKeever, A Fonteh, J Peer, M Choe, K Russ, C Marini, E Hui, C Kimmel, N Kecala, L. Schwent Shultz, Shelley Peery, R Gonzalez, C Spickler, E Lanni, L Flaro, E Talbot, E Giese, A Davis, Sam Vogel, D Hachey, W Mittenberg, Kenneth L. Jones, S Mahdavi, V. Alipio Jocson, M Marquine, B Ivins, S Paisley, E Weber, G Silk-Eglit, R Singer, K Barnes, A Ghias, J Sordahl, M Spiers, J Anderson, C Mathiowetz, S Fritz, R Fazio, E Miles-Mason, M Glusman, Octavio A. Santos, Jessica A. Kaczorowski, T Dugbartey, K Burns, A Gottuso, Nicholas J. Pastorek, Shahid Shafi, Librada Callender, R Dean, M Thomas, S Schleicher-Dilks, C Bermudez, J Muir, E Van Ness, R Odom, R Dye, F van der Fluit, C Lindbergh, J Grups, Monica U. Ellis, M Coe, M Schmitter-Edgecombe, S Lanting, Rosemary Dubiel, Katherine W Sullivan, A Bonner-Jackson, A Lyon, Daniel J. Schwartz, M Pachalska, S Hibyan, J Long, S Watson, N Nardi, L Pinto, Claudia Kernan, F Thomas, J Messerly, B Walsh, A Daros, S Margolis, M Cullum, B Rainwater, K Baerresen, M Steenari, M Vertinski, P Klas, A Harrison, J Stewart, R Carrasco, D Storzbach, E VonDran, K Carter, M Baldassarre, R Fares, A Freeman, J Barnett, Maggie C. Happe, M Harrington, D D'Argenio, J Piehl, Jacob Sheynin, C Young, A Anum, W Garmoe, T Barker, O Selnes, C Lobue, J Gray, A Rossi, B Stephens, M Jarrett, G Gilbert, A Graefe, J Gfeller, M Murphy, R Perna, B Gouaux, C Leibson, M Heinly, A Allart, Joshua Harrison, M Dudley, B Henry, S O'Bryan, D Miller, J Kennedy, B Edner, M Curri, F Tremblay, T Becker, J Neff, K Gillis, M Poon, C Ukpabi, J Hall, Victoria C. Merritt, D Nemeth, K Tyson, L Glukhovsky, P Vik, Karen K. Miller, R Schroeder, Christopher C. Giza, Benjamin Jurek, M Dawson, T Susmaras, K Rajendran, T Swirsky-Sacchetti, Joseph DeGutis, K Isham, P Massman, M Collier, L Klimik, D Moore, C Baum, J DiGangi, J Francis, B Baughman, A Patel, D Zink, V Carrión, Claire D. Coles, Sarah N. Mattson, A Reveles, T Novakovic-Agopian, D Drasnin, G Sutton, K Jacquin, J Tsou, John D. Medaglia, C Kane, A Starza-Smith, G Lafleche, M Bidzan, J Stenclik, C Smith, J Spat, G Mucci, M Legarreta, Frank G. Hillary, A Mouanoutoua, I Armstrong, C Isaacs, K Beene, C Songy, A Steed, R McCaffrey, J Loftis, A Levan, J Marcinak, Lisa Delano-Wood, C Draffkorn, A Harley, J Shewchuk, J Lynch, P Lebby, Preeti Sunderaraman, R Verbiest, E Stranks, B Hill, A Zisk, L Bolshin, P Stolberg, J Zamzow, V Culotta, J Gross, J Davis, M Fisher, S Mohammed, D Rosario, L Baade, J Fischer, M Muniz, M Kaminetskaya, W Gomes, J Park, K Netson, M Fanning, G Wallace, Nicholas S. Thaler, C Ayers, R Ellis, J Gonzalez, L Zhao, J Thelen, J Kiefel, J Halperin, J Uderman, R Stephan, L Sweet, K Whithers, F Fonseca, A Fedio, D Cooper, Jessica E. Meyer, J Capps, G Getz, M Palewjala, E Rinehardt, A Fernandez, S Tanner, J Ang, Audrey M. Carson, W Finch, S Evans, Gray Vargas, Ellen B. Braaten, J Murry, B Klein-Tasman, M Adler, E Culnan, G Richardson, A Dominska, T Olivier, A Dedmon, E Lane, C Prince, A Mannarino, B Casto, J Calloway, J Mackillop, C Garrett, John F. Linck, A Parks, S Sorg, W Andrew, G Fong, W Gouvier, L Lacritz, Jennifer Romesser, G Small, L Lashley, James B. Hoelzle, Predict-Hd Investigators, M Sakamoto, A Hart, F Dadis, D Pina, J Paulsen, N Stricker, G Iverson, R Macher, A Stringer, C Saucier, J Gallegos, P Andrews, A Chappell, D Jeste, K Mulligan, Pouneh K. Fazeli, D Harrison, R Romero, D Maricle, Joshua D. Miller, S Patel, Jeffrey M. Robbins, S Mansinghani, W Hoffman, K Espinoza, R Roberts, N Londono, M Douangratdy, K Kelley, O Alhassoon, A Quinones, J Taylor, E Ringdahl, A Ness, N DeFilippis, K Marshall, S Jaehnert, R Vergara, P Harvey, J Iudicello, C Ellis, S Tun, Thomas D. Parsons, Amanda E. Hahn-Ketter, C McAlister, T Patterson, R Gomez, K Kloezeman, J Wingo, C Barrio, Michael B. Reid, M Vasserman, Jacob Cohen, C Golden, C Ciobanu, F Carla, D Dinishak, Louis M. French, E Scharaga, Kirsten A. Schohl, A Newman, A Gold, J Bunting, A Puente, R Heaton, A Boettcher, D Wolff, R Baek, T Giovannetti, B Hummer, A Loughan, Ryan J. McKindles, M Bunner, M Kral, W Cole, C Love, E Corley, A Zomet, F Loya, K Young, P May, K Constantine, A Duhig, V Pankratz, J Tam, Maria T. Schultheis, A Junod, K Wyman-Chick, A Houshyarnejad, A Kent, J Wall, D Gansler, M Bens, M Jerram, C Dombrowski, J Segovia, J Hoblyn, M Geyer, N Pliskin, J Strang, B Fuller, J Kloss, J Paxton, J Chow, L Guatney, K Smith, F Foley, Elizabeth R. Sowell, L Brenner, M Rivera Mindt, A Levine, C Irwin, S Rome, J Neiman-Kimel, L Segalà, G Saini, Scott A. Loe, P Vekaria, H Woolery, M Francis, S Newton, Daniel J. Heyanka, J Link, Stephen G. West, T Ala, W Burns, H Pedersen, M Norman, L Delgaty, C Mihailescu, S Cowad, T Melville, Leila Glass, Nathan D. Doty, E Simco, A Holland, R Robbs, Warren T. Jones, S Banks, X Bonilla, R McCue, C Ramirez, M Phoong, N Upshaw, H England, S Woods, K Whigham, L Miller, J Etherton, S Rolin, Sawsan Dabit, S Kohlrus, S Thomlinson, Ryan Olmstead, A Chen, S Mahmoud, S Mauro, B Greenberg, B Lukaszewska, C Brown, R Moore, B Freer, W MacAllister, S Schaffer, R Fontanetta, J Vassileva, J Fine, Amy Wilson, C O'Shea, L Barker, Joseph J. Graca, Anthony C. Ruocco, E Schulze, Brian I. Miller, A Kaup, K Julie, A Nolty, P Siddarth, Jeffrey S. Karst, B Rabinovitz, S Yudovin, C Faraco, M Raymond, Anita H. Sim, I Kunkes, J Kamm, K Zakzanis, R Petersen, A Rudd-Barnard, N Fritz, A Bozorg, R Wellington, R Naslednikova, R Nogin, J Moses, L Tiersky, T Lee, L Cooper, M Smith, A Papadakis, L Hoskins, L Ashendorf, Caitlin Miranda, J Sexton, S Barney, M Le, M Putnam, Lillie Weiss, D Baldock, D Grimm, H Westervelt, M Mattingly, Yelena Bogdanova, C Hopewell, J Kahne, C Moore, B Mausbach, Robert F. Asarnow, Peter A. Arnett, Michael M. Merzenich, R Remel, S Coad, J Hertza, C Romers, L Harrison, M Daniel, J Clark, A Rowden, B Bristow-Murray, A Reyes, C Noggle, D Yeh, Bridget K. Dolan, Keith D. Cicerone, G Goodman, D Haberman, Mary K. Colvin, M Noback, Hasan Ayaz, B Natalie, M Cohen, Mary F. Musso, G Abrams, Seth A. Gale, J McGinley, E Bene, Ramon Diaz-Arrastia, S Benbadis, S Northington, S O'Neill, R Ruchinskas, M Hall, B Saffer, L Miarmi, F Webbe, Dobrivoje S. Stokic, C Bowie, B Duda, J Bravo, S Taylor, L Wilson, Henry W. Mahncke, R Scott, Ashita S. Gurnani, K Eichstaedt, H Soper, A Andrews, B Evans, J Bailie, R Poulin, K Evankovich, R Relova, A Gremillion, S Hunter, B Lee, M Beier, Edward P. Riley, S Edmed, M Wills, Sarah M. Kark, E Quasney, K Barrera, Yelena Goldin, Kimberley R. Monden, A Barker, V Sterk, J Fink, J Ikanga, Will Lindstrom, B Hunter, D Denney, S Huberman, C Williams, T Otero, K Spengler, A Pulver, Kathryn L Schmidt, J Meyers, E Gutierrez, V Wheaton, K Downing, A Bhagwat, Stephen A. Olson, E Lande, R Lee, F Vale, F Barwick, Mirella Díaz-Santos, C Mosti, Daniel S. Brown, M Benners, L Horne-Moyer, K Johnson, V Vargas, P Sylvester, E Shapiro, Sarah DeBoard Marion, J Poole, E Strongin, K Fields, M Basso, R Lawson, D Brinckman, E Morgan, A Simone, I Raynov, A Matevosyan, J Emerson, M Motu'apuaka, S Heverly-Fitt, Alexandra L. Clark, E March, B Roper, N Dezhkam, N Dasher, V Patt, Sheryl Stevens, A Choi, S Sautter, A Van Hecke, J. Travis Seidl, T Raines, W Perry, L Moss, M Macaluso, G Carlin, S Sisk, B Bowman, John Hart, Elisabeth M. Vogt, Michael D. Ensley, B Schilling, L Ercoli, M Zupanc, V D'Orio, A Bure-Reyes, L Rabin, J Nunan-Saah, N Rodgers-Neame, Jared M. Bruce, E Crouse, C Boys, H Kletter, T Lo, Brandon E. Gavett, A Sherzai, N Bott, K Walker, J Brubacher, Tanya M. Brown, F Ahmed, Dede M. Ukueberuwa, L Etcoff, K Chu, B Schweinsburg, Y Demsky, K Vitelli, M Huckans, L Nakhutina, A Ghelani, C Higginson, R Zec, A Curiel, David C. Osmon, S Crowe, K Phelps, O Prokhorenko, M Koehle, C Morse, Alice Cronin-Golomb, E Batchelor, J Lum, G Brown, L Silva, M Freeman, C Babika, Janine M. Paxson, P Pimental, W Buddin, J Baker, J Kline, F Hays, M Pollock, M Oganes, Armando Fuentes, M Ring, B Thieme, A Psihogios, A Zimmer, J Thompson, Hannah M. Lindsey, O Graham, Christina L. Casnar, M Arce Rentería, A Rooney, K Bozgunov, M Welch, M Lipowska, M Earleywine, S Lewis, T Floyd, A Tanguay, Yongming Li, C Tai, N Fromm, N Luc, K Barchard, K Musielak, Amir Poreh, R Heinrichs, C Boyd, K Schwab, A Lynch, R Wanlass, K Janke, S Bullard, S Hughes, K Hanson, C Holder, A Legenkaya, J Siegel, S Gold, C Evans, F Hill, Caryn R. Harper, D Binder, S Gill, M Bruhns, E Singer, Sidney O'Bryant, and J Atkinson
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Psychiatry and Mental health ,Clinical Psychology ,Schedule ,Neuropsychology and Physiological Psychology ,business.industry ,Medicine ,Operations management ,General Medicine ,business - Published
- 2013
23. Effects of Aging on Neural Stem/Progenitor Cells and Oligodendrocyte Precursor Cells after Focal Cerebral Ischemia in Spontaneously Hypertensive Rats
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Takakuni Maki, John D. McNeish, Josephine Lok, Eng H. Lo, Ken Arai, Tsu Tshen Chuang, Akihiro Shindo, Kanako Itoh, Angel T. Som, Anna C. Liang, Julie C. Holder, Naohiro Egawa, and Emiri T. Mandeville
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Brain Infarction ,Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,Neurogenesis ,Biomedical Engineering ,Ischemia ,Subventricular zone ,lcsh:Medicine ,CREB ,Article ,03 medical and health sciences ,0302 clinical medicine ,Neural Stem Cells ,Rats, Inbred SHR ,Internal medicine ,medicine ,Animals ,cardiovascular diseases ,Progenitor cell ,Stroke ,Transplantation ,biology ,business.industry ,lcsh:R ,Cell Biology ,Nestin ,medicine.disease ,Neural stem cell ,Rats ,Oligodendroglia ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,biology.protein ,business ,030217 neurology & neurosurgery - Abstract
Aging and vascular comorbidities such as hypertension comprise critical cofactors that influence how the brain responds to stroke. Ischemic stress induces neurogenesis and oligodendrogenesis in younger brains. However, it remains unclear whether these compensatory mechanisms can be maintained even under pathologically hypertensive and aged states. To clarify the age-related remodeling capacity after stroke under hypertensive conditions, we assessed infarct volume, behavioral outcomes, and surrogate markers of neurogenesis and oligodendrogenesis in acute and subacute phases after transient focal cerebral ischemia in 3- and 12-month-old spontaneously hypertensive rats (SHRs). Hematoxylin and eosin staining showed that 3- and 12-month-old SHRs exhibited similar infarction volumes at both 3 and 14 days after focal cerebral ischemia. However, recovery of behavioral deficits (neurological score assessment and adhesive removal test) was significantly less in 12-month-old SHRs compared to 3-month-old SHRs. Concomitantly, numbers of nestin+ neural stem/progenitor cells (NSPCs) near the infarct border area or subventricular zone in 12-month-old SHRs were lower than 3-month-old SHRs at day 3. Similarly, numbers of PDGFR-α+ oligodendrocyte precursor cells (OPCs) in the corpus callosum were lower in 12-month-old SHRs at day 3. Lower levels of NSPC and OPC numbers were accompanied by lower expression levels of phosphorylated CREB. By day 14 postischemia, NSPC and OPC numbers in 12-month-old SHRs recovered to similar levels as in 3-month-old SHRs, but the numbers of proliferating NSPCs (Ki-67+nestin+ cells) and proliferating OPCs (Ki-67+PDGFR-α+ cells) remained lower in the older brains even at day 14. Taken together, these findings suggest that aging may also decrease poststroke compensatory responses for neurogenesis and oligodendrogenesis even under hypertensive conditions.
- Published
- 2016
24. Family PArtners in Lifestyle Support (PALS): Family-based weight loss for African American adults with type 2 diabetes
- Author
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Carmen D, Samuel-Hodge, Judith C, Holder-Cooper, Ziya, Gizlice, Gwendolyn, Davis, Sonia P, Steele, Thomas C, Keyserling, Shiriki K, Kumanyika, Phillip J, Brantley, and Laura P, Svetkey
- Subjects
Adult ,Male ,obesity ,Social Support ,Middle Aged ,Article ,family support ,Black or African American ,intensive behavioral lifestyle intervention ,diabetes self-management ,Diabetes Mellitus, Type 2 ,Weight Loss ,Humans ,Female ,Family Relations ,Life Style ,weight loss intervention - Abstract
Objective To develop and test a family-centered behavioral weight loss intervention for African American adults with type 2 diabetes. Methods In this randomized trial, dyads consisting of African American adult with overweight or obesity and type 2 diabetes (index participant) paired with a family partner with overweight or obesity, but not diagnosed with diabetes, were assigned in a 2:1 ratio to a 20-week special intervention (SI) or delayed intervention (DI) control group. The primary outcome was weight loss among index participants at 20 weeks follow-up. Results One hundred-eight participants (54 dyads – 36 (SI) and 18 (DI) dyads) were enrolled: 81% females; mean age, 51 years; mean weight,103 kg; and mean BMI, 37 kg/m2. At post-intervention, 96 participants (89%) returned for follow-up measures. Among index participants, mean difference in weight loss between groups was −5.0 kg, p
- Published
- 2016
25. Effects of Increasing Space Allowance by Removing a Pig or Gate Adjustment on Finishing Pig Growth Performance
- Author
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Jason C Woodworth, Michael D. Tokach, R. D. Goodband, Steve S Dritz, C. Holder, C. B. Carpenter, and Joel M DeRouchey
- Subjects
OR gate ,Computer Networks and Communications ,Hardware and Architecture ,Allowance (engineering) ,Agricultural engineering ,Space (mathematics) ,Software ,Finishing pig ,Mathematics - Published
- 2016
26. Accolades and Recommendations: A Longitudinal Analysis of Monitoring Reports for Two Charter Schools Serving Native American Students
- Author
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Derek L Anderson and K. C. Holder
- Subjects
Medical education ,Standardization ,education ,Charter ,Academic achievement ,computer.software_genre ,Education ,Content analysis ,Educational assessment ,Political science ,Situated ,Accountability ,Pedagogy ,Curriculum ,computer - Abstract
This longitudinal case study examines 10 years' worth of annual monitoring reports for two rural Native American Charter Schools. Using data from multiple sources including interviews, site visits, and document analyses, the authors used provisional coding and constant comparison analysis to categorize the accolades and recommendations embedded in the annual reports. The reports reveal that both schools received the most feedback related to assessment, curriculum, and administration. Monitoring report emphasis on standardization of curriculum and testing conflicts with the espoused values of making connections between the school and the Native American community in which they are situated.
- Published
- 2012
27. Metabolic Profiling of the Rat Liver After Chronic Ingestion of Alpha-Naphthylisothiocyanate Using In Vivo and Ex Vivo Magnetic Resonance Spectroscopy
- Author
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Simon D. Taylor-Robinson, Jeremy F. L. Cobbold, Eleanor Ross, Po-Wah So, Gina J. Sanchez-Canon, I. Jane Cox, Cheryl L. Scudamore, Jimmy D. Bell, Julie C. Holder, and Bhavana Solanky
- Subjects
Male ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Bilirubin ,In Vitro Techniques ,Toxicology ,Article ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Primary biliary cirrhosis ,In vivo ,Internal medicine ,Animals ,Medicine ,Choline ,Liver injury ,Analysis of Variance ,business.industry ,Body Weight ,Feeding Behavior ,medicine.disease ,Rats ,Endocrinology ,1-Naphthylisothiocyanate ,Liver ,chemistry ,Alkaline phosphatase ,business ,Ex vivo ,Phosphomonoesters - Abstract
Certain human diseases affecting the biliary tree can be modeled in rats by ingestion of the hepatobiliary toxin alpha-naphthylisothiocyanate (ANIT). Phosphorus magnetic resonance spectroscopy (MRS) allows the noninvasive monitoring of cell dynamics through detection of phosphodiesters (PDE) and phosphomonoesters (PME). Hepatic (31)P MRS techniques were therefore used to study the toxic effects of low-dose chronic ANIT ingestion, with a view toward providing biomarkers sensitive to hepatobiliary dysfunction and cholestatic liver injury. Rats were fed an ANIT supplemented diet at three doses (ANIT_0.05%, ANIT_0.04%, and ANIT_0.025%) for 2 weeks. Data from in vivo MRS were compared with results from pair-fed controls (PFCs). Blood and tissue samples were collected at 2 weeks for clinical chemistry, histology, and (1)H magic angle spinning MRS. Increases in PDE, relative to total phosphorus (tPh), were detected in both the ANIT_0.05% and ANIT_0.04% groups (0.07 ± 0.01 and 0.08 ± 0.01, respectively) relative to PFC groups (0.03 ± 0.01 and 0.05 ± 0.01, respectively). An increase in PME/tPh was observed in the ANIT_0.05% group only (0.17 ± 0.02) relative to PFC_0.05% (0.12 ± 0.01). Ex vivo (1)H MRS findings supported this, wherein measured phosphocholines (PCs) were increased in ANIT_0.05% and ANIT_0.04% groups. Increases in relative total choline (tCho) distinguished the ANIT_0.05% group from the ANIT_0.04% group. Markers of hepatotoxicity such as raised total bilirubin and alkaline phosphatase were found at all ANIT doses. Histological findings included a dose-related increase in both severity of biliary hyperplasia and focal hepatocellular necrosis. Here, we found that ANIT-induced moderate hepatobiliary dysfunction was associated with a relative increase in phosphodiesters in vivo and PCs ex vivo. Raised PME/tPh in vivo and tCho ex vivo were also present at high doses corresponding to a higher incidence of marked biliary hyperplasia and moderate hepatocellular necrosis.
- Published
- 2012
28. Novel therapies for high-grade gliomas: A vision for future
- Author
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G Kohanbash, C Belka, RE Coleman, D Barba, JH Kim, H Burris, E Razis, C Sturiale, Lesniak, SA Grossman, B Dhokia, MP Gustafson, ZQ Han, P Traxler, AM Sandmair, LM DeAngelis, G Franceschi, P Msaouel, G Kaur, MJ Zhu, S Taillibert, I Yang, M Brown, AT Bruce, HP Kalofonos, T Todo, TC Liu, HS Hochster, KL Black, C Royce, D Fukumura, NL Spector, P Duic, MP Sayers, M Koslow, C Stanton, KL Fink, L Kim, JM Reid, AK Muhammad, JS Yu, AH Friedman, T Gohongi, KA Kreuzer, R Cozens, GP Dunn, DA Haas-Kogan, KB Hymes, JH Sampson, DD Song, RB Herberman, R Ramina, K Kawakami, GG Gomez, N Jelluma, E Galanis, SC Saris, S Thomas, Sy Lim, FM Iwamoto, AJ Grant, H Bender, W Xia, C Wallace, LH Merchant, S Kunwar, RD Schreiber, RE Merchant, AM Kaplan, Vivek Tandon, JS Hardwick, K Ballman, Berger, I Stroud, D Fabbro, JM Piepmeier, WK Yung, JC Hiserodt, K Moore, YB Wang, L Zhang, R Alemany, N Dmitrieva, HJ Choi, KM Kroeger, CD Stiles, D Schiff, LJ Old, JL Clarke, AL Asher, DV Woo, JL Mahaley, R Brandt, P Clement, JI Kreisberg, M Ehtesham, FK Miura, EM Hiesiger, I Cokgor, PY Wen, IK Na, C Crane, LB Nabors, HI Robins, HT Chung, G Ibrahim, NK Kim, A Arista, K Panageas, S Ahmad, RK Jain, KL Penne, JJ Vredenburgh, GD King, M Weller, CT Kuan, T Tihan, H Wakimoto, R Sakalas, CW Reynolds, JC Buckner, S Lassiter, HF Young, M Kioi, H Fukuhara, J Wykosky, MA Vogelbaum, TN Kreisl, H Okada, RE McLendon, V Jendrossek, CJ Wikstrand, P Puranen, M Puranen, W Xiong, Mahaley, YY Kim, C Sauvageot, JA Quinn, SR Husain, S Labropoulos, IF Pollack, CH Tung, J Laterra, JM Dowell, HS Friedman, A Desjardins, EC Dees, K Shah, BK Cho, C Valiengo Lda, GC Gonzalez, P Forsyth, M Assenberg, W Debinski, P Riva, JC Rodrigues, DA Eberhard, S Xia, SM Chang, Jy Yoo, J Hardcastle, CA Kruse, TJ Liu, R Weissleder, Jr MahaleyMS, D Snook, W Roth, Subhashree Mahapatra, M Frattarelli, KC Wang, FF Lang, KA Jaeckle, EA Chiocca, K Terada, C Gomez-Manzano, PR Lowenstein, JJ Kelly, SA Rosenberg, P Selviaridis, Prados, IV Ulasov, E Tyminski, S Sinha, RL Hayes, J Brueggen, T Kuroda, GJ Baker, J Sul, G Simpson, M Rackover, SK Kim, DD Bigner, S Desideri, K Hopkins, XO Breakefield, JN Rich, H Ikeda, M Kawakami, JM Bruner, M Rosenfeld, ND Arvold, PH Aguiar, LW Brady, D Morris, G Roldan, M Candolfi, S Kesari, B Seed, BH Joshi, M Holdhoff, RL Martuza, YG Kwon, SX Jiang, JT Kemshead, M Campone, NL Vujanovic, Y Chen, DA Reardon, TF Cloughesy, A Dispenzieri, M van den Bent, M Kossila, B Hildebrandt, EH Oldfield, S Puri, T Zhang, K Kurozumi, S Loimas, MK Wibowo, C Holder, EM Rosen, H Hurwitz, G Dresemann, EC Kim, H Assi, BL Liu, N Butowski, C Appelt, Groves, EJ Moore, SJ Han, CA Palmer, N Ramakrishna, J Emrich, MJ Maurer, RK Puri, JL Norris, P Waterman, J Clarke, S Piantadosi, T Peery, JF Curtin, LE Abrey, AS Chi, N Courtenay-Luck, A Hemingway, Y Saeki, AB Lassman, V Papanastassiou, J Boni, ED Day, E Hussain, C Miyamoto, AK Mahapatra, R Scholz, AT Parsa, RB Greeno, KL Low, T Mikkelsen, S Chang, C Sarkar, J Fueyo, DV Cramer, PR Allegrini, A Dowlati, DM Gibo, L Xu, M Dey, MM Ames, M Shaffrey, HA McDonald, SB Omay, TR Pawlikowska, RL Hamilton, D George, N Riva, Ashok Kumar Mahapatra, A Immonen, TA Mattei, M Bamberg, X Ye, and B Woodhall
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Genetic enhancement ,lcsh:Surgery ,Disease ,030105 genetics & heredity ,lcsh:RC346-429 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Glioma ,novel therapy ,medicine ,current studies ,lcsh:Neurology. Diseases of the nervous system ,Chemotherapy ,business.industry ,Standard treatment ,Immunotherapy ,malignant glioma ,lcsh:RD1-811 ,medicine.disease ,gene therapy ,Oncolytic virus ,Radiation therapy ,business ,030217 neurology & neurosurgery - Abstract
The treatment for high-grade glioma remains an enigma. The standard treatment using surgery, radiation therapy and chemotherapy for such highly malignant lesions has only yielded modest results, in terms of survival and improving the quality of life of patients. Less than 10% of such patients survive beyond two years. All conventional therapies have failed to increase the survival beyond this extent. There has been a growing interest in the molecular approaches for the treatment of high-grade gliomas which include gene therapy, oncolytic virotherapy, and immunotherapy. These new therapies are in preclinical and investigational stages. They may not substitute the conventional therapies; they may not be the ultimate elixir for this deadly disease. However, in the coming years, they are likely to have synergistic and complimentary roles alongside conventional therapies. Through this paper, we have attempted to highlight the rationale behind gene therapy which can be used for cytotoxic approaches, immunomodulation strategy, and targeted toxin delivery in the tumor cell. We have reviewed current available literature and through this paper focus on reporting such therapeutic options, their potential usage, benefits and limitations.
- Published
- 2012
29. Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke
- Author
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John D. McNeish, Kanako Itoh, Josephine Lok, Julie C. Holder, Anna C. Liang, Takakuni Maki, Akihiro Shindo, Mia C Borlongan, Emiri T. Mandeville, Hidekazu Tomimoto, Naohiro Egawa, Eng H. Lo, Ken Arai, Naoki Itoh, and Tsu Tshen Chuang
- Subjects
0301 basic medicine ,Male ,Vascular Endothelial Growth Factor A ,Endothelium ,Blood–brain barrier ,Article ,03 medical and health sciences ,0302 clinical medicine ,Rats, Inbred SHR ,medicine ,Animals ,Stroke ,Neuroinflammation ,Advanced and Specialized Nursing ,biology ,Cell Death ,business.industry ,C-reactive protein ,Brain ,Endothelial Cells ,Infarction, Middle Cerebral Artery ,PTX3 ,medicine.disease ,Rats ,Vascular endothelial growth factor B ,Serum Amyloid P-Component ,030104 developmental biology ,medicine.anatomical_structure ,C-Reactive Protein ,Blood-Brain Barrier ,Astrocytes ,Culture Media, Conditioned ,Immunology ,biology.protein ,Neurology (clinical) ,Endothelium, Vascular ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,Astrocyte - Abstract
Background and Purpose— Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood–brain barrier dysfunction during the acute phase of ischemic stroke. Methods— In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood–brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor–mediated endothelial permeability. Results— During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor–induced endothelial permeability. Conclusions— Astrocytes in peri-infarct areas upregulate PTX3, which may support blood–brain barrier integrity by regulating vascular endothelial growth factor–related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood–brain barrier function after ischemic stroke.
- Published
- 2015
30. ChemInform Abstract: Synthesis of Diverse β-Quaternary Ketones via Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Cyclic Enones
- Author
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Brian M. Stoltz, Emmett D. Goodman, Kotaro Kikushima, Jeffrey C. Holder, Michele Gatti, and Alexander N. Marziale
- Subjects
Addition reaction ,Range (particle radiation) ,chemistry ,chemistry.chemical_element ,General Medicine ,Combinatorial chemistry ,Catalysis ,Palladium ,Conjugate - Abstract
Optimized conditions allow the synthesis of a wide range of β-arylated cyclic ketones with high enantioselectivity.
- Published
- 2015
31. ChemInform Abstract: Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Cyclic Electrophiles
- Author
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Samantha E. Shockley, Brian M. Stoltz, and Jeffrey C. Holder
- Subjects
Addition reaction ,Reaction mechanism ,Chemistry ,Electrophile ,chemistry.chemical_element ,General Medicine ,Combinatorial chemistry ,Catalysis ,Palladium ,Stereocenter ,Conjugate - Abstract
This account describes our laboratory’s efforts in the development of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic conjugate acceptors. Specifically, we highlight the study of this transformation in the following areas: (a) construction of all-carbon quaternary stereocenters, (b) elucidation of the reaction mechanism, (c) addition to heterocyclic acceptors to generate tertiary stereocenters, and (d) application in the synthesis of natural products.
- Published
- 2015
32. PGR-1Anti-NMDA Receptor Encephalitis: Neuropsychological Profile of Recovery
- Author
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N Shay and C Holder
- Subjects
medicine.medical_specialty ,business.industry ,Neuropsychology ,General Medicine ,medicine.disease ,Psychiatry and Mental health ,Clinical Psychology ,Neuropsychology and Physiological Psychology ,Endocrinology ,Internal medicine ,Medicine ,NMDA receptor ,business ,Encephalitis - Published
- 2017
33. Loss of the Group A Streptococcus Regulator Srv Decreases Biofilm Formation In Vivo in an Otitis Media Model of Infection
- Author
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Kristie L. Connolly, Amity L. Roberts, Robert C. Holder, Christopher D. Doern, and Sean D. Reid
- Subjects
Streptococcus pyogenes ,Immunology ,Ear, Middle ,Exotoxins ,medicine.disease_cause ,Microbiology ,law.invention ,Bacterial Proteins ,Chinchilla ,law ,In vivo ,Streptococcal Infections ,medicine ,Animals ,Humans ,Host Response and Inflammation ,biology ,Otitis Media with Effusion ,Streptococcus ,Biofilm ,Gene Expression Regulation, Bacterial ,Streptococcaceae ,biology.organism_classification ,Disease Models, Animal ,Infectious Diseases ,Otitis ,Gram staining ,medicine.anatomical_structure ,Biofilms ,Microscopy, Electron, Scanning ,Middle ear ,Parasitology ,medicine.symptom - Abstract
Group A Streptococcus (GAS) is a common causative agent of pharyngitis, but the role of GAS in otitis media is underappreciated. In this study, we sought to test the hypothesis that GAS colonizes the middle ear and establishes itself in localized, three-dimensional communities representative of biofilms. To test this hypothesis, the middle ears of chinchillas were infected with either a strain of GAS capable of forming biofilms in vitro (MGAS5005) or a strain deficient in biofilm formation due to the lack of the transcriptional regulator Srv (MGAS5005 Δ srv ). Infection resulted in the formation of large, macroscopic structures within the middle ears of MGAS5005- and MGAS5005 Δ srv -infected animals. Plate counts, scanning electron microscopy, LIVE/DEAD staining, and Gram staining revealed a difference in the distributions of MGAS5005 versus MGAS5005 Δ srv in the infected samples. High numbers of CFU of MGAS5005 Δ srv were isolated from the middle ear effusion, and MGAS5005 Δ srv was found randomly distributed throughout the excised macroscopic structure. In contrast, MGAS5005 was found in densely packed microcolonies indicative of biofilms within the excised material from the middle ear. CFU levels of MGAS5005 from the effusion were significantly lower than that of MGAS5005 Δ srv early during the course of infection. Allelic replacement of the chromosomally encoded streptococcal cysteine protease ( speB ) in the MGAS5005 Δ srv background restored biofilm formation in vivo . Interestingly, our results suggest that GAS naturally forms a biofilm during otitis media but that biofilm formation is not required to establish infection following transbullar inoculation of chinchillas.
- Published
- 2010
34. Characterization of the N-Acetyl-α-<scp>d</scp>-glucosaminyl <scp>l</scp>-Malate Synthase and Deacetylase Functions for Bacillithiol Biosynthesis in Bacillus anthracis
- Author
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Matthew R. Redinbo, Bret D. Wallace, Chris J. Hamilton, Patricia C. Dos Santos, Al Claiborne, Gerald L. Newton, Sean D. Reid, Carleitta Paige, Derek Parsonage, and Robert C. Holder
- Subjects
Stereochemistry ,Borohydrides ,Biology ,Biochemistry ,Uridine Diphosphate ,Article ,chemistry.chemical_compound ,Glycosyltransferase ,Transferase ,Cysteine ,Sulfhydryl Compounds ,Intramolecular Lyases ,Ternary complex ,Glucosamine ,Antiinfective agent ,Binding Sites ,Glycopeptides ,Glycosyltransferases ,biology.organism_classification ,Bacillus anthracis ,Mycothiol ,carbohydrates (lipids) ,Molecular Weight ,Bacillithiol ,chemistry ,biology.protein ,Oxidation-Reduction ,Inositol - Abstract
Bacillithiol (Cys-GlcN-malate, BSH) has recently been identified as a novel low-molecular weight thiol in Bacillus anthracis, Staphylococcus aureus, and several other Gram-positive bacteria lacking glutathione and mycothiol. We have now characterized the first two enzymes for the BSH biosynthetic pathway in B. anthracis, which combine to produce α-d-glucosaminyl l-malate (GlcN-malate) from UDP-GlcNAc and l-malate. The structure of the GlcNAc-malate intermediate has been determined, as have the kinetic parameters for the BaBshA glycosyltransferase (→GlcNAc-malate) and the BaBshB deacetylase (→GlcN-malate). BSH is one of only two natural products reported to contain a malyl glycoside, and the crystal structure of the BaBshA-UDP-malate ternary complex, determined in this work at 3.3 Å resolution, identifies several active-site interactions important for the specific recognition of l-malate, but not other α-hydroxy acids, as the acceptor substrate. In sharp contrast to the structures reported for the GlcNAc-1-d-myo-inositol-3-phosphate synthase (MshA) apo and ternary complex forms, there is no major conformational change observed in the structures of the corresponding BaBshA forms. A mutant strain of B. anthracis deficient in the BshA glycosyltransferase fails to produce BSH, as predicted. This B. anthracis bshA locus (BA1558) has been identified in a transposon-site hybridization study as required for growth, sporulation, or germination [Day, W. A., Jr., Rasmussen, S. L., Carpenter, B. M., Peterson, S. N., and Friedlander, A. M. (2007) J. Bacteriol. 189, 3296-3301], suggesting that the biosynthesis of BSH could represent a target for the development of novel antimicrobials with broad-spectrum activity against Gram-positive pathogens like B. anthracis. The metabolites that function in thiol redox buffering and homeostasis in Bacillus are not well understood, and we present a composite picture based on this and other recent work.
- Published
- 2010
35. The Spawning Run of Blueback Herring in the St. Johns River, Florida
- Author
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Julianne E. Harris, Jay C. Holder, Richard S. McBride, and A. Reid Hyle
- Subjects
Fish migration ,education.field_of_study ,Alosa ,food.ingredient ,Population ,Aquatic Science ,Biology ,biology.organism_classification ,Fishery ,food ,Electrofishing ,Reproductive biology ,Blueback herring ,education ,Ecology, Evolution, Behavior and Systematics ,Sex ratio ,Semelparity and iteroparity - Abstract
Blueback herring Alosa aestivalis are anadromous, iteroparous, winter spawners in the St. Johns River, Florida, but published data about this population are limited. We collected adults by electrofishing in the upper St. Johns River during the 2002–2005 spawning runs to examine the abundance, distribution, size, sex ratio, reproductive biology, and feeding habits of the population. When possible, data from the present study were compared with those for blueback herring collected with seine nets in the lower St. Johns River during the 1972 and 1973 spawning runs. Blueback herring began upstream migration by January and stayed in the river until at least April. The average fish size was significantly smaller in 2002–2005 than in 1972–1973, but sex ratios were not different from 1:1 in 5 of the 6 years studied. The more recent collections suggest that blueback herring females released multiple batches of eggs during one spawning season (spawning a batch every 3–4 d on average) and that spawning occu...
- Published
- 2010
36. Intestinal Detoxification Limits the Activation of Hepatic Pregnane X Receptor by Lithocholic Acid
- Author
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Julie C. Holder, Mohamed Boudjelal, Roger White, Saskia W.C. van Mil, William Cairns, Alexandra Milona, Bryn M. Owen, Catherine Williamson, Malcolm G. Parker, and Peter Clements
- Subjects
Male ,Receptors, Steroid ,genetic structures ,Administration, Oral ,Gene Expression ,Pharmaceutical Science ,Pharmacology ,Mice ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Cytochrome P-450 CYP3A ,Intestinal Mucosa ,Receptor ,Mice, Knockout ,Pregnane X receptor ,Bile acid ,Pregnane X Receptor ,Alanine Transaminase ,Articles ,Sulfate Adenylyltransferase ,Intestines ,Liver ,Enzyme Induction ,Inactivation, Metabolic ,Female ,Lithocholic Acid ,Aryl Hydrocarbon Hydroxylases ,Chemical and Drug Induced Liver Injury ,Sulfotransferases ,Injections, Intraperitoneal ,medicine.medical_specialty ,Lithocholic acid ,medicine.drug_class ,Biology ,digestive system ,Bile Acids and Salts ,Multienzyme Complexes ,Internal medicine ,medicine ,Animals ,Enzyme inducer ,Cytochrome P450 Family 2 ,Body Weight ,Membrane Proteins ,Membrane Transport Proteins ,digestive system diseases ,eye diseases ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Nuclear receptor ,Steroid Hydroxylases ,biology.protein ,sense organs ,Xenobiotic ,Drug metabolism - Abstract
The intestinal-derived secondary bile acid (BA) lithocholic acid (LCA) is hepatotoxic and is implicated in the pathogenesis of cholestatic diseases. LCA is an endogenous ligand of the xenobiotic nuclear receptor pregnane X receptor (PXR), but there is currently no consensus on the respective roles of hepatic and intestinal PXR in mediating protection against LCA in vivo. Under the conditions reported here, we show that mice lacking Pxr are resistant to LCA-mediated hepatotoxicity. This unexpected phenotype is found in association with enhanced urinary BA excretion and elevated basal expression of drug metabolism enzymes and the hepatic sulfate donor synthesis enzyme Papss2 in Pxr(−/−) mice. By subsequently comparing molecular responses to dietary and intraperitoneal administration of LCA, we made two other significant observations: 1) LCA feeding induces intestinal, but not hepatic, drug-metabolizing enzymes in a largely Pxr-independent manner; and 2) in contrast to LCA feeding, bypassing first-pass gut transit by intraperitoneal administration of LCA did induce hepatic detoxification machinery and in a Pxr-dependent manner. These data reconcile important discrepancies in the reported molecular responses to this BA and suggest that Pxr plays only a limited role in mediating responses to gut-derived LCA. Furthermore, the route of administration must be considered in the future planning and interpretation of experiments designed to assess hepatic responses to BAs, orally administered pharmaceuticals, and dietary toxins.
- Published
- 2009
37. Small intestinal incarceration through an omental rent in a horse
- Author
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T. E. C. Holder, Gal Kelmer, and R. L. Donnell
- Subjects
medicine.medical_specialty ,Equine ,business.industry ,Anatomical relation ,Horse ,Anatomy ,medicine.disease ,Surgery ,Lesion ,medicine.anatomical_structure ,Gastrosplenic ligament ,Medicine ,Hernia ,medicine.symptom ,Presentation (obstetrics) ,business - Abstract
Summary Intestinal incarceration in an omental rent is a rare abdominal disorder in horses. A case of a horse with small intestinal incarceration in an omental rent is described here. The report includes description of the clinical presentation, surgical and post mortem findings and discusses the features unique to this case. The clinical presentation is similar to other small intestinal strangulation lesions; however, the location of the lesion is unusual and the anatomical relation to the gastrosplenic ligament interesting.
- Published
- 2008
38. A Review and Updated Assessment of Florida's Anadromous Shads: American Shad and Hickory Shad
- Author
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Jay C. Holder and Richard S. McBride
- Subjects
Fish migration ,Alosa ,Stock assessment ,food.ingredient ,Ecology ,biology ,Fishing ,Management, Monitoring, Policy and Law ,Aquatic Science ,biology.organism_classification ,Fishery ,Geography ,food ,Electrofishing ,Hickory shad ,American shad ,Netting ,Ecology, Evolution, Behavior and Systematics - Abstract
This paper reviews the history of fishing, regulations, and stock assessments for Florida's anadromous shad species—American shad Alosa sapidissima and hickory shad A. mediocris—and assesses their status in Florida's St. Johns River based on a creel survey and an electrofishing survey. Historically, these anadromous shads constituted an important fishery in Florida. Landings were first reported in the 1860s, and scientific assessments occurred in the 1950s, 1960s, and early 1970s. Netting restrictions effectively ended the commercial fishery in the 1990s. We used recreational catch rates as a proxy for stock size and found it to be low but stable during 1993–2005. The mean length of American shad was significantly less during 2002–2005 than it was historically (1958), and the recent proportions of female American and hickory shad were significantly lower than the historical proportions. These data were interpreted as demonstrating a negative, but perhaps only an historical, effect of fishing. The...
- Published
- 2008
39. Point mutations within the streptococcal regulator of virulence (Srv) alter protein–DNA interactions and Srv function
- Author
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Sean D. Reid, Christopher D. Doern, and Robert C. Holder
- Subjects
Mutant ,Electrophoretic Mobility Shift Assay ,Helix-turn-helix ,Biology ,Microbiology ,Article ,law.invention ,chemistry.chemical_compound ,Bacterial Proteins ,law ,Streptococcal Infections ,Genes, Regulator ,Point Mutation ,Electrophoretic mobility shift assay ,Binding site ,Peptide sequence ,Helix-Turn-Helix Motifs ,Genetics ,Binding Sites ,Base Sequence ,Virulence ,Point mutation ,Genetic Complementation Test ,Streptococcus ,Gene Expression Regulation, Bacterial ,DNA-Binding Proteins ,chemistry ,Recombinant DNA ,DNA - Abstract
Group A Streptococcus (GAS) possesses a complex regulatory system enabling the organism to colonize a range of physiologically distinct host sites. Within this network of regulators is the streptococcal regulator of virulence (Srv). Srv is a member of the CRP/FNR family of transcriptional regulators and is most similar to pleiotropic regulatory factor A (PrfA), a positive regulator of virulence in Listeria monocytogenes. Members of this family possess a characteristic C-terminal helix-turn-helix motif (HTH) that facilitates binding to DNA targets. Genome scanning identified four targets in GAS that were similar to the consensus DNA target recognized by PrfA. Furthermore, previous amino acid sequence alignments identified conserved residues within the Srv HTH which are necessary for function in PrfA and CRP. Here we investigated the ability of Srv to interact with DNA and evaluated the role of the HTH in this interaction. Purified recombinant Srv (rSrv) was found to co-purify with an untagged form of Srv. Glutaraldehyde cross-linking and gel-filtration chromatography indicated that this co-purification is likely due to the ability of Srv to oligomerize. Electrophoretic mobility shift assays (EMSAs) demonstrated that rSrv retarded the mobility of DNA targets and a supershift analysis confirmed the observation was rSrv-dependent. Competition EMSA indicated that rSrv had a higher relative affinity for the DNA targets studied than non-specific DNA. Site-directed mutagenesis of residues predicted to be in or near the HTH resulted in a decrease or abrogation of DNA binding. Complementation of MGAS5005Deltasrv with one of these site-directed mutants failed to restore wild-type SpeB activity. Taken together, these data suggest that the Srv HTH is necessary for DNA binding and Srv function.
- Published
- 2008
40. Compressive Damage to the Deep Branch of the Lateral Plantar Nerve Associated with Lameness Caused by Proximal Suspensory Desmitis
- Author
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Ferenc Tóth, Robert L. Donnell, Michael Schramme, Troy E. C. Holder, James Schumacher, and H. Steve A. Adair
- Subjects
Inflammation ,Male ,medicine.medical_specialty ,Ligaments ,General Veterinary ,business.industry ,Lameness, Animal ,Nerve Compression Syndromes ,Anatomy ,Pelvic limb ,Lateral plantar nerve ,Surgery ,Treatment Outcome ,Lameness ,Animals ,Medicine ,Female ,Horse Diseases ,Horses ,Tibial Nerve ,business ,Nerve resection ,After treatment ,Retrospective Studies ,Tibial Neuropathy - Abstract
Objective— To describe pathologic changes in the deep branch of the lateral plantar nerve (DBLPN) of horses determined to be lame because of proximal suspensory desmitis (PSD), and to report the outcome after treatment by excision of a segment of the horses' DBLPN. Study Design— Retrospective case series. Animals— Adult horses (n=16). Methods— Horses determined to be lame on one or both pelvic limbs because of PSD were treated by excision of a segment of the DBLPN, and 30 nerves were examined histologically. Owners were contacted to obtain information about the horses ≥6 months after surgery. Results— Histologic changes suggestive of chronic nerve compression were identified in both nerves of 11 bilaterally lame horses and in the lame limb of 5 unilaterally lame horses. The nerve of the sound limb of 2 of 3 unilaterally lame horses that had bilateral nerve resection also had histologic changes compatible with nerve compression. Ten of 16 horses (62.5%) with follow-up information returned to soundness after excision of the DBLPN. Conclusions— Pathologic changes of the DBLPN associated with compression may complicate PSD of the pelvic limbs. Excision of the nerve may resolve lameness caused by PSD. Clinical Relevance— Horses lame because of PSD of the pelvic limb may remain lame after desmitis has resolved because of compression of the DBLPN. Excising a portion of this nerve may resolve lameness.
- Published
- 2008
41. Effects of hyperbaric oxygen on full-thickness meshed sheet skin grafts applied to fresh and granulating wounds in horses
- Author
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Barton W Rohrbach, H. Steve A. Adair, Troy E. C. Holder, Robert L. Donnell, and James Schumacher
- Subjects
Pectoral region ,Hyperbaric Oxygenation ,Wound Healing ,medicine.medical_specialty ,integumentary system ,General Veterinary ,Granulation tissue ,Skin Transplantation ,General Medicine ,Biology ,Transplantation, Autologous ,Surgery ,Transplantation ,Hyperbaric oxygen ,medicine.anatomical_structure ,Granulation Tissue ,medicine ,Animals ,Wounds and Injuries ,Female ,Full thickness ,Horses - Abstract
Objective—To determine the effects of hyperbaric oxygen therapy (HBOT) on full-thickness skin grafts applied to fresh and granulating wounds of horses. Animals—6 horses. Procedures—On day 0, two 4-cm-diameter circular sections of full-thickness skin were removed from each of 2 randomly selected limbs of each horse, and two 4-cm-diameter circular skin grafts were harvested from the pectoral region. A skin graft was applied to 1 randomly selected wound on each limb, leaving the 2 nongrafted wounds to heal by second intention. On day 7, 2 grafts were harvested from the pectoral region and applied to the granulating wounds, and wounds grafted on day 0 were biopsied. On day 14, 1 wound was created on each of the 2 unwounded limbs, and the wounds that were grafted on day 7 were biopsied. All 4 ungrafted wounds (ie, 2 fresh wounds and 2 wounds with 1-week-old granulation beds) were grafted. The horses then received HBOT for 1 hour daily at 23 PSI for 7 days. On day 21, the grafts applied on day 14 were biopsied. Results—Histologic examination of biopsy specimens revealed that grafts treated with HBOT developed less granulation tissue, edema, and neovascularization, but more inflammation. The superficial portion of the graft was also less viable than the superficial portion of those not treated with HBOT. Conclusions and Clinical Relevance—The use of HBOT after full-thickness skin grafting of uncompromised fresh and granulating wounds of horses is not indicated.
- Published
- 2008
42. Synthesis of Diverse β-Quaternary Ketones via Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Cyclic Enones
- Author
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Alexander N. Marziale, Jeffrey C. Holder, Emmett D. Goodman, Michele Gatti, Kotaro Kikushima, and Brian M. Stoltz
- Subjects
Organic Chemistry ,Enantioselective synthesis ,chemistry.chemical_element ,Biochemistry ,Article ,Catalysis ,Ring size ,chemistry.chemical_compound ,chemistry ,Reagent ,Drug Discovery ,Organic chemistry ,Enone ,Boronic acid ,Conjugate ,Palladium - Abstract
The development and optimization of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enone conjugate acceptors is described. These reactions employ air-stable and readily-available reagents in an operationally simple and robust transformation that yields β-quaternary ketones in high yields and enantioselectivities. Notably, the reaction itself is highly tolerant of atmospheric oxygen and moisture and therefore does not require the use of dry or deoxygenated solvents, specially purified reagents, or an inert atmosphere. The ring size and β-substituent of the enone are highly variable, and a wide variety of β-quaternary ketones can be synthesized. More recently, the use of NH_4PF_6 has further expanded the substrate scope to include heteroatom-containing arylboronic acids and β-acyl enone substrates.
- Published
- 2015
43. Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to α,β-Unsaturated Cyclic Electrophiles
- Author
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Jeffrey C. Holder, Brian M. Stoltz, and Samantha E. Shockley
- Subjects
Reaction mechanism ,chemistry ,Stereochemistry ,Organic Chemistry ,Electrophile ,chemistry.chemical_element ,Physical and Theoretical Chemistry ,Article ,Catalysis ,Palladium ,Stereocenter ,Conjugate - Abstract
This account describes our laboratory’s efforts in the development of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic conjugate acceptors. Specifically, we highlight the study of this transformation in the following areas: (a) construction of all-carbon quaternary stereocenters, (b) elucidation of the reaction mechanism, (c) addition to heterocyclic acceptors to generate tertiary stereocenters, and (d) application in the synthesis of natural products.
- Published
- 2015
44. Preparation of (S)-tert-ButylPyOx and Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids
- Author
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Hideki Shimizu, Mario P. Wiesenfeldt, Brian M. Stoltz, Samantha E. Shockley, and Jeffrey C. Holder
- Subjects
Aqueous solution ,Chromatography ,010405 organic chemistry ,Silica gel ,Organic Chemistry ,Aqueous two-phase system ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,010402 general chemistry ,Cooling bath ,01 natural sciences ,Article ,0104 chemical sciences ,chemistry.chemical_compound ,N-Methylmorpholine ,chemistry ,Acetone ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Physical and Theoretical Chemistry ,ComputingMilieux_MISCELLANEOUS ,Nuclear chemistry ,Separatory funnel ,Dichloromethane - Abstract
A. (S)-N-(1-Hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2). A 1 L one-necked round-bottomed flask equipped with a 3.0 cm x 1.4 cm, egg-shaped, Teflon-coated magnetic stirring bar is sealed with a septum and connected via needle adapter to a two-tap Schlenk adapter attached to an oil bubbler and a nitrogen/vacuum manifold (Note 1). The flask is dried with a heat gun under vacuum and cooled under a stream of nitrogen. The flask is charged with 2-picolinic acid (1) (6.15 g, 50.0 mmol, 1.00 equiv) (Note 2), evacuated and back-filled with nitrogen three times, then charged with dichloromethane (300 mL, 0.17 M) (Note 3) and N-methylmorpholine (7.59 g, 8.25 mL, 75.0 mmol, 1.50 equiv). The flask is cooled in an ice/water bath and iso-butylchloroformate (6.86 mL, 7.17 g, 52.5 mmol, 1.05 equiv) is added dropwise over 30 min by syringe pump. The reaction mixture is stirred for an additional 30 min while remaining submerged in the ice/water bath. A separate 100 mL one-necked round-bottomed flask is sealed with a septum and connected via needle adapter to the two-tap Schlenk adapter and manifold, dried with a heat gun under vacuum, and allowed to cool under a stream of nitrogen. This flask is charged with (S)-tert-leucinol (6.45 g, 55.0 mmol, 1.10 equiv), dichloromethane (40 mL), and N-methylmorpholine (6.07 mL, 5.56 g, 55.0 mmol, 1.10 equiv). The resulting clear solution is taken up in a syringe and transferred dropwise using a syringe pump over the course of 1 h to the stirring reaction mixture in the ice/water bath. The cooling bath is removed, and the pale gold colored reaction mixture is stirred for an additional 6 h at 23 °C. Upon consumption of starting material (Note 4), the mixture is quenched at ambient temperature with a single addition of an aqueous solution of saturated NH_4Cl (50 mL), diluted with additional H_2O (25 mL), and transferred into a 1 L separatory funnel. The phases are separated, and the aqueous phase is extracted with CH_2Cl_2 (3 x 100 mL). The combined organic phases are washed with an aqueous solution of saturated NaHCO_3 (1 x 50 mL) and brine (1 x 50 mL). The combined organic phases are dried over Na_2SO_4 (10 g, 15 min while agitating), filtered through a M pore glass frit, and concentrated by rotary evaporation (28 °C, 15 mmHg). Excess N-methylmorpholine is further removed by placing the crude residue under high vacuum (< 12 mmHg, 12 h) to provide a pale red solid (Note 5). The crude residue is dissolved in 10 mL of acetone and purified via silica gel flash chromatography (Note 6). The combined product-containing fractions are concentrated by rotary evaporation (40 °C, 15 mmHg) to yield a solid, which is dried under high vacuum (< 12 mmHg, 12 h) to afford (S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide (2) as a white amorphous solid (9.88-9.95 g, 44.4-44.8 mmol, 89-90% yield) (Note 7).
- Published
- 2015
45. Copper Tolerance and Characterization of a Copper-Responsive Operon, copYAZ, in an M1T1 Clinical Strain of Streptococcus pyogenes
- Author
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Robert C. Holder, Christie Young, Lily D. Gordon, Zhong Fang, and Sean D. Reid
- Subjects
Operon ,Streptococcus pyogenes ,Virulence ,Biology ,medicine.disease_cause ,Microbiology ,Bacterial Proteins ,Streptococcal Infections ,medicine ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,Escherichia coli ,Pathogen ,Copper toxicity ,Biofilm ,Articles ,Gene Expression Regulation, Bacterial ,medicine.disease ,RNA, Bacterial ,Biofilms ,Heterologous expression ,Copper - Abstract
Infection with Streptococcus pyogenes is associated with a breadth of clinical manifestations ranging from mild pharyngitis to severe necrotizing fasciitis. Elevated levels of intracellular copper are highly toxic to this bacterium, and thus, the microbe must tightly regulate the level of this metal ion by one or more mechanisms, which have, to date, not been clearly defined. In this study, we have identified two virulence mechanisms by which S. pyogenes protects itself against copper toxicity. We defined a set of putative genes, copY (for a regulator), copA (for a P1-type ATPase), and copZ (for a copper chaperone), whose expression is regulated by copper. Our results indicate that these genes are highly conserved among a range of clinical S. pyogenes isolates. The copY , copA , and copZ genes are induced by copper and are transcribed as a single unit. Heterologous expression assays revealed that S. pyogenes CopA can confer copper tolerance in a copper-sensitive Escherichia coli mutant by preventing the accumulation of toxic levels of copper, a finding that is consistent with a role for CopA in copper export. Evaluation of the effect of copper stress on S. pyogenes in a planktonic or biofilm state revealed that biofilms may aid in protection during initial exposure to copper. However, copper stress appears to prevent the shift from the planktonic to the biofilm state. Therefore, our results indicate that S. pyogenes may use several virulence mechanisms, including altered gene expression and a transition to and from planktonic and biofilm states, to promote survival during copper stress. IMPORTANCE Bacterial pathogens encounter multiple stressors at the host-pathogen interface. This study evaluates a virulence mechanism(s) utilized by S. pyogenes to combat copper at sites of infection. A better understanding of pathogen tolerance to stressors such as copper is necessary to determine how host-pathogen interactions impact bacterial survival during infections. These insights may lead to the identification of novel therapeutic targets that can be used to address antibiotic resistance.
- Published
- 2015
46. Otopathogens Detected in Middle Ear Fluid Obtained during Tympanostomy Tube Insertion: Contrasting Purulent and Non-Purulent Effusions
- Author
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Daniel J. Kirse, Robert C. Holder, William E. Swords, Katherine A. Poehling, Amy S. Whigham, Adele K. Evans, Timothy R. Peters, and Sean D. Reid
- Subjects
Male ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,lcsh:Medicine ,Ear, Middle ,medicine.disease_cause ,Microbiology ,Haemophilus influenzae ,Moraxella catarrhalis ,Otology ,Moraxella (Branhamella) catarrhalis ,Streptococcus pneumoniae ,medicine ,Humans ,Tympanostomy tube ,Carnobacteriaceae ,lcsh:Science ,Retrospective Studies ,Multidisciplinary ,Suppuration ,biology ,business.industry ,Otitis Media with Effusion ,lcsh:R ,Infant ,Bacterial Infections ,biology.organism_classification ,Middle Ear Ventilation ,3. Good health ,Otitis ,medicine.anatomical_structure ,Child, Preschool ,Middle ear ,lcsh:Q ,Female ,medicine.symptom ,business ,Research Article - Abstract
Otitis media is a prominent disease among children. Previous literature indicates that otitis media is a polymicrobial disease, with Haemophilus influenzae, Streptococcus pneumoniae, Alloiococcus otitidis and Moraxella catarrhalis being the most commonly associated bacterial pathogens. Recent literature suggests that introduction of pneumococcal conjugate vaccines has had an effect on the etiology of otitis media. Using a multiplex PCR procedure, we sought to investigate the presence of the aforementioned bacterial pathogens in middle ear fluid collected from children undergoing routine tympanostomy tube placement at Wake Forest Baptist Medical Center during the period between January 2011 and March 2014. In purulent effusions, one or more bacterial organisms were detected in ~90% of samples. Most often the presence of H. influenzae alone was detected in purulent effusions (32%; 10 of 31). In non-purulent effusions, the most prevalent organism detected was A. otitidis (26%; 63 of 245). Half of the non-purulent effusions had none of these otopathogens detected. In purulent and non-purulent effusions, the overall presence of S. pneumoniae was lower (19%; 6 of 31, and 4%; 9 of 245, respectively) than that of the other pathogens being identified. The ratio of the percentage of each otopathogen identified in purulent vs. non-purulent effusions was >1 for the classic otopathogens but not for A. otitidis.
- Published
- 2015
47. Discovery of a novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series promoting neurogenesis of human neural progenitor cells
- Author
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Jie Luo, Emiri T. Mandeville, Hong Lin, Eng H. Lo, Xuedong Dai, Dan Pu, Ken Arai, Jing Zhao, Qinghua Meng, Julie C. Holder, Libo Chen, Tsu Tshen Chuang, Douglas Minick, Jamie Wang, Haiyan Fang, and Sharon Wu
- Subjects
Neurogenesis ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Administration, Oral ,Chemistry Techniques, Synthetic ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,Neural Stem Cells ,Drug Discovery ,Structure–activity relationship ,Animals ,Humans ,Progenitor cell ,Isoquinoline ,Molecular Biology ,Cells, Cultured ,Dose-Response Relationship, Drug ,Chemistry ,Organic Chemistry ,Brain ,Wild type mice ,Cell Differentiation ,Anatomy ,Isoquinolines ,Neural stem cell ,Cell biology ,Mice, Inbred C57BL ,Pyrazines ,Molecular Medicine ,Half-Life - Abstract
A novel neurogenic compound (1), discovered from a mouse neural progenitor cell (NPC) screen, showed profound neurogenic effect on human NPCs. Synthesis and SAR of this novel 2,3,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione series are described. Compound 20 is brain penetrable in rodents, and promotes neurogenesis in wild type mice, therefore it is a good tool molecule to study neurogenesis induction as a potential treatment for conditions associated with neurogenesis impairment diseases.
- Published
- 2015
48. Mechanistic analysis of an asymmetric palladium-catalyzed conjugate addition of arylboronic acids to β-substituted cyclic enones
- Author
-
Brian M. Stoltz, Cornelia L. Boeser, Jeffrey C. Holder, Richard N. Zare, Buck L. H. Taylor, and K. N. Houk
- Subjects
Addition reaction ,Chemistry ,Stereochemistry ,chemistry.chemical_element ,General Chemistry ,Mass spectrometry ,Combinatorial chemistry ,Catalysis ,chemistry.chemical_compound ,Catalytic cycle ,Chemical Sciences ,Reactivity (chemistry) ,Enone ,Palladium ,Conjugate - Abstract
Mechanistic insight into a Pd-catalyzed conjugate addition reaction was gained using desorption electrospray ionization coupled to mass spectrometry., An asymmetric palladium-catalyzed conjugate addition reaction of arylboronic acids to enone substrates was investigated mechanistically. Desorption electrospray ionization coupled to mass spectrometry was used to identify intermediates of the catalytic cycle and delineate differences in substrate reactivity. Our findings provide evidence for the catalytic cycle proceeding through formation of an arylpalladium(ii) cation, subsequent formation of an arylpalladium–enone complex, and, ultimately, formation of the new C–C bond. Reaction monitoring in both positive and negative ion modes revealed that 4-iodophenylboronic acid formed a relatively stable trimeric species under the reaction conditions.
- Published
- 2015
49. Towards the creation of an international toxicology information centre
- Author
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Julie C. Holder, Lutz Müller, Karluss Thomas, Philip N. Judson, Thomas Steger-Hartmann, Paul Cooke, Andreas Rothfuss, Jonathan D. Vessey, Robert P. Hanzlik, David Hinchliffe, Nigel Greene, Mark D. Smith, Errol Zeiger, Nancy G. Doerrer, Andreas Hartmann, and Christopher Hardy
- Subjects
Toxicology ,Data sharing ,Structure-Activity Relationship ,Intranet ,Databases as Topic ,Quantitative analysis (finance) ,Computer science ,International Cooperation ,Feasibility Studies ,Pilot Projects ,Successful completion ,Software - Abstract
A pilot toxicology database system has been created which is accessible on-line via the world-wide web or in-house via an intranet. It is intended to be suitable as a source of toxicological information and to support structure-activity relationship studies, and it can be searched on chemical structural and substructural as well as toxicological and physico-chemical data. Successful completion of the pilot has led to an ongoing project to develop and expand the system.
- Published
- 2005
50. Glycogen Synthase Kinase-3 Mediates Acetaminophen-Induced Apoptosis in Human Hepatoma Cells
- Author
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George E.N. Kass, Patricia Macanas-Pirard, Richard H. Hinton, Pauline C Lee, Julie C. Holder, and Nik-Soriani Yaacob
- Subjects
Pharmacology ,Inhibitor of apoptosis domain ,Programmed cell death ,Carcinoma, Hepatocellular ,p38 mitogen-activated protein kinases ,Intrinsic apoptosis ,Apoptosis ,Biology ,Molecular biology ,Cell biology ,Glycogen Synthase Kinase 3 ,Mitochondrial permeability transition pore ,GSK-3 ,Cell Line, Tumor ,Humans ,Molecular Medicine ,ASK1 ,Protein Kinase Inhibitors ,Acetaminophen - Abstract
The mild analgesic drug acetaminophen (AAP) induces severe hepatic injury when taken at excessive doses. Recent evidence shows that the initial form of damage is through apoptosis, but this fails to go to completion and degenerates into necrosis. The aim of this study was to elucidate the mechanism through which AAP induces apoptosis using human HuH7 hepatoma cells as an in vitro model system to investigate the initial phase of AAP-induced hepatic injury. AAP-induced apoptosis in HuH7 cells as evidenced by chromatin condensation was preceded by the translocation of Bax to mitochondria and the cytoplasmic release of the proapoptotic factors cytochrome c and Smac/DIABLO. A concomitant loss of mitochondrial membrane potential occurred. Activation of the mitochondrial pathway of apoptosis led to the activation of execution caspases-3 and -7. AAP-induced apoptosis and cell death was blocked by inhibitors of caspases but not by inhibitors of calpains, cathepsins, and serine proteases. Apoptosis was unaffected by inhibitors of the mitochondrial permeability transition pore and by inhibitors of Jun NH(2)-terminal kinases, p38 mitogen-activated protein kinase, or mitogen-activated protein kinase kinase 1/2. However, pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) delayed and decreased the extent of AAP-induced apoptosis. In comparison, endoplasmic reticulum stress-induced but not prooxidant-induced apoptosis of HuH7 cells was sensitive to GSK-3 inhibition. It is concluded that AAP-induced apoptosis involves the mitochondrial pathway of apoptosis that is mediated by GSK-3 and most likely initiated through an endoplasmic reticulum stress response.
- Published
- 2005
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