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Jim Kaput,Jose M Ordovas,Lynnette Ferguson,Ben van Ommen,Raymond L Rodriguez,Lindsay Allen,Bruce N Ames,Kevin Dawson,Bruce German,Ronald Krauss,Wasyl Malyj,Michael C Archer,Stephen Barnes,Amelia Bartholomew,Ruth Birk,Peter van Bladeren,Kent J Bradford,Kenneth H Brown,Rosane Caetano,David Castle,Ruth Chadwick,Stephen Clarke,Karine Clément,Craig A Cooney,Dolores Corella,Ivana Beatrice Manica da Cruz,Hannelore Daniel,Troy Duster,Sven O E Ebbesson,Ruan Elliott,Susan Fairweather-Tait,Jim Felton,Michael Fenech,John W Finley,Nancy Fogg-Johnson,Rosalynn Gill-Garrison,Michael J Gibney,Peter J Gillies,Jan-Ake Gustafsson,John L Hartman Iv,Lin He,Jae-Kwan Hwang,Jean-Philippe Jais,Yangsoo Jang,Hans Joost,Claudine Junien,Mitchell Kanter,Warren A Kibbe,Berthold Koletzko,Bruce R Korf,Kenneth Kornman,David W Krempin,Dominique Langin,Denis R Lauren,Jong Ho Lee,Gilbert A Leveille,Su-Ju Lin,John Mathers,Michael Mayne,Warren McNabb,John A Milner,Peter Morgan,Michael Muller,Yuri Nikolsky,Frans van der Ouderaa,Taesun Park,Norma Pensel,Francisco Perez-Jimenez,Kaisa Poutanen,Matthew Roberts,Wim H M Saris,Gertrud Schuster,Andrew N Shelling,Artemis P Simopoulos,Sue Southon,E Shyong Tai,Bradford Towne,Paul Trayhurn,Ricardo Uauy,Willard J Visek,Craig Warden,Rick Weiss,John Wiencke,Jack Winkler,George L Wolff,Xi Zhao-Wilson,Jean-Daniel Zucker Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiologic... ( view more )al studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries. ( view less ) Joanne Borg-Stein,Richard E Seroussi,Lorraine Gomba,Alec Meleger,Susan Schmitt,Eric Leep,Jerel H Glassman,John Revord,Joseph Condon,Elizabeth Bensen,Jeffery E Fitzthum,Bradford C Fowler,Bradford E Gliner,Andrew D Firlik OBJECTIVE: Percutaneous neuromodulation therapy (PNT) is a new minimally invasive, office-based treatment for low back pain in which electrical stimulation is delivered to the paraspinal peripheral nerves. The purpose of this study was to determine the safety, tolerability, and clinical efficacy of... ( view more ) PNT in a population of patients with subacute low back pain with radiation to the lower extremity. DESIGN: Open label prospective clinical trial. Setting: Multi-center outpatient setting. PARTICIPANTS: We enrolled 83 patients who had radiating low back pain for 4 weeks to 6 months with a pain intensity of at least 4 on a visual analog scale of 0-10. INTERVENTIONS: Subjects were treated with PNT 1 to 2 times per week for at least 4 weeks. Based on clinical response patients were treated up to an additional 8 weeks. MAIN OUTCOME MEASURES: We recorded baseline visual analog scale (VAS) scores of radiating pain, low back pain, physical activity, and sleep, as well as the Oswestry Disability Questionnaire. Follow-up assessments were performed at each session, and at 5 and 12 weeks. Patients benefiting from treatments at 12 weeks were followed-up at 6 months. RESULTS: Fifty-nine patients completed the study protocol. Mean VAS scores improved as follows: leg/buttock pain decreased by 37% to 4.0 +/- 2.6 from a baseline of 6.6 +/- 1.7 (P < 0.001); low back pain decreased by 26% to 3.9 +/- 2.4 from a baseline of 5.5 +/- 2.2 (P < 0.001); activity levels improved by 38% to 3.6 +/- 2.2 from a baseline of 6.0 +/- 2.2 (P < 0.001); and sleep improved by 27% to 3.1 +/- 2.5 from a baseline of 4.8 +/- 3.0 (P < 0.001). The Oswestry Low Back Pain Disability scores improved by 24% to 32 +/- 16 from a baseline of 43 +/- 15 (P < 0.001). Pain relief was sustained over a 3-month observation period. CONCLUSION: For many patients with subacute radiating low back pain, PNT significantly reduced pain and self-rated disability, and improved sleep quality and activity level. PNT is safe and generally well tolerated. ( view less ) H Tsukamoto,Y Takei,C J McClain,S Joshi-Barve,D Hill,J Schmidt,I Deaciuc,S Barve,A Colell,C Garcia-Ruiz,N Kaplowitz,J C Fernandez-Checa,H Yokoyama,Y Okamura,Y Nakamura,H Ishii,R K Chawla,S Barve,S Joshi-Barve,W Watson,W Nelson,M Lin,M Ohata,K Motomura,N Enomoto,K Ikejima,T Kitamura,H Oide,M Hirose,B U Bradford,C A Rivera,H Kono,S Peter,S Yamashina,A Konno,M Ishikawa,H Shimizu,N Sato,R Thurman This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Hidekazu Tsukamoto and Yoshiyuki Takei. The presentations were (1) Tribute to Professor Rajendar K. Chawla, by Craig J. McClain; (2) Dysregulated TNF signaling in alcoholic liver dis... ( view more )ease, by Craig J. McClain, S. Joshi-Barve, D. Hill, J Schmidt, I. Deaciuc, and S. Barve; (3) The role of mitochondria in ethanol-mediated sensitization of the liver, by Anna Colell, Carmen Garcia-Ruiz, Neil Kaplowitz, and Jose C. Fernandez-Checa; (4) A peroxisome proliferator (bezafibrate) can prevent superoxide anion release into hepatic sinusoid after acute ethanol administration, by Hirokazu Yokoyama, Yukishige Okamura, Yuji Nakamura, and Hiromasa Ishii; (5) S-adenosylmethionine affects tumor necrosis factor-alpha gene expression in macrophages, by Rajendar K. Chawla, S. Barve, S. Joshi-Barve, W. Watson, W. Nelson, and C. McClain; (6) Iron, retinoic acid and hepatic macrophage TNFalpha gene expression in ALD, by Hidekazu Tsukamoto, Min Lin, Mitsuru Ohata, and Kenta Motomura; and (7) Role of Kupffer cells and gut-derived endotoxin in alcoholic liver injury, by N. Enomoto, K. Ikejima, T. Kitamura, H. Oide, Y. Takei, M. Hirose, B. U. Bradford, C. A. Rivera, H. Kono, S. Peter, S. Yamashina, A. Konno, M. Ishikawa, H. Shimizu, N. Sato, and R. Thurman. ( view less ) L B Schwartz,K Sakai,T R Bradford,S Ren,B Zweiman,A S Worobec,D D Metcalfe Tryptase, a protease produced by all mast cells, was evaluated as a clinical marker of systemic mastocytosis. Two sandwich immunoassays were evaluated, one which used the mAb G5 for capture, the other which used B12 for capture. The B12 capture assay measured both recombinant alpha- and beta-trypta... ( view more )se, whereas the G5 capture assay measured primarily recombinant beta-tryptase. G5 binds with low affinity to both recombinant alpha-tryptase and tryptase in blood from normal and nonacute mastocytosis subjects, and binds with high affinity to recombinant beta-tryptase, tryptase in serum during anaphylaxis, and tryptase stored in mast cell secretory granules. B12 recognizes all of these forms of tryptase with high affinity. As reported previously, during systemic anaphylaxis in patients without known mastocytosis, the ratio of B12- to G5-measured tryptase was always < 5 and approached unity (Schwartz L.B., T.R. Bradford, C. Rouse, A.-M. Irani, G. Rasp, J.K. Van der Zwan and P.-W.G. Van der Linden, J. Clin. Immunol. 14:190-204). In this report, most mastocytosis patients with systemic disease have B12-measured tryptase levels that are elevated (> 20 ng/ml) and are at least 10-fold greater than the corresponding G5-measured tryptase level. Most of those subjects with B12-measured tryptase levels of < 20 ng/ml had only cutaneous manifestations. The B12 assay for alpha-tryptase and beta-tryptase, particularly when performed in conjunction with the G5 assay for beta-tryptase, provides a more precise measure of mast cell involvement than currently available assessments, a promising potential screening test for systemic mastocytosis and may provide an improved means to follow disease progression and response to therapy. ( view less ) B O'Brien,J Bradford,H GibbThis paper describes the development of a new framework for nursing assessment and management of incontinence using action research (Gibb, O'Brien, Bradford and Curtis 1993). The authors worked with nurses and residents in a large extended care setting--clarifying their current understandings of co... ( view more )ntinence issues and looking at ways of improving incontinence management. This process led to the development of a model for assessment and management of incontinence. ( view less ) B U Bradford,C B Seed,J A Handler,D T Forman,R G Thurman Recently, it was demonstrated that 4-methylpyrazole was not only an inhibitor of alcohol dehydrogenase but also caused competitive inhibition of fatty acyl-CoA synthetase, the enzyme which activates fatty acids (B. U. Bradford, D. T. Forman, and R. G. Thurman, 1993, Mol. Pharmacol. 43, 115-119). Ra... ( view more )tes of catalase-dependent alcohol metabolism were decreased in alcohol dehydrogenase-negative (ADH-) deer mice because the H2O2 supply for catalase via peroxisomal fatty acid oxidation was inhibited due to substrate limitation. In light of these findings it became necessary to reevaluate the role of catalase and alcohol dehydrogenase in alcohol metabolism. In this study, methanol, a selective substrate for catalase in rodents, was compared with ethanol. Rates of ethanol and methanol metabolism were studied in vivo at blood alcohol levels ranging from 50 to 500 mg/dl. In the ADH- deer mouse, rates of methanol and ethanol metabolism increased when alcohol was elevated from 0 to 100 mg/dl and were maximal at values around 6-8 mmol/kg/h (half-maximal rates were observed at blood alcohol levels around 50 mg/dl). In the ADH+ deer mouse, rates of ethanol metabolism increased to values around 9 mmol/kg/h at 100 mg/dl and remained constant at blood levels up to 500 mg/dl. In contrast, rates of methanol metabolism increased to values of only 5 mmol/kg/h at levels of 100 mg/dl (the half-maximal rate was about 2.5 mmol/kg/h at 50 mg/dl) followed by a steady increase to 9 mmol/kg/h as the blood level was increased from 100 to 500 mg/dl (the half-maximal rate for this second component was around 6 mmol/kg/h at 300 mg/dl). Rates of methanol uptake were 50 +/- 4 nmol/min/mg protein in 10,000g pellets from ADH- deer mouse livers; however, methanol was not metabolized by isolated microsomes. The catalase inhibitor aminotriazole decreased ethanol and methanol metabolism 75% in ADH- deer mice. Further, olive oil, which is rich in oleate, increased methanol metabolism from 7 to 11.5 mmol/kg/h. This stimulation was blocked by fructose, which diminishes ATP and decreases H2O2 supply. In the ADH+ deer mouse, fructose (2 g/kg) stimulated ethanol metabolism as expected; however, inhibition of both ethanol and methanol metabolism was observed with higher doses of fructose (10 g/kg). Taken together, these data support the hypothesis that catalase is the predominant pathway for alcohol metabolism in the ADH- deer mouse. The contribution of catalase was about 50% in the ADH+ mutant at low doses of ethanol and approached 100% as the alcohol concentration was elevated. ( view less ) S Winn,M BradfordBrighton health authority and Brighton borough council are jointly planning a 'Healthy living centre' to provide a focal point for local health promotion activities. Sandra Winn and Martin Bradford report on a survey of community groups which not only provided information for the development of the... ( view more ) centre but also gave useful insight into the community's concerns about health and people's needs for health information. ( view less ) J K Klarlund,S R Jaspers,N Khalaf,A P Bradford,T B Miller,M P Czech Insulin action leads to the rapid stimulation of a cytosolic Kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) kinase (KIK) that has been recently purified to near homogeneity (Klarlund, J. K., Bradford, A. P., Milla, M. G., and Czech, M. P. (1990) J. Biol. Chem. 265, 227-234). To examine its activation mecha... ( view more )nism, purified KIK was treated with purified protein phosphatases. The catalytic subunit of phosphatase 2A inhibited the activity of control KIK by about 50% and abolished the 5-fold elevation in KIK activity due to insulin action. The catalytic subunit of phosphatase 1 with equivalent activity based on dephosphorylation of 32P-labeled phosphorylase alpha had no effect on either control or insulin-stimulated KIK activity. The deactivation of insulin-stimulated KIK by phosphatase 2A was time- and concentration-dependent and was blocked by phosphatase inhibitors. The purified native complexes of phosphatase 2A, phosphatase 2A1, and phosphatase 2A2 similarly deactivated KIK. Analyis of control or insulin-stimulated KIK with two antiphosphotyrosine antibodies by immunoblotting and immunoprecipitation failed to detect the presence of phosphotyrosine in the kinase. These results indicate that KIK is activated by phosphorylation as part of a kinase cascade emanating from insulin receptor stimulation. ( view less ) J D Bradford,C P Wilkinson,R H BradfordThe outcome of clinical cystoid macular edema (CME) was studied in 20 symptomatic eyes in which extracapsular cataract extraction and posterior chamber intraocular lens implantation had been performed. Resolution of symptoms and apparent resolution of the macular edema were observed in 18 (90%) of ... ( view more )the 20 cases. Clearing occurred within one year in 14 (78%) of these 18 eyes and in 17 (94%) within two years. In all eyes in which macular edema resolved, visual acuity returned to 20/40 or better. This study suggests that clinical cystoid macular edema occurring in association with a posterior chamber intraocular lens has a relatively favorable course. ( view less ) Bradford Siegele,Christopher Cefalu,Neal Holm,Guang Sun,Jesse Tubbs,Carol Meschonat,Yoshinobu Odaka,Arrigo Debenedetti,G E Ghali,Quyen Chu,J Michael Mathis,Benjamin D L Li BACKGROUND: Translation initiation factor eIF4E unwinds long 5'-untranslated regions of certain tightly regulated mRNAs and, thereby, facilitates their translation into proteins. eIF4E has been shown to be overexpressed in a majority of solid tumors, including head and neck cancers. To exploit this... ( view more ) dysregulation, a long 5'-untranslated region was spliced upstream of a thymidine kinase (Tk) gene to enhance translation of this "suicide" gene within cells overexpressing eIF4E. We investigated the efficacy of therapy with an adenovirus incorporating this novel suicide gene (Ad-HSV-UTk) following cytoreductive tumor surgery in improving disease-free and overall survival in a mouse soft-tissue metastasis model for head and neck squamous cell carcinoma. MATERIALS AND METHODS: SCC-7 (orally-derived mouse SCCa) cells were treated with Ad-HSV-Tk, Ad-HSV-UTk, Ad-null, or saline and characterized for eIF4E and Tk levels by Western blot analysis. Cytotoxicities for cells treated with Ad-HSV-Tk, Ad-HSV-UTk, or Ad-null were quantified by MTS assay. Mice bearing SCC-7-induced tumors received cytoreduction followed by Ad-HSV-UTk + ganciclovir (GCV) or control treatment and were followed for disease-free and overall survival. RESULTS: SCC-7 cells showed uniformly high levels of eIF4E but elevated Tk for Ad-HSV-Tk- and Ad-HSV-UTk-treated cells over Ad-null-treated cells. Cytotoxicities for Ad-HSV-Tk- and Ad-HSV-UTk-treated cells were, correspondingly, observed to be 100-fold more sensitive than Ad-null-treated cells to GCV treatment. Cytoreduced mice receiving Ad-HSV-UTk + GCV treatment showed significantly longer disease-free survival (P = 0.0045) than control arm mice. CONCLUSIONS: Ad-HSV-UTk suicide gene therapy prolonged disease-free survival in a mouse minimal residual soft-tissue head and neck squamous cell carcinoma metastasis model. ( view less ) Mary-Clare Cathcart,Rasa Tamosiuniene,Gang Chen,Tomas G Neilan,Aidan Bradford,Kenneth J O'Byrne,Desmond J Fitzgerald,Graham P Pidgeon Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a ... ( view more )chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobaric-hypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 +/- 1.4 versus 13.8 +/- 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 +/- 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B(2) excretion increased following hypoxia (44.6 +/- 11.1 versus 14.7 +/- 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 +/- 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin(1alpha) excretion following hypoxia was reduced by COX-2 gene disruption (29 +/- 3 versus 52 +/- 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA(2)/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA(2), and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia. ( view less ) Bradford S Hoppe,Suzanne L Wolden,Michael J Zelefsky,James G Mechalakos,Jatin P Shah,Dennis H Kraus,Nancy Lee BACKGROUND: Our aim was to review Memorial Sloan-Kettering Cancer Center's experience with postoperative intensity-modulated radiotherapy (IMRT) for paranasal sinus, nasal cavity, and lacrimal gland cancer and report dosimetric measures, toxicity, and outcomes. METHODS: Between September 2000 and J... ( view more )une 2006, 37 patients with paranasal sinus, nasal cavity, or lacrimal gland cancer underwent postoperative IMRT. Median values were as follows: prescription dose, 60 Gy (range, 50-70); PTV(D95), 99% (range, 79-101%); optic nerve Dmax, 53 Gy (range, 2-54); optic chiasm Dmax, 51Gy (range, 2-55). Acute and late toxicities were scored by Radiation Therapy Oncology Group morbidity criteria. RESULTS: Median follow-up was 28 months. Two-year local progression-free and overall survivals were 75% and 80%. No early- or late-grade 3/4 radiation-induced ophthalmologic toxicity occurred. CONCLUSIONS: Preliminary results show that adjuvant IMRT in these patients is feasible, allowed for excellent planning target volume (PTV) coverage, and minimized dose delivered to optic structures. Longer follow-up is warranted to assess the extent of late effects and outcomes. ( view less ) Shih-Hon Li,Natalia V Gorlatova,Daniel A Lawrence,Bradford S Schwartz Plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor (serpin) in which the reactive center loop (RCL) spontaneously inserts into a central beta-sheet, beta-sheet A, resulting in inactive inhibitor. Available x-ray crystallographic studies of PAI-1 in an active conformation ... ( view more )relied on the use of stabilizing mutations. Recently it has become evident that these structural models do not adequately explain the behavior of wild-type PAI-1 (wtPAI-1) in solution. To probe the structure of native wtPAI-1, we used three conformationally sensitive ligands: the physiologic cofactor, vitronectin; a monoclonal antibody, 33B8, that binds preferentially to RCL-inserted forms of PAI-1; and RCL-mimicking peptides that insert into beta-sheet A. From patterns of interaction with wtPAI-1 and the stable mutant, 14-1B, we propose a model of the native conformation of wtPAI-1 in which the bottom of the central sheet is closed, whereas the top of the beta-sheet A is open to allow partial insertion of the RCL. Because the incorporation of RCL-mimicking peptides into wtPAI-1 is accelerated by vitronectin, we further propose that vitronectin alters the conformation of the RCL to allow increased accessibility to beta-sheet A, yielding a structural hypothesis that is contradictory to the current structural model of PAI-1 in solution and its interaction with vitronectin. ( view less ) Parvez M Lokhandwala,Tam-Linh N Nguyen,J Bradford Bowzard,Rebecca C Craven The second helix in the C-terminal domain of retroviral capsid (CA) protein functions as the site of dimerization between subunits in capsid assembly and is believed to participate in a unique interface between Gag molecules in immature particles. This study reports isolation of two substitutions i... ( view more )n the dimerization helix of Rous sarcoma virus CA protein that have the ability to suppress lethal defects in core maturation imposed by alterations to the major homology region (MHR) motif just upstream. Together with two previously published suppressors, these define an extended region of the dimerization helix that is unlikely to contribute directly to CA-CA contacts but whose assembly-competence may be strongly affected by conformation. The broad-spectrum suppression and temperature-sensitivity exhibited by some mutants argues that they act through modulation of protein conformation. These findings provide important biological evidence in support of a significant conformational change involving the dimerization helix and the MHR during maturation. ( view less ) Kimio Satoh,Tetsuya Matoba,Jun Suzuki,Michael R O'Dell,Patrizia Nigro,Zhaoqiang Cui,Amy Mohan,Shi Pan,Lingli Li,Zheng-Gen Jin,Chen Yan,Jun-ichi Abe,Bradford C Berk BACKGROUND: Oxidative stress, generated by excessive reactive oxygen species, promotes cardiovascular disease. Cyclophilin A (CyPA) is a 20-kDa chaperone protein secreted from vascular smooth muscle cells (VSMCs) in response to reactive oxygen species that stimulates VSMC proliferation and inflamma... ( view more )tory cell migration in vitro; however, the role CyPA plays in vascular function in vivo remains unknown. METHODS AND RESULTS: We tested the hypothesis that CyPA contributes to vascular remodeling by analyzing the response to complete carotid ligation in CyPA knockout mice, wild-type mice, and mice that overexpress CyPA in VSMC (VSMC-Tg). After carotid ligation, CyPA expression in vessels of wild-type mice increased dramatically and was significantly greater in VSMC-Tg mice. Reactive oxygen species-induced secretion of CyPA from mouse VSMCs correlated significantly with intracellular CyPA expression. Intimal and medial hyperplasia correlated significantly with CyPA expression after 2 weeks of carotid ligation, with marked decreases in CyPA knockout mice and increases in VSMC-Tg mice. Inflammatory cell migration into the intima was significantly reduced in CyPA knockout mice and increased in VSMC-Tg mice. Additionally, VSMC proliferation assessed by Ki67(+) cells was significantly less in CyPA knockout mice and was increased in VSMC-Tg mice. The importance of CyPA for intimal and medial thickening was shown by strong correlations between CyPA expression and the number of both inflammatory cells and proliferating VSMCs in vivo and in vitro. CONCLUSIONS: In response to low flow, CyPA plays a crucial role in VSMC migration and proliferation, as well as inflammatory cell accumulation, thereby regulating flow-mediated vascular remodeling and intima formation. ( view less ) Choll W Kim,Robert Talac,Lichun Lu,Michael J Moore,Bradford L Currier,Michael J Yaszemski The use of bone grafts for orthopedic applications have increased steadily over the past decade. With improvements in surgical technique, combined with an increasing aged population requiring orthopedic treatment, the need for bone grafts substitutes have also increased. To be useful clinically, th... ( view more )e bone graft substitute must be biocompatible, bioabsorbable, and have convenient handling properties. In addition, it must possess a microarchitecture that allows cellular ingrowth and remodeling while simultaneously providing mechanical strength. Poly(propylene fumarate) (PPF) has been investigated as an injectable, biodegradable scaffold for orthopedic applications. Various methods to create a porous, interconnected polymer scaffold are available. The foaming technique is a convenient method to accomplish this task. Reactions between bicarbonate salts and weak acids generate CO(2) gas, causing a bubbling reaction during the polymerization process. This technique allows the porosity of the scaffold to be modulated. Image analysis and mechanical testing of porous PPF fabricated using the foaming technique shows that a highly porous, interconnected scaffold can be produced. At approximately 50% porosity, the scaffold has excellent handling properties, contains pore sizes ranging from 50 to 500 mum with an elastic modulus ranging from 20 to 40 MPa. The foaming technique provides an additional method by which clinically useful polymers can be fabricated for use in various bone tissue engineering applications. ( view less ) Bradford W Seabourn,Okkyung K Chung,Paul A Seib,Paul R Mathewson Fourier transform horizontal attenuated total reflectance (FT-HATR) was used to examine changes in the secondary structure of gluten proteins in a flour-water dough system during mixing. Midinfrared spectra of mixed dough revealed changes in four bands in the amide III region associated with second... ( view more )ary structure in proteins: 1317 (alpha-helix), 1285 (beta-turn), 1265 (random coil), and 1242 cm (-1) (beta-sheet). The largest band, which also showed the greatest change in second derivative band area (SDBA) during mixing, was located at 1242 cm (-1). The bands at 1317 and 1285 cm (-1) also showed an increase in SDBA over time. Conversely, the band at 1265 cm (-1) showed a corresponding decrease over time as the doughs were mixed. All bands reached an optimum corresponding to the minimum mobility of the dough as determined by the mixograph. Increases in alpha-helix, beta-turn, and beta-sheet secondary structures during mixing suggest that the dough proteins assume a more ordered conformation. These results demonstrate that it is possible, using infrared spectroscopic techniques, to relate the rheological behavior of developing dough in a mixograph directly to changes in the structure of the gluten protein system. ( view less ) C M Stapleton,M D Wyer,J Crowther,A T McDonald,D Kay,J Greaves,A Wither,J Watkins,C Francis,N Humphrey,M Bradford Under the EU Water Framework Directive (WFD) 20/60/EC and the US Federal Water Pollution Control Act 2002 management of water quality within river drainage basins has shifted from traditional point-source control to a holistic approach whereby the overall contribution of point and diffuse sources o... ( view more )f pollutants has to be considered. Consequently, there is a requirement to undertake source-apportionment studies of pollutant fluxes within catchments. The inclusion of the Bathing Water Directive (BWD), under the list of 'protected areas' in the WFD places a requirement to control sources of faecal indicator organisms within catchments in order to achieve the objectives of both the BWD (and its revision - 2006/7/EC) and the WFD. This study was therefore initiated to quantify catchment-derived fluxes of faecal indicator compliance parameters originating from both point and diffuse sources. The Ribble drainage basin is the single UK sentinel WFD research catchment and discharges to the south of the Fylde coast, which includes a number of high profile, historically non-compliant, bathing waters. Faecal indicator concentrations (faecal coliform concentrations are reported herein) were measured at 41 riverine locations, the 15 largest wastewater treatment works (WwTWs) and 15 combined sewer overflows (CSOs) across the Ribble basin over a 44-day period during the 2002 bathing season. The sampling programme included targeting rainfall-induced high flow events and sample results were categorised as either base flow or high flow. At the riverine sites, geometric mean faecal coliform concentrations showed statistically significant elevation at high flow compared to base flow. The resultant faecal coliform flux estimates revealed that over 90% of the total organism load to the Ribble Estuary was discharged by sewage related sources during high flow events. These sewage sources were largely related to the urban areas to the south and east of the Ribble basin, with over half the load associated with the relatively small subcatchment of the River Douglas. The majority of this load was attributed to two WwTWs that discharge through a common outfall close to the tidal limit of this catchment. Budgets adjusted to accommodate the impact of proposed UV disinfection of these effluents showed that the load from these sources would be reduced significantly during base flow conditions. However, during high flow events loads would still remain high due to the operation of storm sewage overflows from stormwater retention tanks. The study identified untreated storm sewage spills from urban infrastructure and WwTW stormwater retention tanks as the dominant component of the high flow flux of faecal indicators to receiving waters of the Fylde coast and the associated bathing waters. ( view less ) Min Zhang,Bradford E Berndt,Kathryn A Eaton,Sivaprakash Rathinavelu,Anna Pierzchala,John Y Kao BACKGROUND: The growing concern over the emergence of antibiotic-resistant Helicobacter pylori infection is propelling the development of an efficacious vaccine to control this highly adaptive organism. AIM: We studied the use of a dendritic cell (DC)-based vaccine against H. pylori infection in mi... ( view more )ce. METHODS: The cellular immune responses to murine bone marrow-derived DCs pulsed with phosphate-buffered saline (PBS-DC) or live H. pylori SS1 (HP-DC) were assessed in vitro and in vivo. The protective immunity against H. pylori SS1 oral challenge was compared between HP-DC or PBS-DC immunized mice. The effect of regulatory T-cell (Treg) depletion by anti-CD25 antibody on HP-DC vaccine efficacy was also evaluated. RESULTS: HP-DC induced a Th1-dominant response in vitro. In vivo, HP-DC immunized mice were characterized by a mixed Th1/Th2 peripheral immune response. However, in the stomach, HP-DC immunized mice expressed a higher level of IFN-gamma compared to PBS-DC immunized mice; no difference was found for interleukin-5 expressions in the stomach. A lower bacterial colonization post-H. pylori challenge was observed in HP-DC immunized mice compared to PBS-DC immunized mice with no significant difference in gastritis severity. H. pylori-specific Th1 response and protective immunity were further enhanced in vivo by depletion of Treg with anti-CD25 antibody. CONCLUSION: DC-based anti-H. pylori vaccine induced H. pylori-specific helper T-cell responses capable of limiting bacterial colonization. Our data support the critical role of effector cellular immune response in the development of H. pylori vaccine. ( view less ) Bradford W Hesse,Neeraj K Arora,Ellen Burke Beckjord,Lila J Finney Rutten Survivors' information-seeking behavior has traditionally been documented through analysis of inquiries to hotlines and cancer information services. Data from these self-selected inquiries tend to be restricted to a time around diagnosis, and to those populations possessing the wherewithal and moti... ( view more )vation to seek information actively. The current study used data from a general population survey to assess 1) the prevalence of information-seeking behavior among survivors in the general population, 2) characteristics of seekers versus nonseekers, 3) ratings of information-seeking experience, and 4) actual versus preferred sources of information. Data were analyzed from the 2005 administration of the Health Information National Trends Survey (HINTS). HINTS is a cross-sectional, random digit dial telephone survey, weighted to provide estimates for the general population. Nearly half of all Americans (48.7%) indicated that they have looked for cancer information from 1 source or another. Percentages were highest for those who have been touched by cancer (63.1% of cancer survivors and 54.6% of those with family histories) and lowest for those with no cancer history (27.6% of those with no history). Quality concerns topped the list of information-seeking experiences for those recalling the last time they looked. Patterns of information-seeking revealed a discrepancy between preferred and actual source when tracked over years since diagnosis. Information-seeking is prevalent among cancer survivors and does not diminish over time. Prescriptions are given for reengineering the information environment to improve long-term outcomes for survivors. ( view less ) Kenneth H Mayer,Judith B Bradford,Harvey J Makadon,Ron Stall,Hilary Goldhammer,Stewart LandersWe describe the emergence of lesbian, gay, bisexual, and transgender (LGBT) health as a key area of study and practice for clinicians and public health professionals. We discuss the specific needs of LGBT populations on the basis of the most recent epidemiological and clinical investigations, metho... ( view more )ds for defining and measuring LGBT populations, and the barriers they face in obtaining appropriate care and services. We then discuss how clinicians and public health professionals can improve research methods, clinical outcomes, and service delivery for lesbian, gay, bisexual, and transgender people. ( view less ) Suzanne Buck,Jolene Bradford,Kyle Gee,Brian Agnew,Scott Clarke,Adrian Salic The 5-bromo-2'-deoxyuridine (BrdU) labeling of cells followed by antibody staining has been the standard method for direct measurement of cells in the S-phase. Described is an improved method for the detection of S-phase cell cycle progression based upon the application of click chemistry, the copp... ( view more )er(I)-catalyzed variant of the Huisgen [3+2] cycloaddition between a terminal alkyne and an azide. 5-ethynyl-2'-deoxyuridine (EdU) is a nucleoside analog of thymidine that is incorporated into DNA during active DNA synthesis, just like BrdU. While the BrdU assay requires harsh chemical or enzymatic disruption of helical DNA structure to allow for direct measurement of cells in the S-phase by the anti-BrdU antibody, the EdU method does not. Elimination of this requirement results in the preservation of helical DNA structure and other cell surface epitopes, decreased assay time, and increased reproducibility. ( view less ) Joseph V Terza,W David Bradford,Clara E Dismuke OBJECTIVE: To investigate potential bias in the use of the conventional linear instrumental variables (IV) method for the estimation of causal effects in inherently nonlinear regression settings. DATA SOURCES: Smoking Supplement to the 1979 National Health Interview Survey, National Longitudinal Al... ( view more )cohol Epidemiologic Survey, and simulated data. STUDY DESIGN: Potential bias from the use of the linear IV method in nonlinear models is assessed via simulation studies and real world data analyses in two commonly encountered regression setting: (1) models with a nonnegative outcome (e.g., a count) and a continuous endogenous regressor; and (2) models with a binary outcome and a binary endogenous regressor. PRINCIPAL FINDINGS: The simulation analyses show that substantial bias in the estimation of causal effects can result from applying the conventional IV method in inherently nonlinear regression settings. Moreover, the bias is not attenuated as the sample size increases. This point is further illustrated in the survey data analyses in which IV-based estimates of the relevant causal effects diverge substantially from those obtained with appropriate nonlinear estimation methods. CONCLUSIONS: We offer this research as a cautionary note to those who would opt for the use of linear specifications in inherently nonlinear settings involving endogeneity. ( view less ) Bradford G Hill,Victor M Darley-UsmarUnderstanding the molecular mechanisms through which the heart could be protected from ischaemic injury is of major interest and offers a potential route for the development of new therapies. Recently, several studies have uncovered intriguing relationships between nitric oxide-induced protein thio... ( view more )l modifications and the cardioprotected phenotype. In a highly cited, seminal article published in the Biochemical Journal in 2006, Burwell and colleagues addressed this issue and provided direct evidence for S-nitrosation of complex I of the mitochondrial electron transport chain. These authors were the first to show increased S-nitrosation of mitochondrial proteins from hearts subjected to the cardioprotective process known as ischaemic preconditioning. This study has paved the way for further investigations that collectively reveal a potential link between the mitochondrial S-nitrosoproteome and ischaemic preconditioning. ( view less ) James Fanning,Bradford Fenton,Manisha Purohit OBJECTIVE: Advanced laparoscopic procedures are increasing being used in gynecologic surgery. The da Vinci robotic system (Intuitive Surgical Corporation, Sunnyvale, CA) can further augment laparoscopic surgery. We describe our initial experience using the da Vinci robotic system to perform radical... ( view more ) hysterectomy. STUDY DESIGN: Twenty consecutive patients with primary stage IB-IIA cervical carcinoma underwent class 3 radical hysterectomy with the use of the da Vinci robotic system. Median age was 44 years, median weight was 69.9 kg, 65% of patients had medical comorbidity, and 40% had prior abdominal surgery. RESULTS: All 20 patients successfully underwent robotic radical hysterectomy. Median operative time was 6.5 hours (3.5-8.5 hours) and median blood loss was 300 mL. All patients were discharged on the first day after surgery. At median follow-up of 2 years (0.6-3 years), 90% of patients are alive and disease free. CONCLUSION: We report the first series of robotic radical hysterectomy for early stage cervical cancer. All cases were successfully performed robotically with minimal complications and all patients were discharged on postoperative day 1. ( view less )
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