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1. Spin flop and crystalline anisotropic magnetoresistance in CuMnAs

Author

Wang, M., Andrews, C., Reimers, S., Amin, O. J., Wadley, P., Campion, R. P., Poole, S. F., Felton, J., Edmonds, K. W., Gallagher, B. L., Rushforth, A. W., Makarovsky, O., Gas, K., Sawicki, M., Kriegner, D., Zubac, J., Olejnik, K., Novak, V., Jungwirth, T., Shahrokhvand, M., Zeitler, U., Dhesi, S. S., and Maccherozzi, F.

Subjects
Condensed Matter - Materials Science
Abstract

Recent research works have shown that the magnetic order in some antiferromagnetic materials can be manipulated and detected electrically, due to two physical mechanisms: Neel-order spin-orbit torques and anisotropic magnetoresistance. While these observations open up opportunities to use antiferromagnets for magnetic memory devices, different physical characterization methods are required for a better understanding of those mechanisms. Here we report a magnetic field induced rotation of the antiferromagnetic Neel vector in epitaxial tetragonal CuMnAs thin films. Using soft x-ray magnetic linear dichroism spectroscopy, x-ray photoemission electron microscopy, integral magnetometry and magneto-transport methods, we demonstrate spin-flop switching and continuous spin reorientation in antiferromagnetic films with uniaxial and biaxial magnetic anisotropies, respectively. From field-dependent measurements of the magnetization and magnetoresistance, we obtain key material parameters including the anisotropic magnetoresistance coefficients, magnetocrystalline anisotropy, spin-flop and exchange fields., Comment: 26 pages, 6 figures

Published
2019
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2. Differential Mental Health Effects of Neighborhood Relocation Among Youth in Vulnerable Families: Results From a Randomized Trial

Author

Osypuk, Theresa L, Tchetgen, Eric J Tchetgen, Acevedo-Garcia, Dolores, Earls, Felton J, Lincoln, Alisa, Schmidt, Nicole M, and Glymour, M Maria

Subjects
Applied Economics, Economics, Public Health, Health Sciences, Human Society, Clinical Trials and Supportive Activities, Clinical Research, Pediatric, Brain Disorders, Behavioral and Social Science, Mental Health, Prevention, Depression, Aetiology, 2.3 Psychological, social and economic factors, Mental health, Good Health and Well Being, Other Medical and Health Sciences, Psychology, Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract

CONTEXT Extensive observational evidence indicates that youth in high-poverty neighborhoods exhibit poor mental health, although not all children may be affected similarly. OBJECTIVE To use experimental evidence to assess whether gender and family health problems modify the mental health effects of moving from high- to low-poverty neighborhoods. DESIGN Randomized controlled trial. SETTING Volunteer low-income families in public housing in 5 US cities between 1994-1997. PARTICIPANTS We analyze 4- to 7-year outcomes in youth aged 12 to 19 years (n = 2829, 89% effective response rate) in the Moving to Opportunity Study. INTERVENTION Families were randomized to remain in public housing (control group) or to receive government-funded rental subsidies to move into private apartments (experimental group). Intention-to-treat analyses included intervention interactions by gender and health vulnerability (defined as prerandomization health/developmental limitations or disabilities in family members). MAIN OUTCOME MEASURES Past-year psychological distress (Kessler 6 scale [K6]) and the Behavioral Problems Index (BPI). Supplemental analyses used past-year major depressive disorder (MDD). RESULTS Male gender (P = .02) and family health vulnerability (P = .002) significantly adversely modified the intervention effect on K6 scores; male gender (P = .01), but not health vulnerability (P = .17), significantly adversely modified the intervention effect on the BPI. Girls without baseline health vulnerabilities were the only subgroup to benefit on any outcome (K6: β = -0.21; 95% CI, -0.34 to -0.07; P = .003; MDD: odds ratio = 0.42; 95% CI, 0.20 to 0.85; P = .02). For boys with health vulnerabilities, intervention was associated with worse K6 (β = 0.26; 95% CI, 0.09 to 0.44; P = .003) and BPI (β = 0.24; 95% CI, 0.09 to 0.40; P = .002) values. Neither girls with health vulnerability nor boys without health vulnerability experienced intervention benefits. Adherence-adjusted instrumental variable analysis found intervention effects twice as large. Patterns were similar for MDD, but estimates were imprecise owing to low prevalence. CONCLUSIONS Although some girls benefited, boys and adolescents from families with baseline health problems did not experience mental health benefits from housing mobility policies and may need additional program supports.

Published
2012

3. Gender and Crime Victimization Modify Neighborhood Effects on Adolescent Mental Health

Author

Osypuk, Theresa L, Schmidt, Nicole M, Bates, Lisa M, Tchetgen-Tchetgen, Eric J, Earls, Felton J, and Glymour, M Maria

Subjects
Health Sciences, Brain Disorders, Depression, Youth Violence, Mental Health, Clinical Research, Violence Research, Behavioral and Social Science, Pediatric, Aetiology, 2.3 Psychological, social and economic factors, Mental health, Good Health and Well Being, Adolescent, Adolescent Behavior, Child, Child, Preschool, Crime, Crime Victims, Family, Female, Humans, Male, Poverty Areas, Psychology, Adolescent, Public Housing, Stress, Psychological, mental health, depression, adolescent behavior, randomized controlled trial, housing, public housing, adolescent, victimization, urban health, Medical and Health Sciences, Psychology and Cognitive Sciences, Pediatrics, Biomedical and clinical sciences, Health sciences, Psychology
Abstract

ObjectiveLeverage an experimental study to determine whether gender or recent crime victimization modify the mental health effects of moving to low-poverty neighborhoods.MethodsThe Moving to Opportunity (MTO) study randomized low-income families in public housing to an intervention arm receiving vouchers to subsidize rental housing in lower-poverty neighborhoods or to controls receiving no voucher. We examined 3 outcomes 4 to 7 years after randomization, among youth aged 5 to 16 years at baseline (n = 2829): lifetime major depressive disorder (MDD), psychological distress (K6), and Behavior Problems Index (BPI). Treatment effect modification by gender and family's baseline report of recent violent crime victimization was tested via interactions in covariate-adjusted intent-to-treat and instrumental variable adherence-adjusted regression models.ResultsGender and crime victimization significantly modified treatment effects on distress and BPI (P < .10). Female adolescents in families without crime victimization benefited from MTO treatment, for all outcomes (Distress B = -0.19, P = .008; BPI B = -0.13, P = .06; MDD B = -0.036, P = .03). Male adolescents in intervention families experiencing crime victimization had worse distress (B = 0.24, P = .004), more behavior problems (B = 0.30, P < .001), and nonsignificantly higher MDD (B = 0.022, P = .16) versus controls. Other subgroups experienced no effect of MTO treatment. Instrumental variable estimates were similar but larger.ConclusionsGirls from families experiencing recent violent crime victimization were significantly less likely to achieve mental health benefits, and boys were harmed, by MTO, suggesting need for cross-sectoral program supports to offset multiple stressors.

Published
2012

5. Violence and Today's Youth.

Author

Earls, Felton J.

Abstract

Reviews the state of knowledge about the magnitude of youth violence, its causes and consequences; and explores the effectiveness of interventions available to criminal justice, school, and mental health authorities, as well as the potential of new treatment initiatives. The article concludes with recommendations for future policymaking and research. (GR)

Published
1994

6. Femoral Neck Shortening After Hip Fracture Fixation Is Associated With Inferior Hip Function: Results From the FAITH Trial

Author

Felton, J, Slobogean, GP, Jackson, SS, Della Rocca, GJ, Liew, S, Haverlag, R, Heetveld, MJ, Van Lieshout, Esther M.M., Zielinski, Stephanie, Patka, Petr, Eversdijk, MG, Peters, RW, den Hartog, Dennis, van Waes, O.J.F., Oprel, Pim, Herriott, C, Dobb, C, Surgery, and Emergency Medicine

Subjects
Male, medicine.medical_specialty, WOMAC, medicine.medical_treatment, Cohort Studies, Fracture Fixation, Internal, 03 medical and health sciences, Fixation (surgical), Postoperative Complications, 0302 clinical medicine, Fracture fixation, Humans, Medicine, Internal fixation, Orthopedics and Sports Medicine, Aged, Retrospective Studies, Femoral neck, Aged, 80 and over, 030222 orthopedics, Hip fracture, Femur Neck, Hip Fractures, business.industry, 030208 emergency & critical care medicine, Retrospective cohort study, Organ Size, General Medicine, Middle Aged, medicine.disease, Surgery, medicine.anatomical_structure, Orthopedic surgery, Female, business
Abstract

To describe the distribution of femoral neck shortening after internal fixation and to determine whether shortening is associated with inferior hip function at 24 months after a hip fracture in patients 50 years of age or older.Retrospective cohort study.A secondary analysis of data from 81 clinical centers included in the Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH) trial.Three hundred fifty patients, 50 years of age or older, who had an isolated femoral neck fracture and underwent timely operative fixation of the fracture.Femoral neck shortening was measured as a categorical variable and classified into one of the following groups, as determined by the Central Adjudication Committee: no shortening, mild shortening (≤5 mm), moderate shortening (6-10 mm), or severe shortening (10 mm).The primary outcome for the current analysis was hip function, as measured by the Western OntarioMcMaster Universities Osteoarthritis Index questionnaire, at 24 months after injury.Two-thirds of patients had no or mild shortening (≤5 mm), whereas one-third of patients had moderate or severe shortening (5 mm). After adjusting for surgical treatment, a greater amount of femoral neck shortening was found to be associated with poorer hip function (P0.01).We found that increasing femoral neck shortening was associated with inferior hip function. Although internal fixation often results in successful union, patients who heal in a shortened position report poorer functional outcomes.Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Published
2019
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9. Cutaneous squamous cell carcinoma in epidermolysis bullosa: A 28 year retrospective study.

Author

Greenblatt D.T., Bernardis C., Mellerio J.E., Martinez A.E., McGrath J.A., Robertson S.J., Orrin E., Lakhan M.K., O'Sullivan G., Felton J., Robso A., Greenblatt D.T., Bernardis C., Mellerio J.E., Martinez A.E., McGrath J.A., Robertson S.J., Orrin E., Lakhan M.K., O'Sullivan G., Felton J., and Robso A.

Abstract

Introduction &objectives: Some forms of epidermolysis bullosa (EB), notably severe generalized recessive dystrophic EB (RDEB-SG), are associated with an increased risk of developing mucocutaneous squamous cell carcinomas (SCCs) which behave aggressively and are the major cause of mortality in early to midadulthood. We report our centres' experience of EB-associated SCCs over the last 28 years. Materials &methods: An observational, retrospective, double institution case record review of EB patients diagnosed with SCC between July 1991-June 2019. Result(s): Forty-four EB patients with SCC were identified with a total of 221 primary SCCs. They comprised: 31 (70%) with RDEB-SG, 1 (2.3%) with RDEB-pruriginosa, 1 with RDEBinversa (2.3%), 2 (4.5%) with RDEB-generalised intermediate, 3 (6.8%) with junctional EB generalised intermediate (JEB-GI), 5 (11.4%) with dominant dystrophic EB, and 1 (2.3%) with Kindler syndrome. Diagnosis of first SCC was earlier in the RDEB-SG group (median 29.5 years (range 13-52 years)) compared to other groups collectively (median 47.1 years (range 30-89 years)). Most SCCs occurred in the RDEB-SG group, and the majority had multiple tumours (mean 5.8 (range 1-44)). SCC-associated mortality was high in this group (64.5%), with a median survival after diagnosis of first SCC of 2.4 years (range 0.5-12.6 years). Most SCCs were well-differentiated (53.4%) and located on the extremities. Wide local excision was undertaken for the majority of tumours (86.4%). Metastatic disease occurred in 16 of 31 (51.6%) RDEB-SG patients and 1 with JEB-GI. Treatments for metastatic disease included lymph node dissection (n = 6), radiotherapy (n= 5), chemotherapy (n=3), electrochemotherapy (n= 2), and targeted cancer therapies erlotinib (n=1), cetuximab (n =2) and cemiplimab (n= 1). Treatments were generally welltolerated, however were limited in response with the exception of cemiplimab. Conclusion(s): EB-associated SCCs differ from those in the general population: th

Published
2021

10. Longitudinal study of child and family social workers (wave 2)

Author

Johnson, C, Beninger, K, Sanders-Earley, A, Felton, J, Earl, S, Winterbotham, M, McLaughlin, H, Pollock, S, Scholar, HF, and McCaughan, S

Abstract

In 2018, the Department for Education (DfE) commissioned a consortium led by IFF\ud Research, working with social work academics at Manchester Metropolitan University\ud and the University of Salford, to conduct a longitudinal study tracking the careers of local\ud authority child and family social workers in England over five years. The landmark new\ud study aimed to collect robust evidence on recruitment, retention and progression in child\ud and family social work by tracking individuals over a five-year period.\ud In Wave 1, 5,621 local authority child and family social workers took part in the survey,\ud comprising almost one in six of the population.\ud 1 This report covers the second year of the\ud research

Published
2020

11. Spin flop and crystalline anisotropic magnetoresistance in CuMnAs

Author

Wang, M., Andrews, C., Reimers, S., Amin, O.J., Wadley, P., Campion, R.P., Poole, S.F., Felton, J., Edmonds, K.W., Gallagher, B.L., Rushforth, A.W., Makarovsky, O., Gas, K., Sawicki, M., Kriegner, D., Zubáč, J., Olejník, K., Novák, V., Jungwirth, T., Shahrokhvand, M., Zeitler, U., Dhesi, S.S., Maccherozzi, F., Wang, M., Andrews, C., Reimers, S., Amin, O.J., Wadley, P., Campion, R.P., Poole, S.F., Felton, J., Edmonds, K.W., Gallagher, B.L., Rushforth, A.W., Makarovsky, O., Gas, K., Sawicki, M., Kriegner, D., Zubáč, J., Olejník, K., Novák, V., Jungwirth, T., Shahrokhvand, M., Zeitler, U., Dhesi, S.S., and Maccherozzi, F.

Abstract

Contains fulltext : 227119.pdf (publisher's version ) (Open Access)

Published
2020

12. Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs

Author

Soares, P, Fidler, K, Felton, J, Tavendale, R, Hövels, A, Bremner, S A, Palmer, C N A, Mukhopadhyay, S, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Afd Pharmacoepi & Clinical Pharmacology, and Pharmacoepidemiology and Clinical Pharmacology

Subjects
Adult, Male, medicine.medical_specialty, Prescription Drugs, Time Factors, Adolescent, Cross-sectional study, DNA Mutational Analysis, Eczema, Dermatology, Filaggrin Proteins, Rate ratio, Drug Prescriptions, law.invention, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Intermediate Filament Proteins, Randomized controlled trial, Loss of Function Mutation, immune system diseases, law, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Anti-Asthmatic Agents, 030212 general & internal medicine, Young adult, Child, Asthma, Emollients, business.industry, S100 Proteins, Health Care Costs, medicine.disease, Confidence interval, Hospitalization, Cross-Sectional Studies, Scotland, Child, Preschool, Chronic Disease, Cohort, Female, business, Filaggrin
Abstract

Background\ud Eczema and asthma are chronic diseases with onset usually before the age of 5 years. More than 50% of individuals with eczema will develop asthma and/or other allergic diseases. Several loss‐of‐function mutations in filaggrin (FLG) have been identified in patients with eczema. However, the association of FLG with healthcare use is unknown.\ud \ud Objectives\ud To determine whether FLG mutations are associated with increased prescribing for eczema and asthma and whether increased prescribing is associated with increased healthcare costs.\ud \ud Methods\ud A secondary analysis of BREATHE, a cross‐sectional study of gene–environment associations with asthma severity, was undertaken. BREATHE data was collected for 1100 participants with asthma, in Tayside and Fife, Scotland during the period 2003–2005. Through collaboration with the Health Informatics Centre in Dundee, BREATHE was linked to accident and emergency, community prescribing and Scottish morbidity records. The data linkage allowed longitudinal exploration of associations between genetic variation and prescribing.\ud \ud Results\ud An association was found between FLG mutations and increased prescribing for mild and moderate eczema, asthma‐reliever medicine and asthma exacerbations. A strong association was found between FLG mutations and prescribing of emollients [incidence rate ratio (IRR) 2·19, 95% confidence interval (CI) 1·36–3·52], treatment for severe eczema (IRR 2·18, 95% CI 1·22–3·91) and a combination of a long‐acting β2‐agonist and corticosteroids (IRR 3·29, 95% CI 1·68–6·43).\ud \ud Conclusions\ud The presence of FLG mutations in this cohort is associated with increased prescribing for eczema and asthma. Randomized controlled trials are required to determine if these individuals could benefit from management strategies to reduce morbidity and treatment costs.

Published
2018
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17. Longitudinal study of local authority child and family social workers (wave 1) \ud \ud \ud Findings from a 5 year study of local authority child and family social workers in England

Author

Scholar, HF, McCaughan, S, McLaughlin, H, Pollock, S, Johnson, C, Coburn, S, Sanders-Earley, A, Felton, J, Winterbotham, M, IFF, and DfE

Subjects
ComputingMilieux_GENERAL, ComputingMilieux_THECOMPUTINGPROFESSION
Abstract

The longitudinal study investigates recruitment, retention and career progression in local authority child and family social work over 5 years. This is the first of 5 reports.\ud \ud It provides workforce information for employers and policy makers.\ud \ud Topics covered in this report include:\ud •entry routes into local authority child and family social work\ud •current employment and career history\ud •workplace wellbeing\ud •management, supervision and working environment\ud •job satisfaction\ud •career progression and future career plans

Published
2019

18. Longitudinal study of local authority child and family social workers (wave 1)

Author

Johnson, C, Coburn, S, Sanders-Earley, A, Felton, J, Winterbotham, M, McLaughlin, H, Pollock, S, Scholar, HF, and McCaughan, S

Abstract

In 2018, the Department for Education (DfE) commissioned a consortium led by IFF\ud Research, working with social work academics at Manchester Metropolitan University\ud and the University of Salford, to conduct a major new longitudinal study tracking the\ud careers of local authority child and family social workers in England over five years. The\ud aim of this landmark new study is to collect robust evidence on recruitment, retention and\ud progression in child and family social work. In particular it aims to establish a much\ud stronger understanding of child and family social work recruitment issues, career\ud pathways, choices and decisions and how these differ across different individual, job and\ud employer characteristics.\ud This report covers the first year (Wave 1) of the survey and follow-up qualitative\ud research, which was conducted between November 2018 and March 2019.

Published
2019

20. Should some illegal drugs be legalized?

Author

Nadelmann, Ethan A., Kleiman, Mark A., and Earls, Felton J.

Subjects
Narcotics -- Laws, regulations and rules, Narcotics, Control of -- Laws, regulations and rules, Legalization of narcotics -- Ethical aspects
Published
1990

21. Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs

Author

Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Soares, P, Fidler, K, Felton, J, Tavendale, R, Hövels, A, Bremner, S A, Palmer, C N A, Mukhopadhyay, S, Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Soares, P, Fidler, K, Felton, J, Tavendale, R, Hövels, A, Bremner, S A, Palmer, C N A, and Mukhopadhyay, S

Published
2018

43. T-cell responses to islet antigens improves detection of autoimmune diabetes and identifies patients with more severe beta-cell lesions in phenotypic type 2 diabetes.

Author

Goel A, Chiu H, Felton J, Palmer JP, and Brooks-Worrell B

Abstract

Latent autoimmune diabetes in adults or type 1.5 diabetes is considered to be a T-cell-mediated autoimmune disease. However, identification of patients is based commonly on autoantibody (Ab) detection. To determine whether measuring T-cell reactivity to islet proteins compared with measuring Abs improves detection of autoimmune diabetes and how beta-cell function correlates with T-cell reactivity compared with Ab positivity, we assessed the T-cell proliferative responses and Ab responses (islet cell autoantibodies, insulin autoantibodies, insulinoma-associated protein-2 autoantibodies, and GAD Abs) to islet proteins of 36 phenotypic type 2 diabetic patients. To be considered Ab(+) or T-cell(+), patients were required to be positive for a minimum of two consecutive time points. beta-Cell function was measured with fasting and glucagon-stimulated C-peptide. Independent of T-cell reactivity, Ab(+) and Ab(-) patients had comparable fasting and glucagon-stimulated C-peptide. Independent of Ab status, T-cell(+) patients demonstrated significantly lower glucagon-stimulated (P < 0.003) C-peptide compared with T-cell(-) patients. These data suggest that measuring T-cell responses to multiple islet proteins in phenotypic type 2 diabetic patients improves identification of patients with autoimmune diabetes and delineates those who have a more severe beta-cell lesion compared with Ab assessment alone. [ABSTRACT FROM AUTHOR]

Published
2007
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45. Minimization of heterocyclic amines and thermal inactivation of Escherichia coli in fried ground beef.

Author

Salmon, Cynthia P., Knize, Mark G., Salmon, C P, Knize, M G, Panteleakos, F N, Wu, R W, Nelson, D O, and Felton, J S

Subjects
HETEROCYCLIC compounds, ESCHERICHIA coli, BEEF, COOKING, AMINES, HEALTH, TEMPERATURE, AMINE analysis, CARCINOGENS, COMPARATIVE studies, HEAT, RESEARCH methodology, MEAT, MEDICAL cooperation, RESEARCH, EVALUATION research
Abstract

Background: Heterocyclic amine carcinogens are formed during the cooking of a number of foods, especially well-done meats. Lower temperatures and shorter cooking times can minimize the formation of these carcinogens, yet a major food safety concern is that pathogens in the meat must be thermally inactivated. This study investigated cooking techniques that minimize heterocyclic amine formation while simultaneously destroying contaminating bacteria.Methods: Ground beef patties were inoculated with Escherichia coli K12 bacteria and fried to internal temperatures ranging from 35 degrees C to 70 degrees C in a skillet preheated to 160 degrees C, 180 degrees C, or 200 degrees C. Each patty was then analyzed for four common heterocyclic amines and for surviving bacteria. Additionally, the frequency of turning of the beef patty during cooking was varied (a single turn or multiple turns), length of time required for each patty to reach 70 degrees C was recorded, and heterocyclic amine levels were determined. An additional pan temperature of 250 degrees C was tested for its effect on heterocyclic amine formation but not on bacterial killing. Statistical tests were two-sided.Results: Colony-forming bacteria were reduced by five orders of magnitude at internal temperatures greater than 60 degrees C, regardless of cooking method, and were completely inactivated at 70 degrees C. For patties turned just once, heterocyclic amine levels increased as the cooking temperatures increased. However, levels of heterocyclic amines were statistically significantly lower with turning every minute. For each pan temperature, patties reached 70 degrees C internal temperature sooner when they were turned every minute than when they were turned just once during cooking.Conclusion: Lowering the pan temperature and turning the patties frequently can greatly reduce the formation of heterocyclic amines and can simultaneously achieve bacterial inactivation with little or no increase in cooking time, ensuring a product that is safe for human consumption. [ABSTRACT FROM AUTHOR]

Published
2000
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46. Agreement of mutational characteristics of heterocyclic amines in lacI of the Big Blue mouse with those in tumor related genes in rodents.

Author

Okonogi, H, Ushijima, T, Zhang, X B, Heddle, J A, Suzuki, T, Sofuni, T, Felton, J S, Tucker, J D, Sugimura, T, and Nagao, M

Abstract

The mutational spectra of carcinogenic heterocyclic amines (HCAs), 2-amino-3,4-dimethylimidazo[4,5-b]quinoline (MeIQ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-9H-pyrido[2,3-b]indole (A alphaC) were studied in the colon of Big Blue mice. In 90, 115 and 105 lacI mutants from mice fed 300 p.p.m. MeIQ, 400 p.p.m. PhIP and 800 p.p.m. A alphaC, respectively, 92, 115 and 105 mutations were identified. G:C-->T:A transversions predominated with these HCAs. Mutational hot spots for base-substitution mutations caused by MeIQ, PhIP and A alphaC were in distinct sequence contexts; at 5'-GC-3', in runs of guanine and in 5'-CGT-3', respectively. Further, 30 of 115 (26%) PhIP-induced mutations were G:C base pair deletions, and eight of these deletions were in 5'-GGGA-3'. The mutational characteristics of MeIQ in the lacI gene coincided well with those in the Ha-ras gene of MeIQ-induced mouse forestomach tumors and rat Zymbal gland tumors. The characteristic single-base deletion induced by PhIP in the lacI gene also coincided well with those in the Apc gene of PhIP-induced rat colon tumors. These results suggest that the mutational characteristics of each chemical are conserved across different genes in different species. [ABSTRACT FROM PUBLISHER]

Published
1997
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47. N-glucuronidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and N_hydroxy-PhIP by specific human UDP-glucuronosyltransferases.

Author

Malfatti, M A and Felton, J S

Abstract

Glucuronidation is a major metabolic pathway in the biotransformation of many xenobiotics. Recent studies have shown that in humans, UDP-glucuronosyltransferase (UGT)-mediated glucuronidation plays a critical role in the detoxification of food-borne carcinogenic heterocyclic amines. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant carcinogenic heterocyclic amine found in well-cooked meats, has been shown to be extensively glucuronidated in humans. To determine which UGT isozymes are involved in the biotransformation of PhIP and the cytochrome P4501A2-mediated reactive intermediate N-hydroxy-PhIP, microsomes expressing human UGT1A1, -1A4, -1A6 or -1A9 were incubated with PhIP and N-hydroxy-PhIP and the reaction products analyzed by HPLC and ESI-MS. Incubations containing N-hydroxy-PhIP and UGT1A1 expressing microsomes, with an apparent Km of 4.58 microM and a Vmax of 4.18 pmol/min/mg protein, had the highest capacity to convert N-hydroxy-PhIP to N-hydroxy-PhIP-N2-glucuronide. Microsomes expressing UGT1A9 produced N-hydroxy-PhIP-N3-glucuronide at the highest rate with an apparent Km and Vmax of 3.73 microM and 4.07 pmol/min/mg, respectively. A third previously undefined glucuronide accounted for 31% of the total glucuronides formed from the UGT1A4 expressing microsomes. No glucuronide conjugates were detected from microsomes expressing UGT1A6. Incubations containing PhIP as substrate formed direct PhIP-glucuronides in microsomes expressing UGT1A1, UGT1A4 and UGT1A9 but at levels averaging 53-fold lower than when N-hydroxy-PhIP was used as the substrate. Knowing the glucuronidation capacity of the specific UGT isozymes involved in PhIP and N-hydroxy-PhIP glucuronidation should help in determining the individual susceptibility to the potential cancer risk from exposure to PhIP.

Published
2001
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48. Identification of urine metabolites of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine following consumption of a single cooked chicken meal in humans.

Author

Kulp, K S, Knize, M G, Malfatti, M A, Salmon, C P, and Felton, J S

Abstract

Many studies suggest that mutagenic/carcinogenic chemicals in the diet, like 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), may play a role in human cancer initiation. We have developed a method to quantify PhIP metabolites in human urine and have applied it to samples from female volunteers who had eaten a meal of cooked chicken. For this analysis, urine samples (5 ml) were spiked with a deuterium-labeled internal standard, adsorbed to a macroporous polymeric column and then eluted with methanol. After a solvent exchange to 0.01 M HCl, the urine extracts were passed through a filter, applied to a benzenesulfonic acid column, washed with methanol/acid and eluted with ammonium acetate and concentrated on a C(18) column. The metabolites were eluted from the C(18) column and quantified by LC/MS/MS. In our studies of human PhIP metabolism, eight volunteers were fed 200 g of cooked chicken containing a total of 27 microg PhIP. Urine samples were collected for 24 h after the meal, in 6 h aliquots. Although no metabolites could be found in urine collected from volunteers before eating the chicken, four major human PhIP metabolites, N:(2)-OH-PhIP-N:(2)-glucuronide, PhIP-N:(2)-glucuronide, 4'-PhIP-sulfate and N:(2)-OH-PhIP-N:3-glucuronide, were found in the urine after the chicken meal. The volunteers in the study excreted 4-53% of the ingested PhIP dose in the urine. The rate of metabolite excretion varied among the subjects, however, in all of the subjects the majority of the metabolites were excreted in the first 12 h. Very little metabolite was detected in the urine after 18 h. In humans, N:(2)-OH-PhIP-N:(2) glucuronide is the most abundant urinary metabolite, followed by PhIP-N:(2)-glucuronide. The variation seen in the total amount, excretion time and metabolite ratios with our method suggests that individual digestion, metabolism and/or other components of the diet may influence the absorption and amounts of metabolic products produced from PhIP.

Published
2000
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49. The identification of [2-<SUP>14</SUP>C]2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine metabolites in humans

Author

Turteltaub, K., Malfatti, M., Lang, N., Kulp, K., Felton, J., Knize, M., Davis, C., Massengill, J., Williams, S., Nowell, S., MacLeod, S., and Dingley, K.

Abstract

[2-14C]2-amino-1-methyl-phenlimidazo[4,5-b]pyridine ([14C]PhIP), a putative human carcinogenic heterocyclic amine found in well-done cooked meat, was administered orally to three colon cancer patients undergoing a partial colonectomy. Forty-eight to seventy-two hours prior to surgery, subjects received a 70-84 μg dose of 14C. Urine and blood were analyzed by HPLC for PhIP and PhIP metabolites. Metabolites were identified based on HPLC co-elution with authentic PhIP metabolite standards, mass spectral analysis and susceptibility to enzymatic cleavage. In two subjects, 90% of the administered [14CPhIP dose was eliminated in the urine, whereas in the other, only 50% of the dose was found in the urine. One subject excreted three times more radioactivity in the first 4 h than did the others. Twelve radioactive peaks associated with PhIP were detected in the urine samples. The relative amount of each metabolite varied by subject, and the amounts of each metabolite within subjects changed over time. In all three subjects the most abundant urinary metabolite was identified as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine- N2-glucuronide (N-hydroxy-PhIP-N2-glucuronide, accounting for 47-60% of the recovered counts in 24 h. PhIP accounted for &lt;1% of the excreted radiolabel in all three patients. Other metabolites detected in the urine at significant amounts were 4-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate, N-hydroxy-PhIP-N3-glucuronide and PhIP-N2-glucuronide. In the plasma, N-hydroxy-PhIP-N2-glucuronide accounted for 60, 18 and 20% of the recovered plasma radioactivity at 1 h post PhIP dose in subjects 1, 2 and 3 respectively. Plasma PhIP was 56-17% of the recovered dose at 1 h post exposure. The relatively high concentration of N-hydroxy-PhIP-N2-glucuronide and the fact that it is an indicator of bioactivation make this metabolite a potential biomarker for PhIP exposure and activation. Determining the relative differences in PhIP metabolites among individuals will indicate metabolic differences that may predict individual susceptibility to carcinogenic risk from this suspected dietary carcinogen.

Published
1999

50. The identification of [2-(14)C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine metabolites in humans.

Author

Malfatti, M A, Kulp, K S, Knize, M G, Davis, C, Massengill, J P, Williams, S, Nowell, S, MacLeod, S, Dingley, K H, Turteltaub, K W, Lang, N P, and Felton, J S

Abstract

[2-(14)C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine ([14C]PhIP), a putative human carcinogenic heterocyclic amine found in well-done cooked meat, was administered orally to three colon cancer patients undergoing a partial colonectomy. Forty-eight to seventy-two hours prior to surgery, subjects received a 70-84 microg dose of 14C. Urine and blood were analyzed by HPLC for PhIP and PhIP metabolites. Metabolites were identified based on HPLC co-elution with authentic PhIP metabolite standards, mass spectral analysis and susceptibility to enzymatic cleavage. In two subjects, approximately 90% of the administered [14C]PhIP dose was eliminated in the urine, whereas in the other, only 50% of the dose was found in the urine. One subject excreted three times more radioactivity in the first 4 h than did the others. Twelve radioactive peaks associated with PhIP were detected in the urine samples. The relative amount of each metabolite varied by subject, and the amounts of each metabolite within subjects changed over time. In all three subjects the most abundant urinary metabolite was identified as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine-N2-glucuron ide (N-hydroxy-PhIP-N2-glucuronide), accounting for 47-60% of the recovered counts in 24 h. PhIP accounted for <1% of the excreted radiolabel in all three patients. Other metabolites detected in the urine at significant amounts were 4-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate, N-hydroxy-PhIP-N3-glucuronide and PhIP-N2-glucuronide. In the plasma, N-hydroxy-PhIP-N2-glucuronide accounted for 60, 18 and 20% of the recovered plasma radioactivity at 1 h post PhIP dose in subjects 1, 2 and 3 respectively. Plasma PhIP was 56-17% of the recovered dose at 1 h post exposure. The relatively high concentration of N-hydroxy-PhIP-N2-glucuronide and the fact that it is an indicator of bioactivation make this metabolite a potential biomarker for PhIP exposure and activation. Determining the relative differences in PhIP metabolites among individuals will indicate metabolic differences that may predict individual susceptibility to carcinogenic risk from this suspected dietary carcinogen.

Published
1999
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