41 results on '"Hanley, JP"'
Search Results
2. Identification and treatment of anaemia in older patients
- Author
-
Osborne, WL, primary, Pemberton, LC, additional, and Hanley, JP, additional
- Published
- 2006
- Full Text
- View/download PDF
3. Interferon treatment for chronic hepatitis C infection in hemophiliacs-- influence of virus load, genotype, and liver pathology on response
- Author
-
Hanley, JP, primary, Jarvis, LM, additional, Andrew, J, additional, Dennis, R, additional, Hayes, PC, additional, Piris, J, additional, Lee, R, additional, Simmonds, P, additional, and Ludlam, CA, additional
- Published
- 1996
- Full Text
- View/download PDF
4. Congenital and acquired bleeding problems in elderly patients.
- Author
-
Nicolle AL, Talks KL, and Hanley JP
- Published
- 2005
- Full Text
- View/download PDF
5. Global report on COVID-19 vaccination and reasons not to vaccinate among adults with intellectual disabilities: Results from secondary analyses of Special Olympics' program planning.
- Author
-
Lincoln AE, Dixon-Ibarra AM, Hanley JP, Smith AL, Martin K, and Bazzano A
- Abstract
The COVID-19 pandemic has disproportionately affected people with intellectual disabilities worldwide. The objective of this study was to identify global rates of COVID-19 vaccination and reasons not to vaccinate among adults with intellectual disabilities (ID) associated with country economic income levels. The Special Olympics COVID-19 online survey was administered in January-February 2022 to adults with ID from 138 countries. Descriptive analyses of survey responses include 95% margins of error. Logistic regression and Pearson Chi-squared tests were calculated to assess associations with predictive variables for vaccination using R 4.1.2 software. Participants (n = 3560) represented 18 low (n = 410), 35 lower-middle (n = 1182), 41 upper-middle (n = 837), and 44 high (n = 1131) income countries. Globally, 76% (74.8-77.6%) received a COVID-19 vaccination while 49.5% (47.9-51.2%) received a COVID-19 booster. Upper-middle (93% (91.2-94.7%)) and high-income country (94% (92.1-95.0%)) participants had the highest rates of vaccination while low-income countries had the lowest rates (38% (33.3-42.7%)). In multivariate regression models, country economic income level (OR = 3.12, 95% CI [2.81, 3.48]), age (OR = 1.04, 95% CI [1.03, 1.05]), and living with family (OR = 0.70, 95% CI [0.53, 0.92]) were associated with vaccination. Among LLMICs, the major reason for not vaccinating was lack of access (41.2% (29.5-52.9%)). Globally, concerns about side effects (42%, (36.5-48.1%)) and parent/guardian not wanting the adult with ID to vaccinate (32% (26.1-37.0%)) were the most common reasons for not vaccinating. Adults with ID from low and low-middle income countries reported fewer COVID-19 vaccinations, suggesting reduced access and availability of resources in these countries. Globally, COVID-19 vaccination levels among adults with ID were higher than the general population. Interventions should address the increased risk of infection for those in congregate living situations and family caregiver apprehension to vaccinate this high-risk population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lincoln et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
- Full Text
- View/download PDF
6. Identifying neuroanatomical and behavioral features for autism spectrum disorder diagnosis in children using machine learning.
- Author
-
Han Y, Rizzo DM, Hanley JP, Coderre EL, and Prelock PA
- Subjects
- Adolescent, Algorithms, Biomarkers, Child, Humans, Machine Learning, Magnetic Resonance Imaging methods, Neuroanatomy, Neuroimaging, Autism Spectrum Disorder diagnostic imaging
- Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can cause significant social, communication, and behavioral challenges. Diagnosis of ASD is complicated and there is an urgent need to identify ASD-associated biomarkers and features to help automate diagnostics and develop predictive ASD models. The present study adopts a novel evolutionary algorithm, the conjunctive clause evolutionary algorithm (CCEA), to select features most significant for distinguishing individuals with and without ASD, and is able to accommodate datasets having a small number of samples with a large number of feature measurements. The dataset is unique and comprises both behavioral and neuroimaging measurements from a total of 28 children from 7 to 14 years old. Potential biomarker candidates identified include brain volume, area, cortical thickness, and mean curvature in specific regions around the cingulate cortex, frontal cortex, and temporal-parietal junction, as well as behavioral features associated with theory of mind. A separate machine learning classifier (i.e., k-nearest neighbors algorithm) was used to validate the CCEA feature selection and for ASD prediction. Study findings demonstrate how machine learning tools might help move the needle on improving diagnostic and predictive models of ASD., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
- Full Text
- View/download PDF
7. Caught in motion: human NTHL1 undergoes interdomain rearrangement necessary for catalysis.
- Author
-
Carroll BL, Zahn KE, Hanley JP, Wallace SS, Dragon JA, and Doublié S
- Subjects
- Amino Acid Sequence, Biocatalysis, DNA genetics, DNA metabolism, Deoxyribonuclease (Pyrimidine Dimer) genetics, Deoxyribonuclease (Pyrimidine Dimer) metabolism, Humans, Models, Molecular, Mutation, Nucleic Acid Conformation, Protein Binding, Protein Conformation, Pyrimidines metabolism, Sequence Homology, Amino Acid, Catalytic Domain, DNA chemistry, DNA Repair, Deoxyribonuclease (Pyrimidine Dimer) chemistry, Protein Domains
- Abstract
Base excision repair (BER) is the main pathway protecting cells from the continuous damage to DNA inflicted by reactive oxygen species. BER is initiated by DNA glycosylases, each of which repairs a particular class of base damage. NTHL1, a bifunctional DNA glycosylase, possesses both glycolytic and β-lytic activities with a preference for oxidized pyrimidine substrates. Defects in human NTHL1 drive a class of polyposis colorectal cancer. We report the first X-ray crystal structure of hNTHL1, revealing an open conformation not previously observed in the bacterial orthologs. In this conformation, the six-helical barrel domain comprising the helix-hairpin-helix (HhH) DNA binding motif is tipped away from the iron sulphur cluster-containing domain, requiring a conformational change to assemble a catalytic site upon DNA binding. We found that the flexibility of hNTHL1 and its ability to adopt an open configuration can be attributed to an interdomain linker. Swapping the human linker sequence for that of Escherichia coli yielded a protein chimera that crystallized in a closed conformation and had a reduced activity on lesion-containing DNA. This large scale interdomain rearrangement during catalysis is unprecedented for a HhH superfamily DNA glycosylase and provides important insight into the molecular mechanism of hNTHL1., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Published
- 2021
- Full Text
- View/download PDF
8. Immunotranscriptomic profiling the acute and clearance phases of a human challenge dengue virus serotype 2 infection model.
- Author
-
Hanley JP, Tu HA, Dragon JA, Dickson DM, Rio-Guerra RD, Tighe SW, Eckstrom KM, Selig N, Scarpino SV, Whitehead SS, Durbin AP, Pierce KK, Kirkpatrick BD, Rizzo DM, Frietze S, and Diehl SA
- Subjects
- Antibodies, Neutralizing, Dengue virology, Gene Expression Regulation, Humans, Immunogenetics, Interferon Type I genetics, Severe Dengue, Transcriptome, Viremia, Antibodies, Viral genetics, Antibodies, Viral immunology, Dengue immunology, Dengue Virus genetics, Dengue Virus immunology, Serogroup
- Abstract
About 20-25% of dengue virus (DENV) infections become symptomatic ranging from self-limiting fever to shock. Immune gene expression changes during progression to severe dengue have been documented in hospitalized patients; however, baseline or kinetic information is difficult to standardize in natural infection. Here we profile the host immunotranscriptome response in humans before, during, and after infection with a partially attenuated rDEN2Δ30 challenge virus (ClinicalTrials.gov NCT02021968). Inflammatory genes including type I interferon and viral restriction pathways are induced during DENV2 viremia and return to baseline after viral clearance, while others including myeloid, migratory, humoral, and growth factor immune regulation factors pathways are found at non-baseline levels post-viremia. Furthermore, pre-infection baseline gene expression is useful to predict rDEN2Δ30-induced immune responses and the development of rash. Our results suggest a distinct immunological profile for mild rDEN2Δ30 infection and offer new potential biomarkers for characterizing primary DENV infection.
- Published
- 2021
- Full Text
- View/download PDF
9. Modeling the impact of school reopening on SARS-CoV-2 transmission using contact structure data from Shanghai.
- Author
-
Lee B, Hanley JP, Nowak S, Bates JHT, and Hébert-Dufresne L
- Subjects
- COVID-19, Child, China epidemiology, Contact Tracing, Coronavirus Infections epidemiology, Humans, Models, Theoretical, Pandemics, Pneumonia, Viral epidemiology, Coronavirus Infections transmission, Pneumonia, Viral transmission, Schools organization & administration
- Abstract
Background: Mathematical modeling studies have suggested that pre-emptive school closures alone have little overall impact on SARS-CoV-2 transmission, but reopening schools in the background of community contact reduction presents a unique scenario that has not been fully assessed., Methods: We adapted a previously published model using contact information from Shanghai to model school reopening under various conditions. We investigated different strategies by combining the contact patterns observed between different age groups during both baseline and "lockdown" periods. We also tested the robustness of our strategy to the assumption of lower susceptibility to infection in children under age 15 years., Results: We find that reopening schools for all children would maintain a post-intervention R
0 < 1 up to a baseline R0 of approximately 3.3 provided that daily contacts among children 10-19 years are reduced to 33% of baseline. This finding was robust to various estimates of susceptibility to infection in children relative to adults (up to 50%) and to estimates of various levels of concomitant reopening in the rest of the community (up to 40%). However, full school reopening without any degree of contact reduction in the school setting returned R0 virtually back to baseline, highlighting the importance of mitigation measures., Conclusions: These results, based on contact structure data from Shanghai, suggest that schools can reopen with proper precautions during conditions of extreme contact reduction and during conditions of reasonable levels of reopening in the rest of the community.- Published
- 2020
- Full Text
- View/download PDF
10. Novel Evolutionary Algorithm Identifies Interactions Driving Infestation of Triatoma dimidiata , a Chagas Disease Vector.
- Author
-
Hanley JP, Rizzo DM, Stevens L, Helms Cahan S, Dorn PL, Morrissey LA, Rodas AG, Orantes LC, and Monroy C
- Subjects
- Algorithms, Animals, Chagas Disease transmission, Chickens, Dogs, Electric Wiring statistics & numerical data, Family Characteristics, Guatemala epidemiology, Humans, Hygiene, Insect Control, Insecticides, Pyrethrins, Risk Factors, Risk Reduction Behavior, Socioeconomic Factors, Animals, Domestic, Chagas Disease epidemiology, Construction Materials statistics & numerical data, Housing statistics & numerical data, Housing, Animal, Insect Vectors, Triatoma
- Abstract
Chagas disease is a lethal, neglected tropical disease. Unfortunately, aggressive insecticide-spraying campaigns have not been able to eliminate domestic infestation of Triatoma dimidiata , the native vector in Guatemala. To target interventions toward houses most at risk of infestation, comprehensive socioeconomic and entomologic surveys were conducted in two towns in Jutiapa, Guatemala. Given the exhaustively large search space associated with combinations of risk factors, traditional statistics are limited in their ability to discover risk factor interactions. Two recently developed statistical evolutionary algorithms, specifically designed to accommodate risk factor interactions and heterogeneity, were applied to this large combinatorial search space and used in tandem to identify sets of risk factor combinations associated with infestation. The optimal model includes 10 risk factors in what is known as a third-order disjunctive normal form (i.e., infested households have chicken coops AND deteriorated bedroom walls OR an accumulation of objects AND dirt floors AND total number of occupants ≥ 5 AND years of electricity ≥ 5 OR poor hygienic condition ratings AND adobe walls AND deteriorated walls AND dogs). Houses with dirt floors and deteriorated walls have been reported previously as risk factors and align well with factors currently targeted by Ecohealth interventions to minimize infestation. However, the tandem evolutionary algorithms also identified two new socioeconomic risk factors (i.e., households having many occupants and years of electricity ≥ 5). Identifying key risk factors may help with the development of new Ecohealth interventions and/or reduce the survey time needed to identify houses most at risk.
- Published
- 2020
- Full Text
- View/download PDF
11. Therapeutic metamorphosis: Findings from a grounded theory study of the impact of low-dose prophylaxis in children living with haemophilia in India.
- Author
-
T R, Thomas G, Paul L, Mathew S, Biss T, Hanley JP, and Narayana Pillai V
- Subjects
- Child, Child, Preschool, Educational Status, Female, Hemophilia A prevention & control, Humans, India epidemiology, Interviews as Topic methods, Male, Models, Theoretical, Qualitative Research, Quality of Life psychology, Grounded Theory, Hemophilia A drug therapy, Hemophilia A psychology, Parents psychology
- Abstract
Introduction: The clinical benefits of administering low-dose prophylaxis in children with haemophilia are well established. Qualitative research describing the impact of prophylaxis on quality of life is comparatively rare in this area., Aim: The aim of this study was to investigate in children the experiences of living and becoming adjusted to haemophilia before prophylaxis, by collecting information directly from children and their parents or guardians. A further goal was to evaluate whether and how the use of low-dose prophylaxis impacts the disease experience., Methods: A grounded theory design according to Strauss and Corbin was chosen for this study. The study was conducted in the Haemophilia Treatment Centre at Aluva, Kerala, India and involved nineteen participants (children, mothers, father and grandmothers) who were selected by theoretical sampling. Data were collected through audiotaped interviews, which included demographic and semi-structured interview questions. Data were coded and evolved into concepts and categories that lead to the emergence of theory., Results: The study resulted in the construction of 'Theory of Therapeutic Metamorphosis'. It comprised two stages: stage of bondage (enduring hardships), experienced during the absence of prophylaxis or on-demand treatment and stage of freedom (deliverance/reductions, energized life/improvements and behaviour to seek prophylaxis) experienced during low-dose prophylaxis., Conclusion: This study illustrates the challenges faced by children with haemophilia and their families and the positive impact of low-dose prophylaxis. Further prospective research studies are required to add to the growing knowledge in this area., (© 2020 John Wiley & Sons Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
12. A Tandem Evolutionary Algorithm for Identifying Causal Rules from Complex Data.
- Author
-
Hanley JP, Rizzo DM, Buzas JS, and Eppstein MJ
- Subjects
- Chagas Disease genetics, Chagas Disease prevention & control, Epistasis, Genetic, Genome, Humans, Probability, Algorithms, Biological Evolution
- Abstract
We propose a new evolutionary approach for discovering causal rules in complex classification problems from batch data. Key aspects include (a) the use of a hypergeometric probability mass function as a principled statistic for assessing fitness that quantifies the probability that the observed association between a given clause and target class is due to chance, taking into account the size of the dataset, the amount of missing data, and the distribution of outcome categories, (b) tandem age-layered evolutionary algorithms for evolving parsimonious archives of conjunctive clauses, and disjunctions of these conjunctions, each of which have probabilistically significant associations with outcome classes, and (c) separate archive bins for clauses of different orders, with dynamically adjusted order-specific thresholds. The method is validated on majority-on and multiplexer benchmark problems exhibiting various combinations of heterogeneity, epistasis, overlap, noise in class associations, missing data, extraneous features, and imbalanced classes. We also validate on a more realistic synthetic genome dataset with heterogeneity, epistasis, extraneous features, and noise. In all synthetic epistatic benchmarks, we consistently recover the true causal rule sets used to generate the data. Finally, we discuss an application to a complex real-world survey dataset designed to inform possible ecohealth interventions for Chagas disease.
- Published
- 2020
- Full Text
- View/download PDF
13. Residual survival and local dispersal drive reinfestation by Triatoma dimidiata following insecticide application in Guatemala.
- Author
-
Cahan SH, Orantes LC, Wallin KF, Hanley JP, Rizzo DM, Stevens L, Dorn PL, Rodas A, and Monroy C
- Subjects
- Animals, DNA genetics, Female, Genotyping Techniques methods, Guatemala, Insect Control, Male, Population Dynamics, Triatoma drug effects, Triatoma genetics, Insecticide Resistance, Insecticides pharmacology, Polymorphism, Single Nucleotide, Pyrethrins pharmacology, Triatoma growth & development
- Abstract
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and transmitted by triatomine insect vectors. In Guatemala, insecticide spraying is an integral part of management of the main vector, Triatoma dimidiata. Spraying typically has low efficacy, which may be due to incomplete elimination from infested houses, within-village dispersal, or influx from other villages or sylvan environments. To evaluate how these mechanisms contribute to reinfestation, we conducted a time-course analysis of T. dimidiata infestation, abundance and household genetic structure in two nearby villages in Jutiapa, Guatemala; houses in the first village were surveyed, treated with insecticide if infested and then re-surveyed at eight and 22 months following spraying, while the second village served as an untreated control to quantify changes associated with seasonal dispersal. Insects were genotyped at 2-3000 SNP loci for kinship and population genetic analyses. Insecticide application reduced overall infestation and abundance, while the untreated village was stable over time. Nevertheless, within two years 35.5% of treated houses were reinfested and genetic diversity had largely recovered. Insects collected from reinfested houses post-spraying were most closely related to pre-spray collections from the same house, suggesting that infestations had not been fully eliminated. Immigration by unrelated insects was also detected within a year of spraying; when it occurred, dispersal was primarily local from neighboring houses. Similar dispersal patterns were observed following the annual dispersal season in the untreated village, with high-infestation houses serving as sources for neighboring homes. Our findings suggest that the efficacy of pyrethroid application is rapidly diminished by both within-house breeding by survivors and annual cycles of among-house movement. Given these patterns, we conclude that house structural improvements, an integral part of the Ecohealth approach that makes houses refractory to vector colonization and persistence, are critical for long-term reduction of T. dimidiata infestation., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
14. Uncovering vector, parasite, blood meal and microbiome patterns from mixed-DNA specimens of the Chagas disease vector Triatoma dimidiata.
- Author
-
Orantes LC, Monroy C, Dorn PL, Stevens L, Rizzo DM, Morrissey L, Hanley JP, Rodas AG, Richards B, Wallin KF, and Helms Cahan S
- Subjects
- Animals, Archaea genetics, Archaea isolation & purification, Bacteria genetics, Bacteria isolation & purification, Central America, Cluster Analysis, Computational Biology, Fungi genetics, Fungi isolation & purification, High-Throughput Nucleotide Sequencing, Humans, Nematoda genetics, Nematoda isolation & purification, Phylogeny, Sequence Analysis, DNA, Triatoma microbiology, Triatoma parasitology, Triatoma physiology, Trypanosoma cruzi genetics, Viruses genetics, Viruses isolation & purification, DNA genetics, DNA isolation & purification, Feeding Behavior, Gastrointestinal Microbiome, Triatoma genetics, Trypanosoma cruzi isolation & purification
- Abstract
Chagas disease, considered a neglected disease by the World Health Organization, is caused by the protozoan parasite Trypanosoma cruzi, and transmitted by >140 triatomine species across the Americas. In Central America, the main vector is Triatoma dimidiata, an opportunistic blood meal feeder inhabiting both domestic and sylvatic ecotopes. Given the diversity of interacting biological agents involved in the epidemiology of Chagas disease, having simultaneous information on the dynamics of the parasite, vector, the gut microbiome of the vector, and the blood meal source would facilitate identifying key biotic factors associated with the risk of T. cruzi transmission. In this study, we developed a RADseq-based analysis pipeline to study mixed-species DNA extracted from T. dimidiata abdomens. To evaluate the efficacy of the method across spatial scales, we used a nested spatial sampling design that spanned from individual villages within Guatemala to major biogeographic regions of Central America. Information from each biotic source was distinguished with bioinformatics tools and used to evaluate the prevalence of T. cruzi infection and predominant Discrete Typing Units (DTUs) in the region, the population genetic structure of T. dimidiata, gut microbial diversity, and the blood meal history. An average of 3.25 million reads per specimen were obtained, with approximately 1% assigned to the parasite, 20% to the vector, 11% to bacteria, and 4% to putative blood meals. Using a total of 6,405 T. cruzi SNPs, we detected nine infected vectors harboring two distinct DTUs: TcI and a second unidentified strain, possibly TcIV. Vector specimens were sufficiently variable for population genomic analyses, with a total of 25,710 T. dimidiata SNPs across all samples that were sufficient to detect geographic genetic structure at both local and regional scales. We observed a diverse microbiotic community, with significantly higher bacterial species richness in infected T. dimidiata abdomens than those that were not infected. Unifrac analysis suggests a common assemblage of bacteria associated with infection, which co-occurs with the typical gut microbial community derived from the local environment. We identified vertebrate blood meals from five T. dimidiata abdomens, including chicken, dog, duck and human; however, additional detection methods would be necessary to confidently identify blood meal sources from most specimens. Overall, our study shows this method is effective for simultaneously generating genetic data on vectors and their associated parasites, along with ecological information on feeding patterns and microbial interactions that may be followed up with complementary approaches such as PCR-based parasite detection, 18S eukaryotic and 16S bacterial barcoding., Competing Interests: The authors have declared that no competing interests exist
- Published
- 2018
- Full Text
- View/download PDF
15. Bilateral upper limb compartment syndrome induced by strenuous exercise in a patient with haemophilia A and a low titre inhibitor.
- Author
-
Abdelhalim MA, Shaw CR, Al-Rub ZA, Hopper D, Hanley JP, Talks KL, Biss TT, and Fearon PV
- Subjects
- Female, Humans, Male, Upper Extremity, Compartment Syndromes diagnosis, Exercise physiology, Hemophilia A complications
- Published
- 2015
- Full Text
- View/download PDF
16. Geospatial and Temporal Analysis of Thyroid Cancer Incidence in a Rural Population.
- Author
-
Hanley JP, Jackson E, Morrissey LA, Rizzo DM, Sprague BL, Sarkar IN, and Carr FE
- Subjects
- Adenocarcinoma, Follicular pathology, Adolescent, Adult, Age Distribution, Aged, Carcinoma pathology, Carcinoma, Neuroendocrine pathology, Carcinoma, Papillary, Child, Female, Humans, Incidence, Linear Models, Logistic Models, Male, Middle Aged, Sex Distribution, Spatio-Temporal Analysis, Thyroid Cancer, Papillary, Thyroid Carcinoma, Anaplastic pathology, Thyroid Neoplasms pathology, Tumor Burden, Vermont epidemiology, Young Adult, Adenocarcinoma, Follicular epidemiology, Carcinoma epidemiology, Carcinoma, Neuroendocrine epidemiology, Rural Population statistics & numerical data, Thyroid Carcinoma, Anaplastic epidemiology, Thyroid Neoplasms epidemiology
- Abstract
Background: The increasing incidence of thyroid cancer has resulted in the rate tripling over the past 30 years. Reasons for this increase have not been established. Geostatistics and geographic information system (GIS) tools have emerged as powerful geospatial technologies to identify disease clusters, map patterns and trends, and assess the impact of ecological and socioeconomic factors (SES) on the spatial distribution of diseases. In this study, these tools were used to analyze thyroid cancer incidence in a rural population., Methods: Thyroid cancer incidence and socio-demographic factors in Vermont (VT), United States, between 1994 and 2007 were analyzed by logistic regression and geospatial and temporal analyses., Results: The thyroid cancer age-adjusted incidence in Vermont (8.0 per 100,000) was comparable to the national level (8.4 per 100,000), as were the ratio of the incidence of females to males (3.1:1) and the mortality rate (0.5 per 100,000). However, the estimated annual percentage change was higher (8.3 VT; 5.7 U.S.). Incidence among females peaked at 30-59 years of age, reflecting a significant rise from 1994 to 2007, while incidence trends for males did not vary significantly by age. For both females and males, the distribution of tumors by size did not vary over time; ≤1.0 cm, 1.1-2.0 cm, and >2.0 cm represented 38%, 22%, and 40%, respectively. In females, papillary thyroid cancer (PTC) accounted for 89% of cases, follicular (FTC) 8%, medullary (MTC) 2%, and anaplastic (ATC) 0.6%, while in males PTC accounted for 77% of cases, FTC 15%, MTC 1%, and ATC 3%. Geospatial analysis revealed locations and spatial patterns that, when combined with multivariate incidence analyses, indicated that factors other than increased surveillance and access to healthcare (physician density or insurance) contributed to the increased thyroid cancer incidence. Nine thyroid cancer incidence hot spots, areas with very high normalized incidence, were identified based on zip code data. Those locations did not correlate with urban areas or healthcare centers., Conclusions: These data provide evidence of increased thyroid cancer incidence in a rural population likely due to environmental drivers and SES. Geospatial modeling can provide an important framework for evaluation of additional associative risk factors.
- Published
- 2015
- Full Text
- View/download PDF
17. VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children.
- Author
-
Biss TT, Avery PJ, Brandão LR, Chalmers EA, Williams MD, Grainger JD, Leathart JB, Hanley JP, Daly AK, and Kamali F
- Subjects
- Adolescent, Age Factors, Algorithms, Child, Child, Preschool, Cross-Sectional Studies, Cytochrome P-450 CYP2C9, Cytochrome P-450 Enzyme System genetics, Cytochrome P450 Family 4, Dose-Response Relationship, Drug, Female, Genotype, Humans, Infant, Infant, Newborn, International Normalized Ratio, Male, Retrospective Studies, Vitamin K Epoxide Reductases, Anticoagulants administration & dosage, Aryl Hydrocarbon Hydroxylases genetics, Body Height genetics, Mixed Function Oxygenases genetics, Polymorphism, Genetic genetics, Warfarin administration & dosage
- Abstract
Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.
- Published
- 2012
- Full Text
- View/download PDF
18. Prolactinoma presenting as chronic anaemia with osteoporosis: a case report.
- Author
-
Maclean FR and Hanley JP
- Abstract
Introduction: Unexplained anaemia is a rare mode of presentation for prolactinoma. We describe a case of a man, with chronic anaemia ascribed to old age. Six years later, he was evaluated and diagnosed with a prolactinoma and resultant osteoporosis. Prolactinoma in old people may present insidiously with chronic anaemia and osteoporosis with or without sexual dysfunction., Case Presentation: We describe the case of a 70-year-old Caucasian man who presented with mild anaemia and tiredness. His anaemia was investigated and ascribed to senescence. Endocrine causes were not considered or tested for. Six years later, he was again referred. Reassessment and direct questioning revealed long-standing sexual dysfunction. It was also discovered that our patient had fractured his radius twice, with minor trauma, during the preceding year. His serum prolactin was massively increased and a magnetic resonance imaging (MRI) scan of the head demonstrated a pituitary mass consistent with a prolactinoma. Dual X-ray absorptiometry revealed osteoporosis. Treatment of the prolactinoma led to a reduction in his serum prolactin with a rise in his haemoglobin to normal levels. This suggested that the prolactinoma was present during the initial presentation and was the cause of his anaemia., Conclusion: This case highlights the importance of fully evaluating and investigating unexplained anaemia in older people and that endocrine causes should be considered. Osteoporosis also requires evaluation with secondary causes considered.
- Published
- 2010
- Full Text
- View/download PDF
19. Hyperemesis gravidarum and first trimester sagittal sinus thrombosis.
- Author
-
Kennelly MM, Baker MR, Birchall D, Hanley JP, Turnbull DM, and Loughney AD
- Subjects
- Adult, Brain diagnostic imaging, Female, Humans, Pregnancy, Pregnancy Trimester, First, Sagittal Sinus Thrombosis complications, Tomography, X-Ray Computed, Hyperemesis Gravidarum, Pregnancy Complications, Hematologic diagnosis, Sagittal Sinus Thrombosis diagnosis, Thrombophilia diagnosis
- Published
- 2008
- Full Text
- View/download PDF
20. Emergency warfarin reversal with prothrombin complex concentrates: UK wide study.
- Author
-
Evans SJ, Biss TT, Wells RH, and Hanley JP
- Subjects
- Emergencies, Guideline Adherence statistics & numerical data, Humans, Practice Guidelines as Topic, United Kingdom, Anticoagulants antagonists & inhibitors, Blood Coagulation Factors pharmacology, Warfarin antagonists & inhibitors
- Published
- 2008
- Full Text
- View/download PDF
21. Use of recombinant factor VIIa (rFVIIa) in the management of intractable haemorrhage: a survey of current UK practice.
- Author
-
Biss TT and Hanley JP
- Subjects
- Drug Administration Schedule, Factor VIIa, Humans, Recombinant Proteins therapeutic use, United Kingdom, Factor VII therapeutic use, Hematology, Hemorrhage drug therapy, Practice Patterns, Physicians'
- Published
- 2007
- Full Text
- View/download PDF
22. Novel mutations in a child with congenital amegakaryocytic thrombocytopenia.
- Author
-
Pemberton LC, Levett D, Skinner R, Hall AG, and Hanley JP
- Subjects
- DNA Mutational Analysis, Heterozygote, Humans, Infant, Newborn, Male, Megakaryocytes, Pedigree, Point Mutation, Receptors, Thrombopoietin genetics, Thrombocytopenia genetics
- Published
- 2006
- Full Text
- View/download PDF
23. Failure of rituximab to induce immune tolerance in a boy with severe haemophilia A and an alloimmune factor VIII antibody: a case report and review of the literature.
- Author
-
Biss TT, Velangi MR, and Hanley JP
- Subjects
- Antibodies immunology, Antibodies, Monoclonal, Murine-Derived, Factor VII immunology, Factor VII therapeutic use, Factor VIII therapeutic use, Factor VIIa, Hemophilia A immunology, Humans, Infant, Male, Recombinant Proteins immunology, Recombinant Proteins therapeutic use, Rituximab, Treatment Failure, Antibodies, Monoclonal therapeutic use, Factor VIII immunology, Hemophilia A drug therapy, Immune Tolerance drug effects, Immunologic Factors therapeutic use
- Abstract
We report the use of rituximab (MabThera); Roche Grenzach-Wyhlen, Germany) in a 6-year-old boy with severe haemophilia A and a high titre alloimmune factor VIII (FVIII) antibody, which had failed to respond to standard immune tolerance therapy. Rituximab was administered in 4 weekly doses with concurrent high-dose i.v. immunoglobulin (Flebogamma); Grifols, Barcelona, Spain) followed by daily high-dose recombinant FVIII concentrate (Recombinate); Baxter, CA, USA). Despite a fall in CD20 positive cell count to undetectable levels the inhibitor persisted. We discuss the possible reasons for failure of immune tolerance induction and review the literature concerning the use of rituximab for this indication.
- Published
- 2006
- Full Text
- View/download PDF
24. Recombinant activated factor VII (rFVIIa/NovoSeven) in intractable haemorrhage: use of a clinical scoring system to predict outcome.
- Author
-
Biss TT and Hanley JP
- Subjects
- Adolescent, Adult, Age Factors, Aged, Blood Loss, Surgical mortality, Child, Child, Preschool, Factor VIIa, Female, Humans, Infant, Male, Middle Aged, Recombinant Proteins administration & dosage, Treatment Outcome, Blood Loss, Surgical prevention & control, Erythrocyte Transfusion adverse effects, Erythrocyte Transfusion methods, Erythrocyte Transfusion mortality, Factor VII administration & dosage
- Abstract
Background and Objectives: Recombinant activated factor VII (rFVIIa/NovoSeven) has been advocated in the treatment of life-threatening haemorrhage, but appropriate clinical indications remain uncertain. The aim of this study was to detect factors predictive of outcome and to incorporate them into a prognostically significant scoring system., Materials and Methods: Thirty-six patients received rFVIIa for uncontrolled surgical, traumatic or obstetric bleeding in the Northern Region of the UK over a 45-month period. Clinical, laboratory and outcome data were examined. Characteristics of survivor and non-survivor groups were compared. A prognostic scoring system was evaluated retrospectively according to the presence of coagulopathy, renal impairment, hypothermia, greater than 10 units of red cell transfusion, advanced age and obstetric indication, with patients allocated to low, intermediate and high-risk groups., Results: Clinical response occurred in 26 patients (72%) with a reduction in prothrombin time and blood product requirements. Death occurred in 19 (53%). Four patients (11%) suffered thrombotic events. Survivors were younger than non-survivors and less likely to have coagulopathy, renal impairment or hypothermia at the time of administration. Survivors were more likely to have had an initial clinical response in terms of an immediate reduction in haemorrhage. Non-survivors were transfused a greater number of red cell units prior to administration. Survival varied according to prognostic score; low-risk patients had a survival rate of 85%, intermediate-risk patients had a survival rate of 50% and high-risk patients had a survival rate of 18%., Conclusions: FVIIa has a role in the cessation of haemorrhage, but may not improve survival. Use of a clinical scoring system may help to predict outcome.
- Published
- 2006
- Full Text
- View/download PDF
25. Warfarin reversal.
- Author
-
Hanley JP
- Subjects
- Administration, Oral, Anticoagulants administration & dosage, Anticoagulants adverse effects, Blood Coagulation physiology, Blood Coagulation Factors administration & dosage, Blood Coagulation Factors therapeutic use, Child, Coagulants administration & dosage, Coagulants therapeutic use, Drug Administration Schedule, Factor VII therapeutic use, Factor VIIa, Hemorrhage chemically induced, Hemorrhage prevention & control, Humans, Intracranial Hemorrhages chemically induced, Intracranial Hemorrhages prevention & control, Plasma, Practice Guidelines as Topic, Recombinant Proteins therapeutic use, Vitamin K administration & dosage, Warfarin administration & dosage, Warfarin adverse effects, Anticoagulants antagonists & inhibitors, Warfarin antagonists & inhibitors
- Abstract
Warfarin is the most commonly used oral anticoagulant in the UK. It is associated with few side effects apart from haemorrhage. The most appropriate way to reverse the anticoagulant effect of warfarin depends on the clinical circumstances. In serious bleeding, rapid reversal is required, whereas in minor bleeding or asymptomatic over anticoagulation, a more leisurely approach is usually appropriate. This review discusses the current approaches to warfarin reversal in clinical practice. The development of a uniform approach to warfarin reversal in the Northern Region is described.
- Published
- 2004
- Full Text
- View/download PDF
26. The use of recombinant factor viia in a jehovah's witness with auto-immune thrombocytopenia and post-splenectomy haemorrhage.
- Author
-
Waddington DP, McAuley FT, Hanley JP, and Summerfield GP
- Subjects
- Aged, Female, Humans, Recombinant Proteins, Splenectomy adverse effects, Autoimmune Diseases drug therapy, Factor VIIa therapeutic use, Jehovah's Witnesses, Postoperative Hemorrhage prevention & control, Thrombocytopenia drug therapy
- Published
- 2002
- Full Text
- View/download PDF
27. Successful high dose therapy for relapsed mediastinal large B cell lymphoma following surgical repair of anterior chest wall defect.
- Author
-
MacLean FR, Hanley JP, Patton WN, Hart DN, Langley S, Bayston K, and Jeffery GM
- Subjects
- Abscess etiology, Abscess surgery, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Dose-Response Relationship, Drug, Fistula etiology, Fistula surgery, Humans, Lymphoma, B-Cell complications, Lymphoma, B-Cell surgery, Lymphoma, Large B-Cell, Diffuse complications, Lymphoma, Large B-Cell, Diffuse surgery, Male, Mediastinal Neoplasms complications, Mediastinal Neoplasms surgery, Middle Aged, Recurrence, Sepsis surgery, Thorax pathology, Lymphoma, B-Cell drug therapy, Lymphoma, Large B-Cell, Diffuse drug therapy, Mediastinal Neoplasms drug therapy, Plastic Surgery Procedures methods, Salvage Therapy, Thoracic Surgical Procedures methods, Thorax microbiology
- Abstract
We describe a man with relapsed large B cell mediastinal lymphoma and associated infected large anterior chest wall defect who required high dose salvage therapy for his underlying disease. An initial mediastinotomy wound, associated with recurrent sepsis, had developed into an abscess, then fistula and eventually a large anterior chest wall defect. Safe use of salvage chemotherapy required reconstructive surgery consisting of a pedicled muscle flap. The subsequent high dose chemotherapy was carried out without complications and 15 months later the patient is alive and well.
- Published
- 2000
- Full Text
- View/download PDF
28. Hemorrhagic lymphadenopathy as a presenting feature of primary al amyloidosis.
- Author
-
Hanley JP, MacLean FR, Evans JL, Colls BM, Robinson BA, Patton WN, and Heaton DC
- Subjects
- Adult, Amyloid metabolism, Amyloidosis metabolism, Amyloidosis therapy, Diagnosis, Differential, Factor X Deficiency diagnosis, Fatal Outcome, Hematopoietic Stem Cell Transplantation, Hemophilia B diagnosis, Hemorrhage metabolism, Hemorrhage therapy, Humans, Liver chemistry, Liver pathology, Lymphatic Diseases metabolism, Lymphatic Diseases therapy, Male, Melphalan therapeutic use, Microscopy, Polarization, Middle Aged, Amyloidosis diagnosis, Hemorrhage diagnosis, Lymphatic Diseases diagnosis
- Abstract
Lymphadenopathy associated with hemorrhage as a presenting feature of primary (AL) amyloidosis has not previously been described. We report two such cases one of whom had an acquired factor X and IX deficiency. The clinical presentations were characterized by sudden spontaneous enlargement of lymph nodes followed by partial regression. In both cases significant delay in diagnosis, and hence treatment, occurred due to the mode of presentation. One patient died with rapidly progressive disease but the other has had an excellent response to therapy with high-dose melphalan (HDM, 200 mg/m2) and peripheral blood stem cell rescue. AL amyloid should be considered in all patients presenting with hemorrhagic lymphadenopathy.
- Published
- 2000
- Full Text
- View/download PDF
29. The biology of interferon-alpha and the clinical significance of anti-interferon antibodies.
- Author
-
Hanley JP and Haydon GH
- Subjects
- Antibodies analysis, Antibodies metabolism, Antibody Specificity, Antineoplastic Agents immunology, Antiviral Agents immunology, Humans, Interferon-alpha immunology, Treatment Failure, Antibodies immunology, Antineoplastic Agents pharmacology, Antiviral Agents pharmacology, Interferon-alpha pharmacology
- Abstract
The therapeutic indications for Interferons (IFNs) have dramatically increased in number in recent years to include many different diseases of viral, malignant, angiogenic, allergic, inflammatory and fibrotic origin. In particular, the current pandemic of hepatitis C virus infection has further stimulated the requirement for a comprehensive understanding of both the mechanism of action of IFN and the reasons for therapeutic failure. The role of anti-IFN antibodies as a cause of treatment failure has been a particularly controversial area. In this review we will outline the biology and proposed mechanisms of action of IFN-alpha (IFN-alpha) and discuss the incidence, methods of detection and clinical significance of anti-IFN antibodies.
- Published
- 1998
- Full Text
- View/download PDF
30. Safety, efficacy and cost-effectiveness of home therapy with recombinant activated factor VII in a patient with severe haemophilia A and an anti-factor VIII inhibitor.
- Author
-
Stewart AJ, Hanley JP, and Ludlam CA
- Subjects
- Cost-Benefit Analysis, Denmark, Dose-Response Relationship, Drug, Factor VIIa adverse effects, Factor VIIa economics, Humans, Infant, Male, Recombinant Proteins adverse effects, Recombinant Proteins economics, Recombinant Proteins therapeutic use, Factor VIII antagonists & inhibitors, Factor VIIa therapeutic use, Hemophilia A drug therapy, Home Care Services
- Abstract
We report the use of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) in a patient with severe haemophilia A and a high-titre anti-factor VIII inhibitor. A home therapy protocol was devised and its cost and efficacy were assessed after 2 years. rFVIIa (90 microg/kg) was self-administered at the onset of symptoms of bleeding. Doses were subsequently repeated at 2-h intervals until adequate haemostasis was achieved. The patient experienced a total of 25 bleeding episodes over the 2-year period, of which 23 were treated with up to three doses of rFVIIa. On two occasions, there was a recurrence of bleeding in the same area within 24 h, necessitating retreatment. There was a reduction in the number of inpatient hospital days compared with the 2 years before the use of rFVIIa and, overall, the cost of rFVIIa treatment was less than that of the previously used activated prothrombin complex concentrate (FEIBA; Immuno Ltd, Vienna, Austria). Our experience suggests that in selected haemophiliacs with inhibitors, home treatment with rFVIIa may be safe and cost-effective.
- Published
- 1998
31. Patterns of hepatitis G viraemia and liver disease in haemophiliacs previously exposed to non-virus inactivated coagulation factor concentrates.
- Author
-
Hanley JP, Jarvis LM, Hayes PC, Lee AJ, Simmonds P, and Ludlam CA
- Subjects
- Adolescent, Adult, Blood Coagulation Factors therapeutic use, Child, Child, Preschool, Drug Contamination, Humans, Middle Aged, Viremia, Blood Coagulation Factors adverse effects, Flaviviridae isolation & purification, Hemophilia A therapy, Hemophilia B therapy, Hepatitis, Viral, Human etiology, von Willebrand Diseases therapy
- Abstract
Hepatitis G virus (HGV), a novel flavivirus, has been implicated as a cause of posttransfusion hepatitis. We have performed a longitudinal study in a cohort of haemophiliacs (n = 68) who previously received non-virus inactivated coagulation factor concentrates to assess both patterns of HGV viraemia and any associated liver disease. Hepatitis C virus (HCV) RNA was present in 58/68 and co-infection with human immunodeficiency virus (HIV) was present in 15/68. HGV RNA was detected in 17/68 (25%) samples from the mid-1980s. There was no association between either HIV infection (p = 0.74) or co-infection with a particular HCV genotype (p = 0.62). However, there was a relationship between HGV viraemia and the severity of haemophilia (p = 0.0004) with HGV RNA detected in 5/19, 9/16 and 3/32 patients with mild, moderate and severe haemophilia respectively. A longitudinal study was performed in 15/17 haemophiliacs with HGV viraemia using stored serum samples from the 1980s and 1990s. HGV viraemia persisted in 8/15 and cleared in 7/15 over a variable period of time. A Weibull model was constructed to estimate the duration of HGV viraemia in the study group. The 75th and 90th percentiles for the duration of HGV were estimated to be 8.7 years (95%, confidence interval 4.8-15.7) and 23.6 years (95% confidence interval 11.8-47.1) respectively. Laparoscopic liver inspection/biopsy was performed in 25/68. There was no association between severity of liver disease and HGV viraemia (p = 0.43). This study demonstrates considerable variation in patterns of HGV viraemia in haemophiliacs. We found little evidence to implicate HGV as a major cause of chronic liver disease in haemophiliacs.
- Published
- 1998
32. Liver biopsy in haemophilia.
- Author
-
Ludlam CA, Hanley JP, and Hayes PC
- Subjects
- Hemorrhage etiology, Humans, Biopsy adverse effects, Hemophilia A complications
- Published
- 1997
33. Development of anti-interferon antibodies and breakthrough hepatitis during treatment for HCV infection in haemophiliacs.
- Author
-
Hanley JP, Jarvis LM, Simmonds P, and Ludlam CA
- Subjects
- Adolescent, Adult, Aged, Female, Hepatitis C immunology, Humans, Interferon alpha-2, Interferon-alpha therapeutic use, Male, Middle Aged, Recombinant Proteins, Antibodies immunology, Hemophilia A complications, Hepatitis C therapy, Interferon-alpha immunology
- Abstract
The development of anti-interferon antibodies may lead to treatment failure during interferon therapy. We have studied the development of such antibodies in a group of 39 haemophiliacs receiving interferon-alpha 2a for chronic hepatitis C virus (HCV) infection. Anti-interferon antibodies developed in five (13%) patients and were associated with "breakthrough hepatitis' in three cases. There was an association between the development of anti-interferon antibodies and infection with HCV genotype 3a (P = 0.01). This study suggests that the development of anti-interferon antibodies may lead to treatment failure in a proportion of haemophiliacs with HCV infection. The association with genotype 3a has not previously been reported. Monitoring for the development of breakthrough hepatitis due to anti-interferon antibodies may provide the opportunity to develop strategies to overcome their effects.
- Published
- 1996
- Full Text
- View/download PDF
34. Investigation of chronic hepatitis C infection in individuals with haemophilia: assessment of invasive and non-invasive methods.
- Author
-
Hanley JP, Jarvis LM, Andrews J, Dennis R, Lee R, Simmonds P, Piris J, Hayes P, and Ludlam CA
- Subjects
- Adolescent, Adult, Aged, Biopsy methods, Child, Chronic Disease, Cohort Studies, Endoscopy, Evaluation Studies as Topic, Female, Genotype, HIV Infections complications, Hepatitis C diagnosis, Humans, Laparotomy, Male, Middle Aged, Predictive Value of Tests, Ultrasonography, Hemophilia A complications, Hepatitis C complications
- Abstract
Hepatitis C virus (HCV) infection is the major cause of chronic liver disease in individuals with haemophilia. A wide spectrum of disease severity is found in this group, ranging from mild hepatitis to cirrhosis. We have studied a cohort of 87 anti-HCV positive haemophiliacs who have been infected with HCV for 10-25 years and assessed the relative value of invasive and non-invasive methods of evaluating liver disease. The severity of liver disease was assessed using ultrasound scan (n = 77), upper GI endoscopy (n = 50), laparoscopic liver inspection (n = 33) and liver biopsy (n = 22). Invasive investigations were performed without any significant bleeding complications. Evidence of severe liver disease was found in approximately 25% of patients. There was agreement between the severity of liver histology and the information derived from the laparoscopic liver inspection, endoscopy and ultrasound in 86%. Co-infection with HIV was significantly associated with more severe liver disease (P = 0.006). This study provides further evidence that liver disease is emerging as a major complication in haemophiliacs and severe liver disease is more common in those co-infected with HIV. We have shown the potential value of laparoscopic liver inspection, in combination with endoscopy and ultrasound, in staging the extent of liver disease, and suggest that most patients may be managed without resorting to liver biopsy.
- Published
- 1996
- Full Text
- View/download PDF
35. Treatment of hepatitis C infection in haemophiliacs: the Edinburgh experience.
- Author
-
Hanley JP, Jarvis LM, Andrews J, Hayes PC, Simmonds P, and Ludlam CA
- Published
- 1995
- Full Text
- View/download PDF
36. Interaction of hepatitis B and hepatitis C infection in haemophilia.
- Author
-
Hanley JP, Dolan G, Day S, Skidmore SJ, and Irving WL
- Subjects
- Cohort Studies, HIV Infections complications, Humans, Male, Polymerase Chain Reaction, RNA-Directed DNA Polymerase, Viral Interference, Hemophilia A complications, Hepatitis B complications, Hepatitis C complications
- Abstract
The management of haemophilia has been greatly complicated by the clinical sequelae of viral infection acquired through contaminated blood products. Many haemophiliacs have been infected by several viruses and the interaction between these viruses may be complex. In a cohort of 42 anti-HCV positive haemophiliacs, five were also found to be positive for HBsAg. All five were HCV reverse transcriptase/PCR negative compared to the 4/37 (11%) anti-HCV positive haemophiliacs who were HBsAg negative (P = 0.0001). We have identified a striking interaction between hepatitis C (HCV) and hepatitis B (HBV) in haemophiliacs co-infected by these agents, suggestive of the phenomenon of viral interference.
- Published
- 1993
- Full Text
- View/download PDF
37. The carboxyl terminus of RAP30 is similar in sequence to region 4 of bacterial sigma factors and is required for function.
- Author
-
Garrett KP, Serizawa H, Hanley JP, Bradsher JN, Tsuboi A, Arai N, Yokota T, Arai K, Conaway RC, and Conaway JW
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Base Sequence, Cloning, Molecular, DNA genetics, Humans, Immunoblotting, Kinetics, Liver physiology, Molecular Sequence Data, Peptides chemical synthesis, Peptides immunology, Rats, Recombinant Proteins analysis, Recombinant Proteins metabolism, Sequence Deletion, Sequence Homology, Amino Acid, Sigma Factor analysis, Transcription Factors analysis, Sigma Factor genetics, Sigma Factor metabolism, Transcription Factors genetics, Transcription Factors metabolism, Transcription Factors, TFII, Transcription, Genetic
- Abstract
Transcription factor beta gamma (RAP30/74) from rat liver was previously shown in biochemical studies to control the binding of RNA polymerase II to promoters by a mechanism analogous to that utilized by bacterial sigma factors, by decreasing the affinity of polymerase for nonpromoter sites on DNA and by increasing the affinity of the enzyme for the preinitiation complex (Conaway, R. C., Garrett, K. P., Hanley, J. P., and Conaway, J. W. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 6205-6209). By constructing and analyzing mutants of beta gamma, we have identified a novel functional domain located in the carboxyl terminus of the gamma (RAP30) subunit. This domain shares sequence similarity with region 4 of bacterial sigma factors; in particular, it exhibits striking similarity to the carboxyl-terminal regions 4.1 and 4.2 of SpoIIIC (Bacillus subtilis sigma k). Evidence from biochemical studies argues that a mutant gamma (RAP30), lacking amino acid sequences similar to sigma homology region 4.2, is able to assemble with the beta (RAP74) subunit to form a mutant beta gamma (RAP30/74) with impaired ability to interact with RNA polymerase II.
- Published
- 1992
38. Mechanism of promoter selection by RNA polymerase II: mammalian transcription factors alpha and beta gamma promote entry of polymerase into the preinitiation complex.
- Author
-
Conaway RC, Garrett KP, Hanley JP, and Conaway JW
- Subjects
- Animals, Macromolecular Substances, Protein Binding, Rats, Transcription Factors isolation & purification, Liver metabolism, Promoter Regions, Genetic, RNA Polymerase II metabolism, TATA Box, Transcription Factors metabolism, Transcription, Genetic
- Abstract
Productive binding of RNA polymerase II at the core region of TATA box-containing promoters is controlled by the action of the TATA factor and four additional transcription factors, designated alpha, beta gamma, delta, and epsilon, which have each been purified to near homogeneity from rat liver. This process is accomplished in three distinguishable stages. In the first stage (initial complex formation), the core promoter is packaged with the TATA factor into a binary complex that serves as the recognition site for RNA polymerase II. Here we show that, in the second stage (site selection), transcription factors alpha and beta gamma act in combination to promote selective binding of RNA polymerase II to the initial complex. Several lines of evidence argue that alpha and beta gamma function at this stage by a mechanism related to that utilized by bacterial sigma factors. In the third stage, transcription factors delta and epsilon promote assembly of the functional preinitiation complex. Our evidence supports the model that delta and epsilon enter the preinitiation complex and direct formation of stable protein-DNA contacts that anchor the transcription apparatus to the core promoter at sequences near the cap site.
- Published
- 1991
- Full Text
- View/download PDF
39. Bicycle safety. What's new in '92?
- Author
-
Hanley JP
- Subjects
- Accidents, Traffic prevention & control, Child, Education, Equipment Design, Humans, Safety, Bicycling
- Abstract
There are over 100 million bicycle riders in America, according to the National Safety Council, and in the last two years more than 1.25 million accidents have been reported. About 77% of these accidents occurred among children under 15 years old. Nearly 44% of reportable injuries were in the 5-14 year old age group and 30% occurred among children under five years of age, according to the National Center for Health Statistics.
- Published
- 1991
40. Transcription initiated by RNA polymerase II and transcription factors from liver. Structure and action of transcription factors epsilon and tau.
- Author
-
Conaway JW, Hanley JP, Garrett KP, and Conaway RC
- Subjects
- Animals, Chromatography, Liquid, Electrophoresis, Polyacrylamide Gel, Male, Rats, Rats, Inbred Strains, Structure-Activity Relationship, Transcription Factors isolation & purification, RNA Polymerase II genetics, Transcription Factors genetics, Transcription, Genetic
- Abstract
We have fractionated rat liver and identified a set of transcription factors that are essential for accurate initiation by RNA polymerase II. These factors were resolved into five distinct enzyme fractions designated alpha, beta gamma, delta, epsilon, and tau. Four of these fractions can now be replaced with purified proteins. alpha and beta gamma were previously purified to apparent homogeneity (Conaway, J. W., and Conaway, R. C. (1989) J. Biol. Chem. 264, 2357-2362). Here, we report purification to near homogeneity of transcription factor epsilon. Epsilon has a native molecular mass of approximately 90 kDa and is composed of 34- and 58-kDa polypeptides. Both the 34- and 58-kDa polypeptides are required for runoff transcription. In addition, we show that transcription factor tau is a rat liver homologue of the TATA factor (TFIID or BTF1) that can be efficiently replaced in transcription in vitro by recombinant yeast TFIID. Comparison of the two factors reveals, however, that they differ significantly in their abilities to direct the transcription system to discriminate between promoters of different sequences.
- Published
- 1991
41. Togetherness.
- Author
-
Hanley JP and Hanley KK
- Subjects
- Humans, Interpersonal Relations, Marriage, Pediatrics
- Published
- 1979
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.