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Search Results: 1 - 10 of 201849 matches for " Patrick D. Mitchell "
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A Case of DIPNECH and Review of the Current Literature  [PDF]
Patrick D. Mitchell, Marcus P. Kennedy, Michael T. Henry
Open Journal of Respiratory Diseases (OJRD) , 2013, DOI: 10.4236/ojrd.2013.32011
Abstract: Diffuse Idiopathic Neuroendocrine Cell Hyperplasia (DIPNECH) is a rare pulmonary disease. It was first described by Aguayo et al. in 1992, and recognised by the World Health Organisation in 2004 as a precursor lesion to the development of pulmonary carcinoid tumour. DIPNECH has been described in several isolated case reports and series. This article describes a case of DIPNECH and summaries the recent literature in an attempt to raise awareness of this disease and management options.
Hypoxemia in patients with COPD: cause, effects, and disease progression
Brian D Kent, Patrick D Mitchell, Walter T McNicholas
International Journal of Chronic Obstructive Pulmonary Disease , 2011, DOI: http://dx.doi.org/10.2147/COPD.S10611
Abstract: xemia in patients with COPD: cause, effects, and disease progression Review (14763) Total Article Views Authors: Brian D Kent, Patrick D Mitchell, Walter T McNicholas Published Date March 2011 Volume 2011:6 Pages 199 - 208 DOI: http://dx.doi.org/10.2147/COPD.S10611 Brian D Kent1,2, Patrick D Mitchell1, Walter T McNicholas1,2 1Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin; 2Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.
Hypoxemia in patients with COPD: cause, effects, and disease progression
Brian D Kent,Patrick D Mitchell,Walter T McNicholas
International Journal of COPD , 2011,
Abstract: Brian D Kent1,2, Patrick D Mitchell1, Walter T McNicholas1,21Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin; 2Conway Institute of Biomolecular and Biomedical Research, University College Dublin, IrelandAbstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.Keywords: COPD, hypoxia, sleep, inflammation, pulmonary hypertension
Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference
Patrick F McArdle, Brian W Whitcomb, Keith Tanner, Braxton D Mitchell, Alan R Shuldiner, Afshin Parsa
BMC Cardiovascular Disorders , 2012, DOI: 10.1186/1471-2261-12-16
Abstract: Study subjects included 868 asymptomatic individuals. Study subjects were genotyped at the UGT1A1*28 locus, which is strongly associated with bilirubin levels.Serum bilirubin levels were inversely associated with levels of several cardiovascular disease risk factors, including body mass index (p = 0.003), LDL (p = 0.0005) and total cholesterol (p = 0.0002). In contrast, UGT1A1*28 genotype, a known cause of elevated bilirubin levels, was not significantly associated with any of these traditional CVD risk factors. We did observe an association between genotype and brachial artery diameter (p = 0.003) and cold pressor reactivity (p = 0.01).Our findings imply that the observed association of serum bilirubin levels with body mass index and cholesterol are likely due to confounding and suggest that previously established CVD benefits of increased bilirubin may in part be mediated by the early regulation of vascular structure and reactivity.Bilirubin is a metabolic byproduct of the breakdown of hemoglobin degradation which itself must be metabolized for appropriate excretion. High levels of bilirubin are associated with decreased risk of coronary heart disease (CHD) and cardiovascular disease (CVD) [1]. While the full spectrum by which bilirubin acts to protect against CVD is not fully understood, there has been evidence of protecting against oxidative stress by reducing reactive oxygen species and possibly having additional anti-atherogenetic properties [2,3]. Previous studies have reported associations of serum bilirubin levels to cardiovascular disease risk factors, including total cholesterol and blood pressure [4-6]. Serum bilirubin levels have also been associated with socioeconomic and behavioral CVD risk factors such as smoking and alcohol intake [7,8]. However, the nature of these associations is unclear, including the potential for residual confounding among serum bilirubin levels and the associated CVD risk factors due to factors measured poorly or not measured
Update on the Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II): statistical analysis plan
Gregson Barbara A,Murray Gordon D,Mitchell Patrick M,Rowan Elise N
Trials , 2012, DOI: 10.1186/1745-6215-13-222
Abstract: Background Previous studies had suggested that the outcome for patients with spontaneous lobar intracerebral haemorrhage (ICH) and no intraventricular haemorrhage (IVH) might be improved with early evacuation of the haematoma. The Surgical Trial in Lobar Intracerebral Haemorrhage (STICH II) set out to establish whether a policy of earlier surgical evacuation of the haematoma in selected patients with spontaneous lobar ICH would improve outcome compared to a policy of initial conservative treatment. It is an international, multi-centre, prospective randomised parallel group trial of early surgery in patients with spontaneous lobar ICH. Outcome is measured at six months via a postal questionnaire. Results Recruitment to the study began on 27 November 2006 and closed on 15 August 2012 by which time 601 patients had been recruited. The protocol was published in Trials (http://www.trialsjournal.com/content/12/1/124/). This update presents the analysis plan for the study without reference to the unblinded data. The trial data will not be unblinded until after follow-up is completed in early 2013. The main trial results will be presented in spring 2013 with the aim to publish in a peer-reviewed journal at the same time. Conclusion The data from the trial will provide evidence on the benefits and risks of early surgery in patients with lobar ICH. Trial registration ISRCTN: ISRCTN22153967
Quantifying the Ki-67 Heterogeneity Profile in Prostate Cancer
Shane Mesko,Patrick Kupelian,D. Jeffrey Demanes,Jaoti Huang,Pin-Chieh Wang,Mitchell Kamrava
Prostate Cancer , 2013, DOI: 10.1155/2013/717080
Abstract: Background: Ki-67 is a robust predictive/prognostic marker in prostate cancer; however, tumor heterogeneity in prostate biopsy samples is not well studied. Methods: Using an MRI/US fusion device, biopsy cores were obtained systematically and by targeting when indicated by MRI. Prostate cores containing cancer from 77 consecutive men were analyzed. The highest Ki-67 was used to determine interprostatic variation. Ki-67 range (highest minus lowest) was used to determine intraprostatic and intralesion variation. Apparent diffusion coefficient (ADC) values were evaluated in relation to Ki-67. Results: Interprostatic Ki-67 mean ± standard deviation (SD) values for NCCN low (L), intermediate (I), and high (H) risk patients were 5.1 ± 3.8%, 7.4 ± 6.8%, and 12.0 ± 12.4% (ANOVA ). Intraprostatic mean ± SD Ki-67 ranges in L, I, and H risk patients were 2.6 ± 3.6%, 5.3 ± 6.8%, and 10.9 ± 12.3% (ANOVA ). Intralesion mean ± SD Ki-67 ranges in L, I, and H risk patients were 1.1 ± 0.9%, 5.2 ± 7.9%, and 8.1 ± 10.8% (ANOVA ). ADC values at Ki-67 > and <7.1% were 860 ± 203 and 1036 ± 217, respectively ( ). Conclusions: High risk patients have significantly higher inter- and intraprostatic Ki-67 heterogeneity. This needs to be considered when utilizing Ki-67 clinically. 1. Introduction Progress in multiparametric MRI imaging has improved our ability to visualize specific target lesions within the prostate. Ultrasound/MRI fusion devices allow for targeted biopsies of these specific MRI defined lesions. These advances create an opportunity to evaluate biomarkers from specific target lesions for integration into radiation treatment stratification. The Ki-67 protein functions as a nuclear antigen that is only expressed in proliferating cells. It is a marker of the growth fraction in malignant tissue [1–3]. It is determined via immunohistochemistry and expressed as a percentage of cells showing activity in a given tissue sample (e.g., Ki-67 of 10% equates to 10% of the cells expressing the antigen). It is a promising biomarker in prostate cancer with independent predictive/prognostic value following radiotherapy [4–6]. A range of percentage cut points has correlated with outcomes but has not been prospectively validated [7–11]. One limitation to integrating biomarkers into clinical practice is being able to account for tumor heterogeneity. Ki-67 heterogeneity has been acknowledged in liver, breast, and several other cancers but has not been well studied in prostate cancer [12–14]. Previous studies have used the highest Ki-67 level found on routine systematic prostate biopsy
Homozygosity by descent mapping of blood pressure in the Old Order Amish: evidence for sex specific genetic architecture
Patrick F McArdle, Harvey Dytch, Jeffery R O'Connell, Alan R Shuldiner, Braxton D Mitchell, Mark Abney
BMC Genetics , 2007, DOI: 10.1186/1471-2156-8-66
Abstract: Areas of two chromosomes were identified as suggestive of linkage to SBP and 5 areas to DBP in either the overall or sex specific analyses. The strongest evidence for linkage in the overall sample was to Chromosome 18q12 (LOD = 2.6 DBP). Sex specific analyses identified a linkage on Chromosome 4p12-14 (LOD in men only = 3.4 SBP). At Chromosome 2q32-33, an area where we previously reported significant evidence for linkage to DBP using a conventional identity by descent approach, the LOD was 1.4; however an appreciable sex effect was observed with men accounting for most of the linkage (LOD in men only = 2.6).These results add evidence to a sex specific genetic architecture to blood pressure related traits, particularly in regions of linkage on chromosome 2, 4 and 18.Hypertension is a common chronic condition in the United States and leads to severe morbidity and mortality through heart disease, stroke, congestive heart failure, end stage renal disease and peripheral vascular disease. Among these, heart disease and stroke are two of the leading cause of death in the United States [1,2]. Much effort and expense has been spent attempting to identify genes responsible for blood pressure variation and hypertension. At this point nearly all human chromosomes have been linked to hypertension related traits through linkage analysis [3-6]. It seems clear that a single gene is not responsible for hypertension and that etiology is a complex combination of both genetic and environmental risk factors [7,8]. Sex may be an important and easily identifiable "environmental" risk factor that may interact with putative genetic factors to increase risk [9].To attempt to identify genetic causes to blood pressure variation and other complex diseases, we have studied a population of Old Order Amish (OOA) in Lancaster County, Pennsylvania. The OOA are a closed founder population with several beneficial qualities for the genetic study of complex diseases [10]. A relatively homogenous lifesty
Using previously genotyped controls in genome-wide association studies (GWAS): application to the Stroke Genetics Network (SiGN)
Braxton D. Mitchell,Myriam Fornage,Patrick F. McArdle,Sara L. Pulit,Tushar Dave,Paul I. W. de Bakker
Frontiers in Genetics , 2014, DOI: 10.3389/fgene.2014.00095
Abstract: Genome-wide association studies (GWAS) are widely applied to identify susceptibility loci for a variety of diseases using genotyping arrays that interrogate known polymorphisms throughout the genome. A particular strength of GWAS is that it is unbiased with respect to specific genomic elements (e.g., coding or regulatory regions of genes), and it has revealed important associations that would have never been suspected based on prior knowledge or assumptions. To date, the discovered SNPs associated with complex human traits tend to have small effect sizes, requiring very large sample sizes to achieve robust statistical power. To address these issues, a number of efficient strategies have emerged for conducting GWAS, including combining study results across multiple studies using meta-analysis, collecting cases through electronic health records, and using samples collected from other studies as controls that have already been genotyped and made publicly available (e.g., through deposition of de-identified data into dbGaP or EGA). In certain scenarios, it may be attractive to use already genotyped controls and divert resources to standardized collection, phenotyping, and genotyping of cases only. This strategy, however, requires that careful attention be paid to the choice of “public controls” and to the comparability of genetic data between cases and the public controls to ensure that any allele frequency differences observed between groups is attributable to locus-specific effects rather than to a systematic bias due to poor matching (population stratification) or differential genotype calling (batch effects). The goal of this paper is to describe some of the potential pitfalls in using previously genotyped control data. We focus on considerations related to the choice of control groups, the use of different genotyping platforms, and approaches to deal with population stratification when cases and controls are genotyped across different platforms.
Improving the Representativeness of Behavioral and Clinical Surveillance for Persons with HIV in the United States: The Rationale for Developing a Population-Based Approach
A. D. McNaghten, Mitchell I. Wolfe, Ida Onorato, Allyn K. Nakashima, Ronald O. Valdiserri, Eve Mokotoff, Raul A. Romaguera, Alice Kroliczak, Robert S. Janssen, Patrick S. Sullivan
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000550
Abstract: The need for a new surveillance approach to understand the clinical outcomes and behaviors of people in care for HIV evolved from the new challenges for monitoring clinical outcomes in the HAART era, the impact of the epidemic on an increasing number of areas in the US, and the need for representative data to describe the epidemic and related resource utilization and needs. The Institute of Medicine recommended that the Centers for Disease Control and Prevention and the Heath Resources and Services Administration coordinate efforts to survey a random sample of HIV-infected persons in care, in order to more accurately measure the need for prevention and care services. The Medical Monitoring Project (MMP) was created to meet these needs. This manuscript describes the evolution and design of MMP, a new nationally representative clinical outcomes and behavioral surveillance system, and describes how MMP data will be used locally and nationally to identify care and treatment utilization needs, and to plan for prevention interventions and services.
Nicotinic acetylcholine receptor subunit variants are associated with blood pressure; findings in the Old Order Amish and replication in the Framingham Heart Study
Patrick F McArdle, Sue Rutherford, Braxton D Mitchell, Coleen M Damcott, Ying Wang, Vasan Ramachandran, Sandy Ott, Yen-Pei C Chang, Daniel Levy, Nanette Steinle
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-67
Abstract: We sequenced CHRNA1, CHRND and CHRNG in 24 Amish subjects from the Amish Family Diabetes Study (AFDS) and identified 20 variants. We then performed association analysis of non-redundant variants (n = 12) in the complete AFDS cohort of 1,189 individuals, and followed by genotyping blood pressure-associated variants (n = 5) in a replication sample of 1,759 individuals from the Framingham Heart Study (FHS).The minor allele of a synonymous coding SNP, rs2099489 in CHRNG, was associated with higher systolic blood pressure in both the Amish (p = 0.0009) and FHS populations (p = 0.009) (minor allele frequency = 0.20 in both populations).CHRNG is currently thought to be expressed only during fetal development. These findings support the Barker hypothesis, that fetal genotype and intra-uterine environment influence susceptibility to chronic diseases later in life. Additional studies of this variant in other populations, as well as the effect of this variant on acetylcholine receptor expression and function, are needed to further elucidate its potential role in the regulation of blood pressure. This study suggests for the first time in humans, a possible role for genetic variation in the neuromuscular nicotinic acetylcholine receptor, particularly the gamma subunit, in systolic blood pressure regulation.Hypertension is one of the most important risk factors for cardiovascular disease, and end-stage renal disease. Globally hypertension is the leading risk factor for morbidity and mortality [1], having multifactorial causal agents, including genetic and environmental components. We previously reported a genome wide scan of subjects from the Amish Family Diabetes study that provided strong evidence for linkage to diastolic (LOD = 3.36; p = 0.00004) and systolic (LOD = 1.64; p = 0.003) blood pressure on chromosome 2q31-q34 [2]. Follow-up analyses with additional markers resulted in an increase in the LOD score to 4.23 (p = 0.00001) for diastolic blood pressure (Figure 1). Initial
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