PubMed Health⌕ Search

Biomedical subjects

Craig M Lilly

Publications and source records attributed to Craig M Lilly.

At least 19 recordsLinked to original sources
PubMed2006

The PTGDR gene is not associated with asthma in 3 ethnically diverse populations.

BACKGROUND: The prostanoid DP receptor (PTGDR) gene on chromosome 14q22.1 has been identified as an asthma susceptibility gene. A haplotype with decreased transcription factor binding and transcription efficiency was associated with decreased asthma susceptibility in African American and white subjects. The significance of PTGDR gene variants in asthma has yet to be determined in Latinos, the largest US minority population, nor has the association been replicated in other populations. OBJECTIVE: To determine the role of PTGDR gene variants in asthma susceptibility and asthma-related traits among the Mexican, Puerto Rican, and African American populations. METHODS: We determined whether single nucleotide polymorphisms (SNPs) and haplotypes in PTGDR were associated with asthma and asthma-related traits by family-based and cross-sectional cohort analyses in 336 Puerto Rican and 273 Mexican asthmatic trios and by case-control analysis among African American subjects with asthma and healthy controls (n = 352). RESULTS: We identified 13 SNPs in the PTGDR gene, and 6 were further analyzed. There was no significant association between PTGDR variants and asthma by family-based or case-control analyses. SNPs -441C and -197C and haplotype TTT showed marginal association with asthma-related traits in Mexican subjects. SNP -441 genotype TT (P = .05) and haplotype TTT (P = .02) were associated with increased IgE levels in African Americans. CONCLUSION: We conclude that the PTGDR gene is not a significant risk factor for asthma among Puerto Ricans, Mexicans, or African Americans. CLINICAL IMPLICATIONS: Asthma candidate genes provide insights to pathophysiology and potentially new therapeutic targets, although the PTGDR gene was not found to be a significant risk factor for asthma in 3 populations.

Adolescent↗
PubMed2006

Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics.

Beta2-adrenergic receptor (beta2AR) gene polymorphisms have been reported to be associated with various asthma-related traits in different racial/ethnic populations. However, it is unknown whether beta2AR genetic variants are associated with asthma in African Americans. In this study, we have examined whether there is association between beta2AR genetic variants and asthma in African Americans. We have recruited 264 African American asthmatic subjects and 176 matched healthy controls participating in the Study of African Americans, Asthma, Genes and Environments (SAGE). We genotyped seven known and recently identified beta2AR SNP variants, then tested genotype and haplotype association of asthma-related traits with the beta2AR SNPs in our African American cohort with adjustment of confounding effect due to admixture background and environmental risk factors. We found a significant association of the SNP -47 (Arg-19Cys) polymorphism with DeltaFEF(25-75), a measure of bronchodilator drug responsiveness, in African American asthmatics after correction for multiple testing (P = 0.001). We did not observe association of the SNP +46 (Arg16Gly) variant with asthma disease diagnosis and asthma-related phenotypes. In contrast to previous results between the Arg16Gly variant and traits related to bronchodilator responsiveness, our results indicate that the Arg-19Cys polymorphism in beta upstream peptide may play an important role in bronchodilator drug responsiveness in African American subjects. Our findings highlight the importance of investigating genetic risk factors for asthma in different populations.

Adolescent↗
PubMed2006

Effect of moderate hypothermia on gene expression by THP-1 cells: a DNA microarray study.

The mechanisms by which moderate hypothermia (32 degrees C for 12-72 h) affect human cellular function are unclear. We tested the hypothesis that it produces broad changes in mRNA expression in vitro. Acute monocytic leukemia (THP-1) cells were incubated under control conditions (37 degrees C) or moderate hypothermia (32 degrees C) for 24 h. RNA was extracted, and the hypothermic response was confirmed by examining the expression of the cold-induced RNA-binding protein (CIRBP) gene by RT-PCR. Gene expression analysis was performed on seven sets of paired samples with Affymetrix U133A chips using established statistical methods. Sequences were considered affected by cold if they showed statistically significant changes in expression and also met published post hoc filter criteria (changes in geometric mean expression of > or =2-fold and expression calls of "present" or "marginal" in at least half of the experiments). Changes in the expression of selected sequences were further confirmed by PCR. Sixty-seven sequences met the criteria for increased expression (including cold-inducible genes CIRBP and RNA binding motif 3), and 100 sequences showed decreased expression as a result of hypothermia. Functional categories affected by hypothermia included genes involved in immune responses; cell growth, proliferation, and differentiation; and metabolism and biosynthesis. Several heat shock proteins (HSPs) showed decreases in expression. Moderate hypothermia produces substantial changes in gene expression, in categories potentially of systemic importance. Cold exposure without rewarming decreased the expression of several HSPs. These in vitro findings suggest that prolonged hypothermia in vivo might be capable of producing physiologically relevant changes in gene expression by circulating leukocytes.

Cell Line, Tumor↗
PubMed2005

Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations.

Case-control genetic association studies in admixed populations are known to be susceptible to genetic confounding due to population stratification. The transmission/disequilibrium test (TDT) approach can avoid this problem. However, the TDT is expensive and impractical for late-onset diseases. Case-control study designs, in which, cases and controls are matched by admixture, can be an appealing and a suitable alternative for genetic association studies in admixed populations. In this study, we applied this matching strategy when recruiting our African American participants in the Study of African American, Asthma, Genes and Environments. Group admixture in this cohort consists of 83% African ancestry and 17% European ancestry, which was consistent with reports from other studies. By carrying out several complementary analyses, our results show that there is a substructure in the cohort, but that the admixture distributions are almost identical in cases and controls, and also in cases only. We performed association tests for asthma-related traits with ancestry, and only found that FEV(1), a measure for baseline pulmonary function, was associated with ancestry after adjusting for socio-economic and environmental risk factors (P=0.01). We did not observe an excess of type I error rate in our association tests for ancestry informative markers and asthma-related phenotypes when ancestry was not adjusted in the analyses. Furthermore, using the association tests between genetic variants in a known asthma candidate gene, beta(2) adrenergic receptor (beta(2)AR) and DeltaFEF(25-75), an asthma-related phenotype, as an example, we demonstrated population stratification was not a confounder in our genetic association. Our present work demonstrates that admixture-matched case-control strategies can efficiently control population stratification confounding in admixed populations.

Adolescent↗
PubMed2005

The leukotriene B4 lipid chemoattractant receptor BLT1 defines antigen-primed T cells in humans.

We have recently shown that the leukotriene B(4) (LTB(4))-BLT1 pathway is important in early effector T-cell recruitment in mouse models of inflammation. Here we characterize the phenotype and function of human peripheral blood BLT1(+) T cells in health and illustrate their involvement in asthma and acute infection. In healthy individuals, BLT1(+) T cells are a rare peripheral blood T-cell population enriched for the activation markers CD38 and HLA-DR. Compared with BLT1(-) T cells, a larger proportion of peripheral blood BLT1(+) T cells express the effector cytokines IFNgamma and IL-4 and inflammatory chemokine receptors, CCR1, CCR2, CCR6, and CXCR1. Consequently, in healthy individuals peripheral blood BLT1(+) T cells are a rare antigen-primed T-cell subset with unique phenotypic, migratory, and functional properties. BLT1 expression on T cells is tightly regulated by inflammation and only transiently expressed after naive T-cell activation by dendritic cells. Although rare in the peripheral blood of healthy individuals, BLT1(+) T cells are markedly increased in frequency in the peripheral blood in response to acute Epstein-Barr virus (EBV) infection and moderately increased in the airways of asymptomatic allergic asthmatics. Our studies provide novel insights into the LTB(4)-BLT1 lipid chemoattractant pathway in human T-cell responses, and how it may link innate and adaptive immunity.

ADP-ribosyl Cyclase 1↗
PubMed2005

Roundtable debate: Controversies in the management of the septic patient--desperately seeking consensus.

Despite continuous advances in technologic and pharmacologic management, the mortality rate from septic shock remains high. Care of patients with sepsis includes measures to support the circulatory system and treat the underlying infection. There is a substantial body of knowledge indicating that fluid resuscitation, vasopressors, and antibiotics accomplish these goals. Recent clinical trials have provided new information on the addition of individual adjuvant therapies. Consensus on how current therapies should be prescribed is lacking. We present the reasoning and preferences of a group of intensivists who met to discuss the management of an actual case. The focus is on management, with emphasis on the criteria by which treatment decisions are made. It is clear from the discussion that there are areas where there is agreement and areas where opinions diverge. This presentation is intended to show how experienced intensivists apply clinical science to their practice of critical care medicine.

Anti-Bacterial Agents↗
PubMed2005

Diversity of asthma: evolving concepts of pathophysiology and lessons from genetics.

Asthma is a complex respiratory disorder characterized by reversible airflow obstruction and bronchial hyperreactivity. In recent years, our understanding of the mechanisms underlying allergic asthma has grown, and this has resulted in complex paradigms to define the immunobiology of the disorder. These paradigms conceive of asthma as a disorder with complex genetic and environmental interactions that affect the developing immune system and ultimately result in the episodic release of procontractile mediators, including leukotrienes and prostaglandins, causing susceptible individuals to wheeze. Genetic studies seek to advance our knowledge by identifying the differences in our genetic make-up that cause us to be susceptible. Surprisingly few of the verified asthma genes involve known asthma mediators. This article reviews several of the best-established asthma genes, including a disintegrin and metalloprotease 33, dipeptidyl peptidase 10, PHD finger protein 11 (PHF11), and the prostanoid DP1 receptor. Identification of these unsuspected genes is leading to models of asthma pathogenesis that go beyond our conception of asthma as a disease of smooth muscle abnormalities, inflammatory cell presence, and airway structural changes.

Arachidonic Acids↗
PubMed2005

The Critical Care Safety Study: The incidence and nature of adverse events and serious medical errors in intensive care.

OBJECTIVE: Critically ill patients require high-intensity care and may be at especially high risk of iatrogenic injury because they are severely ill. We sought to study the incidence and nature of adverse events and serious errors in the critical care setting. DESIGN: We conducted a prospective 1-year observational study. Incidents were collected with use of a multifaceted approach including direct continuous observation. Two physicians independently assessed incident type, severity, and preventability as well as systems-related and individual performance failures. SETTING: Academic, tertiary-care urban hospital. PATIENTS: Medical intensive care unit and coronary care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcomes of interest were the incidence and rates of adverse events and serious errors per 1000 patient-days. A total of 391 patients with 420 unit admissions were studied during 1490 patient-days. We found 120 adverse events in 79 patients (20.2%), including 66 (55%) nonpreventable and 54 (45%) preventable adverse events as well as 223 serious errors. The rates per 1000 patient-days for all adverse events, preventable adverse events, and serious errors were 80.5, 36.2, and 149.7, respectively. Among adverse events, 13% (16/120) were life-threatening or fatal; and among serious errors, 11% (24/223) were potentially life-threatening. Most serious medical errors occurred during the ordering or execution of treatments, especially medications (61%; 170/277). Performance level failures were most commonly slips and lapses (53%; 148/277), rather than rule-based or knowledge-based mistakes. CONCLUSIONS: Adverse events and serious errors involving critically ill patients were common and often potentially life-threatening. Although many types of errors were identified, failure to carry out intended treatment correctly was the leading category.

Aged↗
PubMed2005

Pathogenic T-cell recruitment into the airway in human disease.

Effector T cells significantly contribute to inflammatory diseases. These cells are recruited into tissue, where they orchestrate an inflammatory response that can either protect against infection or sometimes stimulate human disease. The recruitment of T cells into tissue from the blood and lymphoid compartments is an active process controlled by chemokines and the chemokine receptors expressed on distinct effector T-cell subsets. Thus, the chemokines secreted in the tissue will determine the specific types of T lymphocyte recruited into that tissue based on the chemokine receptors expressed on these cells. It follows that the chemokine receptor profile on T cells isolated from the lungs of patients with inflammatory pulmonary disease will define the subtype of pathogenic T lymphocytes mediating the disease process and will identify the mechanisms that recruit these cells into the lung. This article reviews data from both human and animal studies that define the chemokine receptors involved in the recruitment of T lymphocytes into the lung in various inflammatory pulmonary diseases, including asthma, obliterative bronchiolitis, sarcoidosis, and chronic eosinophilic pneumonia. We then speculate on the potential role of these chemokine receptors in the pathogenesis of these disorders and potential novel therapeutic approaches suggested by these data.

Animals↗
PubMed2005

Azacitidine-induced interstitial and alveolar fibrosis in a patient with myelodysplastic syndrome.

A 71-year-old Caucasian man diagnosed with myelodysplastic syndrome developed interstitial and alveolar fibrosis after receiving a 7-day course of azacitidine therapy. The patient's pulmonary function began to deteriorate immediately after the administration of his chemotherapy regimen. Other potential causes of pulmonary toxicity were ruled out such as viral, fungal, and bacterial pathogens, as well as other concomitant drugs. To our knowledge, this is the first case report documenting biopsy-proven interstitial and alveolar fibrosis associated with azacitidine. The frequency of this adverse drug reaction is unknown but may become more evident with increasing exposure of the population to azacitidine.

Aged↗
PubMed2004

Effects of allergen challenge on airway epithelial cell gene expression.

Allergen exposure induces the airway epithelium to produce chemoattractants, proallergic interleukins, matrix-modifying proteins, and proteins that influence the growth and activation state of airway structural cells. These proteins, in turn, contribute to the influx of inflammatory cells and changes in structure that characterize the asthmatic airway. To use the response of the airway epithelium to allergen to identify genes not previously associated with allergic responses, we compared gene expression in cytokeratin-positive cells before and after segmental allergen challenge. After challenge with concentrations of allergen in the clinically relevant range, 755 (6%) of the detectable sequences had geometric mean fold-changes in expression, with 95% confidence intervals that excluded unity. Using a prospectively defined conservative filtering algorithm, we identified 141 sequences as upregulated and eight as downregulated, with confirmation by conventional polymerase chain reaction in all 10 sequences studied. Using this approach, we identified asthma-associated sequences including interleukin (IL-)-3, IL-4, and IL-5 receptor subunits, the p65 component of nuclear factor-kappaB, and lipocortin. The genomic response of the human airway to concentrations of allergen in the clinically relevant range involves a greater number of genes than previously recognized, including many not previously associated with asthma that are differentially expressed after airway allergen exposure.

Algorithms↗
PubMed2004

Effect of reducing interns' weekly work hours on sleep and attentional failures.

BACKGROUND: Knowledge of the physiological effects of extended (24 hours or more) work shifts in postgraduate medical training is limited. We aimed to quantify work hours, sleep, and attentional failures among first-year residents (postgraduate year 1) during a traditional rotation schedule that included extended work shifts and during an intervention schedule that limited scheduled work hours to 16 or fewer consecutive hours. METHODS: Twenty interns were studied during two three-week rotations in intensive care units, each during both the traditional and the intervention schedule. Subjects completed daily sleep logs that were validated with regular weekly episodes (72 to 96 hours) of continuous polysomnography (r=0.94) and work logs that were validated by means of direct observation by study staff (r=0.98). RESULTS: Seventeen of 20 interns worked more than 80 hours per week during the traditional schedule (mean, 84.9; range, 74.2 to 92.1). All interns worked less than 80 hours per week during the intervention schedule (mean, 65.4; range, 57.6 to 76.3). On average, interns worked 19.5 hours per week less (P<0.001), slept 5.8 hours per week more (P<0.001), slept more in the 24 hours preceding each working hour (P<0.001), and had less than half the rate of attentional failures while working during on-call nights (P=0.02) on the intervention schedule as compared with the traditional schedule. CONCLUSIONS: Eliminating interns' extended work shifts in an intensive care unit significantly increased sleep and decreased attentional failures during night work hours.

Adult↗
PubMed2004

Effect of reducing interns' work hours on serious medical errors in intensive care units.

BACKGROUND: Although sleep deprivation has been shown to impair neurobehavioral performance, few studies have measured its effects on medical errors. METHODS: We conducted a prospective, randomized study comparing the rates of serious medical errors made by interns while they were working according to a traditional schedule with extended (24 hours or more) work shifts every other shift (an "every third night" call schedule) and while they were working according to an intervention schedule that eliminated extended work shifts and reduced the number of hours worked per week. Incidents were identified by means of a multidisciplinary, four-pronged approach that included direct, continuous observation. Two physicians who were unaware of the interns' schedule assignments independently rated each incident. RESULTS: During a total of 2203 patient-days involving 634 admissions, interns made 35.9 percent more serious medical errors during the traditional schedule than during the intervention schedule (136.0 vs. 100.1 per 1000 patient-days, P<0.001), including 56.6 percent more nonintercepted serious errors (P<0.001). The total rate of serious errors on the critical care units was 22.0 percent higher during the traditional schedule than during the intervention schedule (193.2 vs. 158.4 per 1000 patient-days, P<0.001). Interns made 20.8 percent more serious medication errors during the traditional schedule than during the intervention schedule (99.7 vs. 82.5 per 1000 patient-days, P=0.03). Interns also made 5.6 times as many serious diagnostic errors during the traditional schedule as during the intervention schedule (18.6 vs. 3.3 per 1000 patient-days, P<0.001). CONCLUSIONS: Interns made substantially more serious medical errors when they worked frequent shifts of 24 hours or more than when they worked shorter shifts. Eliminating extended work shifts and reducing the number of hours interns work per week can reduce serious medical errors in the intensive care unit.

Humans↗
PubMed2004

Role of prostanoid DP receptor variants in susceptibility to asthma.

BACKGROUND: Previous genetic studies have associated the region of the human genome (14q22.1) containing the gene for the prostanoid DP receptor (PTGDR) with asthma. A study of a mouse model suggests that the receptor is required for the expression of the asthma phenotype. Our associations of asthma with functional genetic variants of PTGDR link these observations. METHODS: We identified and evaluated combinations of genetic variants that influence PTGDR transcription for disease association in case-control studies of 518 white patients with asthma and 175 white controls and 80 black patients with asthma and 45 black controls. RESULTS: We identified four novel and two previously reported single-nucleotide polymorphisms (SNPs) in PTGDR and its vicinity. These define four common three-SNP haplotypes, which vary in their ability to support transcription of PTGDR and have distinct DNA-binding-protein affinity profiles. Individual PTGDR SNPs were significantly associated with asthma in both populations. Specific PTGDR haplotypes were significantly associated with a diagnosis of asthma in a large case-control study of whites (P=0.002); we confirmed these findings in a second population of blacks (P=0.01). Multivariate analysis of the haplotype combinations (diplotypes) demonstrated that both whites (odds ratio, 0.55; 95 percent confidence interval, 0.38 to 0.80; P=0.002) and blacks (odds ratio, 0.32; 95 percent confidence interval, 0.12 to 0.89; P=0.03) who had at least one copy of the haplotype with a low transcriptional efficiency had a lower risk of asthma than subjects with no copies of the haplotype. CONCLUSIONS: Our functional and genetic findings identify PTGDR as an asthma-susceptibility gene.

Adult↗
PubMed2004

Mechanotransduction through growth-factor shedding into the extracellular space.

Physical forces elicit biochemical signalling in a diverse array of cells, tissues and organisms, helping to govern fundamental biological processes. Several hypotheses have been advanced that link physical forces to intracellular signalling pathways, but in many cases the molecular mechanisms of mechanotransduction remain elusive. Here we find that compressive stress shrinks the lateral intercellular space surrounding epithelial cells, and triggers cellular signalling via autocrine binding of epidermal growth factor family ligands to the epidermal growth factor receptor. Mathematical analysis predicts that constant rate shedding of autocrine ligands into a collapsing lateral intercellular space leads to increased local ligand concentrations that are sufficient to account for the observed receptor signalling; direct experimental comparison of signalling stimulated by compressive stress versus exogenous soluble ligand supports this prediction. These findings establish a mechanism by which mechanotransduction arises from an autocrine ligand-receptor circuit operating in a dynamically regulated extracellular volume, not requiring induction of force-dependent biochemical processes within the cell or cell membrane.

Animals↗