The SERPINE2 gene is associated with chronic obstructive pulmonary disease.
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Amyloid beta-Protein Precursor↗
Biomedical subjects
Stephen Lake
Publications and source records attributed to Stephen Lake.
Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma.
BACKGROUND: Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lung development and asthma pathogenesis. METHODS: We genotyped six single nucleotide polymorphisms (SNPs) in the STAT3 gene in a cohort of 401 Caucasian adult asthmatics. The associations between each SNP and forced expiratory volume in 1 second (FEV1), as a percent of predicted, at the baseline exam were tested using multiple linear regression models. Longitudinal analyses involving repeated measures of FEV1 were conducted with mixed linear models. Haplotype analyses were conducted using imputed haplotypes. We completed a second association study by genotyping the same six polymorphisms in a cohort of 652 Caucasian children with asthma. RESULTS: We found that three polymorphisms were significantly associated with baseline FEV1: homozygotes for the minor alleles of each polymorphism had lower FEV1 than homozygotes for the major alleles. Moreover, these associations persisted when we performed an analysis on repeated measures of FEV1 over 8 weeks. A haplotypic analysis based on the six polymorphisms indicated that two haplotypes were associated with baseline FEV1. Among the childhood asthmatics, one polymorphism was associated with both baseline FEV1 and the repeated measures of FEV1 over 4 years. CONCLUSION: Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV1 in both adults and children with asthma, and suggest that STAT3 may participate in inflammatory pathways that have an impact on level of lung function.
Adult↗
Association of defensin beta-1 gene polymorphisms with asthma.
BACKGROUND: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. OBJECTIVE: We characterized the genetic diversity in the defensin beta-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. METHODS: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. RESULTS: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5' genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma ( P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion ( P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted ( P = .04) and was more prominent in female subjects ( P = .007). CONCLUSION: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.
Asthma↗
Using the modified Schirmer test to measure mouth dryness: a preliminary study.
BACKGROUND: Current methods of measuring saliva volume often are difficult to perform in a general dental or medical office setting. This study seeks to determine whether the Schirmer test for measuring eye dryness can be modified to measure mouth dryness. METHODS: The authors performed a modified Schirmer test (MST) on a control group composed of 41 healthy adult volunteers and a study group composed of 10 patients who had received head and neck radiation and 10 patients who had oral chronic graft-versus-host disease (CGVHD). The authors placed the strip on the floor of each subject's mouth and took readings at one minute, two minutes and three minutes. Fourteen control subjects also spat into a container over a five-minute interval, and the authors weighed the collected saliva. RESULTS: The mean reading for the control subjects at three minutes was 29.5 millimeters, while the mean reading for the test subjects was 6.9 mm (P < .00005). CONCLUSIONS: The results of the MST were able to distinguish between healthy adult volunteers and subjects who experienced profound xerostomia and hyposalivation. CLINICAL IMPLICATIONS: The MST as used in this preliminary study is an objective, inexpensive, easy-to-perform and well-tolerated test for measuring mouth dryness. It readily distinguishes between patients who are healthy and asymptomatic and those who experienced profound xerostomia and hyposalivation.
Adult↗
Association of the DTNBP1 locus with schizophrenia in a U.S. population.
Linkage and association studies have recently implicated dystrobrevin-binding protein 1 (DTNBP1) in the etiology of schizophrenia. We analyzed seven previously tested DTNBP1 single-nucleotide polymorphisms (SNPs) in a cohort of 524 individuals with schizophrenia or schizoaffective disorder and 573 control subjects. The minor alleles of three SNPs (P1578, P1763, and P1765) were positively associated with the diagnosis of schizophrenia or schizoaffective disorder in the white subset of the study cohort (258 cases, 467 controls), with P1578 showing the most significant association (odds ratio 1.76, P =.0026). The same three SNPs were also associated in a smaller Hispanic subset (51 cases, 32 controls). No association was observed in the African American subset (215 cases, 74 controls). A stratified analysis of the white and Hispanic subsets showed association with the minor alleles of four SNPs (P1578, P1763, P1320, and P1765). Again, the most significant association was observed for P1578 (P =.0006). Haplotype analysis supported these findings, with a single risk haplotype significantly overrepresented in the white sample (P =.005). Our study provides further evidence for a role of the DTNBP1 gene in the genetic etiology of schizophrenia.
Black or African American↗
Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids.
Corticosteroids mediate a variety of immunological actions and are commonly utilized in the treatment of a wide range of diseases. Unfortunately, therapy with this class of medications is associated with a large proportion of non-responders and significant side effects. Inhaled corticosteroids are the most commonly used asthma controller therapy. However, asthmatic response to corticosteroids also varies widely between individuals. We investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma. The association of longitudinal change in lung function and single nucleotide polymorphisms from candidate genes crucial to the biologic actions of corticosteroids were evaluated in three independent asthmatic clinical trial populations utilizing inhaled corticosteroids as the primary therapy in at least one treatment arm. Variation in one gene, corticotropin-releasing hormone receptor 1 (CRHR1) was consistently associated with enhanced response to therapy in each of our three populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with lack of the variants (P-values ranging from 0.006 to 0.025 for our three asthmatic populations). As the primary receptor mediating the release of adrenocorticotropic hormone, which regulates endogenous cortisol levels, CRHR1 plays a pivotal, pleiotropic role in steroid biology. These data indicate that genetic variants in CRHR1 have pharmacogenetic effects influencing asthmatic response to corticosteroids, provide a rationale for predicting therapeutic response in asthma and other corticosteroid-treated diseases, and suggests this gene pathway as a potential novel therapeutic target.
Administration, Inhalation↗
Two macroscopic and microscopic brain imaging studies of human hippocampus in early Alzheimer's disease and schizophrenia research.
Among the many diseases that affect the hippocampus, a small yet highly important brain region responsible for memory and identity, Alzheimer's disease and schizophrenia are among the most devastating. We describe a two-stage, region-of-interest based linear mixed model approach to the analysis of a longitudinal functional magnetic resonance (FMRI) study of human memory function under several drug challenges. We then describe a Monte Carlo approach to testing members of nested hierarchies of linear models in a stereological study of different types and locations of human hippocampal neurons. Last, we attempt to draw the attention of the biostatistical community interested in imaging neuroscience to the intriguing complexities of human hippocampal research in early Alzheimer's disease, schizophrenia and other brain diseases via brain imaging methods.
Alzheimer Disease↗
IL10 gene polymorphisms are associated with asthma phenotypes in children.
IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3' UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3' UTR SNP was significantly associated with FEV(1) as a percent of predicted (FEV(1)PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV(1)PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC(20) and FEV(1)PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.
3' Untranslated Regions↗
Accumulation of porcine insulin in the rat brain and cerebrospinal fluid following ocular application.
We previously reported that insulin accumulated in the retina and optic nerve following ocular application. Since the optic nerve is surrounded by meninges and cerebrospinal fluid (CSF) and since it extends back to the thalamus, we examined whether the topical application of insulin eye drops also resulted in the accumulation of insulin in the CSF and brain. The data presented in this paper show that this is in fact the case. Following the ocular application of a 0.75% solution of porcine insulin, significant concentrations of insulin were demonstrable in the CSF extracted from the cisterna magnum, as well as in three brain regions. While it is not yet clear how insulin got into these target tissues, our data argue against a mechanism involving uptake from the blood (a fraction of topically applied compounds normally enters the vasculature through the conjunctiva and nasal mucosa). It is theorized that insulin may enter the CSF surrounding the optic nerve and by so doing, not only disseminate throughout the CSF space but also throughout the brain. The implications of these findings for central nervous system drug delivery are discussed.
Absorption↗
Insulin and tropicamide accumulate in the contralateral, untreated eye of rats following ipsilateral topical administration by a mechanism that does not involve systemic uptake.
BACKGROUND: This study was designed to determine: (1) whether the accumulation of insulin in the contralateral retina and aqueous humor following ipsilateral topical insulin administration was due to systemic uptake and (2) whether tropicamide, applied to one eye, could induce dilation in the contralateral eye by a mechanism that did not involve systemic uptake. METHODS: Insulin eye drops were applied to the left eye of intact and decapitated rats, and their retinas and aqueous humors were then removed and their insulin levels quantified. In a separate experiment live animals received 0.1% tropicamide in their left eye and had their pupillary dilation response in both eyes measured at different time points. RESULTS: Administration of insulin to the left eye of decapitated rats resulted in its significant accumulation not only in the left retina and aqueous humor, but also in the retina and aqueous humor of the right eye. Similar aqueous humor results were obtained when live animals were used. Tropicamide drops induced marked pupillary dilation in treated eyes; the pupils of the contralateral, untreated eyes also dilated significantly, but less than did the treated pupils. The pupils of rats injected with tropicamide intravenously showed negligible dilation. CONCLUSIONS: These results showed that insulin accumulated in the retina and aqueous humor of contralateral, untreated eyes following topical application, by a mechanism that did not appear to involve systemic uptake. Similarly, tropicamide provoked a dilation response in the unheated eye by a mechanism that similarly did not appear to involve uptake from the blood.
Absorption↗
Sample size re-estimation in cluster randomization trials.
Cluster randomization trials in which families are the unit of allocation are commonly adopted for the evaluation of disease prevention interventions. Sample size estimation for cluster randomization trials depends on parameters that quantify the variability within and between clusters and the variability in cluster size. Accurate advance estimates of these nuisance parameters may be difficult to obtain and misspecification may lead to an underpowered study. Since families are typically recruited over time, we propose using a portion of the data to estimate the nuisance parameters and to re-estimate sample size based on the estimates. This extends the standard internal pilot study methods to the setting of cluster randomization trials. The effect of this design on the power, significance level and sample size is analysed via simulation and is shown to provide a flexible and practical approach to cluster randomization trials.
Cluster Analysis↗
Accumulation of topically applied porcine insulin in the retina and optic nerve in normal and diabetic rats.
PURPOSE: To explore the pharmacokinetics of topical insulin administration in relation to retinal and optic nerve retention. METHODS: Insulin eye drops (approximately 15 microL: 0.75% porcine insulin + 0.5% permeation enhancer) were applied to the eyes of normal and diabetic rats. The rats were killed at various intervals up to 16 hours, and the retinas and optic nerves from both eyes were analyzed for the presence of insulin in an ELISA. The extent to which systemically absorbed insulin accounted for the findings of insulin in the retina was explored by examining the effects of intravenously injected insulin on retinal insulin levels and by examining the effects of eye drop administration in decapitated rats. RESULTS: Insulin levels rose significantly and peaked in the retina of normal rats 20 minutes after eye drop application (0.7 pg/microg; P < 0.00001). Levels in diabetic retinas peaked at 60 minutes (0.66 pg/microg; P < 0.004) and remained elevated for a longer period than in normal rats. The contralateral retina showed delayed accumulation of lesser amounts of insulin in both normal and diabetic rats. Significant elevations also occurred in the optic nerves in normal and diabetic rats, with concentrations reaching 13 pg/microg in normal rats at 20 minutes and 26 pg/microg in diabetic rats at 5 hours. Topical insulin application resulted in a decrease in serum glucose concomitant with an increase in serum porcine insulin. It did not appear, however, that the systemic absorption of insulin contributed to the accumulation of insulin in the ipsilateral retinas, for two reasons: The intravenous injection of a high concentration of insulin did not appreciably influence retinal insulin levels, and the application of insulin eye drops to decapitated rats still resulted in the accumulation of insulin in the retina. CONCLUSIONS: These results led to the conclusion that topically applied insulin accumulates in the retina and optic nerve in normal and diabetic rats, with levels remaining elevated longer in diabetic animals. It did not appear that systemically absorbed insulin, resulting from ocular drainage, contributed to this effect.
Absorption↗
Functional MRI detection of pharmacologically induced memory impairment.
To examine alterations in brain activation associated with pharmacologically induced memory impairment, we used functional MRI (fMRI) to study the effects of lorazepam and scopolamine on a face-name associative encoding paradigm. Ten healthy young subjects were scanned on four occasions, 2 weeks apart; they were administered i.v. saline during two placebo-scanning sessions and then alternately administered i.v. lorazepam (1 mg) or scopolamine (0.4 mg) in a double-blind, randomized, cross-over design. Both the extent and magnitude of activation within anatomic regions of interest (ROIs) were examined to determine the reproducibility of activation in the placebo sessions and the regional specificity of the pharmacologic effects. Activation within all ROIs was consistent across the two placebo scans during the encoding of novel face-name pairs (compared with visual fixation). With the administration of either lorazepam or scopolamine, significant decreases were observed in both the extent and magnitude of activation within the hippocampal, fusiform, and inferior prefrontal ROIs, but no significant alterations in activation in the striate cortex were found. Both medications impaired performance on postscan memory measures, and significant correlations between memory performance and extent of activation were found in hippocampal and fusiform ROIs. These findings suggest that pharmacologic effects can be detected with fMRI by using a reproducible experimental paradigm and that medications that impair memory also diminish activation in specific brain regions thought to subserve complex memory processes.
Adult↗
The north american control animal database: a resource based on standardized nomenclature and diagnostic criteria.
Historical control data have been shown to be valuable in the interpretation and evaluation of results from rodent carcinogenicity studies. Standardization of terminology and histopathology procedures is a prerequisite for meaningful comparison of control data across studies and analysis of potential carcinogenic effects. Standardization is particularly critical for the construction of a database that includes incidence data from different studies evaluated by pathologists in different laboratories. Standardized nomenclature and diagnostic criteria have been established for neoplasms and proliferative lesions. Efforts of the National Toxicology Program, the Society of Toxicologic Pathology (STP), and the Registry of Industrial Toxicology Animal-data (RITA) have led to a harmonized pathology nomenclature for the rat and the mouse. This nomenclature with detailed descriptions of lesions is available in publications by the STP and International Agency for Research on Cancer (IARC). A listing of these terms is available on the World Wide Web. Utilizing the model established by RITA and working with the International Life Sciences Institute (ILSI), companies with laboratories in North America formed a working group in 1994 to establish and maintain a database of neoplastic and proliferative lesions from control animals in carcinogenicity studies. The rationale for development of the North American Control Animal Database (NACAD), the factors that influence tumor incidence, operation of the database, and the benefits to be realized by using a standardized approach are discussed.
Animals↗