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PubMed1991

Myectomy reduces ileal motility after ileoanal anastomosis.

The hypothesis tested was that myectomy of the distal ileum would produce a long-lasting decrease in ileal motility, and so render single-lumen ileum more suitable for use as a rectal substitute in the course of restorative proctocolectomy, without the need for a pelvic ileal reservoir. Ileal motility, both spontaneous and in response to intraluminal volatile fatty acids (VFA), was studied after proctocolectomy in 25 female adult beagles, at least 6 months after ileoanal anastomosis alone (IAA, n = 6), IAA with myectomy (n = 8), IAA with myectomy and an ileal valve (n = 5) or IAA with a duplicated (J) ileal reservoir (n = 6). VFA were found to stimulate ileal motility significantly in each group. Myectomy significantly reduced the number of ileal contractions (P less than 0.01), the mean amplitude of contractions (P less than 0.05) and the motility index (P less than 0.01). The addition of the valve to myectomy made no significant difference.

Anal Canal↗
PubMed1986

Thin layer chromatography overlay technique in the analysis of the binding of the solubilized protoxin of Bacillus thuringiensis var. kurstaki to an insect glycosphingolipid of known structure.

The hypothesis tested was that a particular glycoconjugate(s) in the exposed cell-surface membrane of susceptible insect cells acts as a receptor and/or modulator for the specific interaction with the protoxin/activated toxin of the delta-endotoxin of Bacillus thuringiensis var. kurstaki. As candidates, the total neutral and acidic fraction glycolipids, and the isolated neutral glycosphingolipid components, were screened for binding activity by the thin layer chromatogram overlay technique. The main protoxin/activated toxin-binding glycolipid in the neutral fraction (5B) had the structure: Gal(alpha 1-3)GalNAc(beta 1-4)GlcNAc(beta 1-3)Man(beta 1-4)Glc(beta 1-1)Cer. The main protoxin/activated toxin-binding glycolipid in the acidic fraction was designated band 1, the structure of which is at present unknown. The possibility that the component 5B carbohydrate sequence may also function as a toxin-binding site of relevant insect plasma membrane glycoproteins is discussed.

Animals↗
PubMed1997

Reverse remodeling in heart failure with intensification of vasodilator therapy.

BACKGROUND: Heart failure therapy with beta-receptor blockade has been shown to effect a partial reversal of left ventricular (LV) remodeling in heart failure. HYPOTHESIS: We tested the hypothesis that, in the absence of beta blockade, uptitration of angiotensin-converting enzyme (ACE) inhibitor and nitrate therapy over conventional dosages would improve symptoms as well as LV function in patients with severe heart failure. METHODS: For patients with nonischemic or ischemic cardiomyopathy, intensive high-dose angiotensin-converting enzyme inhibitor and nitrate therapy was uptitrated. Echocardiograms were obtained semiannually and evaluated in a blinded fashion. Of 99 patients in the study, aged 55 +/- 13 years, with heart failure for 5.2 +/- 3.1 years, 74 were men, 69 were Caucasian, and 34 had ischemic cardiomyopathy. The final dosage of enalapril was 40 +/- 23 mg/day of isosorbide dinitrate it was 153 +/- 127 mg/day. RESULTS: Initial New York Heart Association classification improved from 2.8 +/- 0.9 to 1.7 +/- 0.9 (p < 0.001) in 2.7 years of follow-up. Of the 99 patients, 72 further improved their ejection fraction. For the whole group, ejection fraction increased from 21 +/- 9% to 30 +/- 13% in 6 months (p < 0.001), with a reduction in LV end-diastolic size from 6.6 +/- 0.9 to 6.3 +/- 1.0 cm (p = 0.002), a decrease in the severity of mitral regurgitation from mild/moderate to only mild. Resting heart rate declined with no change over time in systemic systolic blood pressure. Final ejection fraction for nonischemic patients (n = 65) was 36 +/- 16% versus 23 +/- 9% for the ischemic population. CONCLUSIONS: Uptitration of high-dose ACE inhibitor and nitrate therapy to higher doses is well tolerated in severe heart failure, further improves both clinical status and LV systolic function, and is more effective in nonischemic than in ischemic cardiomyopathy.

Adrenergic beta-Antagonists↗
PubMed2002

Effects of distension of urinary bladder on coronary conduit and resistance vessels in hyperlipidemic patients.

BACKGROUND: Distension of the urinary bladder reflexly causes a change of coronary vasomotor response. The effect of such distension on the coronary circulation in hyperlipidemic patients, a condition with impaired endothelial function, remains unknown. HYPOTHESIS: We tested the hypothesis whether urinary bladder distension caused an exaggerated vasomotor response of epicardial and resistance vasoconstriction in hyperlipidemic patients. METHODS: Thirty patients with early atherosclerosis (< 50% diameter stenosis) were divided into three groups: Group 1 (n = 10): hyperlipidemia without doxazosin administration; Group 2 (n = 10): hyperlipidemia with pretreatment of alpha1-adrenergic receptor blocker (oral doxazosin 2 mg); and Group 3 (n = 10): normolipidemia. A prospective analysis of the results of quantitative angiograms, intracoronary Doppler flow, and lactate concentrations from aortic root and coronary sinus was performed during distension of urinary bladder. RESULTS: Bladder distension significantly decreased coronary diameter at the stenotic segments (p = 0.004), coronary blood flow (p = 0.05), and increased coronary resistance (p = 0.006) compared with baseline values, in Group 1 patients. In Group 2 patients during bladder distension, coronary diameter, coronary blood flow, and coronary resistance showed no significant changes compared with baseline values. There were significant differences of stenotic coronary diameter (p = 0.01) between Groups 1 and 3 during bladder distension despite similar changes in rate-pressure product. No significant differences were noted among the groups in the responses of coronary diameter, coronary blood flow, and coronary resistance after nitroglycerin administration. CONCLUSIONS: The present study showed that urinary bladder distension caused an abnormal vasomotor response of epicardial vasoconstriction and that a concomitant increased coronary resistance involved mechanisms related to alpha1-adrenoceptors. Hyperlipidemia may further impair the response. Pretreated administration of doxazosin had reversed the changes toward baseline. Vasoconstriction during bladder distension can be relieved after nitroglycerin administration, suggesting an unchanged responsiveness of vascular smooth muscle cells to such distension.

Aged↗
PubMed1990

Stylized chromosome images.

Stylized chromosome images 1) serve as a format to test effects of preprocessing algorithms used in automated karyotyping; 2) enhance the ability of humans to perform quantitative analysis of chromosomal aberrations; 3) provide an alternative format for karyotype hard copies produced by automated systems. Stylized chromosomes are two-dimensional computer-generated images based on information extracted from one-dimensional width and density profiles. These profiles correspond to what cytogeneticists observe through the microscope as the shape and banding patterns of stained chromosomes. Stylized presentation sharpens chromosome band boundaries and perimeters, reduces "noise," and enhances gray level variations, which are difficult to distinguish by humans on photographic or computer generated karyotypes. Karyotyping accuracy using stylized images was used to detect difficult areas for automated chromosome identification. Landmark bands sufficient to classify chromosomes were identified; shapes of chromosomes reflected in width profiles were said to aid classification. A two-step automated karyotyping strategy proposed is: 1) classify chromosomes by landmarks, minimum information needed for identification; 2) subsequently employ the full banding pattern with maximum resolution to detect aberrations. Stylized images of abnormal chromosomes have potential for testing hypothesis regarding breakpoints and quantitative analysis, but improvements are needed in homologue normalization and definition of termini of chromosomes.

Algorithms↗
PubMed2001

Presence of proliferating (MiB-1-positive) cells in cervical smears of women infected with HIV is associated with clinical outcome: a study of Brazilian women.

The hypothesis tested was that there is an association between the presence of proliferating (MiB-1-positive) cervical cells and clinical outcome of women infected with human immunodeficiency virus (HIV). Female partners (attending the Gynecology Outpatients Clinic of the University Hospital of Rio Grande, Brazil) of known HIV-positive (HIV+) men were used for this pilot study. Among these women, 25 were also HIV+. Papanicolaou smears of these 25 HIV+ women and of 44 HIV- women were graded as negative, CIN I, CIN II, or CIN III, using neural network screening. MiB-1 grading and HPV identification were also performed. The immune status of patients was determined using the current Centers for Disease Control classification. In agreement with the scientific literature, in these Brazilian women both CIN and HPV were associated with HIV. In the HIV+ women, the immune status tends to correlate with MiB-1 grading. Also, in the one case in whom progression from CIN I to invasive cervical carcinoma was observed, the smear contained many MiB-1-positive cells. Staining cervical smears of HIV+ women is a simple procedure to get an indication of clinical outcome of the patient.

Adult↗
PubMed1994

Comparative mutagenicity of plant-activated aromatic amines using Salmonella strains with different acetyltransferase activities.

Plant systems can activate aromatic amines into mutagens. In the plant cell/microbe coincubation assay, we earlier demonstrated that 2-aminofluorene and m-phenylenediamine were activated by plant cells into mutagens with reversion at the hisD3052 allele in Salmonella typhimurium strain TA98 as the genetic endpoint. New derivatives have been developed which possess elevated levels of acetyl-CoA:N-hydroxyarylamine O-acetyltransferase which are very sensitive to N-hydroxylated amines [Watanabe et al., 1990: Mutat Res 234:337-348]. The objectives of this research were to examine Salmonella strains with different acetyltransferase activities in the plant cell/microbe coincubation assay with a series of structurally related aromatic amines. The hypothesis tested was whether and to what degree a plant-activated metabolite of these aromatic amines could serve as a substrate for bacterial O-acetyltransferase and induce mutation in Salmonella. Every aromatic amine examined was activated by plant cells with YG1024 (the strain with elevated O-acetyltransferase activity) as the genetic indicator organism. The rank order of the mutagenic responses of YG1024 to the plant-activated aromatic amines was 2-aminofluorene > benzidine > m-phenylenediamine > 4-aminobiphenyl > 2,4-diaminotoluene > 2-naphthylamine. This rank order was expressed by TA98 but to a much lower degree. There was a very slight mutagenic response observed in TA98/1,8-DNP6 (a strain lacking O-acetyltransferase activity) with the plant-activated metabolites of benzidine and 4-aminobiphenyl. We conclude that the plant-activated aromatic amines are substrates for bacterial O-acetyltransferases.

2-Naphthylamine↗
PubMed1995

Statistical design and analysis of mutation studies in transgenic mice.

We have been working on identifying sources of variability in data from transgenic mouse mutation assays in order to develop appropriate statistical methods and designs for routine studies. Data from our lab and elsewhere point to the presence of significant animal-to-animal variability, which must be taken into account in statistical hypothesis tests. Here, the usual Cochran-Armitage (CA) test for trend in mutant frequencies, which takes the transgene as the experimental unit, and a generalized Cochran-Armitage test (GCA), which takes the animal as the experimental unit, are contrasted in computer simulations that help to quantify the differences between these statistical tests. The simulations report the statistical power of each test to detect treatment group differences, and their type I error rates. We find in general that the GCA test performs poorly compared to the CA test when it is appropriate to take the transgene as the experimental unit, and the study also uses a small number of animals. However, the CA test performs poorly in small group-size studies when the animal is the appropriate experimental unit. Extensions of the computer simulations allow for identification of cost-effective experimental designs. The results emphasize that the benefits of using additional animals in these mutation studies can be realized without substantial increases in costs. Here we illustrate the methods for liver studies in our lab. These methods can be used to derive optimal experimental designs for any combination of spontaneous mutant frequency and animal-to-animal variability.

Animals↗
PubMed2002

Unified sampling approach for multipoint linkage disequilibrium mapping of qualitative and quantitative traits.

Rapid development in biotechnology has enhanced the opportunity to deal with multipoint gene mapping for complex diseases, and association studies using quantitative traits have recently generated much attention. Unlike the conventional hypothesis-testing approach for fine mapping, we propose a unified multipoint method to localize a gene controlling a quantitative trait. We first calculate the sample size needed to detect linkage and linkage disequilibrium (LD) for a quantitative trait, categorized by decile, under three different modes of inheritance. Our results show that sampling trios of offspring and their parents from either extremely low (EL) or extremely high (EH) probands provides greater statistical power than sampling in the intermediate range. We next propose a unified sampling approach for multipoint LD mapping, where the goal is to estimate the map position (tau) of a trait locus and to calculate a confidence interval along with its sampling uncertainty. Our method builds upon a model for an expected preferential transmission statistic at an arbitrary locus conditional on the sampling scheme, such as sampling from EL and EH probands. This approach is valid regardless of the underlying genetic model. The one major assumption for this model is that no more than one quantitative trait locus (QTL) is linked to the region being mapped. Finally we illustrate the proposed method using family data on total serum IgE levels collected in multiplex asthmatic families from Barbados. An unobserved QTL appears to be located at tau; = 41.93 cM with 95% confidence interval of (40.84, 43.02) through the 20-cM region framed by markers D12S1052 and D12S1064 on chromosome 12. The test statistic shows strong evidence of linkage and LD (chi-square statistic = 18.39 with 2 df, P-value = 0.0001).

Asthma↗
PubMed1992

Numerical comparisons of two formulations of the logistic regressive models with the mixed model in segregation analysis of discrete traits.

Segregation analysis of discrete traits can be conducted by the classical mixed model and the recently introduced regressive models. The mixed model assumes an underlying liability to the disease, to which a major gene, a multifactorial component, and random environment contribute independently. Affected persons have a liability exceeding a threshold. The regressive logistic models assume that the logarithm of the odds of being affected is a linear function of major genotype effects, the phenotypes of older relatives, and other covariates. A formulation of the regressive models, based on an underlying liability model, has been recently proposed. The regression coefficients on antecedents are expressed in terms of the relevant familial correlations and a one-to-one correspondence with the parameters of the mixed model can thus be established. Computer simulations are conducted to evaluate the fit of the two formulations of the regressive models to the mixed model on nuclear families. The two forms of the class D regressive model provide a good fit to a generated mixed model, in terms of both hypothesis testing and parameter estimation. The simpler class A regressive model, which assumes that the outcomes of children depend solely on the outcomes of parents, is not robust against a sib-sib correlation exceeding that specified by the model, emphasizing testing class A against class D. The studies reported here show that if the true state of nature is that described by the mixed model, then a regressive model will do just as well. Moreover, the regressive models, allowing for more patterns of family dependence, provide a flexible framework to understand gene-environment interactions in complex diseases.

Computer Simulation↗
PubMed1999

Oligogenic model selection using the Bayesian Information Criterion: linkage analysis of the P300 Cz event-related brain potential.

The traditional likelihood-based approach to hypothesis testing may not be an optimal strategy for evaluating oligogenic models of inheritance. Under oligogenic inheritance the number of possible multilocus models can become very large; there may be several competing linkage models having similar likelihoods; and comparisons among non-nested models can be required to determine if a given multilocus model provides a significantly better fit to observed phenotypic variation than an alternative model. We propose an efficient Bayesian approach to oligogenic model selection that makes use of existing model likelihoods, and show how model uncertainty can be incorporated into parameter estimation.

Alcoholism↗
PubMed2005

Reduction of selection bias in genomewide studies by resampling.

The accuracy of gene localization, the reliability of locus-specific effect estimates, and the ability to replicate initial claims of linkage and/or association have emerged as major methodological concerns in genomewide studies of complex diseases and quantitative traits. To address the issue of multiple comparisons inherent in genomewide studies, the use of stringent criteria for assessing statistical significance has been generally acknowledged as a strategy to control type I error. However, the application of genomewide significance criteria does not take account of the selection bias introduced into parameter estimates, e.g., estimates of locus-specific effect size of disease/trait loci. Some have argued that reliable locus-specific parameter estimates can only be obtained in an independent sample. In this report, we examine statistical resampling techniques, including cross-validation and the bootstrap, applied to the initial sample to improve the estimation of locus-specific effects. We compare them with the naive method in which all data are used for both hypothesis testing and parameter estimation, as well as with the split-sample approach in which part of the data are reserved for estimation. Upward bias of the naive estimator and inadequacy of the split-sample approach are derived analytically under a simple quantitative trait model. Simulation studies of the resampling methods are performed for both the simple model and a more realistic genomewide linkage analysis. Our results suggest that cross-validation and bootstrap methods can substantially reduce the estimation bias, especially when the effect size is small or there is no genetic effect.

Algorithms↗
PubMed2007

Family-based association analysis with ordered categorical phenotypes, covariates and interactions.

Genetic association analyses of family-based studies with ordered categorical phenotypes are often conducted using methods either for quantitative or for binary traits, which can lead to suboptimal analyses. Here we present an alternative likelihood-based method of analysis for single nucleotide polymorphism (SNP) genotypes and ordered categorical phenotypes in nuclear families of any size. Our approach, which extends our previous work for binary phenotypes, permits straightforward inclusion of covariate, gene-gene and gene-covariate interaction terms in the likelihood, incorporates a simple model for ascertainment and allows for family-specific effects in the hypothesis test. Additionally, our method produces interpretable parameter estimates and valid confidence intervals. We assess the proposed method using simulated data, and apply it to a polymorphism in the c-reactive protein (CRP) gene typed in families collected to investigate human systemic lupus erythematosus. By including sex interactions in the analysis, we show that the polymorphism is associated with anti-nuclear autoantibody (ANA) production in females, while there appears to be no effect in males.

Autoantibodies↗
PubMed2003

Robust Bayesian estimation of the hemodynamic response function in event-related BOLD fMRI using basic physiological information.

In BOLD fMRI data analysis, robust and accurate estimation of the Hemodynamic Response Function (HRF) is still under investigation. Parametric methods assume the shape of the HRF to be known and constant throughout the brain, whereas non-parametric methods mostly rely on artificially increasing the signal-to-noise ratio. We extend and develop a previously proposed method that makes use of basic yet relevant temporal information about the underlying physiological process of the brain BOLD response in order to infer the HRF in a Bayesian framework. A general hypothesis test is also proposed, allowing to take advantage of the knowledge gained regarding the HRF to perform activation detection. The performances of the method are then evaluated by simulation. Great improvement is shown compared to the Maximum-Likelihood estimate in terms of estimation error, variance, and bias. Robustness of the estimators with regard to the actual noise structure or level, as well as the stimulus sequence, is also proven. Lastly, fMRI data with an event-related paradigm are analyzed. As suspected, the regions selected from highly discriminating activation maps resulting from the method exhibit a certain inter-regional homogeneity in term of HRF shape, as well as noticeable inter-regional differences.

Adult↗
PubMed2001

The death of cost-minimization analysis?

Four different types of evaluation methods, cost-benefit analysis (CBA), cost-utility analysis (CUA), cost-effectiveness analysis (CEA) and cost-minimization analysis (CMA), are usually distinguished. In this note, we pronounce the (near) death of CMA by showing the rare circumstances under which CMA is an appropriate method of analysis. We argue that it is inappropriate for separate and sequential hypothesis tests on differences in effects and costs to determine whether incremental cost-effectiveness (or cost-utility) should be estimated. We further argue that the analytic focus should be on the estimation of the joint density of cost and effect differences, the quantification of uncertainty surrounding the incremental cost-effectiveness ratio and the presentation of such data as cost-effectiveness acceptability curves. Two examples from recently published CEA are employed to illustrate the issues. The first shows a situation where analysts might be tempted (inappropriately) to employ CMA rather than CEA. The second illustrates one of the rare circumstances in which CMA may be justified as a legitimate form of analysis.

Anticoagulants↗
PubMedDate not supplied

Intravenous fluid administration and urine output during radical neck surgery.

This study examines perioperative urine output (UO) and hemodynamics in 24 patients who underwent radical head and neck surgery. The hypothesis tested was that "UO was not important in patients with normal renal function as long as hemodynamics were maintained." Intraoperatively, a "wet" group (13 patients) had generous amounts of intravenous (IV) fluid administered during surgery receiving 1,018 +/- 58 mL.h-1. The other "dry" group (11 patients) had fluids restricted to 426 +/- 23 mL.h-1. The intraoperative UOs for the wet and dry groups were 1.33 +/- 0.27 and 0.39 +/- 0.10 mL.kg-1 x h-1, respectively (p < 0.05). Postoperatively, the UOs for the wet and dry groups were 1.9 +/- 0.3 and 1.1 +/- 0.1 mL.kg-1 x h-1, respectively (p < 0.05). Perioperatively, there were no statistically significant differences between groups in systemic or pulmonary hemodynamics. Postoperatively, ordinary indices of renal function remained normal in both groups. We conclude that intraoperative oliguria due to moderate fluid restriction is not detrimental to renal outcome as long as systemic hemodynamics are maintained. Furthermore, not only does this relatively "dry" status not compromise hemodynamics, it affords the patient other benefits.

Fluid Therapy↗
PubMed1997

Chronic alcohol intoxication induces hepatic injury through enhanced macrophage inflammatory protein-2 production and intercellular adhesion molecule-1 expression in the liver.

This study tested the hypothesis that prolonged consumption of alcohol directly or indirectly, through endotoxin influx in the circulation, stimulates the Kupffer cells to produce macrophage inflammatory protein-2 (MIP2) and up-regulates the expression of adhesion molecules, i.e., CD18 on PMNs and its counter-receptor, intercellular adhesion molecule-1 (ICAM-1), on hepatic cells. As a result, enhanced sequestration and cell-cell interaction among these cell types may occur in the liver, which in turn could result in altered hepatic function and hepatotoxicity. This hypothesis was tested in alcohol-fed, specific pathogen-free, male Sprague-Dawley rats. After 16 weeks of feeding, endotoxin (0.2 +/- 0.043 EU/mL) and MIP2 (625 +/- 100 pg/mL) were detected in the sera of alcoholic rats but not in the pair-fed rats. Concomitantly, serum aspartate transaminase (AST) activity was significantly increased. Small lipid deposition and inflammatory-like changes in the liver were also observed. Isolated Kupffer cells from alcohol-fed rats released large amount of MIP2 (> 600 pg/10(6) Kupffer cells/24 hr) in vitro compared with Kupffer cells from pair-fed rats (< 150 pg/10(6) Kupffer cells/24 hr). At the same time, the expression of CD18 and ICAM-1 on polymorphonuclear neutrophils (PMNs) and hepatic cells was increased more than twofold. Monoclonal antibody 1F12, an anti-CD18 antibody, attenuated hepatic injury in vivo, and in PMN-hepatocyte coculture in vitro in the alcohol-fed group. Another factor that could contribute to hepatic injury was MIP2, which was cytotoxic to alcoholic hepatocytes in vitro. This was reversed by cycloheximide, thus suggesting the indirect hepatotoxic effect of MIP2. In addition, isolated PMNs and Kupffer cells from alcohol-fed rats released large amounts of superoxide, which may also play a role in hepatic injury. These results demonstrate that MIP2 and adhesion molecules may contribute, at least in part, in the initiation of hepatic injury during alcohol intoxication.

Alcohol Drinking↗
PubMed2003

Childhood cancer in relation to infections in the community during pregnancy and around the time of birth.

In a retrospective cohort study of 404,106 live births in the northern region of England, 1975-1986, we investigated whether higher levels of community infections during the mother's pregnancy and in early life were risk factors for cancer, by diagnostic group (leukaemia and non-Hodgkin's lymphoma, Hodgkin's disease, brain/spinal tumours, neuroblastoma, other tumours), diagnosed 1975-2001 under age 15 years. Logistic regression was used to relate risk to measures of community infections (measles, respiratory and other infections) in 3 prenatal and 2 postnatal quarters. There was an increased risk of Hodgkin's disease among children exposed around birth to higher levels of measles (odds ratio for trend = 2.3, 95% confidence interval 1.3-4.2, p = 0.01). For other diagnostic groups, there was no consistent evidence of an association between risk and exposure to infections. Although the significant association observed for Hodgkin's disease may be a chance finding, consequent to multiple hypothesis testing or the ecologic nature of the study, it is consistent with other recent epidemiologic results suggesting that the risk of Hodgkin's disease may be associated with exposure to infections.

Adolescent↗