Testing the Statistical Certainty of a Response to Increasing Doses of a Drug

Tukey, John W.; Ciminera, Joseph L.; Heyse, Joseph F.

doi:10.2307/2530666

Cited by 475 publications

(221 citation statements)

References 5 publications

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“…Differences between patients with and without MTS were evaluated using Student's t tests, while the correlation between histological characteristics and DTI parameters were evaluated with one-tailed Pearson's correlation coefficient (r) including all TLE patients, regardless of the presence of MTS. We performed correction for multiple comparisons for the correlations between histological parameters and FA measurements (our main outcome measure) using the Tukey-Ciminera-Heyse procedure (a variant of the Bonferroni correction) (Tukey et al, 1985;Sankoh et al, 1997). Likewise, correction for multiple comparisons was performed separately for correlations between quantitative histology and MD, parallel and perpendicular diffusivities (i.e., 24 tests), and between-group differences (i.e., 8 tests).…”

Section: Methodsmentioning

confidence: 99%

In VivoDiffusion Tensor Imaging and Histopathology of the Fimbria-Fornix in Temporal Lobe Epilepsy

Concha¹,

Livy²,

Beaulieu³

et al. 2010

J. Neurosci.

201

165

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While diffusion tensor imaging (DTI) has been extensively used to infer micro-structural characteristics of cerebral white matter in human conditions, correlations between human in vivo DTI and histology have not been performed. Temporal lobe epilepsy (TLE) patients with mesial temporal sclerosis (MTS) have abnormal DTI parameters of the fimbria-fornix (relative to TLE patients without MTS) which are presumed to represent differences in axonal/myelin integrity. Medically intractable TLE patients who undergo temporal lobe resection including the fimbria-fornix provide a unique opportunity to study the anatomical correlates of water diffusion abnormalities in freshly excised tissue. Eleven patients with medically intractable TLE were recruited (six with and five without MTS) for presurgical DTI followed by surgical excision of a small specimen of the fimbria-fornix which was processed for electron microscopy. Blinded quantitative analysis of the microphotographs included axonal diameter, density and area, cumulative axon membrane circumference, and myelin thickness and area. As predicted by DTI the fimbria-fornix of TLE patients with MTS had increased extra-axonal fraction, and reduced cumulative axonal membrane circumference and myelin area. Consistent with the animal literature, water diffusion anisotropy over the crus of the fimbria-fornix was strongly correlated with axonal membranes (cumulative membrane circumference) within the surgical specimen (ϳ15% of what was analyzed with DTI). The demonstration of a correlation between histology and human in vivo DTI, in combination with the observation that in vivo DTI accurately predicted white matter abnormalities in a human disease condition, provides strong validation of the application of DTI as a noninvasive marker of white matter pathology.

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Section: Methodsmentioning

confidence: 99%

In VivoDiffusion Tensor Imaging and Histopathology of the Fimbria-Fornix in Temporal Lobe Epilepsy

Concha¹,

Livy²,

Beaulieu³

et al. 2010

J. Neurosci.

201

165

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“…To identify the lowest effective dose, a step-down dose-finding procedure based on linear contrast was employed. 25,26 For BMI, leptin, Beck Depression Inventory, carbohydrate craving, QoL, and waist-to-hip circumference, we used analysis of covariance (ANCOVA) with baseline measurement as a covariate and treatment group and center as factors and a baseline measurement by treatment group interaction term included in the model. For these variables, missing data were not imputed.…”

Section: Statisticsmentioning

confidence: 99%

A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion

et al. 2005

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Objective: To compare changes in weight in obese patients who received long-acting octreotide (octreotide LAR) at one of three dose levels (20, 40, or 60 mg) or placebo over 6 months and to identify the lowest dose of octreotide LAR that safely achieved optimal weight loss. Design: Randomized, double-blind, placebo-controlled trial of octreotide LAR at three dose levels. Patients: A total of 172 adults (28 men and 144 women) with at least moderate obesity (body mass index (BMI) range 30-65 kg/m 2 ) and evidence of insulin hypersecretion were enrolled. Patients were predominantly either Caucasian (50.0%) or African American (45.3%). The mean age (38711 year), weight (110.7723 kg), and BMI (39.876.5 kg/m 2 ) were similar across the four treatment groups. Measurements: Efficacy measures included weight, BMI, fasting serum glucose; triglycerides; percentage of total body fat and abdominal fat as measured by dual-energy X-ray absorptiometry; skin fold thickness; waist-to-hip circumference; leptin; percentage of carbohydrates, fat, and protein ingested; nutritional evaluation (including dietary analysis -3-day food record); quality of life (QoL; using the Impact of Weight on Quality of Life-Litet); Beck Depression Inventory; and Carbohydrate Craving Questionnaire. Safety measures included medical history, vital signs, physical examinations, hematology, blood chemistries, thyroid function tests, hemoglobin A1c, gallbladder ultrasound, electrocardiograms, and adverse events. Results: After 6 months of treatment, patients receiving 40 or 60 mg of octreotide LAR experienced statistically significant weight loss compared to baseline, with mean differences from placebo in percent weight change of À1.98 and À1.87%, respectively. This finding was accompanied by statistically significant mean decreases in BMI compared to baseline, that is, a mean decrease of 0.73 and 0.79 kg/m 2 for the 40 and 60 mg treatment arms, respectively. The observed weight loss was progressive during the 6-month treatment in the two higher dose groups. The lowest dose to reach statistical significance in weight loss after 6 months' treatment was 40 mg. Post hoc analysis revealed a 3.5-3.8% weight loss at month 6 in the two higher dose groups among Caucasian patients having insulin secretion greater than the median of the cohort, defined as CIR gp (corrected insulin response at the glucose peak) X1.43. There were no statistically significant changes in QoL scores, body fat, leptin concentration, Beck Depression Inventory, or macronutrient intake. Mean changes of blood glucose AUC 0-180 min during an oral glucose tolerance test in patients taking octreotide LAR were 39-40 mg/dl h higher than those on placebo. A total of 7-21% of the patients taking octreotide LAR reached a 5% or greater decrease in body weight from Baseline, compared to 11% for the placebo group. This was not statistically significant. The most common adverse events included diarrhea, headache, cholelithiasis, nausea, and abdominal pain. Conclusion: Octreotide LAR given at 40 or 60 mg r...

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“…of three separate experiments. For each experiment, the data were subjected to one-way analysis of variance followed by the means multiple comparison method of Tukey (24). p Ͻ 0.05 was considered as the level of statistical significance.…”

Section: P-labeled P47mentioning

confidence: 99%

Nonstructural 3 Protein of Hepatitis C Virus Triggers an Oxidative Burst in Human Monocytes via Activation of NADPH Oxidase

Bureau

Bernad

Chaouche

et al. 2001

Journal of Biological Chemistry

147

121

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It has been shown that oxidative stress occurs in chronic hepatitis C. Release of reactive oxygen species (ROS) from sequestered phagocytes and activated resident macrophages represents the predominant component of oxidative stress in the liver. However, little is known about the ability of the monocyte to produce ROS in response to protein of hepatitis C virus. In this study, we investigated the ROS production in human monocytes stimulated by several viral proteins of hepatitis C virus. Human monocytes from healthy blood donors were incubated with recombinant viral protein: Core, NS3, NS4, and NS5. ROS production was measured by chemiluminescence. Only NS3 triggered ROS production in human monocytes. Generated ROS were mainly the anion superoxide. NS3 also induced a rapid and transient increase in intracellular calcium concentration measured by a video digital microscopy technique. By using different metabolic inhibitors, we showed that ROS production requires calcium influx, tyrosine kinases, and the stress-activated protein kinase, p38. The study of p47 PHOX phosphorylation and translocation showed that NADPH oxidase was activated and involved in ROS production induced by NS3. In a second experiment, NS3 inhibited the oxidative burst induced by phorbol 12-myristate 13-acetate. These results indicate that NS3 activates NADPH oxidase and modulates ROS production, which may be involved in the natural history of hepatitis C infection.

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Testing the Statistical Certainty of a Response to Increasing Doses of a Drug

Cited by 475 publications

References 5 publications

In VivoDiffusion Tensor Imaging and Histopathology of the Fimbria-Fornix in Temporal Lobe Epilepsy

In VivoDiffusion Tensor Imaging and Histopathology of the Fimbria-Fornix in Temporal Lobe Epilepsy

A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion

Nonstructural 3 Protein of Hepatitis C Virus Triggers an Oxidative Burst in Human Monocytes via Activation of NADPH Oxidase

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