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PubMed1995

Fasting insulin concentration is related to cardiovascular reactivity to exercise in children.

OBJECTIVE: One mechanism through which hyperinsulinemia is linked to hypertension is through its stimulation of sympathetic nervous activity. Thus, insulin concentration may be correlated with indices of sympathetic activity before it is associated with resting blood pressure. We tested this hypothesis by determining the relationship of insulin concentration and sympathetically mediated cardiovascular reactivity to exercise in children. DESIGN: Survey. SETTING: General community. PARTICIPANTS: Volunteer sample of 46 black and white boys and girls, 9 to 11 years of age. INTERVENTIONS: None. Fasting insulin concentration was the main independent variable. MAIN OUTCOME MEASURES: Systolic blood pressure and heart rate during a standard submaximal bout of treadmill exercise, and systolic blood pressure at peak effort. RESULTS: The hypothesis was tested by multiple regression analyses controlled for resting values. Insulin contributed significantly to the regression models for submaximal heart rate (P < .001), submaximal systolic blood pressure (P = .001), and peak systolic blood pressure (P = .006). CONCLUSIONS: Fasting insulin concentration is associated with cardiovascular reactivity to exercise in young children. This supports the hypothesis that the relationship between hyperinsulinemia and hypertension is mediated by sympathetic nervous tone and that the process begins in childhood. Because percent body fat was positively associated with both insulin and cardiovascular reactivity to exercise, prevention of childhood obesity may be a valuable prophylactic measure for these health problems.

Analysis of Variance↗
PubMed2000

Intra- and extracellular dehydration has no effect on plasma levels of angiotensin II in an amphibian.

Previous studies have demonstrated that both dehydration (intra and extracellular) and treatment with angiotensin II (A-II) induce changes in thirst-related behavior in the spadefoot toad, Scaphiopus couchii. One of the steps in determining a causal relationship between a hormone and a behavior is to determine that there is association between an animal's performance of the behavior and changes in endogenous hormonal concentrations. The hypothesis tested that plasma levels of the peptide hormone A-II would change as a result of dehydration known to induce water absorption response (WR) behavior in the spadefoot toad. Plasma samples were taken from toads dehydrated intracellularly by injection of hypertonic solutions of NaCl or sucrose at levels known to induce WR behavior. As an osmotic control, a group of animals was injected with urea, which has been demonstrated to not induce WR behavior. In order to determine the effects of extracellular dehydration on plasma, A-II levels in toads dehydrated by plasma volume depletion via cardiac puncture were compared to sham-punctured controls. None of the treatments in any experiment resulted in significant differences in plasma levels of angiotensin II among groups sampled at the time when WR behavior occurs. These results do not support the hypothesis that dehydration-induced thirst is stimulated by changes in plasma A-II concentrations at the onset of WR behavior. J. Exp. Zool. 286:343-349, 2000.

Angiotensin II↗
PubMed1998

Effect of a re-wetting agent on the performance of acetone-based dentin adhesives.

PURPOSE: To compare the in vitro bond strengths of two acetone-based one-bottle dentin adhesives applied to four surface moisture conditions. The tested hypothesis was that wetting a dried dentin surface with an aqueous HEMA solution would result in bond strengths similar or higher than those obtained by leaving the surface moist as per manufacturers' instructions. MATERIALS AND METHODS: Eighty flat dentin bonding sites were polished to 600-grit on middle dentin of the labial surface of bovine incisors mounted in acrylic resin. The specimens were equally and randomly divided between two acetone-based dentin adhesives (One-Step and Prime & Bond 2.1) and four different levels of surface moisture (moist dentin, dentin dried for 1 s, dentin dried for 5 s, and dentin dried for 5 s followed by re-wetting with Aqua-Prep, an aqueous HEMA solution). A composite post was then adapted to the treated area and light-cured. After thermocycling, the bond strengths were determined by testing the specimens in shear. Field Emission SEM examinations were carried out to evaluate the effects of different treatments on the dentin-resin interface. RESULTS: Statistical analysis revealed that the application of One-Step resulted in similar mean shear bond strengths for the groups in which moisture was present on the dentin surface (12.0-14.2 MPa). The mean shear bond strengths for the group in which One-Step was applied to a dried dentin surface was significantly lower (6.0 MPa). For Prime & Bond 2.1, the application of a re-wetting solution significantly increased mean shear bond strengths (13.9 MPa). The remaining three Prime & Bond 2.1 groups yielded statistically similar mean bond strengths, regardless of the surface condition (6.6-8.1 MPa).

Acetone↗
PubMed1999

Impact of nicotine on bone healing.

A limited number of experimental animal studies and in vitro data confirm that nicotine impairs bone healing, diminishes osteoblast function, causes autogenous bone graft morbidity, and decreases graft biomechanical properties. Therefore, our long-term goal is to develop an effective therapy to reverse the adverse impact of nicotine from tobacco products. However, before accomplishing this goal, we had to develop an animal model. Our hypotheses were nicotine administration preceding and following autogenous bone grafting adversely affected autograft incorporation and depressed donor site healing in a characterized animal wound model. Hypothesis testing was accomplished in bilateral, 4-mm diameter parietal bone defects prepared in 60 Long-Evans rats (male, 35-day-old). A 4-mm diameter disk of donor bone was removed from the left parietal bone and placed in the contralateral defect. The donor site served as a spontaneously healing bone wound. The rats were partitioned equally among three doses of nicotine administered orally in the drinking water (12.5, 25, and 50 mg/L). For each dose, the duration and sequence of nicotine treatment followed four courses, including no nicotine and designated combinations of nicotine administration and abatement prior to and following osseous surgery. Experimental sites were recovered on 14 and 28 days postsurgery, responses quantitated, and data analyzed by analysis of variance and post hoc statistics (p < or = 0.05). We developed a convenient and effective osseous model, and the results validated our hypothesis that nicotine negatively impacts on bone healing.

Animals↗
PubMed1999

False positive rates of randomized phase II designs.

The randomized Phase II design for the purpose of selecting a treatment for eventual Phase III testing has recently gained popularity in cancer clinical research. Unfortunately, along with its wider use also come frequent misapplications. The major misuse of the design is the treatment of the Phase II results as ends in themselves without further, definitive evaluation. For binary and censored exponential survival data, we quantify the chance of observing "impressive" between-group differences when underlying distributions are exactly the same in 2-, 3-, and 4-arm selection designs. Depending on one's view of what is impressive, the "false-positive" rates range from 20% to over 40%. We stress that randomized Phase II results are pilots to Phase III evaluations. One should not regard them as conclusive. We caution especially against the inclusion of control arms in such designs because of the propensity for erroneous inferences. We also discuss the inappropriate practice of performing post-hoc hypothesis testing and presenting p-values that are less than 0.05.

Clinical Trials, Phase II as Topic↗
PubMed2004

Analyzing time-to-event data in a clinical trial when an unknown proportion of subjects has experienced the event at entry.

In some clinical trials, where the outcome is the time until development of a silent event, an unknown proportion of subjects who have already experienced the event will be unknowingly enrolled due to the imperfect nature of the diagnostic tests used to screen potential subjects. For example, commonly used diagnostic tests for evaluating HIV infection status in infants, such as DNA PCR and HIV Culture, have low sensitivity when given soon after infection. This can lead to the inclusion of an unknown proportion of HIV-infected infants into clinical trials aimed at the prevention of transmission from HIV-positive mothers to their infants through breastfeeding. The infection status of infants at the end of the trial, when they are more than a year of age, can be determined with certainty. For those infants found to be infected with HIV at the end of the trial, it cannot be determined whether this occurred during the study or whether they were already infected when they were enrolled. In these settings, estimates of the cumulative risk of the event by the end of the study will overestimate the true probability of event during the study period and hypothesis tests comparing two or more intervention strategies can also be biased. We present inference methods for the distribution of time until the event of interest in these settings, and investigate issues in the design of such trials when there is a choice of using both imperfect and perfect diagnostic tests.

Biometry↗
PubMed1999

Effect of energy restriction on the expression of cyclin D1 and p27 during premalignant and malignant stages of chemically induced mammary carcinogenesis.

The restriction of energy intake has a profound inhibitory effect on carcinogenesis, yet the mechanism or mechanisms that account for this effect are unknown. In this experiment, the hypothesis tested was that energy restriction upregulates the expression of p27/kip1, a gene product associated with cell-cycle growth arrest, while downregulating cyclin D1, a protein that combines with cyclin-dependent kinases to promote phosphorylation of retinoblastoma protein and the progression of cells through the cell cycle. We studied levels of these proteins in uninvolved mammary epithelial cells and in mammary intraductal proliferations, ductal carcinomas in situ, and adenocarcinomas induced in response to administration of 1-methyl-1-nitrosourea in animals fed either ad libitum or 90%, 80%, or 60% of ad libitum intake. Protein levels were evaluated immunohistochemically by using computer-assisted image analysis to quantify differences in protein expression among treatment groups. The expression of p27 increased and the expression of cyclin D1 decreased dose-dependently in response to energy restriction. The effect was greater on p27 than on cyclin D1. The hypothesis proposed is that energy restriction inhibits carcinogenesis by arresting cell-cycle progression by regulating p27/kip1.

Adenocarcinoma↗
PubMed2006

Use of the pupal survey technique for measuring Aedes aegypti (Diptera: Culicidae) productivity in Puerto Rico.

The hypothesis tested was that most pupae of Aedes aegypti are produced in a few types of containers so that vector control efforts could concentrate on eliminating the most productive ones and thus prevent dengue outbreaks. Pupal surveys were conducted twice in 2004 in an urban area in southern Puerto Rico. A total 35,030 immature mosquitoes (III and IV instars, pupae) was counted in 1,367 containers found with water in 624 premises during the first survey. Only pupae were counted in the second survey in 829 premises, 257 of which had containers with water, and 124 contained Ae. aegypti pupae (15%, 22% in the first survey). We found fewer (583) containers with water than in the first survey, but 202 had pupae (35%; 18.5% in first survey). Containers yielded 3,189 Ae. aegypti pupae, which was slightly fewer than those found in the first survey (3,388 pupae). The hypothesis was supported by the data, showing that 7 of 18 types of containers contained 80% of all female pupae. The most productive containers generally were also common. We used several criteria (i.e., container use, two-step cluster analysis based on environmental variables of containers and premises) to classify the containers and premises and to evaluate pupal distribution at various spatial scales (container, premise, and residences versus public areas). Most pupae were in 4 of 10 types of container usage categories. The cluster technique showed that most pupae were in unattended, rain-filled containers in the yards, particularly in receptacles in the shade of trees that received rainfall through foliage and had lower water temperatures. Pupal counts were adjusted to a negative binomial distribution, confirming their highly aggregated dispersal pattern. Cluster analysis showed that 61.3% of female pupae were in 40 (6.4%) of 624 premises that had in common their larger yards, number of trees, and container water volume. Using number of Ae. aegypti larvae, Breteau Index, or the presence of immature forms as indicators of pupal productivity is not as efficient in identifying the most productive types of containers as direct pupal counts.

Aedes↗
PubMed2005

Oral dosage form performance tests: new dissolution approaches.

The performance test is one of a series of tests that compose the specification in a United States Pharmacopeia (USP) dosage form monograph. For an orally administered, nonsolution dosage form, it is usually satisfied by either a dissolution or disintegration procedure. Dissolution acceptance criteria are usually set in private negotiations between an applicant and a regulatory agency. With information about this private agreement and other information provided in a sponsor's Request for Revision to USP, the USP's Council of Experts elaborates a public dosage form monograph. Based on the relationship between the regulatory decisions and the Request for Revision, the USP dissolution procedure links to a regulatory judgment about bioavailability and bioequivalence and, ultimately, to a judgment about safety and efficacy. The current dissolution procedure and acceptance criteria are perceived as having worked well over the years and are generally accepted. This article discusses new approaches that merit consideration. These approaches focus on a) explicit use of hypothesis testing, b) use of parametric tolerance intervals, c) improved ways to set dissolution acceptance criteria, and d) a more flexible protocol to assess conformity. Application of the proposed approaches may better assess, manage, and communicate both manufacturer and consumer risk for dissolution testing.

Administration, Oral↗
PubMed2004

Testing the phylogenetic position of a parasitic plant (Cuscuta, Convolvulaceae, asteridae): Bayesian inference and the parametric bootstrap on data drawn from three genomes.

Previous findings on structural rearrangements in the chloroplast genome of Cuscuta (dodder), the only parasitic genus in the morning-glory family, Convolvulaceae, were attributed to its parasitic life style, but without proper comparison to related nonparasitic members of the family. Before molecular evolutionary questions regarding genome evolution can be answered, the phylogenetic problems within the family need to be resolved. However, the phylogenetic position of parasitic angiosperms and their precise relationship to nonparasitic relatives are difficult to infer. Problems are encountered with both morphological and molecular evidence. Molecular data have been used in numerous studies to elucidate relationships of parasitic taxa, despite accelerated rates of sequence evolution. To address the question of the position of the genus Cuscuta within Convolvulaceae, we generated a new molecular data set consisting of mitochondrial (atpA) and nuclear (RPB2) genes, and analyzed these data together with an existing chloroplast data matrix (rbcL, atpB, trnL-F, and psbE-J), to which an additional chloroplast gene (rpl2) was added. This data set was analyzed with an array of phylogenetic methods, including Bayesian analysis, maximum likelihood, and maximum parsimony. Further exploration of data was done by using methods of phylogeny hypothesis testing. At least two nonparasitic lineages are shown to diverge within the Convolvulaceae before Cuscuta. However, the exact sister group of Cuscuta could not be ascertained, even though many alternatives were rejected with confidence. Caution is therefore warranted when interpreting the causes of molecular evolution in Cuscuta. Detailed comparisons with nonparasitic Convolvulaceae are necessary before firm conclusions can be reached regarding the effects of the parasitic mode of life on patterns of molecular evolution in Cuscuta.

Base Sequence↗
PubMed1997

Acoustic cavitation nuclei survive the apparent ultrasonic destruction of Albunex microspheres.

The hypothesis tested was that gas bodies capable of nucleating violent cavitation activity in vitro would survive the rapid disruption of Albunex microspheres by 1-MHz ultrasound. Human erythrocyte hemolysis was used as a proxy measure of cavitation. Fluid (5% human serum albumin [HSA]) with or without Albunex (ALX) was exposed or sham-exposed to 1-MHz ultrasound (P+ = 1.25 +/- 0.01 MPa, P- = 0.81 +/- 0.01 MPa; ISPTP approximately 35 W/cm2) for 60 s using 10-microseconds pulses and a duty factor of 0.5. An equal volume of whole human blood was then added to the fluid, followed by a second 60-s treatment. Insonation of cell suspensions prepared in previously sham-exposed HSA + ALX fluid produced about 4% hemolysis, a level significantly greater than in the controls. Insonation of cell suspensions prepared in previously insonated HSA + ALX fluid produced about 0.4% hemolysis; this also differed significantly from the controls. The data thus support the hypothesis.

Albumins↗
PubMed1995

Long-term effects of brief antihypertensive treatment on systolic blood pressure and vascular reactivity in young genetically hypertensive rats.

Recent studies have shown that angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR) reduces blood pressure into adulthood. This study explored changes in vascular reactivity in adult normotensive (WKY) rats and stroke-prone SHR (SHRSP) receiving the following treatments at 6-10 weeks of age: (a) ACE inhibitor (ramipril); (b) hydralazine/hydrochlorothiazide (hydral/HCTZ); or (c) no treatment. The hypothesis tested was that vascular changes and blood pressure would be reduced in adult SHRSP treated with ramipril during development. At 17 weeks of age, rats were anesthetized and vascular tissue was excised. Isolated experiments in the aorta included characterization of initial phasic and tonic contractions to 0.1 microM angiotensin II (AII). A phenylephrine (PE) concentration-response curve was performed on carotid arteries, and threshold values were determined. All WKY groups showed lower systolic blood pressure (131 +/- 4 mmHg) and reduced phasic AII induced contraction (7.4 +/- 4.7%) compared with SHRSP (217 +/- 4 mmHg; 37.2 +/- 4%). Antihypertensive treatment reduced blood pressure (ramipril: 168 +/- 2; hydral/HCTZ: 198 +/- 6 mmHg) but not phasic AII responses in adult SHRSP; adult WKY rats were unaffected by treatment. Threshold values for PE in carotid arteries were lower in SHRSP than in WKY, indicating increased sensitivity. However, SHRSP treated with ramipril did not demonstrate increased sensitivity to PE. These data support the hypothesis that blood pressure and sensitivity to PE but not contractile responsiveness to AII in adult SHRSP are determined by an AII-sensitive mechanism during development.

Aging↗
PubMed1998

Hyposexuality produced by temporal lobe epilepsy in the cat.

PURPOSE: The hypothesis tested in this study was that a unilateral irritative focal epileptic lesion in the temporal lobe results in hyposexuality. METHODS: Focal epilepsy was produced in male cats by unilateral injection of aluminum hydroxide into either the basolateral amygdala (temporal lobe group) or anterior sigmoid gyrus (motor cortex group). Weekly sex testing trials with estrous females were conducted prior to and after aluminum hydroxide injection, and mating performance scores were compared with those of normal, unoperated cats (normal control group). RESULTS: All animals receiving aluminum hydroxide developed electroencephalographic and behavioral manifestations of epilepsy; i.e., interictal EEG spiking and partial or generalized seizures. Cats in the temporal lobe group exhibited a dramatic and complete suppression of sexual behavior at periods from 6 to 26 weeks after aluminum hydroxide injection. The duration of the hyposexuality varied between individual animals and returned to normal as suddenly as the onset occurred, despite the use of AEDs to prevent or control generalized seizure activity. Interictal EEG epileptiform spiking in the amygdala preceded the onset of hyposexuality by 1-12 weeks. By contrast, cats in the motor cortex and normal control groups showed no sign of sexual dysfunction throughout the experimental period, independent of seizure activity and/or antiepileptic drug (AED) treatment. CONCLUSIONS: These data support the hypothesis that hyposexuality occurs as a result of epileptiform activity in the temporal lobe, but not in the motor cortex. The precise mechanisms by which this occurs are unknown, but are likely to involve abnormally high-frequency neuronal activity in temporal lobe structures known to connect with and/or to regulate hypothalamic nuclei that organize male sexual behavior toward receptive females.

Aluminum Hydroxide↗
PubMed2002

Response-surface modeling of the effect of 5alpha-dihydrotestosterone and androgen receptor levels on the response to the androgen antagonist vinclozolin.

Androgens secreted by the testes bind the androgen receptor in developing target tissues to induce the expression of genes required for male sexual differentiation and development. Androgen concentration and androgen receptor levels vary in male reproductive target tissues during development. Exposure to environmental androgen antagonists during critical windows of fetal and postnatal development can inhibit male sexual development by blocking transcription of androgen-dependent genes. As the sensitivity to androgen antagonists under conditions of varying androgen concentrations and varying androgen receptor levels is unknown, we used a luciferase reporter assay to investigate the transcriptional effects of a known androgen antagonist (the vinclozolin metabolite M2) at different androgen concentrations and different androgen receptor levels. The ability of M2 to inhibit transcription was greater at lower concentrations of androgen (5alpha-dihydrotestosterone) and androgen receptor. The data were modeled to determine the dose-response surface of M2 and androgen receptor concentrations at different 5alpha-dihydrotestosterone levels and the relationship of the 3 components to the response. The model and hypothesis testing results suggest that, at 0.01 and 0.1 nM 5alpha-dihydrotestosterone concentrations within the expected in vivo range of free androgen levels during development, the response-surface shapes were similar and the interaction of the androgen receptor and M2 concentrations to the response were similarly antagonistic. Thus, two components of the developmental stage, androgen and androgen receptor concentrations, are critical for sensitivity to the inhibitory effects of an androgen antagonist.

Algorithms↗
PubMed1999

Effect of a longitudinal course on student performance in clerkships.

OBJECTIVE: To determine the effect that a 3-year primary-care course experience with family medicine, internal medicine, or pediatric preceptors would have on clerkship performance in pediatrics and internal medicine. DESIGN: In 1 academic year, third-year students were divided retrospectively into 3 groups based on preceptor type in the primary care course. An analysis of variance was conducted. When the analysis of variance showed statistical significance, a multiple-comparison t test was performed. SETTING: University medical school with a longitudinal preceptor experience. PARTICIPANTS: One hundred nine third-year medical students who participated in the primary care course and completed the pediatric and internal medicine clerkships. Fifty-six students took part in the self-assessment portion of the study. MAIN OUTCOME MEASURES: Student performance scores in the pediatric clerkship and internal medicine clerkship were analyzed for significant differences based on preceptor type. Student self-assessment on pediatric objectives was analyzed for significant differences based on preceptor experience. RESULTS: Students with pediatric preceptors received higher clinical scores in the pediatric clerkship (P = .04) and perceived themselves as more advanced on 18 of the 39 pediatric curriculum pretest self-assessment items. Students with pediatric or internal medicine preceptors received significantly higher scores on the written patient medical history and physical examinations (P = .02). There were no significant differences on the pediatric written examination. There were no significant performance differences in the internal medicine clerkship. All hypothesis testing was conducted at the 95% confidence level. CONCLUSION: Experiences with pediatric preceptors in the early years of medical school may improve a student's performance and confidence in the pediatric clerkship.

Analysis of Variance↗
PubMed2005

At first sight: how do restrained eaters evaluate high-fat palatable foods?

Two experiments tested the hypothesis that restrained eaters display a greater liking for high-fat palatable foods, than do unrestrained eaters. This hypothesis was tested in the affective priming paradigm and in the extrinsic affective Simon task . Both paradigms were successful in uncovering food likes and dislikes, and both showed that participants were able to evaluate the palatability of foods relatively automatically. However, contrary to the hypothesis, food likes were not substantially affected by fat content, nor were they affected by restraint-status. Restrained and unrestrained eaters may like high-fat palatable foods to the same extent, but may differ in their craving for these foods.

Adult↗
PubMed2006

Prior cocaine exposure disrupts extinction of fear conditioning.

Psychostimulant exposure has been shown to cause molecular and cellular changes in prefrontal cortex. It has been hypothesized that these drug-induced changes might affect the operation of prefrontal-limbic circuits, disrupting their normal role in controlling behavior and thereby leading to compulsive drug-seeking. To test this hypothesis, we tested cocaine-treated rats in a fear conditioning, inflation, and extinction task, known to depend on medial prefrontal cortex and amygdala. Cocaine-treated rats conditioned and inflated similar to saline controls but displayed slower extinction learning. These results support the hypothesis that control processes in the medial prefrontal cortex are impaired by cocaine exposure.

Animals↗
PubMed2006

Power to detect clinically relevant carry-over in a series of cross-over studies.

The potential for carry-over effects is an important consideration in the design of any cross-over study, and can cause an investigator to abandon the design altogether. In cross-over studies, carry-over is the lingering effect of a treatment into the subsequent period. Carry-over effects are differences in the extent of the carry-over between the treatments under consideration. It is well known that the test for carry-over effects in individual studies has low power. Empirical evidence of carry-over effects, or the absence of carry-over effects, could be useful for investigators considering the design. Here we develop methods for expressing the power to detect carry-over as a function of the power to detect a clinically relevant treatment effect. Our results suggest that for two-treatment, two-period cross-over studies the power to detect clinically relevant carry-over effects is often less than 15 per cent, and the number of studies needed to differentiate this effect from the type I error rate of 10 per cent is prohibitive. For the three-treatment three-period cross-over design, the power to detect carry-over effects was larger than for the two-period study, but still approached the type I error rate in a number of cases. Unequivocal conclusions about the absence of carry-over effects based on collections of hypothesis tests appear unlikely. Similar findings are presented for bioequivalence studies. For bioequivalence studies, small carry-over effects (e.g. 12.5 per cent of the treatment effect) can seriously inflate the type I error rate, particularly when the power to detect equivalence is high.

Cross-Over Studies↗