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Regulation of perfusive O2 transport during exercise in humans: effects of changes in haemoglobin concentration.

1. Recently it was suggested that submaximal cardiac output (Q) could vary in response to changes in arterial O2 concentration (Ca,O2), so that arterial O2 delivery (Qa,O2 = Q x Ca,O2, in ml min-1) is kept constant. 2. This hypothesis was tested on eight healthy male subjects, at rest and during exercise (50, 100 and 150 W) in three conditions: normaemia (N), after 6 weeks of endurance training (T), and 2 days after subsequent autologous blood reinfusion (P). 3. Measured variables were oxygen consumption (VO2), by open circuit method, Q, by a CO2 rebreathing method, and haemoglobin concentration ([Hb]), by a photometric method. Ca,O2 was calculated as the product of [Hb], arterial O2 saturation (0.97), and the O2 binding coefficient. 4. [Hb] and thus Ca,O2 increased by 2.6% (T vs. N) and subsequently by further 5.8% (P vs. T). VO2 and Qa,O2 were linear functions of power (w), both relationships being unaffected by changes in Ca,O2. As a consequence, the linear Q vs. VO2 relationships were shifted downward as Ca,O2 increased. 5. The VO2 vs. w and the Qa,O2 vs. w relationships had the same slope. Therefore, the difference between Qa,O2 (w) and VO2 (w), equal to O2 flow in mixed venous blood (Qv,O2), was constant. 6. In conclusion, the tested hypothesis was supported by the present results. The observed constancy of Qv,O2 suggested that Qv,O2 may play a key role in regulating the cardiovascular response to exercise.

Adult↗

Bile salt hydrolase activity and resistance to toxicity of conjugated bile salts are unrelated properties in lactobacilli.

Bacteria of numerous species isolated from the human gastrointestinal tract express bile salt hydrolase (BSH) activity. How this activity contributes to functions of the microorganisms in the gastrointestinal tract is not known. We tested the hypothesis that a BSH protects the cells that produce it from the toxicity of conjugated bile salts. Forty-nine strains of numerous Lactobacillus spp. were assayed to determine their capacities to express BSH activities (taurodeoxycholic acid [TDCA] hydrolase and taurocholic acid [TCA] hydrolase activities) and their capacities to resist the toxicity of a conjugated bile acid (TDCA). Thirty of these strains had been isolated from the human intestine, 15 had been recovered from dairy products, and 4 had originated from other sources. Twenty-six of the strains expressed both TDCA hydrolase and TCA hydrolase activities. One strain that expressed TDCA hydrolase activity did not express TCA hydrolase activity. Conversely, in one strain for which the assay for TDCA hydrolase activity gave a negative result there was evidence of TCA hydrolase activity. Twenty-five of the strains were found to resist the toxicity of TDCA. Fourteen of these strains were of human origin, nine were from dairy products, and two were from other sources. Of the 26 strains expressing both TDCA hydrolase and TCA hydrolase activities, 15 were resistant to TDCA toxicity, 6 were susceptible, and 5 gave inconclusive results. Of the 17 strains that gave negative results for either of the enzymes, 7 were resistant to the toxicity, 9 were susceptible, and 1 gave inconclusive results. These findings do not support the hypothesis tested. They suggest, however, that BSH activity is important at some level for lactobacillus colonization of the human intestine.

Amidohydrolases↗

Chronic mevastatin modulates receptor-dependent vascular contraction in eNOS-deficient mice.

We tested the hypothesis that endothelial nitric oxide (NO) synthase (eNOS)-derived NO modulates rho-kinase-mediated vascular contraction. Because 3-hydroxy-3-methylglutaryl (HMG)-CoA-reductase inhibition can both upregulate eNOS expression and inhibit rhoA/rho-kinase function, a second hypothesis tested was that statin treatment modulates rho-kinase-mediated contraction and that this can occur independently of eNOS. Contractile responses to the receptor-dependent agonists serotonin and phenylephrine but not to the receptor-independent agent KCl were greater in aortic rings from eNOS-null (eNOS(-/-)) vs. wild-type (eNOS(+/+)) mice. Similarly enhanced responses were seen in eNOS(+/+) rings after acute NOS inhibition. The rho-kinase inhibitor Y-27632 abolished or profoundly attenuated responses to receptor agonists in both eNOS(+/+) and eNOS(-/-) rings, but responses in eNOS(+/+) were more sensitive to Y-27632. Mevastatin treatment (20 mg/kg sc per day, 14 days) reduced responses to serotonin and phenylephrine in female mice of both strains. KCl-induced contractions were slightly smaller in eNOS(+/+)-derived aortic rings only. Levels of plasma cholesterol, and aortic expression of rhoA and rho-kinase, did not differ between groups. Thus eNOS-derived NO suppresses rhoA/rho-kinase-mediated vascular contraction. Moreover, a similar suppressive effect on rho-kinase-mediated vasoconstriction by statin therapy occurs independently of effects on eNOS or plasma cholesterol.

Amides↗

Pattern of caries experience in permanent molars in a 15-year-old African population.

Some epidemiologic studies from Africa report higher DMF values in second than in first molars. It is generally accepted that the maturation of dental enamel influences the susceptibility of teeth to caries. The purpose of the present study was to test the hypothesis that DMF values of second molars will be higher than those of first molars if the first molars have reached a high degree of maturation before being exposed to increased cariogenic challenge. The study was carried out in a group of 15-year-old students attending secondary schools in Botswana (n = 287). The results showed that in children who assumingly had had a traditional diet during childhood the DMF values were higher in second molars than in first molars. In children who grew up in a more urbanized setting, the results were opposite. The observed differences were due to differences in caries experience in first molars only. The DMF values of second molars did not vary among the groups. Oral hygiene, sugar consumption and knowledge level at age 15 seemed to have no effect upon the caries pattern studied. It is concluded that the results support the hypothesis tested.

Adolescent↗

Gap junction uncoupler heptanol prevents cell-to-cell progression of hypercontracture and limits necrosis during myocardial reperfusion.

BACKGROUND: The objective of this study was to test the hypothesis that chemical interaction through gap junctions may result in cell-to-cell progression of hypercontracture and that this phenomenon contributes to the final extent of reperfused infarcts. METHODS AND RESULTS: Cell-to-cell transmission of hypercontracture was studied in pairs of freshly isolated adult rat cardiomyocytes. Hypercontracture induced by microinjection of a solution containing 1 mmol/L Ca2+ and 2% lucifer yellow (LY) was transmitted to the adjacent cell (11 of 11 pairs), and the gap junction uncoupler heptanol (2 mmol/L) prevented transmission in 6 of 8 pairs (P=.003), with a perfect association between passage of the LY and transmission of hypercontracture. In the isolated, perfused rat heart submitted to 30 minutes of hypoxia, addition of heptanol to the perfusion media during the first 15 minutes of reoxygenation had a dose-related protective effect against the oxygen paradox, as demonstrated by a reduction of diastolic pressure and marked recovery of developed pressure (P<.001), as well as less lactate dehydrogenase release during reoxygenation (P<.001) and less contraction band necrosis (P<.001) than controls. In the in situ pig heart submitted to 48 minutes of coronary occlusion, the intracoronary infusion of heptanol during the first 15 minutes of reperfusion at a final concentration of 1 mmol/L limited myocardial shrinkage, reflecting hypercontracture (P<.05), reduced infarct size after 5 hours of reperfusion by 54% (P=.04), and modified infarct geometry with a characteristic fragmentation of the area of necrosis. Heptanol at 1 mmol/L had no significant effect on contractility of nonischemic myocardium. CONCLUSIONS: These results demonstrate that hypercontracture may be transmitted to adjacent myocytes through gap junctions and that heptanol may interfere with this transmission and reduce the final extent of myocardial necrosis during reoxygenation or reperfusion. These findings are consistent with the hypothesis tested and open a new approach to limitation of infarct size by pharmacological control of gap junction conductance.

Animals↗

Occlusal force and condylar motion in patients with anterior open bite.

Patients with open bite often show a weak occlusal force and temporomandibular disorders (TMDs). If these are the main cause of open bite, it may be hypothesized that both pre-pubertal and adult open-bite patients would show a weak occlusal force and abnormal condylar motion. The purpose of this study was to test this hypothesis. Test group subjects consisted of 13 consecutive pre-pubertal and 13 adult patients with anterior open bite. They were compared with age-matched normal subjects. The adult open-bite group showed a weaker occlusal force and a shorter range of condylar motion compared with the control subjects. In the pre-pubertal subjects, however, there were no significant differences in the occlusal force and range of condylar motion between the open-bite and control groups. Therefore, these results suggest that a weak occlusal force or TMDs may not be the main cause of open bite.

Adolescent↗

Developmental and hormonal regulation of transforming growth factor-beta1 (TGFbeta1), -2, and -3 gene expression in isolated prostatic epithelial and stromal cells: epidermal growth factor and TGFbeta interactions.

Growth factors are postulated to mediate stromal-epithelial interactions in the prostate to maintain normal tissue physiology. Transforming growth factor-beta (TGFbeta) has been shown to influence the prostate and probably mediate stromal-epithelial interactions. TGFbeta1 messenger RNA (mRNA) expression is stimulated after castration and can be suppressed by in vivo treatment with androgens. The hypothesis tested is that TGFbeta is regulated not only by androgen, but also by a network of locally produced growth factors that influence prostatic growth and differentiation. Epithelial and stromal cells from 20-day-old rat ventral prostate were isolated and used to test this hypothesis. The expression of mRNA for TGFbeta1, -2, and -3 was analyzed by a quantitative RT-PCR procedure. Observations from this assay demonstrate that both epithelial and stromal cells express the mRNA for TGFbeta1, -2, and -3. TGFbeta1 mRNA expression was constant during development of the prostate. TGFbeta2 mRNA expression was elevated at birth, then declined and elevated again at 100 days of age. TGFbeta3 mRNA expression was high during puberty and young adult ages then declined at 100 days of age. TGFbeta2 and TGFbeta3 expression are inversely related during prostate development. After castration of 60-day-old rats, both TGFbeta1 and TGFbeta2 mRNA were enhanced. Interestingly, TGFbeta3 mRNA was significantly suppressed after castration. Epidermal growth factor (EGF) stimulated TGFbeta1 mRNA expression in stromal cells (6-fold increase), whereas keratinocyte growth factor stimulated TGFbeta2 mRNA in epithelial cells. TGFbeta inhibited both testosterone- and EGF-stimulated prostatic stromal and epithelial cell growth. EGF and TGFbeta also inhibited prostatic ductal morphogenesis and growth in organ culture. Immunocytochemical localization of TGFbeta in 20-day-old prostate demonstrated predominately stromal localization of the protein. These results indicate that the isoforms of TGFbeta2 and TGFbeta3 are differentially regulated during prostate development, suggesting distinct regulatory mechanisms. Testosterone did not affect TGFbeta expression in cultured prostatic cells. These observations suggest that the in vivo effects of castration on TGFbetas are regulated indirectly through a complex network of growth factors, not simply by direct androgen depletion. The ability of EGF to inhibit prostatic ductal morphogenesis and growth in organ culture is postulated to be in part mediated by the increase in TGFbeta1 expression. In summary, a network of growth factor-mediated stromal-epithelial interactions is needed to maintain prostate growth and development. TGFbeta is postulated to have an important role in this process.

Animals↗

Some results on extensions and modifications of the Theil-Sen regression estimator.

Many robust regression estimators have been proposed that have a high, finite-sample breakdown point, roughly meaning that a large proportion of points must be altered to drive the value of an estimator to infinity. But despite this, many of them can be inordinately influenced by two properly placed outliers. With one predictor, an estimator that appears to correct this problem to a fair degree, and simultaneously maintain good efficiency when standard assumptions are met, consists of checking for outliers using a projection-type method, removing any that are found, and applying the Theil-Sen estimator to the data that remain. When dealing with multiple predictors, there are two generalizations of the Theil-Sen estimator that might be used, but nothing is known about how their small-sample properties compare. Also, there are no results on testing the hypothesis of zero slopes, and there is no information about the effect on efficiency when outliers are removed. In terms of hypothesis testing, using the more obvious percentile bootstrap method in conjunction with a slight modification of Mahalanobis distance was found to avoid Type I error probabilities above the nominal level, but in some situations the actual Type I error probabilities can be substantially smaller than intended when the sample size is small. An alternative method is found to be more satisfactory.

Humans↗

Clinical versus statistical significance as they relate to the efficacy of periodontal therapy.

BACKGROUND: The author discusses the shortcomings of using statistical significance testing as a method to infer that results of periodontal clinical trials are clinically meaningful. To compensate for these deficiencies, he also identifies criteria and periodontal parameters that can be used to reflect clinically significant outcomes. TYPES OF STUDIES REVIEWED: The author searched the medical and dental literature to identify commentaries that addressed the problems associated with interpreting statistical significance testing, or hypothesis testing, and defining clinical significance. RESULTS: The limitations of statistical significance testing related to identifying clinically significant changes include failure to indicate if the detected differences between variables in test and control groups are large or important. After reviewing various definitions of the term "clinical significance," the author reviews and proposes a comprehensive working definition of it. Regarding the efficacy of periodontal therapy, he delineates the advantages and limitations of specific criteria (such as absolute values, cut points) that can be used to define clinical significance. CLINICAL IMPLICATIONS: The author suggests that clinically significant results should be defined before initiating a study and statistical significance testing should be used to validate that findings did not occur by chance. This would help place the importance of clinical data into perspective, and it would enhance clinicians' ability to select the most appropriate therapies for particular sites in periodontal patients.

Clinical Trials as Topic↗

Power-frequency electromagnetic fields and the capacitative calcium entry system in SV40-transformed Swiss 3T3 cells.

The present study was designed to test the hypothesis that a 60 Hz electromagnetic field could affect the influx of calcium ions across the plasma membrane through the so-called capacitative calcium entry system. Recordings of cytosolic calcium-ion concentrations in SV40-transformed Swiss 3T3 cells were obtained in real time during exposure to magnetic fields ranging from 0.3-50 mT or to sham conditions using the calcium-sensitive photoprotein aequorin. This was done for cell populations whose capacitative entry system was activated by either bradykinin or thapsigargin under a variety of experimental conditions. No effects of the magnetic field were observed on bradykinin-induced calcium transients and, with the exception of a small but statistically significant increase observed in experiments performed at 50 mT, no effects of the fields were observed on baseline calcium levels prior to or after such transients. The magnetic fields also had no effects on the size or kinetics of any of the thapsigargin-induced calcium transients. Overall, the data fail to support the hypothesis tested in this work.

3T3 Cells↗

Empirical bayes estimation of a sparse vector of gene expression changes.

Gene microarray technology is often used to compare the expression of thousand of genes in two different cell lines. Typically, one does not expect measurable changes in transcription amounts for a large number of genes; furthermore, the noise level of array experiments is rather high in relation to the available number of replicates. For the purpose of statistical analysis, inference on the "population'' difference in expression for genes across the two cell lines is often cast in the framework of hypothesis testing, with the null hypothesis being no change in expression. Given that thousands of genes are investigated at the same time, this requires some multiple comparison correction procedure to be in place. We argue that hypothesis testing, with its emphasis on type I error and family analogues, may not address the exploratory nature of most microarray experiments. We instead propose viewing the problem as one of estimation of a vector known to have a large number of zero components. In a Bayesian framework, we describe the prior knowledge on expression changes using mixture priors that incorporate a mass at zero, and we choose a loss function that favors the selection of sparse solutions. We consider two different models applicable to the microarray problem, depending on the nature of replicates available, and show how to explore the posterior distributions of the parameters using MCMC. Simulations show an interesting connection between this Bayesian estimation framework and false discovery rate (FDR) control. Finally, two empirical examples illustrate the practical advantages of this Bayesian estimation paradigm.

Journal Article↗

Replication of "speech fluency fluctuations during the menstrual cycle".

This study tested the hypothesis suggested by our earlier research that the principal effect of heightened anxiety on speech fluency is an interference with language formulation. 20 women read contexual material aloud at ovulation (when the typical woman experiences her greatest feelings of well-being) and at premenstrution (when she experiences a significant increase in anxiety level). They were no less fluent at premenstruation than at ovulation. These data are consistent with the hypothesis tested.

Adult↗

Evidence for a procedural-learning-based system in perceptual category learning.

The consistency of the mapping from category to response location was investigated to test the hypothesis that abstract category labels are learned by the hypothesis testing system to solve rule-based tasks, whereas response position is learned by the procedural-learning system to solve information-integration tasks. Accuracy rates were examined to isolate global performance deficits, and model-based analyses were performed to identify the types of response strategies used by observers. A-B training (consistent mapping) led to more accurate responding relative to yes-no training (variable mapping) in the information-integration category learning task. Model-based analyses indicated that the yes-no accuracy decline was due to an increase in the use of rule-based strategies to solve the information-integration task. Yes-no training had no effect on the accuracy of responding or distribution of best-fitting models relative to A-B training in the rule-based category learning tasks. These results both provide support for a multiple-systems approach to category learning in which one system is procedural-learning-based and argue against the validity of single-system approaches.

Humans↗

Neutralization of maternal IL-4 modulates congenital protozoal transmission: comparison of innate versus acquired immune responses.

IL-4 levels were modulated in mice to test the hypothesis that induction of a maternal type 1 response would decrease the frequency of congenital Neospora caninum transmission. This hypothesis tested the relationship between IL-4 and both innate and adaptive immunity utilizing two basic experimental designs. In the first, maternal IL-4 was neutralized with mAb during pregnancy in naive mice concomitant with initial, virulent infection. In the second, maternal IL-4 was neutralized before pregnancy concomitant with a priming inoculation consisting of live, avirulent N. caninum tachyzoites followed by virulent challenge during subsequent gestation. In mice that were naive before pregnancy, neutralization of IL-4 during gestational challenge did not result in decreased congenital transmission as measured by PCR performed on 1-day-old neonatal mice. In mice that were primed and modulated before pregnancy, congenital transmission from gestational challenge was significantly decreased compared with control mice. Reduction in transmission constituted a decrease in the numbers of mice transmitting N. caninum and a lower frequency of transmission by individual dams (p < 0.05). Decreased congenital transmission was associated with significantly lower levels of maternal splenocyte IL-4 secretion, lower IL-4 mRNA levels, and higher levels of IFN-gamma secretion. Protected mice had significantly decreased Neospora-specific IgG1 compared with nonmodulated mice. These studies define a relationship between maternal Ag-specific immunity and the frequency of congenital transmission and demonstrate that modulation of type 2 cytokine responses can change the frequency of congenital protozoal transmission.

Animals↗

Psychometric assessment of the Adult-Adolescent Parenting Inventory in a sample of low-income single mothers.

The Adult-Adolescent Parenting Inventory (AAPI) is a 32-item inventory widely used to identify adolescents and adults at risk for inadequate parenting behaviors. It includes four subscales representing the most frequent patterns associated with abusive parenting: (a) Inappropriate Expectations; (b) Lack of Empathy; (c) Parental Value of Corporal Punishment; and (d) Parent-Child Role Reversal. Although it has been used in a variety of samples, the psychometric properties of the AAPI have not been examined in low-income single mothers. The purposes of this study were to: (a) examine the reliability and validity of the Adult-Adolescent Parenting Inventory (AAPI) in a sample of 206 low-income single mothers; (b) assess the mother's risk for inadequate parenting by comparing their AAPI subscale scores with normative subscale scores on the AAPI; (c) assess the construct validity of the AAPI by testing the hypothesis that mothers with lower AAPI scores have a higher level of depressive symptoms and lower self-esteem in comparison to mothers with higher AAPI scores; and (d) determine whether the 4-factor structure proposed by Bavolek (1984) could be replicated. AAPI scores indicated these mothers were at high risk for child abuse when compared with normative data for parents with no known history of abuse. Higher risk for abusive parenting was associated with a higher level of depressive symptoms, less education, and unemployment. The subscales, Inappropriate Expectations and Parental Value of Corporal Punishment demonstrated poor internal consistency with Cronbach's alphas of .40 and .54, respectively. Hypothesis testing supported the construct validity of the AAPI. Bavolek's 4-factor structure was not supported. A 19-item modified version of the AAPI with three dimensions was identified. This modified version of the AAPI may provide a more efficacious tool for use with low-income single mothers.

Adolescent↗

Fiscal determinants of migration to a fast-growing state: how the aged differ from the general population.

"This paper utilizes 1980-89 data on Florida's metropolitan areas to test the hypothesis that fiscal variables have differing influences on the in-migration of the aged as compared to the general population. The model, which is based on the Tiebout hypothesis, tests the role of variables which represent public school-related finances and public assistance.... Consistent with the Teibout theory, the general population is found to prefer high public school-related spending and low taxes. The elderly, in contrast, choose locations where school spending and taxes are low. Nonschool-related taxes positively impact the migration of both groups. Contrary to previous studies, there is evidence of a role, albeit a mostly negative one, for the economic determinants of elderly migration. The possible importance of quality of life influences is also suggested by the findings."

Adult↗

Morphological analyses of ice-free and frozen cryopreserved heart valve explants.

BACKGROUND AND AIM OF THE STUDY: The pathophysiology of allogeneic heart valve failure is not fully understood. It is hypothesized that the rapid deterioration seen in some allograft heart valve recipients is due to disruptive interstitial ice damage that occurs during cryopreservation by freezing. METHODS: The hypothesis was tested by comparing a standard commercial heart valve freezing and ice-free, vitrification cryopreservation methods with fresh controls in: (i) a subcutaneous, juvenile rat implant model of calcification; and (ii) a descending thoracic aorta implant rat model for histopathology. Calcium concentrations in one- to six-week explants were determined using atomic absorption spectroscopy; calcification rates were also determined. RESULTS: The calcification rate of frozen valves was significantly greater (p < 0.01) than that of vitrified valves in both syngeneic and allogeneic recipients, supporting prior observations that ice-free cryopreservation reduces allogeneic heart valve calcification. Cryopreservation by freezing and vitrification resulted in mild morphological changes in two- and four-week explants, a slight decrease in leaflet cellularity, and a more rapid onset of intimal hyperplasia than in fresh valve explants. The allograft explant groups exhibited similar changes, regardless of how the valves were processed. CONCLUSION: These findings provide only weak support for the tested hypothesis, and further studies in a large animal model are warranted.

Animals↗

Statistical significance versus clinical relevance. Part I. The essential role of the power of a statistical test.

When comparing two treatment groups, hypothesis testing is widely used. However, clinical trialists should be more interested in statistical methods which elicit the magnitude of the differences between treatment groups, rather than a simple indication of whether or not the differences are statistically significant. Statistical significance does not necessarily imply clinical relevance. If the true difference between two treatment groups is so small that it is clinically irrelevant, a sample size can be found for which this difference is statistically significant. On the other hand, if the difference between treatment groups is statistically non-significant, it may still be clinically important. The limitations of conventional hypothesis testing of equal true means as such are highlighted. The need to control the power of the test--which takes into account the difference in treatment means which is considered important (clinically relevant) by the researcher--is discussed.

Clinical Trials as Topic↗