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At least 199 records · Page 11Linked to original sources
PubMed2007

Increased expression of activating factors in large osteoclasts could explain their excessive activity in osteolytic diseases.

Large osteoclasts (>or=10 nuclei) predominate at sites of pathological bone resorption. We hypothesized this was related to increased resorptive activity of large osteoclasts and have demonstrated previously that larger osteoclasts are 8-fold more likely to be resorbing than small osteoclasts (2-5 nuclei). Here we ask whether these differences in resorptive activity can be explained by differences in expression of factors involved in osteoclast signaling, fusion, attachment, and matrix degradation. Authentic rabbit osteoclasts and osteoclasts derived from RAW264.7 cells showed similar increases in c-fms expression (1.7- to 1.8-fold) in large osteoclasts suggesting that RAW cells are a viable system for further analysis. We found 2- to 4.5-fold increases in the expression of the integrins alpha(v) and beta(3), the proteases proMMP9, matMMP9 and pro-cathepsinK, and in activating receptors RANK, IL-1R1, and TNFR1 in large osteoclasts. In contrast, small osteoclasts had higher expression of the fusion protein SIRPalpha1 and the decoy receptor IL-1R2. The higher expression of activation receptors and lower expression of IL-1R2 in large osteoclasts suggest they are hyperresponsive to extracellular factors. This is supported by the observation that the resorptive activity in large osteoclasts was more responsive to IL-1beta, and that this increased activity was inhibited by the IL-1 receptor antagonist, IL-1ra. This increased responsiveness of large osteoclasts to IL-1 may, in part, explain the pathological bone loss noted in inflammatory diseases. The heterogeneity in receptor expression and the differential response to cytokines and their antagonists could prove useful for selective inhibition of large osteoclasts actively engaged in pathological bone loss.

Acid Phosphatase↗
PubMed1996

NO is not sufficient to explain maximal cytotoxicity of tumoricidal macrophages against an NO-sensitive cell line.

Nitric oxide (NO) is a macrophage cytotoxic effector. Results presented here, however, demonstrate that NO does not fully explain macrophage cytotoxicity against NO-sensitive cells because (1) inhibition of NO production by activated macrophages reduces, not eliminates, cytotoxicity; (2) NO produced chemically in amounts equimolar to those released from macrophages fails to lyse P815 cells; and (3) macrophages isolated from wounds 10 days after injury generate NO just as tumoricidal activated macrophages but are not tumor cytotoxic. The noncytotoxic nature of these wound-derived macrophages is not explained by the release of inactive forms of NO, because they suppress lymphocyte proliferation in an NO-dependent manner, nor by the production of cytoprotective molecules, because their addition to activated macrophage-tumor cell cocultures does not quench cytotoxicity. Interestingly, cytotoxicity can be aroused in day 10 wound-derived macrophages by culture with lipopolysaccharide, and macrophages harvested earlier in the development of the wound are cytotoxic. By generating NO but not killing an NO-sensitive cell, day 10 wound-derived macrophages demonstrate that NO production is not sufficient to account for the killing of an NO-sensitive tumor by macrophages.

Animals↗
PubMed2002

Intracellular acidification and volume increases explain R(2) decreases in exercising muscle.

Exercise-induced decreases in the (1)H transverse relaxation rate (R(2)) of muscle have been well documented, but the mechanism remains unclear. In this study, the hypothesis was tested that R(2) decreases could be explained by pH decreases and apparent intracellular volume (V(i)') increases. (31)P and (1)H spectroscopy, biexponential R(2) analysis, and imaging were performed prior to and following fatiguing exercise in iodoacetate-treated (IAA, to inhibit glycolysis), NaCN-treated (to inhibit oxidative phosphorylation), and untreated frog gastrocnemii. In all exercised muscles, the apparent intracellular R(2) (R(2i)') and pH decreased, while intracellular osmolytes and V(i)' increased. These effects were larger in NaCN-treated and untreated muscles than in IAA-treated muscles. Multiple regression analysis showed that pH and V(i)' changes explain 70% of the R(2i)' variance. Separate experiments in unexercised muscles demonstrated causal relationships between pH and R(2i)' and between V(i)' and R(2i)'. These data indicate that the R(2) change of exercise is primarily an intracellular phenomenon caused by the accumulation of the end-products of anaerobic metabolism. In the NaCN-treated and untreated muscles, the R(2i)' change increased as field strength increased, suggesting a role for pH-modulated chemical exchange.

Animals↗
PubMed1988

An embryogenic model to explain cytogenetic inconsistencies observed in chorionic villus versus fetal tissue.

While the fetus and placenta have a common ancestry, chorionic villus tissue does not always reflect fetal genotype. Data are presented from 15 CVS subjects in whom cytogenetic inconsistencies were observed when comparing (1) cultured chorionic villi, (2) direct chromosome preparations of intact villi, and (3) cultured fetal tissue. Embryogenic models are presented to explain these discrepancies. Mosaicism confined to direct chromosome preparations was the most commonly observed inconsistency. This can be explained by postzygotic non-disjunction limited to cytotrophoblast. In all but one instance, the abnormal cell line was limited to the placenta, with the normal cell line reflecting fetal genotype. Analysis of direct chromosome preparations from multiple individually processed villus fragments may be helpful in recognizing mosaicism confined to the placenta. While both direct chromosome preparations and villus cultures can be misleading, the latter are more likely to reflect fetal genetic status since they are derived from the extraembryonic mesoderm.

Chorionic Villi↗
PubMedDate not supplied

Explaining quality of life with crisis theory.

Based on the premises of crisis theory, we expected cancer patients in-crisis to report a poorer quality of life (QL) and cancer patients post-crisis to report a similar level of overall QL in comparison to healthy individuals. To explain these hypothesized findings, we expected the coping resources and strategies of patients in-crisis to be equally effective and those of patients post-crisis to be more effective as compared to those of healthy individuals. The sample consisted of: (a) 217 consecutive cancer patients in the acute phases of their illness (patients in-crisis); (b) 192 disease-free cancer patients (patients post-crisis); and (c) 201 randomly selected healthy individuals. Established measures of QL, self-esteem and neuroticism (coping resources) and coping behavior (coping strategies) were mailed. As expected, patients in-crisis reported a poorer QL (p < 0.001) and patients post-crisis a similar overall QL as compared to healthy individuals. There were no significant or systematic differences between the mean levels of coping resources and strategies between the respective groups. Two-way analysis of variance indicated a group X coping resource interaction effect on overall QL for self-esteem (p < 0.01). As expected, the amount of variance of overall QL explained by self-esteem was largest for patients post-crisis (27%) and comparable for patients in-crisis and healthy individuals (10 and 11%). Patients in-crisis were not able to make their coping resources and strategies more effective, whereas patients post-crisis seemed to have enhanced the effectiveness of self-esteem in restoring their QL as compared to healthy persons.

Adaptation, Psychological↗
PubMed1995

Active site model for gamma-aminobutyrate aminotransferase explains substrate specificity and inhibitor reactivities.

A homology model for the pig isozyme of the pyridoxal phosphate-dependent enzyme gamma-aminobutyrate (GABA) aminotransferase has been built based mainly on the structure of dialkylglycine decarboxylase and on a multiple sequence alignment of 28 evolutionarily related enzymes. The proposed active site structure is presented and analyzed. Hypothetical structures for external aldimine intermediates explain several characteristics of the enzyme. In the GABA external aldimine model, the pro-S proton at C4 of GABA, which abstracted in the 1,3-azaallylic rearrangement interconverting the aldimine and ketimine intermediates, is oriented perpendicular to the plane of the pyridoxal phosphate ring. Lys 329 is in close proximity and is probably the general base catalyst for the proton transfer reaction. The carboxylate group of GABA interacts with Arg 192 and Lys 203, which determine the specificity of the enzyme for monocarboxylic omega-amino acids such as GABA. In the proposed structure for the L-glutamate external aldimine, the alpha-carboxylate interacts with Arg 445. Glu 265 is proposed to interact with this same arginine in the GABA external aldimine, enabling the enzyme to act on omega-amino acids in one half-reaction and on alpha-amino acids in the other. The reactivities of inhibitors are well explained by the proposed active site structure. The R and S isomers of beta-substituted phenyl and p-chlorophenyl GABA would bind in very different modes due to differential steric interactions, with the reactive S isomer leaving the orientation of the GABA moiety relatively unperturbed compared to that of the natural substrate. In our model, only the reactive S isomer of the mechanism-based inhibitor vinyl-GABA, an effective anti-epileptic drug known clinically as Vigabatrin, would orient the scissile C4-H bond perpendicular to the coenzyme ring plane and present the proton to Lys 329, the proposed general base catalyst of the reaction. The R isomer would direct the vinyl group toward Lys 329 and the C4-H bond toward Arg 445. The active site model presented provides a basis for site-directed mutagenesis and drug design experiments.

4-Aminobutyrate Transaminase↗
PubMed2005

Explaining racial differences in prostate cancer in the United States: sociology or biology?

Black men in the United States have the highest incidence and mortality from prostate cancer in the world. Even after adjusting for stage at diagnosis, black men have higher mortality rates than white men. Multiple reasons have been postulated to explain these findings including access to care, attitudes about care, socioeconomic and education differences, differences in type and aggressiveness of treatment, dietary, and genetic differences. While each reason may contribute to the higher incidence or higher mortality, likely combinations of reasons will best explain all the findings. Racial differences in socioeconomic status have been well established and we review the significance of these findings in relationship to prostate cancer. Also, with recent advances in the understanding of genetic variation in the human genome, in general, and in the genes involved in pathways relevant to prostate cancer biology, in particular, a number of genes with alleles which differ in frequency between black and white men have been proposed as a genetic cause or contributor to the increased prostate cancer risk in black men. However, the clinical significance of these genetic differences is not fully known. Finally, we conclude with some thoughts as to how to integrate the findings from sociological as well as biological studies and touch upon methods to reduce the disparate burden of prostate cancer among blacks in the United States.

Attitude to Health↗
PubMed2003

Comparing the importance of disease rate versus practice style variations in explaining differences in small area hospitalization rates for two respiratory conditions.

Many studies have reported large variations in age- and sex-adjusted rates of hospitalizations across small geographic areas. These variations have often been attributed to differences in medical practice style which are not reflected in differences in health care outcomes. There is, however, another potentially important source of variation that has not been examined much in the literature: geographic differences in the age-sex adjusted size of the pool of patients who present with the disease and are candidates for hospitalization. Previous studies of small area variations in hospitalization rates have only used data on hospitalizations. Thus, it has not been possible to distinguish the extent to which differences in hospitalization rates are due to (i). differences in the chance that patients diagnosed with a disease are admitted to a hospital, which we refer to as the 'practice style effect,' versus (ii). geographic differences in the total amount of diagnosed disease, which we refer to as the 'disease effect.' Elementary methods for estimating the relative strength of the two effects directly from the data can be misleading, since equal amounts of variability in each effect result in unequal impacts on hospitalization rates. In this paper we describe a model-based approach for estimating the relative importance of the practice style effect and the disease effect in explaining variations in hospitalization rates. The key to our approach is the use of data on both inpatient and outpatient visits. We use 1997 Medicare data for two respiratory medical conditions across 71 small areas in Massachusetts: chronic bronchitis and emphysema, and bacterial pneumonia. Based on a Poisson model for the process generating hospitalizations and outpatient visits, we use a Bayesian framework and Gibbs sampling to compute and compare the correlation between the number of people hospitalized and each of these two sources of variation. Our results show that for the two conditions, disease rate variation explains at least as much of the variation in hospitalization rates as does practice style variation.

Aged↗
PubMed2003

Predictive accuracy and explained variation.

Measures of the predictive accuracy of regression models quantify the extent to which covariates determine an individual outcome. Explained variation measures the relative gains in predictive accuracy when prediction based on covariates replaces unconditional prediction. A unified concept of predictive accuracy and explained variation based on the absolute prediction error is presented for models with continuous, binary, polytomous and survival outcomes. The measures are given both in a model-based formulation and in a formulation directly contrasting observed and expected outcomes. Various aspects of application are demonstrated by examples from three forms of regression models. It is emphasized that the likely degree of absolute or relative predictive accuracy often is low even if there are highly significant and relatively strong covariates.

Austria↗
PubMed2007

Quantifying the treatment effect explained by markers in the presence of measurement error.

Surrogate markers or intermediate markers are important in identifying subjects with high risk of a serious disease or for monitoring disease progression of a subject on treatment. Quantifying the proportion of treatment effect (PTE) explained by markers has been studied extensively. Due to reasons such as biological variation, limited machine precision, etc. markers are generally measured with error. The estimated PTE ignoring the measurement error could be biased, which may lead to incorrect conclusions. In this article, we adjust for the measurement error using regression calibration to construct a less biased estimator of excess relative odds, a quantity to measure the treatment effect explained by markers. The method is applied to data from a clinical study in osteoporosis.

Absorptiometry, Photon↗
PubMed1991

Explaining certain human limb anomalies and the limb-hematopoiesis community of syndromes using a model of determination.

Disturbances of determination, the process of limitation of developmental potential, can cause structural as well as histologic anomalies. A polar coordinate model (PCM) developed from studies in animals, in which determination depends upon positional information arranged along polar coordinates, can be used to explain certain classes of human limb anomalies. Under the model, interference with this system primarily affects distal patterning. If the radial area is distal to the zone of polarizing activity in embryological development, as it appears to be, the PCM explains the teratologic equivalence of preaxial duplications and deficiencies in certain circumstances and the prevalence of ulnar dimelias in forearm duplications. Also, failures of hematopoiesis can be considered late problems with determination and may be markers for abnormalities of a determinative process that also has earlier developmental consequences. Abnormalities of retinoic acid morphogen receptors would be one possible mechanism. This would provide a rationale for the known association of postnatal hematologic problems with developmental anomalies preferentially affecting the radial area. Syndromes with limb and hematopoietic problems may well be a community of determinative disorders.

Abnormalities, Multiple↗
PubMed2001

Can receiver psychology explain the evolution of aposematism?

The evolution of aposematism is difficult to explain because: (1) new aposematic morphs will be relatively rare and thus risk extinction during predator education; and (2) aposematic morphs lack the protection of crypsis, and thus appear to invite attacks. I describe a simple method for evaluating whether rare aposematic morphs may be selectively advantaged by their effects on predator psychologies. Using a simulated virtual predator, I consider the advantages that might accrue to dispersed and aggregated morphs if aposematic prey can cause neophobic avoidance, accelerate avoidance learning and decelerate predator forgetting. Simulations show that aposematism is very hard to explain unless there are particular combinations of ecological and psychological factors. If prey are dispersed throughout a locality then aposematism will be favoured only if (1) there is neophobia, learning effects and forgetting or if (2) there are learning effects and warning signals reduce forgetting rates. However, the best scenario for aposematic advantage involves learning rates, forgetting and neophobia when prey are aggregated. Prey aggregation has two important effects. First, it is a highly effective way to maximize the per capita benefits of the neophobia. Second, after an attack on a single prey the benefits of learnt aversions will be immediately conferred on the surviving members of an aggregation without the diluting effects of forgetting. Aggregation therefore provides good protection against forgetting. The simulations thus provide new insights into the complexities of aposematic protection and suggest some important directions for empirical work. Copyright 2001 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1999

Does Math-Fact Retrieval Explain Sex Differences in Mathematical Test Performance? A Commentary.

We focus on four issues in commenting on Royer et al.'s work testing their hypothesis that sex differences in test performance can be explained by differences in math-fact retrieval latency. The first issue is whether the studies conducted by Royer et al. directly test their hypothesis; we argue that they do not. The second issue involves questions about the strength of the gender differences in math-fact retrieval. The third is whether math-fact retrieval should be considered the major mechanism in explaining the differences in test performance. In considering this third issue we discuss other theories regarding the nature of math problem solving that are useful for understanding test performance differences between males and females. The fourth issue is what particular experiential differences boys and girls have in math classrooms could contribute to the sex differences in test performance. We also consider sex differences in math attitudes and motivation. Copyright 1999 Academic Press.

Journal Article↗
PubMed1996

Do sex differences in the brain explain sex differences in the hormonal induction of reproductive behavior? What 25 years of research on the Japanese quail tells us.

Early workers interested in the mechanisms mediating sex differences in morphology and behavior assumed that differences in behavior that are commonly observed between males and females result from the sex specificity of androgens and estrogens. Androgens were thought to facilitate male-typical traits, and estrogens were thought to facilitate female-typical traits. By the mid-20th century, however, it was apparent that administering androgens to females or estrogens to males was not always effective in sex-reversing behavior and that in some cases a "female" hormone such as an estrogen could produce male-typical behavior and an androgen could induce female-typical behavior. These conceptual difficulties were resolved to a large extent by the seminal paper of C. H. Phoenix, R. W. Goy, A. A. Gerall, and W. C. Young in (1959, Endocrinology 65, 369-382) that illustrated that several aspects of sexual behavior are different between males and females because the sexes have been exposed during their perinatal life to a different endocrine milieu that has irreversibly modified their response to steroids in adulthood. Phoenix et al. (1959) therefore formalized a clear dichotomy between the organizational and activational effects of sex steroid hormones. Since this paper, a substantial amount of research has been carried out in an attempt to identify the aspects of brain morphology or neurochemistry that differentiate under the embryonic/neonatal effects of steroids and are responsible for the different behavioral response of males and females to the activation by steroids in adulthood. During the past 25 years, research in behavioral neuroendocrinology has identified many sex differences in brain morphology or neurochemistry; however many of these sex differences disappear when male and female subjects are placed in similar endocrine conditions (e.g., are gonadectomized and treated with the same amount of steroids) so that these differences appear to be of an activational nature and cannot therefore explain sex differences in behavior that are still present in gonadectomized steroid-treated adults. This research has also revealed many aspects of brain morphology and chemistry that are markedly affected by steroids in adulthood and are thought to mediate the activation of behavior at the central level. It has been explicitly, or in some cases, implicitly assumed that the sexual differentiation of brain and behavior driven by early exposure to steroids concerns primarily those neuroanatomical/neurochemical characteristics that are altered by steroids in adulthood and presumably mediate the activation of behavior. Extensive efforts to identify these sexually differentiated brain characteristics over the past 20 years has only met with limited success, however. As regards reproductive behavior, in all model species that have been studied it is still impossible to identify satisfactorily brain characteristics that differentiate under early steroid action and explain the sex differences in behavioral activating effects of steroids. This problem is illustrated by research conducted on Japanese quail (Coturnix japonica), an avian model system that displays prominent sex differences in the sexual behavioral response to testosterone, and in which the endocrine mechanisms that control sexual differentiation of behavior have been clearly identified so that subjects with a fully sex-reversed behavioral phenotype can be easily produced. In this species, studies of sex differences in the neural substrate mediating the action of steroids in the brain, including the activity of the enzymes that metabolize steroids such as aromatase and the distribution of steroid hormone receptors as well as related neurotransmitter systems, did not result in a satisfactory explanation of sex differences in the behavioral effectiveness of testosterone. Possible explanations for the relative failure to identify the organized brain characteristics responsible for behavio

Animals↗
PubMed1997

Clonality and life cycles of intestinal crypts explained by a state dependent stochastic model of epithelial stem cell organization.

The organization and control of stem cells is a key issue in epithelial cell biology. The small intestinal murine crypt is a useful tissue to study such problems since stem cells are known to be located at specific positions at the bottom of the crypt where they are self maintaining. Recent data suggest, that (1) the number of active stem cells in a crypt can fluctuate, (2) the immediate progeny of a single stem cell can replace other stem cells eventually leading to monoclonality and (3) the life cycle of crypts may be linked to stem cell dynamics. It is the objective of this paper to suggest a stochastic state-dependent model of stem cell and crypt growth which can explain and-link these phenomena into one comprehensive framework. Monte Carlo simulations are performed to show consistently with available data. The model explains the size distribution of small intestinal crypts in steady state, the observations of stem cell fluctuations and monoclonality conversion, recovery of the crypt population after moderate damage and the rate of crypt fission and extinction. The key assumption of this model is an autoregulatory control of stem cell growth.

Animals↗
PubMed1999

Intramitotic and intraclonal variation in proliferative potential of human diploid cells: explained by telomere shortening.

Normal human diploid cells can only divide for a limited number of times (known as the Hayflick limit). They manifest two unique features during in vitro senescence. The division capability of individual cells in a clone, though all derived from a same ancestor, is heterogeneous with a distinct bimodal distribution. Two sister cells derived from a same parent cell can have a large difference in their doubling potentials. These two unique features have not been properly explained by any known physiological process since their observation in 1980. Here I represent a telomere-shortening model based on recent experimental measurement of telomere deletion in human cells. Using computer simulation, I show that the model satisfactorily explains the intraclonal and intramitotic variation in division capability of human diploid cells. Moreover, the simulations predict that human cells may only monitor the shortening of a few, most likely two, telomeres to regulate their proliferative potential.

Clone Cells↗
PubMed1993

Alterations in biodistribution of cocaine may explain differential toxicity in pregnant and postpartum rats.

Biodistribution of cocaine in female rats before and after delivery of litters was studied in order to provide an explanation for the observed differences in cocaine-induced toxicity in pregnant and postpartum rats. Cocaine (20 mg/kg, ip) given to female rats at 16 days of gestation or 20 days of gestation did not have any apparent neurotoxic effects in the mothers. Similarly, no apparent toxicity was observed in virgin animals injected with the same dosage of cocaine. However, administration of the same dosage of cocaine to rats after delivery caused clonic-tonic convulsions and death within 5 min of injection. In an effort to explain these differences, the biodistribution of cocaine was investigated by injecting levo-[benzoyl-3,4-3H(N)] cocaine (20 mg/20 microCi/kg, ip) to nonpregnant rats and rats at different gestation periods and after delivery. The mean serum/brain ratios (concentration of cocaine in serum divided by cocaine concentration in the brain) of cocaine 5 min after injection in rats at 16 days gestation, 20 days gestation, within a 12-hr period after delivery, and in control virgin animals were 2099, 1132, 427, and 632, respectively. These results indicate that the biodistribution of cocaine is altered at parturition. This may explain the increased central nervous system toxicity in rats treated with cocaine after delivery. Results from this investigation may be useful in evaluating complications during labor and delivery which have been associated with cocaine abuse by pregnant women.

Animals↗
PubMed1994

Non-uniformity of sarcomere lengths can explain the 'catch-like' effect of arthropod muscle.

The 'catch-like' effect, a hysteresis phenomenon in arthropod skeletal muscle contraction thought to be related to the catch of molluscan smooth muscle, was investigated in the closer muscle of the crab Eriphia spinifrons. Several parameters were varied to determine their influence on the catch-like effect. These parameters were (1) the frequency of repetitive stimulation of the slow excitatory neuron, (2) additional stimulation of the inhibitory neuron, (3) the amount of stretch applied to the muscle and (4) the stiffness of the mechano-electrical transducer. The results show that the catch-like effect is not related to the catch of molluscan smooth muscle but rather to the 'residual force enhancement' or 'creep' phenomenon described for vertebrate muscle. A hypothesis for residual force enhancement implies that the increase in force is caused by non-uniformity of sarcomere lengths along the muscle fibre. Based on this hypothesis and the actual force-length relationship of the crab muscle studied, calculations were carried out to determine, if the observed catch-like effect can be explained by such a model. The calculations corroborate the experimental evidence. The catch-like effect of arthropod muscles can thus be explained by the same mechanism responsible for residual force enhancement and creep in vertebrate muscle. A physiological relevance of the catch-like effect in arthropod muscle is inferred.

Animals↗