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[Colon cancer and nutritional genetics: modifier genes].

About 5% of colon cancer cases correspond to classic hereditary monogenic mendelian transmission involving at least 8 major genes of predisposition to this tumor. Genes with more moderate effects, in association with other genes can contribute to the occurrence of sporadic polygenic forms. These genes confer susceptibility to environmental factors and can play the role of aggravating or protective modifier genes in the different hereditary forms. Foods can interact with these genes and modulate their expression. Moreover sequence variations (polymorphisms) in these genes may also be responsible for slower or more rapid metabolism of nutrients leading to toxic or carcinogenic compounds. If some foods, or "pharmafoods" can have beneficial effects in some individuals with a particular subtype of the disease, others can be inefficient or even detrimental in patients with the same disease but with a different genetic origin or if the genetic background is different. Moreover tumorigenic processes are diverse. Tumor progression depends on genetic and environmental factors different from tumor initiation and on the site of the tumor along the colon tract. Interactions with the gut flora, the lymphoid system and specific features of growth of the colon mucosa are also important parameters. Today with a formidable genetic knowledge arising from the genome project, new epidemiological data integrating the genetic data for multiple markers and a better knowledge of the tumorigenic processes involved, a new discipline is emerging. "Nutrigenetics" which is the study of hereditary basis of individual variations in response to foods opens for the oncoming decade the era of a personalised predictive medecine based on a nutrition adapted to the genetic make up of each of us.

Cocarcinogenesis↗

Prediction of dose-response relations based on patient characteristics.

The recent discussion of evidence-based, adaptive treatment planning highlights the need for models for the prediction of courses of treatment response. We combine a dose-response model with growth curve modeling to determine dose-response relations for well-being, symptoms, and functioning. Hierarchical linear modeling was used to model each patient's expected course of improvement. The resulting predictions were cross-validated on two samples of psychotherapy outpatients. The results give further empirical support for the dose-response model and the phase model of psychotherapy as well as for the usefulness of patient treatment response profiling for individual treatment management.

Adult↗

Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Mutation rate and the cost of complexity.

Two recent theoretical studies of adaptation suggest that more complex organisms tend to adapt more slowly. Specifically, in Fisher's "geometric" model of a finite population where multiple traits are under optimizing selection, the average progress ensuing from a single mutation decreases as the number of traits increases--the "cost of complexity." Here, I draw on molecular and histological data to assess the extent to which on a large phylogenetic scale, this predicted decrease in the rate of adaptation per mutation is mitigated by an increase in the number of mutations per generation as complexity increases. As an index of complexity for multicellular organisms, I use the number of visibly distinct types of cell in the body. Mutation rate is the product of mutational target size and population mutation rate per unit target. Despite much scatter, genome size appears to be positively correlated with complexity (as indexed by cell-type number), which along with other considerations suggests that mutational target size tends to increase with complexity. In contrast, effective population mutation rate per unit target appears to be negatively correlated with complexity. The net result is that mutation rate probably does tend to increase with complexity, although probably not fast enough to eliminate the cost of complexity.

Animals↗

Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator.

BACKGROUND: Reliable prediction of prognosis allowing risk-adapted therapy remains a major issue in the management of multisystem Langerhans cell histiocytosis (LCH). In a recent publication of the International LCH Study Group, response to initial therapy appears to be a reliable outcome predictor. The aim of this study is to test this observation in a cohort of patients treated with more intensive initial therapy. Furthermore, we compare the predictive value of response to initial therapy to some other well-established stratification systems. PROCEDURE: Response to initial combination chemotherapy (prednisolone, vinblastine, and etoposide) at 6 weeks and its prognostic value was evaluated retrospectively in 63 patients with multisystem LCH from the DAL-HX 83 and 90 Studies, and correlated to some established scoring systems from the literature. RESULTS: After 6 weeks of therapy, 50/63 (79%) patients qualified as responders, 4/63 (7%) patients showed intermediate response, and 9/63 (14%) patients did not respond. Probability of survival at 5 years was 0.94 +/- 0.03 for responders, 0.75 +/- 0.22 for patients with intermediate response, and only 0.11 +/- 0.10 for non-responders. CONCLUSIONS: Response to initial therapy appears to be a reliable prognostic predictor. Compared to the published international LCH-I Study, our results suggest that more intensive initial treatment allows a better discrimination between responders and non-responders. This allows to identify a subgroup of patients with extremely poor prognosis (mortality rate 90%) relatively early in the disease course.

Adolescent↗

Characterization of an adapter subunit to a phosphatidylinositol (3)P 3-phosphatase: identification of a myotubularin-related protein lacking catalytic activity.

The D3-phosphoinositides act as second messengers by recruiting, and thereby activating, diverse signaling proteins. We have previously described the purification of a rat phosphatidylinositol 3-phosphate [PtdIns(3)P] 3-phosphatase, comprising a heterodimer of a 78-kDa adapter subunit in complex with a 65-kDa catalytic subunit. Here, we have cloned and characterized the cDNA encoding the human 3-phosphatase adapter subunit (3-PAP). Sequence alignment showed that 3-PAP shares significant sequence similarity with the protein and lipid 3-phosphatase myotubularin, and with several other members of the myotubularin gene family including SET-binding factor 1. However, unlike myotubularin, 3-PAP does not contain a consensus HCX(5)R catalytic motif. The 3-PAP sequence contains several motifs that predict interaction with proteins containing Src homology-2 (SH2) domains, phosphotyrosine-binding (PTB) domains, members of the 14-3-3 family, as well as proteins with SET domains. Northern blot analysis identified two transcripts (5.5 kb and 2.5 kb) with highest abundance in human liver, kidney, lung, and placenta. 3-PAP immunoprecipitates isolated from platelet cytosol hydrolyzed the D3-phosphate from PtdIns(3)P and PtdIns 3,4-bisphosphate [PtdIns(3,4)P(2)]. However, insect cell-expressed 3-PAP recombinant protein was catalytically inactive, confirming our prior prediction that this polypeptide represents an adapter subunit.

Amino Acid Sequence↗

Self-organizing neural systems based on predictive learning.

The ability to predict future events based on the past is an important attribute of organisms that engage in adaptive behaviour. One prominent computational method for learning to predict is called temporal-difference (TD) learning. It is so named because it uses the difference between successive predictions to learn to predict correctly. TD learning is well suited to modelling the biological phenomenon of conditioning, wherein an organism learns to predict a reward even though the reward may occur later in time. We review a model for conditioning in bees based on TD learning. The model illustrates how the TD-learning algorithm allows an organism to learn an appropriate sequence of actions leading up to a reward, based solely on reinforcement signals. The second part of the paper describes how TD learning can be used at the cellular level to model the recently discovered phenomenon of spike-timing-dependent plasticity. Using a biophysical model of a neocortical neuron, we demonstrate that the shape of the spike-timing-dependent learning windows found in biology can be interpreted as a form of TD learning occurring at the cellular level. We conclude by showing that such spike-based TD-learning mechanisms can produce direction selectivity in visual-motion-sensitive cells and can endow recurrent neocortical circuits with the powerful ability to predict their inputs at the millisecond time-scale.

Action Potentials↗

Skeletal structural adaptations to mechanical usage (SATMU): 1. Redefining Wolff's law: the bone modeling problem.

From the nature of a bone's endload and its local surface strains, the theory computes a modeling operator, Gamma (gamma), that predicts whether mechanical factors will cause lamellar bone modeling drifts, and where and of what kind. A given mechanical bone strain history then provides a separate modeling rate function, M, to specify the rate of such modeling drifts as fractions of the largest possible ones. Multiplying the two functions, e.g., gamma.M, then predicts mechanically controlled bone modeling responses for cortical and trabecular bone, both quantitatively and qualitatively. The theory correctly predicts each of the 6 known "principal adaptations" of lamellar bone, which provide a critical test of any such theory for this organ. The theory accounts for biologic, biomechanical, and clinical-pathologic knowledge not available in Wolff's time nor accounted for by most biomechanicians since. Existing proven methods can provide all numerical data needed to satisfy the theory's mathematical equations and already suggest provisional values for most of them. Its originator views the theory as the kernel of more and better theories to come rather than a finished work, a kernel that suggests a new and in some respects novel logical framework for analysing the problems, and a kernel that invites critique, refinement, and/or exploitation by others.

Adaptation, Physiological↗

The relation of rhodopsin and scotopic sensitivity in choroideremia.

We examined two patients who had clinical characteristics typical of choroideremia using psychophysical and reflection retinal densitometric techniques. In the dark-adapted state, sensitivity was more compromised than would be predicted on the basis of the modest losses of rhodopsin. In the dark-adapted state, studies of spatial and temporal summation suggested that postreceptoral processes are similar to normal. The kinetics of rhodopsin regeneration after bleaching exposures were abnormal in some retinal regions.

Adult↗

Predicting intentions to consume functional foods and supplements to offset memory loss using an adaptation of protection motivation theory.

The widespread use of dietary supplements and so-called 'functional foods' is thought to be partially motivated by self-control of health. However, whilst consumers want foods associated with well-being or disease prevention, they are unlikely to be willing to compromise on taste or technology. This presents a dilemma for promoters of functional foods. Middle-aged consumers' intentions to consume functional foods or supplements that may improve memory were tested within an adaptation of Protection Motivation theory (PMT). Participants evaluated text descriptions of four products described as: having an unpleasant bitter taste (Natural-FF); having 'additives' to reduce bitterness (Sweetened-FF); being genetically modified to enhance function (GM-FF) and Supplements. Participants were recruited as being of high and low perceived vulnerability to memory failure. In total, 290 middle-aged consumers (aged 40-60 years) participated in the study. Motivations to consume the GM-FF were the lowest. There were gender differences between intention to consume the supplements, Natural-FF and Sweetened-FF and product differences within genders. Women were less favourable than men in their attitudes towards genetic modification in general. Regression analyses indicated that PM predictors of intention to consume functional foods or supplements explained 59-63% of the variance (R2). Overall, perceived 'efficacy' (of the behaviour) and self-efficacy were the most important predictors of intentions to consume.

Adult↗

[Human adaptation to climatic changes].

The causes for the currently predicted change in climate result from behaviours of the rapidly growing human population consuming more natural resources for fulfillment of more natural resources for fulfillment of basic needs and high demands on health and comfort and interfering with homeostasis mechanisms of nature beyond adaptive capacities. Human adaptive potential is considered and strategies for adaptation are outlined aiming at an equilibrium between human and natural systems by behavioural modification, without loss of basic needs for health.

Adaptation, Physiological↗

Muscle-joint models incorporating activation dynamics, moment-angle, and moment-velocity properties.

Muscle input/output models incorporating activation dynamics, moment-angle, and moment-velocity factors are commonly used to predict the moment produced by muscle during nonisometric contractions; the three factors are generally assumed to be independent. We examined the ability of models with independent factors, as well as models with coupled factors, to fit input/output data measured during simultaneous modulation of the fraction of muscle stimulated (recruitment) and joint angle inputs. The models were evaluated in stimulated cat soleus muscles producing ankle extension moment, with regard to their potential applications in neuroprostheses with either fixed parameters or parameter adaptation. Both uncoupled and coupled models predicted the output moment well for random angle perturbation sizes ranging from 10 degrees to 30 degrees. For the uncoupled model, the best parameter values depended on the range of perturbations and the mean angle. Introducing coupling between activation and velocity in the model reduced this parameter sensitivity; one set of model parameter values fit the data for all perturbation sizes and also fit the data under isometric or constant stimulation conditions. Thus, the coupled model would be the most appropriate for applications requiring fixed parameter values. In contrast, with continuous parameter adaptation, errors due to changing test conditions decreased more quickly for the uncoupled model, suggesting that it would perform well in adaptive control of neuroprostheses.

Animals↗

Robust adaptive microphone array processing for hearing aids: realistic speech enhancement.

The problem of combining the outputs of an array of microphones as a single input for a hearing aid is investigated. Emphasis is placed on the conservative prediction of realistically achievable performance gains provided by the array over a single microphone. Performance improvement is measured as a change in the speech reception threshold (SRT) between single microphone and multimicrophone conditions. Consistent with previous work, predictions of this change in SRT using intelligibility averaged gain, [symbol: see text] are shown to be good. Consequently, this measure is used, along with changes in signal-to-noise ratios (SNRs), to evaluate array performance. The results presented include the effects of acoustic headshadow, small room reverberation, microphone placement uncertainty, and desired speaker location uncertainty. It is in this context that realistic predictions of speech enhancement provided by robust adaptive microphone array processors are discussed. Performance improvements are demonstrated relative to the "best" single microphone in the array for three types of spatial filters: Fixed, robust block processed, and robust adaptive. The performance of the robust block processed arrays is shown to be attainable with adaptive implementations. One fundamental criterion employed in robust beamformer design directly limits the amount of cancellation of the desired signal that can occur.

Adult↗

Quantification of ventilation on distribution of gaseous pollutants emitted from stored swine manure.

This paper describes the quantification of the effects of ventilation on distribution of gaseous pollutants as a result of mass transfer from stored manure to ventilation air in a swine confinement building. A multiple airflow regions model is developed and used to simulate the dynamics of gaseous pollutants in any airspace within a ventilated slotted-inlet enclosure. The model predictions compared favorably with the measured results adapted from a literature research at ventilation rates between 443 and 932 m3/hr (deviations of 5.1-14.68%) for carbon dioxide and ammonia concentrations. A comparison between predictions and measured carbon dioxide concentrations derived from an environmental chamber test found deviations ranged from 3.1-5.6% at ventilation rates between 281 and 995 m3/hr. The results suggest that the model can be experimentally applied between ventilation rates of 443 and 995 m3/hr. The model also capable of predicting air exchange rate required to maintain acceptable levels of gaseous pollutants in swine confinement buildings based on gas emission rates.

Air Pollutants↗

Internal models in sensorimotor integration: perspectives from adaptive control theory.

Internal models and adaptive controls are empirical and mathematical paradigms that have evolved separately to describe learning control processes in brain systems and engineering systems, respectively. This paper presents a comprehensive appraisal of the correlation between these paradigms with a view to forging a unified theoretical framework that may benefit both disciplines. It is suggested that the classic equilibrium-point theory of impedance control of arm movement is analogous to continuous gain-scheduling or high-gain adaptive control within or across movement trials, respectively, and that the recently proposed inverse internal model is akin to adaptive sliding control originally for robotic manipulator applications. Modular internal models' architecture for multiple motor tasks is a form of multi-model adaptive control. Stochastic methods, such as generalized predictive control, reinforcement learning, Bayesian learning and Hebbian feedback covariance learning, are reviewed and their possible relevance to motor control is discussed. Possible applicability of a Luenberger observer and an extended Kalman filter to state estimation problems-such as sensorimotor prediction or the resolution of vestibular sensory ambiguity-is also discussed. The important role played by vestibular system identification in postural control suggests an indirect adaptive control scheme whereby system states or parameters are explicitly estimated prior to the implementation of control. This interdisciplinary framework should facilitate the experimental elucidation of the mechanisms of internal models in sensorimotor systems and the reverse engineering of such neural mechanisms into novel brain-inspired adaptive control paradigms in future.

Adaptation, Physiological↗

Constraints on masticatory system evolution in anthropoid primates.

It is well established that some observed patterns of force production in the primate masticatory system match those predicted by a simplified lever model. This model is also commonly invoked in adaptive explanations of craniodental diversity. However, systematic studies of the predictive power of this model are missing, leaving open the possibility that factors not traditionally included in the model alter the function and evolution of the masticatory system. One such factor was proposed for mammals generally by Greaves ([1978] J. Zool. (Lond.) 184:271-285), who argued that the temporomandibular joint (TMJ) was poorly suited to being pulled apart. In this constrained lever model, the avoidance of joint distraction leads to limitations on masticatory system form and function. The goal of the present study was to quantify masticatory system diversity in anthropoid primates for comparison with these predictions. Results indicate that all sampled taxa exhibit a form that is consistent with selection against regular distraction of the TMJ. Also apparent from observed patterns of scaling is a regular interaction among a limited set of cranial and dental dimensions, in accordance with the constrained model. However, the data indicate that specific positional relationships among the muscles, joints, and teeth differ from those predicted by Greaves (1978). The pattern of deviation suggests that selection has favored a conservative masticatory system configuration that safeguards the TMJ from distraction during the dynamic processing of irregular foods. The resulting buffered model leads to alternative hypotheses regarding the response of the masticatory system to dietary selection pressures. It may, therefore, improve our understanding of the adaptive significance of primate craniofacial form.

Animals↗

Energy expenditure, fat oxidation, and body weight regulation: a study of metabolic adaptation to long-term weight change.

Relatively low rates of energy expenditure and fat oxidation predict body weight gain. Weight gain, in turn, is associated with increases in energy expenditure and fat oxidation that may oppose further weight change. In response to experimental weight gain induced by overfeeding, increases in energy expenditure and fat oxidation are overcompensatory, i.e. greater than predicted for the change in body composition. To determine whether such metabolic adaptation occurs in response to spontaneous long term weight change, we conducted a longitudinal study in which 24-h energy expenditure (24-EE) and 24-h respiratory quotient (24-RQ; i.e. fat to carbohydrate oxidation) were repeatedly measured in 102 Pima Indians at baseline and after a mean follow-up of 3.6 +/- 2.7 yr, during which changes in body weight varied widely (-21 to +28 kg). We found that changes in 24-EE and 24-RQ in response to weight change were related to the amount of weight change, even after adjustment for body composition (partial r = 0.23 and -0.30, respectively; both P < 0.05). For a 15-kg weight gain, the increases in 24-EE (+244 Cal/day) and 24-h fat oxidation (+152 Cal/day) were 33 and 53 Cal/day greater than predicted from the cross-sectional relationship between both measures and body weight. Changes in 24-EE and 24-RQ varied substantially among individuals. Thus, on the average, spontaneous long term weight changes are accompanied by small metabolic adaptations in both energy expenditure and fat oxidation. The metabolic responses to weight changes are highly variable among individuals, however.

Adaptation, Physiological↗

Vineland adaptive behavior profiles in children with autism and moderate to severe developmental delay.

The purpose of this study was to examine adaptive behaviour profiles in children with autism and moderate to severe developmental delay. Previous research has found that children with autism present a characteristic pattern of adaptive behaviour, as measured by the Vineland Adaptive Behavior Scales (VABS) (deficit in the domain of socialization, relative deficit in the domain of communication and relative strength in the domain of daily living). In this study VABS were administered (as part of a comprehensive evaluation of abilities) to a sample of 50 children with moderate to severe developmental delay (23 children with autism and 27 chronological and developmental age matched non-autistic children). Contrary to initial predictions, the sample presented fairly homogeneous adaptive behaviour profiles. Results are discussed with respect to the effectiveness of adaptive behaviour profiles in the detection of autism and the importance of employing limited chronological and developmental age ranges in the study of autism in infancy.

Adaptation, Psychological↗

FDG-PET after two to three cycles of chemotherapy predicts progression-free and overall survival in high-grade non-Hodgkin lymphoma.

BACKGROUND: Less than 50% of all high-grade non-Hodgkin lymphoma (NHL) patients experience lasting disease-free survival. Risk-adapted treatment strategies require better tools for prediction of outcome. This investigation aimed to assess the value of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) after two to three cycles of chemotherapy for prediction of progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: One hundred and twenty-one patients with high-grade NHL underwent FDG-PET. The therapy response on FDG-PET was correlated to PFS and OS using Kaplan-Meier survival analysis. Cox regression analyses were employed to test for independence of known pretreatment prognostic factors. RESULTS: Fifty FDG-PET scans were negative, 19 scans showed minimal residual uptake (MRU), and 52 scans were positive. The estimated 5 year PFS was 88.8% for the PET-negative group, 59.3% for the MRU group, and 16.2% for the PET-positive group. Kaplan-Meier analyses showed strong associations between FDG-PET results and PFS (P <0.0001) and OS (P <0.01). Early interim FDG-PET was independent of the other prognostic factors. CONCLUSIONS: Early interim FDG-PET is an accurate and independent predictor of PFS and OS. An early assessment of chemotherapy response with FDG-PET could provide the basis for selection of patients for alternative therapeutic strategies.

Adult↗