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PubMed2002

Biomechanical models to simulate consequences of maxillofacial surgery.

This paper presents the biomechanical finite element models that have been developed in the framework of the computer-assisted maxillofacial surgery. After a brief overview of the continuous elastic modelling method, two models are introduced and their use for computer-assisted applications discussed. The first model deals with orthognathic surgery and aims at predicting the facial consequences of maxillary and mandibular osteotomies. For this, a generic three-dimensional model of the face is automatically adapted to the morphology of the patient by the mean of elastic registration. Qualitative simulations of the consequences of an osteotomy of the mandible can thus be provided. The second model addresses the Sleep Apnoea Syndrome. Its aim is to develop a complete modelling of the interaction between airflow and upper airways walls during breathing. Dynamical simulations of the interaction during a respiratory cycle are computed and compared with observed phenomena.

Biomechanical Phenomena↗
PubMed1999

The long-term consequences of intra-uterine protein malnutrition for glucose metabolism.

Our initial observations, in epidemiological studies, linking indices of poor early (fetal and infant) growth to the subsequent development of poor glucose tolerance and the insulin resistance syndrome in adult life, have been confirmed in studies in a wide variety of populations around the world. These findings led us 5 years ago to propose the 'thrifty phenotype' hypothesis. Tests of this hypothesis in an animal model in which the pregnant and/or lactating rat dams are fed on an isoenergetic diet containing just under half the normal protein content are consistent with the ideas put forward. They have also allowed us to refine the hypothesis in the light of the new data as follows: (1) the growth of the fetus (and possibly infant) is quantitatively and qualitatively altered by its nutritional environment (which may include maternal diet-dependent changes in maternal hormones); (2) these changes serve to select between the growth rates of different tissues according to priorities which differ between males and females (nutritional thrift) and to alter organ function to constitute a thrifty offspring adapted to survival in poor nutritional circumstances (thrifty phenotype); (3) an individual so constituted suffers adverse consequences in adult life if he/she experiences good or supranormal nutrition; (4) both poor insulin secretion and insulin resistance can result from these adaptive processes; (5) the adverse consequences include loss of glucose tolerance and hypertension. The precise outcome of growth retardation during early life may vary according to the type and timing of the factors responsible for the retardation. It remains to be determined to what extent these potentially adverse effects can be delayed or prevented by a suitable postnatal diet. Experiments in animal models are largely consistent with the concepts proposed from human epidemiological studies. They show that the metabolism of the liver, muscle and adipose tissue may be programmed by maternal nutrition during gestation and lactation. The combination of early growth restriction and subsequent adult obesity reproduced in the rat are the main features of the insulin resistance syndrome.

Animals↗
PubMed2003

The consequences of self-fertilization and outcrossing of the cestode Schistocephalus solidus in its second intermediate host.

Many hermaphroditic parasites reproduce by both cross-fertilization and self-fertilization. To understand the maintenance of such mixed mating systems it is necessary to compare the fitness consequences of the two reproductive modes. This has, however, almost never been done in the context of host-parasite coevolution. Here we show the consequences of outcrossing and selfing in an advanced life-stage of the cestode Schistocephalus solidus, i.e. in its second intermediate host, the three-spined stickleback (Gasterosteus aculeatus). Each juvenile stickleback was simultaneously exposed to 2 experimentally infected copepods, one harbouring outcrossed the other selfed parasites. At 60 days p.i. parasites were removed from the fish's body cavity and, with microsatellite markers, assigned to either outcrossed or selfed origin. Prevalence was not significantly higher in outcrossed parasites. However, those fish that were infected contained significantly more out-crossed than selfed parasites. Thus the probability of a selfed parasite to progress in the life-cycle is reduced in the second intermediate host. Furthermore, we found that even the multiply infected fish increased in weight during the experiment. Nevertheless, total worm weight in multiply infected fish was significantly lower than in singly infected ones, which thus might be a parasite life-history strategy.

Animals↗
PubMed1986

Possible determinants, correlates and consequences of high levels of anxiety in primiparous mothers.

Groups of highly anxious, moderately anxious and minimally anxious primiparous mothers (N = 147) were obtained on the basis of Spielberger trait anxiety scores in the postpartum period, and subjects were compared. Allocation to those groups appeared to be more likely to reflect constitutional levels of anxiety, rather than recent or current social stressors. Highly anxious mothers were distinguished on a number of presumed correlates of anxiety measured by clinical questions (e.g. terminating of anxious situations), hospital notes (e.g. mood problems noted by nursing staff) and blind rater assessments (e.g. unassertiveness). While highly anxious mothers were more likely to report more recent life events, less social support, and negative interpretations of the pregnancy, the hospital experience and the hospital staff, such variables were less discriminating when neuroticism levels were effectively controlled. This suggests an intrinsic perceptual bias, rather than that the factors were determinants. Highly anxious mothers had more delivery complications, while their babies were more likely to be dysmature and slow to suckle, features we interpret as consequences of the anxiety levels. In the postpartum period these mothers were more depressed, had more concerns about their baby, themselves and their marriage, and were less confident about coping and their parenting capacities. Such variables may be correlates or consequences of anxiety.

Anxiety↗
PubMed1999

Consequences of anxiety in older persons: its effect on disability, well-being and use of health services.

BACKGROUND: Although anxiety is quite prevalent in late life, its impact on disability, well-being, and health care utilization of older persons has not been studied. Older persons are a highly relevant age group for studying the consequences of anxiety, since their increasing numbers put an extra strain on already limited health care resources. METHODS: Data of a large community-based random probability sample (N = 659) of older subjects (55-85 year) in the Netherlands were used to select three groups: subjects with a diagnosed anxiety disorder, subjects with merely anxiety symptoms and a reference group without anxiety. These groups were compared with regard to their functioning, subjective well-being, and use of health care services, while controlling for potentially confounding variables. RESULTS: Anxiety was associated with increased disability and diminished well-being. Older persons with a diagnosed anxiety disorder were equally affected in their functioning as those with merely anxiety symptoms. Although use of health services was increased in anxiety sufferers, their use of appropriate care was generally low. CONCLUSIONS: Anxiety has a clear negative impact on the functioning and well-being of older subjects. The similarity of participants with an anxiety disorder and those having merely anxiety symptoms regarding quality of life variables and health care use was quite striking. Finally, in spite of its grave consequences for the quality of life, appropriate care for anxiety is seldom received. Efforts to improve recognition, disseminate effective treatments in primary care, and referring to specialized care may have positive effects on the management of anxiety in late life.

Aged↗
PubMed1982

The social consequences of high unemployment.

Forecasts suggest that unemployment will remain above 2 million in Britain for the best part of the 1980s. The social consequences of protracted high levels of unemployment are explored. The evidence comes from four types of source: cross-sectional surveys of (unemployed) individuals; longitudinal and cohort studies; aggregate time series; and area-based studies. The advantages and limitations of each are identified. The available evidence on the consequences of unemployment for poverty; health and mortality; mental health; crime and delinquency; and the social fabric is reviewed. The implications for policy and public expenditure are explored.

Crime↗
PubMed1998

Anticipating the consequences for the primary therapy of breast cancer after introducing screening. A more global picture for health care policy making.

A breast cancer screening program mainly aims at reducing mortality. However, it also has an effect, often not assessed, on the utilization of health care resources that is relevant to health care policy making. Using a simulation model, this paper forecasts the impact of introducing a breast cancer screening program on the utilization of resources for the primary therapy of breast cancer. The most important consequences from a health care point of view will be an increased use of breast-conserving therapy and an increased need for postoperative radiotherapy; there will also be a higher number of women diagnosed with noninvasive breast cancer. The results of this study could provide support for health care decision making by showing the consequences of policy decisions on the introduction of screening programs for health care utilization.

Adult↗
PubMedDate not supplied

Rod and cone visual cycle consequences of a null mutation in the 11-cis-retinol dehydrogenase gene in man.

Vertebrate vision starts with photoisomerization of the 11-cis-retinal chromophore to all-trans-retinal. Biosynthesis of 11-cis-retinal is required to maintain vision. A key enzyme catalyzing the oxidation of 11-cis-retinol is 11-cis-retinol dehydrogenase (11-cis-RDH), which is encoded by the RDH5 gene. 11-cis-RDH is expressed in the RPE and not in the neural retina. The consequences of a lack of 11-cis-RDH were studied in a family with fundus albipunctatus. We identified the causative novel RDH5 mutation, Arg157Trp, that replaces an amino acid residue conserved among short-chain alcohol dehydrogenases. Three-dimensional structure modeling and in vitro experiments suggested that this mutation destabilizes proper folding and inactivates the enzyme. Studies using RPE membranes indicated the existence of an alternative oxidizing system for the production of 11-cis-retinal. In vivo visual consequences of this null mutation showed complex kinetics of dark adaptation. Rod and cone resensitization was extremely delayed following full bleaches; unexpectedly, the rate of cone recovery was slower than rods. Cones showed a biphasic recovery with an initial rapid component and an elevated final threshold. Other unanticipated results included normal rod recovery following 0.5% bleach and abnormal recovery following bleaches in the 2-12% range. These intermediate bleaches showed rapid partial recovery of rods with transitory plateaux. Pathways in addition to 11-cis-RDH likely provide 11-cis-retinal for rods and cones and can maintain normal kinetics of visual recovery but only under certain constraints and less efficiently for cone than rod function.

Adaptation, Ocular↗
PubMed2001

Stress and development: behavioral and biological consequences.

Childhood abuse is an important public health problem; however, little is known about the effects of abuse on the brain and neurobiological development. This article reviews the behavioral and biological consequences of childhood abuse and places them in a developmental context. Animal studies show that both positive and negative events early in life can influence neurobiological development in unique ways. Early stressors such as maternal separation result in lasting effects on stress-responsive neurobiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic systems. These studies also implicate a brain area involved in learning and memory, the hippocampus. in the long-term consequences of early stress. Clinical studies of patients with a history of abuse also implicate dysfunction in the HPA axis and the noradrenergic and hippocampal systems; however, there are multiple questions related to chronicity of stress, developmental epoch at the time of the stressor, presence of stress-related psychiatric disorders including posttraumatic stress disorder and depression. and psychological factors mediating the response to trauma that need to be addressed in this field of research. Understanding the effects of abuse on the development of the brain and neurobiology will nevertheless have important treatment and policy implications.

Age Factors↗
PubMed1985

Phosphoenolpyruvate synthetase and pyruvate, orthophosphate dikinase: stereochemical consequences at both the beta-phospho and gamma-phospho groups of ATP.

[(R)-16O,17O,18O]Phosphoenolpyruvate and adenosine 5'-O-[(gamma S)-beta gamma-17O,gamma-17O,18O](3-thiotriphosphate) have been synthesized and used to determine the stereochemical course of the several displacements at phosphorus catalyzed by phosphoenolpyruvate synthetase and by pyruvate, orthophosphate dikinase, two enzymes that catalyze the formation of phosphoenolpyruvate from pyruvate and ATP. The catalytic mechanisms for each of these enzymes are believed to involve both phospho- and pyrophospho-enzyme intermediates. The stereochemical results are entirely in accord with these pathways: the beta-phospho group of ATP suffers overall retention of configuration that is presumably the consequence of two displacements with inversion, and the gamma-phospho group of ATP gamma S suffers inversion of configuration that is most probably the consequence of a single displacement at this center.

Adenosine Triphosphate↗
PubMed2005

Changes produced in the antioxidative activity of phospholipids as a consequence of their oxidation.

The antioxidative activities of native and oxidized soybean phosphatidylcholine (PC), phosphatidylthanolamine (PE), and phosphatidylinositol (PI) in the protection of soybean oil heated in the dark under air at 60 degrees C were studied in an attempt to clarify the consequences that phospholipid oxidation has on antioxidative activities. The three native phospholipids protected the oil when assayed at 200 ppm, and phospholipid oxidation decreased the antioxidative activity of both PC and PI. However, slightly oxidized PE was more antioxidative than native PE, most likely as a consequence of the formation by amino-carbonyl reactions of pyrrolized phospholipids, which were determined and for which antioxidative properties are known. Nevertheless, further increases in PE oxidation produced a decrease in its antioxidative activity. These results suggest that two opposite reactions are competing in the antioxidative activity of amino phospholipids upon oxidation: fatty acid chain oxidation, which decreases phospholipid antioxidative activity, and amino-carbonyl reactions, which produce derivatives with antioxidant properties. This last property may be useful to increase the antioxidative activity of commercial lecithins containing amino phospholipids.

Antioxidants↗
PubMed1996

Influence of glutathione on the oxidation of 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline: chemistry of potential relevance to the addictive and neurodegenerative consequences of ethanol use.

Recent evidence suggests that intraneuronal metabolism of ethanol by catalase/H2O2 and an ethanol-inducible form of cytochrome P450 together generate acetaldehyde and oxygen radicals including the hydroxyl radical (HO.). Within the cytoplasm of serotonergic neurons, these metabolic processes would thus provide acetaldehyde, which would react with unbound 5-hydroxytryptamine (5-HT) to give 1-methyl-6-hydroxy-1,2,3,4-tetrahydro-beta-carboline (1), known to be formed at elevated levels in the brain following ethanol drinking, and HO. necessary to oxidize this alkaloid. In this study, it is demonstrated that the HO.-mediated oxidation of 1 at physiological pH yields 1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (8) that reacts avidly with free glutathione (GSH), a significant constituent of axons and nerve terminals, to give diastereomers of 8-S-glutathionyl-1-methyl-1,2,3,4-tetrahydro-beta-carboline-5,6-dione (9A and 9B). In the presence of free GSH, ascorbic acid, other intraneuronal antioxidants/reductants, and molecular oxygen diastereomers, 9A/9B redox cycle in reactions that generate H2O2 and, via trace transition metal ion catalyzed decomposition of the latter compound, HO.. Further reactions of 9A/9B with GSH and/or HO. generate several additional glutathionyl conjugates that also redox cycle in the presence of intraneuronal reductants and molecular oxygen forming H2O2 and HO.. Thus, intraneuronal formation of 1 and HO. as a consequence of ethanol drinking and resultant endogenous synthesis of 8,9A, and 9B would, based on these in vitro chemical studies, be expected to generate elevated fluxes of H2O2 and HO. leading to oxidative damage to serotonergic axons and nerve terminals and the irreversible loss of GSH, both of which occur in the brain as a consequence of ethanol drinking. Furthermore, deficiencies of 5-HT and loss of certain serotonergic pathways in the brain have been linked to the preference for and addiction to ethanol.

Acetaldehyde↗
PubMed2005

A systematically generated, pressure-dependent mechanism for high-conversion ethane pyrolysis. 2. Radical disproportionations, missing reaction families, and the consequences of pressure dependence.

A previous, companion paper of this work (preceding paper in this issue) systematically developed a pressure-dependent reaction mechanism for the high-conversion pyrolysis of ethane, as studied experimentally by Glasier and Pacey. By combining conventional equilibrium, sensitivity, and reaction pathway analyses, that study identified a complex set of reaction pathways governing the formation and destruction of the important minor products acetylene, propylene, 1,3-butadiene, and benzene, which are pyrocarbon deposition precursors. To more confidently understand, and potentially manipulate, the complex chemistry governing deposition precursors, this work examines in more detail (1) the role of large sets of radical disproportionation reactions in forming the minor products, (2) the consequence of ignoring certain reactions during mechanism construction, (3) the appropriateness of the plug flow assumption used to model the reactor, and (4) the importance of reaction pressure dependence to the predictions of the minor product concentrations. We find that the predicted benzene concentration is sensitive to the presence of a specific, large collection of radical disproportionation reactions, typically neglected in most modeling efforts and of consequence only in the aggregate. Reaction families allowing Diels-Alder reaction, ene reaction, and triplet ethylene formation are safely ignored during model construction for the experimental conditions, but two specific reactions proposed in the literature, which rapidly convert fulvene to benzene, potentially explain the underprediction of benzene by the generated model. However, the rates proposed for these reactions are either unrealistically fast, or unconfirmed. We find the plug flow assumption reasonable in most respects, but its neglect of H-atom diffusion could explain the mechanism's systematic underprediction of hydrogen concentration at longer residence times. Finally, we demonstrate that accurate predictions of the minor product predictions appear to require the systematic treatment of pressure dependence employed by our mechanism generation algorithm. Changing the pressure in the experimental reactor alters the distribution of the minor products, or deposition precursors, through changes in the pressure-dependent reaction rates involved in their formation. We close with suggestions for the future development of automated mechanism generation tools, based on the current results.

Journal Article↗
PubMed2000

Autoimmune and antitumor consequences of antibodies against antigens shared by normal and malignant tissues.

There is now a considerable body of information documenting the autoimmune consequences of antibodies induced by growing malignancies, or by passively administered and actively induced antibodies, in cancer patients against antigens shared by normal and malignant tissues. This provides a rich source of information addressing the consequences of autoantibodies against a range of antigens. Antibodies against cell-surface or intracellular antigens in the central nervous system (CNS) or on epithelial surfaces of normal tissues do not generally result in autoimmunity, but the same types and titers of antibodies against cell surface antigens in the subepidermal skin, peripheral nerves, blood, or vascular sites such as the spleen and bone marrow readily induce autoimmunity. The blood brain barrier of the CNS and apical antigen expression and the basement membrane in epithelial tissues, may protect these sites from antibody induced damage. Cancer cells, however, are protected by neither unidirectional antigen expression nor basement membranes. Vaccine induced antibodies against a variety of cancer cell surface antigens have been associated with prevention of tumor recurrence in preclinical models and in vaccinated cancer patients, in the absence of demonstrable autoimmunity. This forms the basis for a series of ongoing Phase III trials with single or polyvalent antigen cancer vaccines designed for optimal antibody induction.

Animals↗
PubMed1998

Physiological consequences of expression of the Na+/H+ antiporter sod2 in Escherichia coli.

Sod2 is the sodium-proton antiporter on the plasma membrane of the fission yeast Schizosaccharomyces pombe. It is vitally important for sodium export and pH homeostasis in this organism. Recently, the sod2 gene has been cloned and sequenced. However, initial attempts to express sod2 in Escherichia coli using the T7 promoter failed. In the present work we examined physiological consequences of expression of sod2 in E. coli. To alleviate problems caused by expression of sod2 we: (i) used sodium-free media at all steps; (ii) used the moderate tac promoter for expression and; (iii) used E. coli strain MH1 which has impaired sodium exchange. The effect of sod2 expression on E. coli varied depending on the E. coli genotype. When sod2 was expressed in BL21 cells which have normal Na+/H+ antiporters, the result was a Li+ sensitive phenotype. LiCl completely arrested or prevented growth of BL21 E. coli transformed with the sod2 gene. The effect on growth was pronounced in media of low external pH. Sod2 was then expressed in E. coli MH1 which is devoid of endogenous Na+/H+ antiporters. These cells became more resistant to external LiCl, but only in Na+ containing media. In the absence of external Na+, the presence of sod2 reduced growth. The results are explained in a model which demonstrates the physiological consequences of interference by expression of a foreign electroneutral Na+/H+ antiporter in conjunction with different housekeeping systems of E. coli host cells.

Escherichia coli↗
PubMed1997

Basic Science Reasoning and Clinical Reasoning Intertwined: Epistemological Analysis and Consequences for Medical Education.

The aim of this paper is to emphasize the distinction between basic medical science (and reasoning) and clinical science (and reasoning) in order to illuminate some basic philosophical and cognitive issues in medical education. The Kunhian concept of exemplar refers to the field of growth of scientific knowledge and in this sense is related to the "anti-theoretical" emphasis on problem solving performance. In cognitive science this (and similar) types of postpositivistic objections to the formalistic excess of the neopositivistic tradition are exploited to stress the relevance of the distinction between theories and their domains of application. This objection is exploited to stress the difference between established bodies of scientific knowledge and their processes of discovery and/or application and, in medical knowledge, between clinical reasoning (situated, concerned with attributes of people) and basic science reasoning (unsituated, concerned with attributes of entities such as organs, bacteria, viruses). Exploiting the theoretical consequences of the previous analysis I will try to answer some questions: What is the role of problem solving in teaching and learning, as different from conventional basic science-centred education? Is it relevant, in medical education, an epistemological and logical awareness of the main methodological topics? Finally, the analysis of the significance of abduction in a unified epistemological model of medical reasoning is exploited to individuate the proper ontological level dealing with the entities and relationships belonging to the dynamism of the underlying domain knowledge (for instance biomedical physics) and the consequences for medical education.

Journal Article↗
PubMedDate not supplied

Modeling of substance P and 5-HT induced synaptic plasticity in the lamprey spinal CPG: consequences for network pattern generation.

Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed by means of simulations. This is motivated by the effects substance P (a tachykinin) and serotonin (5-hydroxytryptamin; 5-HT) have on synaptic transmission in the locomotor network. Activity-dependent synaptic depression and potentiation have recently been shown experimentally using paired intracellular recordings. Although normally activity-dependent plasticity presumably does not contribute to the patterning of network activity, this changes in the presence of the neuromodulators substance P and 5-HT, which evoke significant plasticity. Substance P can induce a faster and larger depression of inhibitory connections but potentiation of excitatory inputs, whereas 5-HT induces facilitation of both inhibitory and excitatory inputs. Changes in the amplitude of the first postsynaptic potential are also seen. These changes could thus be a potential mechanism underlying the modulatory role these substances have on the rhythmic network activity. The aim of the present study has been to implement the activity dependent synaptic depression and facilitation induced by substance P and 5-HT into two alternative models of the lamprey spinal locomotor network, one relying on reciprocal inhibition for bursting and one in which each hemicord is capable of oscillations. The consequences of the plasticity of inhibitory and excitatory connections are then explored on the network level. In the intact spinal cord, tachykinins and 5-HT, which can be endogenously released, increase and decrease the frequency of the alternating left-right burst pattern, respectively. The frequency decreasing effect of 5-HT has previously been explained based on its conductance decreasing effect on K(Ca) underlying the postspike afterhyperpolarization (AHP). The present simulations show that short-term synaptic plasticity may have strong effects on frequency regulation in the lamprey spinal CPG. In the network model relying on reciprocal inhibition, the observed effects substance P and 5-HT have on network behavior (i.e., a frequency increase and decrease respectively) can to a substantial part be explained by their effects on the total extent and time dynamics of synaptic depression and facilitation. The cellular effects of these substances will in the 5-HT case further contribute to its network effect.

Action Potentials↗
PubMed1998

Antecedents and consequences of victimization of lesbian, gay, and bisexual young people: a structural model comparing rural university and urban samples.

Research indicates that antigay victimization is widespread and that lesbian, gay, and bisexual young people may be very vulnerable to such victimization. The current study builds upon previous work by Hershberger and D'Augelli (1995), who studied the consequences of sexual orientation-based victimization in 194 urban lesbian, gay, and bisexual youths. Using structural equation modeling, the present study models both antecedents and consequences (including psychological distress, self-esteem, and suicidality) of victimization via a secondary analysis of their data set. In addition, a second sample of 54 lesbian, gay, and bisexual youths from a rural university setting was examined to cross-validate and generalize the relationships found in urban settings. Results indicated that a revised model of victimization exhibited sufficient fit to the urban sample data and provided preliminary support for the generalizability of the model beyond the initial sample. Additional similarities were found between the urban and rural university community samples, including a high prevalence of reported suicide attempts: 42% of the urban sample and 32% of the rural university sample had attempted suicide at least once. Results indicated that victimization based on sexual orientation has similar correlates for young people in different community settings.

Bisexuality↗