The effects of hyperoxic and hypercarbic gases on tumour blood flow.
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Carbogen (95% O2 and 5% CO2) has been used in preference to 100% oxygen (O2) as a radiosensitizer, because it is believed that CO2 blocks O2-induced vasoconstriction. However, recent work suggests that both normal and tumour arterioles of dorsal flap window chambers exhibit the opposite: no vasoconstriction vs constriction for O2 vs carbogen breathing respectively. We hypothesized that CO2 content might cause vasoconstriction and investigated the effects of three O2-CO2 breathing mixtures on tumour arteriolar diameter (TAD) and blood flow (TBF). Fischer 344 rats with R3230Ac tumours transplanted into window chambers breathed either 1%, 5%, or 10% CO2 + O2. Intravital microscopy and laser Doppler flowmetry were used to measure TAD and TBF respectively. Animals breathing 1% CO2 had increased mean arterial pressure (MAP), no change in heart rate (HR), transient reduction in TAD and no change in TBF. Rats breathing 5% CO2 (carbogen) had transiently increased MAP, decreased HR, reduced TAD and a sustained 25% TBF decrease. Animals exposed to 10% CO2 experienced a transient decrease in MAP, no HR change, reduced TAD and a 30-40% transient TBF decrease. The effects on MAP, HR, TAD and TBF were not CO2 dose-dependent, suggesting that complex physiologic mechanisms are involved. Nevertheless, when > or = 5% CO2 was breathed, there was clear vasoconstriction and TBF reduction in this model. This suggests that the effects of hypercarbic gases on TBF are site-dependent and that use of carbogen as a radiosensitizer may be counterproductive in certain situations. (+info)
Latent class analysis permits unbiased estimates of the validity of DAT for the diagnosis of visceral leishmaniasis.
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BACKGROUND: Substantial uncertainty surrounds the specificity of the Direct Agglutination Test (DAT) for visceral leishmaniasis (VL) in clinical suspects, since no good gold standard exists for unequivocally identifying diseased subjects. We explored the Latent Class Analysis (LCA) modelling technique to circumvent this problem. PATIENTS AND METHODS: Data on 149 clinical suspects recruited in 1993-96 during a multicentre study in Sudan were re-examined. Clinical data, lymph node and bone marrow aspirate and DAT results were available. IFAT was performed in 1997 on stored filter paper blood of 80 individuals. Classical Validity Analysis (CVA) in a 2 x 2 contingency table with parasitology as a gold standard was compared with the parameter estimates produced by the best fitting LCA model. RESULTS: The sensitivity estimates of DAT produced by CVA (98% (89%-100%)) were almost exactly reproduced by LCA. The specificity estimates by LCA were substantially higher than those obtained in CVA. Specificity of DAT depended, however, on whether the subject was treated for VL before. In subjects without prior treatment, CVA estimated DAT specificity at 68% (56%-79%), whereas LCA estimated it at 85% (63%-100%). CONCLUSION: LCA modelling proved a useful tool, as it gave consistent estimates of test characteristics and allowed for control of confounding factors and interaction effects. Since VL is a life-threatening disease for which expensive but effective and safe treatment exists, a clinical suspect in an endemic area should be treated on the basis of a positive DAT result. (+info)
Mathematical models for peritoneal transport characteristics.
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Four mathematical models and for the description of peritoneal transport of fluid solutes are reviewed. The membrane model is usually applied for (1) separation of transport components, (2) formulation of the relationship between flow components and their driving forces, and (3) estimation of transport parameters. The three-pore model provides correct relationships between various transport parameters and demonstrates that the peritoneal membrane should be considered heteroporous. The extended three-pore model discriminates between heteroporous capillary wall and tissue layer, which are assumed to be arranged in series; the model improves and modifies the results of the three-pore model. The distributed model includes all parameters involved in peritoneal transport and takes into account the real structure of the tissue with capillaries distributed at various distances from the surface of the tissue. How the distributed model may be applied for the evaluation of the possible impact of perfusion rate on peritoneal transport, as recently discussed for clinical and experimental studies, is demonstrated. The distributed model should provide theoretical bases for the application of other models as approximate and simplified descriptions of peritoneal transport. However, an unsolved problem is the theoretical description of bi-directional fluid transport, which includes ultrafiltration to the peritoneal cavity owing to the osmotic pressure of dialysis fluid and absorption out of the peritoneal cavity owing to hydrostatic pressure. (+info)
Dynamics of Helicobacter pylori colonization in relation to the host response.
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The dynamics of Helicobacter pylori colonization from its acquisition through the development of steady-state are examined through a mathematical model that includes the host response. The model encompasses both host and microbiological variation. The individual capacity of the host response is shown to be a key model parameter, leading to either transient or persistent colonization, whereas the growth rate of that response has little effect. Analyses of competing strains indicate that each must occupy a specific niche, otherwise exclusion occurs. The model implies that there exists a lower bound on the host response to the indigenous microflora that is consistent with current biological views of H. pylori. Parallel models may be useful in understanding other persistent host-microbial interactions. (+info)
Is there a rational basis for post-surgical lifting restrictions? 2. Possible scientific approach.
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Lifting restrictions postoperatively are quite common but there appears to be little scientific basis for them. Lifting restricitions are inhibitory in terms of return to work and may be a factor in chronicity. The mean changes in functional spinal motion unit (FSU) stiffness with in vitro or computer-simulated discectomies, facetectomies and laminectomies were reviewed from the literature. We modified the NIOSH lifting equation to include another multiplier related to stiffness change post surgery. The new recommended lifts were computed for different lifting conditions seen in industry. The reduction of rotational stiffness ranged from 21% to 41% for a discectomy, 1% to 59% for a facetectomy and 4% to 16% for a partial laminectomy. The recommended lifts based on our modified equation were adjusted accordingly. There is no rational basis for current lifting resctrictions. The risk to the spine is a function of many other variables as well as weight (i.e., distance of weight from body). The adjusted NIOSH guidelines provide a reasonable way to estimate weight restrictions and accomodations such as lifting aids. Such resitrictions should be as liberal as possible so as to facilitate, not prevent, return to work. Patients need more advice regarding lifting activities and clinicians should be more knowledgeable about the working conditions and constraints of a given workplace to effectively match the solution to the patient's condition. (+info)
On the role of feedback in promoting conflicting goals of the adaptive immune system.
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We explored here the implications of two premises. 1) In their response over days or weeks to pathogen invasion, cells of the immune system combine several overlapping and perhaps contradictory goals. 2) The immune system has ways to monitor progress toward these goals via receptors that bind chemicals whose concentrations are related to such progress. We illustrate with simple mathematical models how such monitoring can lead to feedbacks that improve the efficiency of a given effector type in accomplishing its specialized task, and also how feedbacks can shift the balance among a variety of effectors toward a preponderance of the more effective. Specific suggestions are given for feedback molecules. (+info)
Species, interindividual, and tissue specificity in endocrine signaling.
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The activity of endocrine-active agents exhibits specificity at many levels. Differential responsiveness to these agents has been observed between different species and extends to interindividual differences within a species and between different tissues as well. In cases where they have been identified, the biologic and molecular mechanisms underlying this specificity are quite diverse. Determinants of species specificity include differences that exist in receptor binding, gene transcription, and cellular responses to endocrine-active compounds between species. Interindividual differences in responsiveness may be determined at the level of genetic polymorphisms in hormone-metabolizing enzymes, hormone receptors, and in those genes that are transactivated by these receptors, as well as during changing windows of susceptibility that occur as a function of age, such as prenatal and postmenopausal exposures. Extrinsic factors such as diet can also impact individual susceptibility to endocrine-active agents. Tissue-specific determinants of susceptibility are well documented, but little is known regarding the mechanisms underlying these different responses. Differences in the expression of accessory proteins for steroid hormone receptors and different patterns of receptor expression, estrogen receptor alpha and estrogen receptor beta; for example, may contribute to tissue specificity, as may differences in the pattern of expression of other genes such as hormone-metabolizing enzymes. The use of animal model systems and development of appropriate mathematical models has the potential to yield additional valuable information for elucidating the role of these determinants of specificity at low-dose exposures and for improved risk assessments for the adverse health effects of endocrine-active compounds. (+info)
Quantitative mechanistically based dose-response modeling with endocrine-active compounds.
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A wide range of toxicity test methods is used or is being developed for assessing the impact of endocrine-active compounds (EACs) on human health. Interpretation of these data and their quantitative use in human and ecologic risk assessment will be enhanced by the availability of mechanistically based dose-response (MBDR) models to assist low-dose, interspecies, and (italic)in vitro(/italic) to (italic)in vivo(/italic) extrapolations. A quantitative dose-response modeling work group examined the state of the art for developing MBDR models for EACs and the near-term needs to develop, validate, and apply these models for risk assessments. Major aspects of this report relate to current status of these models, the objectives/goals in MBDR model development for EACs, low-dose extrapolation issues, regulatory inertia impeding acceptance of these approaches, and resource/data needs to accelerate model development and model acceptance by the research and the regulatory community. (+info)