| 1. |
- Painter, Page R, et al.
(författare)
-
Pulsatile blood flow, shear force, energy dissipation and Murray's Law
- 2006
-
Ingår i: Theoretical Biology Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 3:31
-
Tidskriftsartikel (refereegranskat)abstract
- Background Murray's Law states that, when a parent blood vessel branches into daughter vessels, the cube of the radius of the parent vessel is equal to the sum of the cubes of the radii of daughter blood vessels. Murray derived this law by defining a cost function that is the sum of the energy cost of the blood in a vessel and the energy cost of pumping blood through the vessel. The cost is minimized when vessel radii are consistent with Murray's Law. This law has also been derived from the hypothesis that the shear force of moving blood on the inner walls of vessels is constant throughout the vascular system. However, this derivation, like Murray's earlier derivation, is based on the assumption of constant blood flow. Methods To determine the implications of the constant shear force hypothesis and to extend Murray's energy cost minimization to the pulsatile arterial system, a model of pulsatile flow in an elastic tube is analyzed. A new and exact solution for flow velocity, blood flow rate and shear force is derived. Results For medium and small arteries with pulsatile flow, Murray's energy minimization leads to Murray's Law. Furthermore, the hypothesis that the maximum shear force during the cycle of pulsatile flow is constant throughout the arterial system implies that Murray's Law is approximately true. The approximation is good for all but the largest vessels (aorta and its major branches) of the arterial system. Conclusion A cellular mechanism that senses shear force at the inner wall of a blood vessel and triggers remodeling that increases the circumference of the wall when a shear force threshold is exceeded would result in the observed scaling of vessel radii described by Murray's Law.
|
|
| 2. |
- Eriksen, Kasper
(författare)
-
Localization of DNA damage by current exchanging repair enzymes
- 2005
-
Ingår i: Theoretical Biology Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 2:1, s. 15-15
-
Tidskriftsartikel (refereegranskat)abstract
- Background How DNA repair enzymes find the relatively rare sites of damage is not known in great detail. Recent experiments and molecular data suggest that individual repair enzymes do not work independently of each other, but interact with each other through charges exchanged along the DNA. A damaged site in the DNA hinders this exchange. The hypothesis is that the charge exchange quickly liberates the repair enzymes from error-free stretches of DNA. In this way, the sites of damage are located more quickly; but how much more quickly is not known, nor is it known whether the charge exchange mechanism has other observable consequences. Results Here the size of the speed-up gained from this charge exchange mechanism is calculated and the characteristic length and time scales are identified. In particular, for Escherichia coli, I estimate the speed-up is 50000/N, where N is the number of repair enzymes participating in the charge exchange mechanism. Even though N is not exactly known, a speed-up of order 10 is not entirely unreasonable. Furthermore, upon over expression of all the repair enzymes, the location time only varies as N-1/2 and not as 1/N. Conclusion The revolutionary hypothesis that DNA repair enzymes use charge exchange along DNA to locate damaged sites more efficiently is actually sound from a purely theoretical point of view. Furthermore, the predicted collective behavior of the location time is important in assessing the impact of stress-ful and radioactive environments on individual cell mutation rates.
|
|
| 3. |
- Hahn, Robert, et al.
(författare)
-
A simple intravenous glucose tolerance test for assessment of insulin sensitivity
- 2011
-
Ingår i: Theoretical Biology and Medical Modelling. - : BioMed Central. - 1742-4682. ; 8:12
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe aim of the study was to find a simple intravenous glucose tolerance test (IVGTT) that can be used to estimate insulin sensitivity.MethodsIn 20 healthy volunteers aged between 18 and 51 years (mean, 28) comparisons were made between kinetic parameters derived from a 12-sample, 75-min IVGTT and the Mbw (glucose uptake) obtained during a hyperinsulinemic euglycemic glucose clamp. Plasma glucose was used to calculate the volume of distribution (Vd) and the clearance (CL) of the injected glucose bolus. The plasma insulin response was quantified by the area under the curve (AUCins). Uptake of glucose during the clamp was corrected for body weight (Mbw).ResultsThere was a 7-fold variation in Mbw. Algorithms based on the slope of the glucose-elimination curve (CL/Vd) in combination with AUCins obtained during the IVGTT showed statistically significant correlations with Mbw, the linearity being r2 = 0.63-0.83. The best algorithms were associated with a 25-75th prediction error ranging from -10% to +10%. Sampling could be shortened to 30-40 min without loss of linearity or precision.ConclusionSimple measures of glucose and insulin kinetics during an IVGTT can predict between 2/3 and 4/5 of the insulin sensitivity.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Caster, Ola, et al.
(författare)
-
Computing limits on medicine risks based on collections of individual case reports
- 2014
-
Ingår i: Theoretical Biology and Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Quantifying a medicine's risks for adverse effects is crucial in assessing its value as a therapeutic agent. Rare adverse effects are often not detected until after the medicine is marketed and used in large and heterogeneous patient populations, and risk quantification is even more difficult. While individual case reports of suspected harm from medicines are instrumental in the detection of previously unknown adverse effects, they are currently not used for risk quantification. The aim of this article is to demonstrate how and when limits on medicine risks can be computed from collections of individual case reports. Methods: We propose a model where drug exposures in the real world may be followed by adverse episodes, each containing one or several adverse effects. Any adverse episode can be reported at most once, and each report corresponds to a single adverse episode. Based on this model, we derive upper and lower limits for the per-exposure risk of an adverse effect for a given drug. Results: An upper limit for the per-exposure risk of the adverse effect Y for a given drug X is provided by the reporting ratio of X together with Y relative to all reports on X, under two assumptions: (i) the average number of adverse episodes following exposure to X is one or less; and (ii) adverse episodes that follow X and contain Y are more frequently reported than adverse episodes in general that follow X. Further, a lower risk limit is provided by dividing the number of reports on X together with Y by the total number of exposures to X, under the assumption that exposures to X that are followed by Y generate on average at most one report on X together with Y. Using real data, limits for the narcolepsy risk following Pandemrix vaccination and the risk of coeliac disease following antihypertensive treatment were computed and found to conform to reference risk values from epidemiological studies. Conclusions: Our framework enables quantification of medicine risks in situations where this is otherwise difficult or impossible. It has wide applicability, but should be particularly useful in structured benefit-risk assessments that include rare adverse effects.
|
|
| 7. |
- Hahn, Robert, et al.
(författare)
-
Plasma volume expansion from the intravenous glucose tolerance test before and after hip replacement surgery
- 2013
-
Ingår i: Theoretical Biology and Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 10:48
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundHyperosmotic glucose is injected intravenously when an intravenous glucose tolerance test (IVGTT) is initiated. The extent and time period of plasma volume expansion that occurs in response to the glucose load has not been studied in the perioperative setting.MethodsTwenty-two non-diabetic patients aged between 57 and 76 years (mean 68) underwent an IVGTT, during which 0.3 g/kg of glucose 30% (1 ml/kg) was injected as a bolus over one minute, one day before and two days after hip replacement surgery. Twelve blood samples were collected over 75 minutes from each patient. The turnover of both the exogenous glucose and the injected fluid volume was calculated by means of mass balance and volume kinetic analysis.ResultsThe IVGTT raised plasma glucose by 9 mmol/L and the plasma volume by 8%. The extracellular fluid volume increased by 320 (SD 60) ml of which 2/3 could be accounted for in the plasma. The half-life of the exogenous glucose averaged 30 minutes before surgery and 36 minutes postoperatively (P < 0.02). The glucose elimination governed 86% of the decay of the plasma volume expansion, which occurred with a half-life of 12 minutes before to 21 minutes after the surgery (median, P < 0.001).ConclusionHyperosmotic glucose translocated intracellular water to the plasma volume rather than to the entire extracellular fluid volume. The preferential re-distribution acts to dilute the plasma concentrations used to quantify insulin sensitivity and ß-cell function from an IVGTT. The greater-than-expected plasma dilution lasted longer after than before surgery.
|
|
| 8. |
- Konkoli, Zoran, 1966
(författare)
-
A danger of low copy numbers for inferring incorrect cooperativity degree
- 2010
-
Ingår i: Theoretical Biology and Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 7:1, s. 40-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: A dose-response curve depicts fraction of bound proteins as a function of unbound ligands. Dose-response curves are used to measure the cooperativity degree of a ligand binding process. Frequently, the Hill function is used to fit the experimental data. The Hill function is parameterized by the value of the dissociation constant, and the Hill coefficient which describes the cooperativity degree. The use of Hill's model and the Hill function have been heavily criticised in this context, predominantly the assumption that all ligands bind at once, which lead to further refinements of the model. In this work, the validity of the Hill function has been studied from an entirely different point of view. In the limit of low copy numbers the dynamics of the system becomes noisy. The goal was to asses the validity of the Hill function in this limit, and to see in which ways the effects of the fluctuations change the form of the dose-response curves. Results: Dose-response curves were computed taking into account effects of fluctuations. The effects of fluctuations were described at the lowest order (the second moment of the particle number distribution) by using previously developed Pair Approach Reaction Noise EStimator (PARNES) method. The stationary state of the system is described by nine equations with nine unknowns. To obtain fluctuation corrected dose-response curves the equations have been investigated numerically.Conclusions: The Hill function cannot describe dose-response curves in a low particle limit. First, dose-response curves are not solely parameterized by the dissociation constant and the Hill coefficient. In general, the shape of a dose-response curve depends on the variables that describe how an experiment (ensemble) is designed. Second, dose-response curves are multi valued in a rather non-trivial way.
|
|
| 9. |
- Konkoli, Zoran, 1966, et al.
(författare)
-
Fluctuations in Tat copy number when it counts the most: a possible mechanism to battle the HIV latency
- 2013
-
Ingår i: Theoretical Biology and Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- The HIV-1 virus can enter a dormant state and become inactive, which reduces accessibility by antiviral drugs. We approach this latency problem from an unconventional point of view, with the focus on understanding how intrinsic chemical noise (copy number fluctuations of the Tat protein) can be used to assist the activation process of the latent virus. Several phase diagrams have been constructed in order to visualize in which regions of the parameter space noise can drive the activation process. Essential to the study is the use of a hyperbolic coordinate system, which greatly facilitates quantification of how the various reaction rate combinations shape the noise behavior of the Tat protein feedback system. We have designed a mathematical manual of how to approach the problem of activation quantitatively, and introduce the notion of an “operating point” of the virus. For both noise-free and noise-based strategies we show how operating point off-sets induce changes in the number of Tat molecules. The major result of the analysis is that for every noise-free strategy there is a noise-based strategy that requires lower dosage, but achieves the same anti-latency effect. It appears that the noise-based activation is advantageous for every operating point.
|
|
| 10. |
- Konkoli, Zoran, 1966
(författare)
-
Mathematical explanation of the predictive power of the X-level approach reaction noise estimator method
- 2012
-
Ingår i: Theoretical Biology and Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 9:1, s. 12-
-
Tidskriftsartikel (refereegranskat)abstract
- The X-level Approach Reaction Noise Estimator (XARNES) method has been developed previously to study reaction noise in well mixed reaction volumes. The method is a typical moment closure method and it works by closing the infinite hierarchy of equations that describe moments of the particle number distribution function. This is done by using correlation forms which describe correlation effects in a strict mathematical way. The variable X is used to specify which correlation effects (forms) are included in the description. Previously, it was argued, in a rather informal way, that the method should work well in situations where the particle number distribution function is Poisson-like. Numerical tests confirmed this. It was shown that the predictive power of the method increases, i.e. the agreement between the theory and simulations improves, if X is increased. In here, these features of the method are explained by using rigorous mathematical reasoning. Three derivative matching theorems are proven which show that the observed numerical behavior is generic to the method.
|
|
