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1.  Coping with Variability in Small Neuronal Networks 
Experimental and corresponding modeling studies indicate that there is a 2- to 5-fold variation of intrinsic and synaptic parameters across animals while functional output is maintained. Here, we review experiments, using the heartbeat central pattern generator (CPG) in medicinal leeches, which explore the consequences of animal-to-animal variation in synaptic strength for coordinated motor output. We focus on a set of segmental heart motor neurons that all receive inhibitory synaptic input from the same four premotor interneurons. These four premotor inputs fire in a phase progression and the motor neurons also fire in a phase progression because of differences in synaptic strength profiles of the four inputs among segments. Our work tested the hypothesis that functional output is maintained in the face of animal-to-animal variation in the absolute strength of connections because relative strengths of the four inputs onto particular motor neurons is maintained across animals. Our experiments showed that relative strength is not strictly maintained across animals even as functional output is maintained, and animal-to-animal variations in strength of particular inputs do not correlate strongly with output phase. Further experiments measured the precise temporal pattern of the premotor inputs, the segmental synaptic strength profiles of their connections onto motor neurons, and the temporal pattern (phase progression) of those motor neurons all in the same animal for a series of 12 animals. The analysis of input and output in this sample of 12 individuals suggests that the number (four) of inputs to each motor neuron and the variability of the temporal pattern of input from the CPG across individuals weaken the influence of the strength of individual inputs. Moreover, the temporal pattern of the output varies as much across individuals as that of the input. Essentially, each animal arrives at a unique solution for how the network produces functional output.
PMCID: PMC3223479  PMID: 21724619
2.  Impact of very long time output variation in the treatment of total marrow irradiation with helical tomotherapy 
Beam-on time in Total Marrow Irradiation (TMI) delivery with helical tomotherapy is more than 30 minutes. The purpose of this study was to investigate extended time output variation in tomotherapy machine without dose servo system and its impact on the dosimetry of TMI planning.
Materials and methods
The calibration procedures with 1800 seconds delivery were conducted. The slab and cylindrical phantoms were used for static and rotational output variation measurements, respectively. All measurements were performed in 0.1 second interval with an Exradin A1SL ionization chamber (Standard Imaging Inc., Madison, WI, USA) connected to the tomoelectrometer supplied by the manufacture. Simulated TMI treatment planning with a slab phantom was delivered and verified with ion chamber and EDR-2 films.
The static output variations during 30 min averaged −2.9% ± 0.2%, -3.4% ± 0.3%, and −3.4% ± 0.3% at 10 min, 20 min, and 30 min, respectively. The rotational output variations from start averaged −2.5% ± 0.7%, -3.1% ± 0.7%, and −3.5% ± 0.8% at 10 min, 20 min, and 30 min, respectively. The maximum output variation was up to 4.5%. In a TMI planning model, in which beam-on time was over 30 min, planned dose and dose measured with ion chambers in both cranial and caudal sides agreed within 3%. Film measurements in cranial and caudal sides also showed the pass rates of 97.7% and 92.2% with the criteria of 3 mm/3% in gamma analysis.
These results suggest that long TMI delivery by helical tomotherapy, even without dose servo system, does not pose a risk for significant deviations from the original treatment plan regardless of the output variation. However, very long time output variation should be checked before the first treatment.
PMCID: PMC3679448  PMID: 23688298
Radiation therapy; Tomotherapy; Total marrow irradiation; Total body irradiation; Very long time output variation
3.  Gross Domestic Product (GDP) and productivity of schizophrenia trials: an ecological study 
BMC Psychiatry  2003;3:18.
The 5000 randomised controlled trials (RCTs) in the Cochrane Schizophrenia Group's database affords an opportunity to research for variables related to the differences between nations of their output of schizophrenia trials.
Ecological study – investigating the relationship between four economic/demographic variables and number of schizophrenia RCTs per country. The variable with closest correlation was used to predict the expected number of studies.
GDP closely correlated with schizophrenia trial output, with 76% of the total variation about the Y explained by the regression line (r = 0.87, 95% CI 0.79 to 0.92, r2 = 0.76). Many countries have a strong tradition of schizophrenia trials, exceeding their predicted output. All nations with no identified trial output had GDPs that predicted zero trial activity. Several nations with relatively small GDPs are, nevertheless, highly productive of trials. Some wealthy countries seem either not to have produced the expected number of randomised trials or not to have disseminated them to the English-speaking world.
This hypothesis-generating study could not investigate causal relationships, but suggests, that for those seeking all relevant studies, expending effort searching the scientific literature of Germany, Italy, France, Brazil and Japan may be a good investment.
PMCID: PMC305357  PMID: 14656379
4.  A Radiometric Study of Factors Affecting Drug Output of Jet Nebulizers 
Jet nebulizers show an unreasonable variation in drug output and nebulization rates that leads to clinical and regulatory problems. Current evaluation methods appear inadequate for the purpose. Our objective was to evaluate Technetium-99m radiometry to study nebulizer parameters and the factors influencing it quantitatively. Drug output, output rate and residual mass and the effect of excipient, temperature, surface tension, air-jet speed, and equipment brand and aging were studied. Though nebulization of radiolabeled drugs followed first-order kinetics, the rates were significantly different; the heaviest drug (Tc-99m colloid) and Tc-99m salbutamol had the least nebulization. Nebulization rate for the first minute was invariably higher than the mean rate signifying the concentration effect of the solute. Drug residue was 35-75%. Drug output of different nebulizer chamber and air compressor brands was different to the extent of 270% and 180% respectively. ‘Aging’ of fluid chamber, cold drug fluid and obstruction in air-jet resulted in significant reduction in output, while addition of 2% saline as excipient did not change the output rate. Addition of ethyl alcohol resulted in a maximum of 260% enhancement (with Tc-99m salbutamol), while further reduction in surface tension was counterproductive irrespective of the drug used. We conclude that radiometry can provide valuable parametric information on the performance of different jet nebulizers.
PMCID: PMC2883224  PMID: 20582187
Jet nebulizer performance; radiometry; Technetium-99m
5.  Cardiovascular system in larval zebrafish responds to developmental hypoxia in a family specific manner 
Genetic and environmental variation are both known to influence development. Evolution of a developmental response that is optimized to the environment (adaptive plasticity) requires the existence of genetic variation for that developmental response. In complex traits composed of integrated sets of subsidiary traits, the adaptive process may be slowed by the existence of multiple possible integrated responses. This study tests for family (sibship) specific differences in plastic response to hypoxia in an integrated set of cardiovascular traits in zebrafish.
Cardiac output, which is the integrated product of several subsidiary traits, varied highly significantly between families, and families differed significantly in the degree and direction of response to developmental oxygen level. The cardiac output response to oxygen environment was entirely family specific with no significant overall trend due to oxygen level. Constituent physiological variables that contribute to cardiac output all showed significant family specific response to hypoxia. Traits that were not directly related to cardiac output, such as arterial and venous diameter, and red blood cell velocities did not respond to hypoxia in a family specific manner.
Zebrafish families vary in their plastic response to hypoxia. Genetic variation in plastic response to hypoxia may therefore provide the basic ingredient for adaptation to a variable environment. Considerable variation in the degree of familial response to hypoxia exists between different cardiovascular traits that may contribute to cardiac output. It is possible that the integration of several subsidiary traits into cardiac output allows the maintenance of genetic variance in cardiac response.
PMCID: PMC1479343  PMID: 16539736
6.  Constancy and variability in the output of a central pattern generator 
Experimental and corresponding modeling studies have demonstrated a 2–5 fold variation of intrinsic and synaptic parameters across animals, while functional output is maintained. These studies have led to the hypothesis that correlated, compensatory changes in particular parameters can at least partially explain the biological variability in parameters. Using the leech heartbeat CPG, we selected three different segmental motor neurons that fire in a functional phase progression but receive input from the same four premotor interneurons. Previous work suggested that the phase progression arises because the pattern of relative strength of the four inputs varies systematically across the segmental motor neurons. Nevertheless, there was considerable animal-to-animal variation in the absolute strengths of these connections. We tested the hypothesis that functional output is maintained in the face of variation in the absolute strength of connections because relative strengths onto particular motor neurons are maintained. We found relative strength is not strictly maintained across animals even as functional output is maintained, and animal-to-animal variations in relative strength of particular inputs do not correlate strongly with output phase. In parallel with this variation in synaptic strength, the firing phase of the premotor inputs to these motor neurons varies considerably across individuals. We conclude that the number (four) of inputs to each motor neuron, which each vary in strength, and the phase diversity of the temporal pattern of input from the CPG diminish the influence of individual inputs. We hypothesize that each animal arrives at a unique solution for how the network produces functional output.
PMCID: PMC3071692  PMID: 21430165
leech; synaptic strength; motor neurons; network model
7.  Reproductive Efficiency of a Mediterranean Endemic Zooxanthellate Coral Decreases with Increasing Temperature along a Wide Latitudinal Gradient 
PLoS ONE  2014;9(3):e91792.
Investments at the organismal level towards reproduction and growth are often used as indicators of health. Understanding how such energy allocation varies with environmental conditions may, therefore, aid in predicting possible responses to global climatic change in the near future. For example, variations in seawater temperature may alter the physiological functioning, behavior, reproductive output and demographic traits (e.g., productivity) of marine organisms, leading to shifts in the structure, spatial range, and abundance of populations. This study investigated variations in reproductive output associated with local seawater temperature along a wide latitudinal gradient on the western Italian coast, in the zooxanthellate Mediterranean coral, Balanophyllia europaea. Reproductive potential varied significantly among sites, where B. europaea individuals from the warmest site experienced loss of oocytes during gametogenesis. Most of the early oocytes from warmest sites did not reach maturity, possibly due to inhibition of metabolic processes at high temperatures, causing B. europaea to reabsorb the oocytes and utilize them as energy for other vital functions. In a progressively warming Mediterranean, the efficiency of the energy invested in reproduction could be considerably reduced in this species, thereby affecting vital processes. Given the projected increase in seawater temperature as a consequence of global climate change, the present study adds evidence to the threats posed by high temperatures to the survival of B. europaea in the next decades.
PMCID: PMC3950289  PMID: 24618568
8.  Multiple-input multiple-output causal strategies for gene selection 
BMC Bioinformatics  2011;12:458.
Traditional strategies for selecting variables in high dimensional classification problems aim to find sets of maximally relevant variables able to explain the target variations. If these techniques may be effective in generalization accuracy they often do not reveal direct causes. The latter is essentially related to the fact that high correlation (or relevance) does not imply causation. In this study, we show how to efficiently incorporate causal information into gene selection by moving from a single-input single-output to a multiple-input multiple-output setting.
We show in synthetic case study that a better prioritization of causal variables can be obtained by considering a relevance score which incorporates a causal term. In addition we show, in a meta-analysis study of six publicly available breast cancer microarray datasets, that the improvement occurs also in terms of accuracy. The biological interpretation of the results confirms the potential of a causal approach to gene selection.
Integrating causal information into gene selection algorithms is effective both in terms of prediction accuracy and biological interpretation.
PMCID: PMC3323860  PMID: 22118187
9.  MARS Approach for Global Sensitivity Analysis of Differential Equation Models with Applications to Dynamics of Influenza Infection 
Differential equation models are widely used for the study of natural phenomena in many fields. The study usually involves unknown factors such as initial conditions and/or parameters. It is important to investigate the impact of unknown factors (parameters and initial conditions) on model outputs in order to better understand the system the model represents. Apportioning the uncertainty (variation) of output variables of a model according to the input factors is referred to as sensitivity analysis. In this paper, we focus on the global sensitivity analysis of ordinary differential equation (ODE) models over a time period using the multivariate adaptive regression spline (MARS) as a meta model based on the concept of the variance of conditional expectation (VCE). We suggest to evaluate the VCE analytically using the MARS model structure of univariate tensor-product functions which is more computationally efficient. Our simulation studies show that the MARS model approach performs very well and helps to significantly reduce the computational cost. We present an application example of sensitivity analysis of ODE models for influenza infection to further illustrate the usefulness of the proposed method.
PMCID: PMC3496759  PMID: 21656089
Global sensitivity analysis; Variable selection; Variance decomposition; Multivariate adaptive regression splines; Ordinary differential equation model
10.  The impact of linac output variations on dose distributions in helical tomotherapy 
Physics in medicine and biology  2007;53(2):417-430.
It has been suggested for quality assurance purposes that linac output variations for helical tomotherapy (HT) be within ±2% of the long-term average. Due to cancellation of systematic uncertainty and averaging of random uncertainty over multiple beam directions, relative uncertainties in the dose distribution can be significantly lower than those in linac output. The sensitivity of four HT cases with respect to linac output uncertainties was assessed by scaling both modelled and measured systematic and random linac output uncertainties until a dose uncertainty acceptance criterion failed. The dose uncertainty acceptance criterion required the delivered dose to have at least a 95% chance of being within 2% of the planned dose in all of the voxels in the treatment volume. For a random linac output uncertainty of 5% of the long-term mean, the maximum acceptable amplitude of the modelled, sinusoidal, systematic component of the linac output uncertainty for the four cases was 1.8%. Although the measured linac output variations represented values that were outside of the ±2% tolerance, the acceptance criterion did not fail for any of the four cases until the measured linac output variations were scaled by a factor of almost three. Thus the ±2% tolerance in linac output variations for HT is a more conservative tolerance than necessary.
PMCID: PMC2713685  PMID: 18184996
Helical tomotherapy; intensity modulation; output variations; dose uniformity; dose uncertainty
11.  Optical Limiting Using the Two-Photon Absorption Electrical Modulation Effect in HgCdTe Photodiode 
The Scientific World Journal  2013;2013:245310.
The electrical modulation properties of the output intensity of two-photon absorption (TPA) pumping were analyzed in this paper. The frequency dispersion dependence of TPA and the electric field dependence of TPA were calculated using Wherrett theory model and Garcia theory model, respectively. Both predicted a dramatic variation of TPA coefficient which was attributed into the increasing of the transition rate. The output intensity of the laser pulse propagation in the pn junction device was calculated by using function-transfer method. It shows that the output intensity increases nonlinearly with increasing intensity of incident light and eventually reaches saturation. The output saturation intensity depends on the electric field strength; the greater the electric field, the smaller the output intensity. Consequently, the clamped saturation intensity can be controlled by the electric field. The prior advantage of electrical modulation is that the TPA can be varied extremely continuously, thus adjusting the output intensity in a wide range. This large change provides a manipulate method to control steady output intensity of TPA by adjusting electric field.
PMCID: PMC3807540  PMID: 24198721
12.  Ability of pleth variability index to detect hemodynamic changes induced by passive leg raising in spontaneously breathing volunteers 
Critical Care  2008;12(2):R37.
Pleth Variability Index (PVI) is a new algorithm that allows continuous and automatic estimation of respiratory variations in the pulse oximeter waveform amplitude. Our aim was to test its ability to detect changes in preload induced by passive leg raising (PLR) in spontaneously breathing volunteers.
We conducted a prospective observational study. Twenty-five spontaneously breathing volunteers were enrolled. PVI, heart rate and noninvasive arterial pressure were recorded. Cardiac output was assessed using transthoracic echocardiography. Volunteers were studied in three successive positions: baseline (semirecumbent position); after PLR of 45° with the trunk lowered in the supine position; and back in the semirecubent position.
We observed significant changes in cardiac output and PVI during changes in body position. In particular, PVI decreased significantly from baseline to PLR (from 21.5 ± 8.0% to 18.3 ± 9.4%; P < 0.05) and increased significantly from PLR to the semirecumbent position (from 18.3 ± 9.4% to 25.4 ± 10.6 %; P < 0.05). A threshold PVI value above 19% was a weak but significant predictor of response to PLR (sensitivity 82%, specificity 57%, area under the receiver operating characteristic curve 0.734 ± 0.101).
PVI can detect haemodynamic changes induced by PLR in spontaneously breathing volunteers. However, we found that PVI was a weak predictor of fluid responsiveness in this setting.
PMCID: PMC2447559  PMID: 18325089
13.  Cardiac output after burn injury. 
Cardiac output after burn injury has been measured by the non-invasive method of impedance plethysmography. An initial study of 143 normal subjects was undertaken in order to investigate variations in cardiac output with age. Fifteen patients were monitored during resuscitation after extensive burns. Fourteen patients showed a depression of stroke volume below the lower limits of the normal range, derived from the initial study on normal people.
PMCID: PMC2493656  PMID: 6691694
14.  Novel use of cardiac pacemakers in heart failure to dynamically manipulate the respiratory system through algorithmic changes in cardiac output 
Circulation. Heart failure  2009;2(3):166-174.
Alternation of heart rate (HR) between two values using a pacemaker generates oscillations in end-tidal CO2 (et-CO2).
This study examined (a) whether modulating AV delay can also do this, and (b) whether more gradual variation of cardiac output can achieve comparable changes in et-CO2 with less-sudden changes in blood pressure (BP).
Methods and Results
We applied pacemaker fluctuations by adjusting HR (by 30 bpm) or atrioventricular (AV) delay (between optimal and non-optimal values) or both, with period of 60 seconds in 19 heart failure patients (age 73±11, EF 29%±12%). The changes in cardiac output, by either HR or AV delay or both, were made either as a step (“square wave”) or more gradually (“sine wave”).
We obtained changes in cardiac output sufficient to engender comparable oscillations in et-CO2 (p=NS) in all 19 patients either by manipulation of HR (14), or by AV delay (2) or both (3). The square wave produced 191 % larger and 250 % more sudden changes in BP than the sine wave alternations (22.4±11.7 versus 13.6±4.5 mmHg, p<0.01 and 19.8±10.0 versus 7.9±3.2 mmHg over 5s, p<0.01), but peak-to-trough et-CO2 elicited was only 45 % higher (0.45±0.18 versus 0.31±0.13 kPa, p=0.01).
This study shows that cardiac output is the key to dynamically manipulating the respiratory system with pacing sequences. When manipulating respiration by this route, a sine wave pattern may be preferable to a square wave, because it minimizes sudden BP fluctuations.
PMCID: PMC2759294  PMID: 19808336
respiration; hemodynamics; reflex; pacemakers; heart failure
15.  Case management to improve adherence for HIV-infected patients receiving antiretroviral therapy in Ethiopia: a micro-costing study 
Adherence to antiretroviral medication regimens is essential to good clinical outcomes for HIV-infected patients. Little is known about the costs of case management (CM) designed to improve adherence for patients identified as being at risk for poor adherence in resource-constrained settings. This study analyzed the costs, outputs, unit costs and correlates of unit cost variation for CM services in 14 ART sites in Ethiopia from October 2008 through September 2009.
This study applied standard micro-costing methods to identify the incremental costs of the CM program. We divided total CM-attributable costs by three output measures (patient-quarters of CM services delivered, number of patients served and successful patient exits) to derive three separate indices of unit costs. The relationships between unit costs and two operational factors (scale and service-volume to staff ratios) were quantified through bivariate analyses.
The CM program delivered 4,598 patient-quarters of services, serving 5,056 patients and 1,995 successful exits at a cost of $167,457 over 12 months, or $36 per patient-quarter, $33 per patient served and $84 per successful exit from the CM program. Among the 14 sites, mean costs were $11,961 (sd, $3,965) for the 12-month study period, and $51 (sd, $36) per patient-quarter; $48 (sd, $32) per patient served; and $183 (sd, $157) per successful exit. Unit costs varied inversely with scale (r, -0.70 for cost per patient-quarter versus patient-quarters of service) and with the service-volume to staff ratio (r, -0.68 for cost per patient-quarter versus staff per patient-quarter).
For those receiving CM, the program adds 0.52% to the lifetime cost of ART. These data reflect wide variation in unit costs among the study sites and suggest that high patient volume may be a major determinant of CM program efficiency. The observed variations in unit costs also indicate that there may be opportunities to identify staffing patterns that increase overall program efficiency.
PMCID: PMC3264532  PMID: 22185656
16.  Application of a Genetically Encoded Biosensor for Live Cell Imaging of L-Valine Production in Pyruvate Dehydrogenase Complex-Deficient Corynebacterium glutamicum Strains 
PLoS ONE  2014;9(1):e85731.
The majority of biotechnologically relevant metabolites do not impart a conspicuous phenotype to the producing cell. Consequently, the analysis of microbial metabolite production is still dominated by bulk techniques, which may obscure significant variation at the single-cell level. In this study, we have applied the recently developed Lrp-biosensor for monitoring of amino acid production in single cells of gradually engineered L-valine producing Corynebacterium glutamicum strains based on the pyruvate dehydrogenase complex-deficient (PDHC) strain C. glutamicum ΔaceE. Online monitoring of the sensor output (eYFP fluorescence) during batch cultivation proved the sensor's suitability for visualizing different production levels. In the following, we conducted live cell imaging studies on C. glutamicum sensor strains using microfluidic chip devices. As expected, the sensor output was higher in microcolonies of high-yield producers in comparison to the basic strain C. glutamicum ΔaceE. Microfluidic cultivation in minimal medium revealed a typical Gaussian distribution of single cell fluorescence during the production phase. Remarkably, low amounts of complex nutrients completely changed the observed phenotypic pattern of all strains, resulting in a phenotypic split of the population. Whereas some cells stopped growing and initiated L-valine production, others continued to grow or showed a delayed transition to production. Depending on the cultivation conditions, a considerable fraction of non-fluorescent cells was observed, suggesting a loss of metabolic activity. These studies demonstrate that genetically encoded biosensors are a valuable tool for monitoring single cell productivity and to study the phenotypic pattern of microbial production strains.
PMCID: PMC3895001  PMID: 24465669
17.  Intraluminal gastric pH in chronic pancreatitis. 
Gut  1995;36(2):294-298.
The aim of this study was to assess the circadian variations of intragastric pH in 28 inpatients with chronic pancreatitis (mean (SD) age 46.8 (12.4) years) and in 14 controls (45.4 (9.8)). pH Metry was performed using a monocrystalline antimony electrode placed in the body of the stomach under fluoroscopic control and connected up to a recorder (MKII Digitrapper, Synectics). The evaluation parameters, expressed as median and interquartile range, were: total period, postprandial periods (P1 and P2), interdigestive, and nocturnal phases. Patients with chronic pancreatitis were subdivided into three groups on the basis of severity of exocrine pancreatic insufficiency (secretin-caerulein test: lipase output at 60-90 min)--that is, those with severe insufficiency (chronic pancreatitis-SI: 13 patients, lipase output < 10% normal values and pancreolauryl test < 20%), those with only mild insufficiency (chronic pancreatitis-MI: seven patients), and those with normal secretion (chronic pancreatitis-NF: eight patients). The chronic pancreatitis-SI patients present significantly greater gastric acidification in the postprandial periods compared with controls (P1: p < 0.001; P2: p < 0.01), and with chronic pancreatitis-MI plus chronic pancreatitis-NF subjects (P1: p < 0.01; P2: p < 0.05), taken together. In conclusion, gastric acidity, exocrine pancreatic insufficiency, and impaired digestion are closely related during the course of chronic pancreatitis.
PMCID: PMC1382420  PMID: 7883232
18.  Infant mortality and famine: a study in historical epidemiology in northern England. 
OBJECTIVE--To examine whether periodic variations in annual infant mortality were associated with malnutrition and the poor quality of the food supply available to the community. DESIGN--Retrospective study of historical epidemiology of infant mortality by time series analysis and family reconstitution of parish registers of burials and baptisms. SETTING--Penrith, Cumbria, England, 1557-1812. SUBJECTS--A total of 17,500 births during 1557-1812. RESULTS--This community in the Eden Valley, Cumbria, close to the Scottish borders, was living under marginal conditions with high mortality and low fertility. Clear oscillations in infant mortality synchronise with the oscillations in the wheat price index which is regarded as a measure of the availability of food to the community, and to pregnant and nursing mothers in particular. Input-output analysis showed that the relationship between the wheat price index (input) and infant mortality (output) was highly significant (p < 0.001). Events during the famine of 1623 have been analysed in detail: high wheat prices during pregnancy caused subsequent severe infant mortality but did not have indirect effects on the subsequent mortality of the surviving children over the age of 1 year. Non-stationary oscillations in neonatal and post neonatal mortality were strongly coherent (p < 0.001) with the wheat price index throughout the period. CONCLUSIONS--Infant mortality is particularly sensitive to famine and also to the quality of the food supply available to pregnant and nursing mothers. The lags between neonatal and post-neonatal mortalities and wheat prices, together with the analysis of the famine of 1623, support the hypothesis that neonatal mortality was related to malnutrition in pregnancy whereas post-neonatal mortality was primarily directly dependent on exogenous causes in the first year of life.
PMCID: PMC1060792  PMID: 7629458
19.  Partial derivative—Based sensitivity analysis of models describing target-mediated drug disposition 
The AAPS Journal  2007;9(2):E181-E189.
Sensitivity analysis is commonly used to characterize the effects of parameter perturbations on model output. One use for the approach is the optimization of an experimental design enabling estimation of model parameters with improved accuracy. The primary objective of this study is to conduct a sensitivity analysis of selected target-mediated pharmacokinetic models, ascertain the effect of parameter variations on model predictions, and identify influential model parameters. One linear model (Model 1, control) and 2 target-mediated models (Models 2 and 3) were evaluated over a range of dose levels. Simulations were conducted with model parameters being perturbed at the higher and lower ends from literature mean values. Profiles of free plasma drug concentrations and their partial derivatives with respect to each parameter vs time were analyzed. Perturbations resulted in altered outputs, the extent of which reflected parmater influence. The model outputs were highly sensitive to perturbations of linear disposition parameters in all 3 models. The equilibrium dissociation constant (KD) was less influential in Model 2 but was influential in the terminal phase in Model 3, highlighting the role ofKD in this region. An equation for Model 3 in support of the result forKD was derived. Changes in the initial receptor concentration [Rtot(0)] paralleled the observed effects of initial plasma volume (Vc) perturbations, with increased influence at higher values. Model 3 was also sensitive to the rates of receptor degradation and internalization. These results suggest that informed sampling may be essential to accurately estimate influential parameters of target-mediated models.
PMCID: PMC2751407  PMID: 17614360
Nonlinear pharmacokinetics; quasiequilibrium models; equilibrium dissociation constant; receptor internalization
20.  Constraints on muscular performance: trade-offs between power output and fatigue resistance. 
An important functional and evolutionary constraint on the physical performance of vertebrates is believed to be the trade-off between speed and endurance capacity. However, despite the pervasiveness of physiological arguments, most studies have found no evidence of the trade-off when tested at the whole-animal level. We investigated the existence of this trade-off at the whole-muscle level, the presumed site of this physiological conflict, by examining inter-individual variation in both maximum power output and fatigue resistance for mouse extensor digitorum longus (EDL) muscle using the work-loop technique. We found negative correlations between several measures of in vitro maximum power output and force production with fatigue resistance for individual mouse EDL muscles, indicating functional trade-offs between these performance parameters. We suggest that this trade-off detected at the whole-muscle level has imposed an important constraint on the evolution of vertebrate physical performance.
PMCID: PMC1810012  PMID: 15252990
21.  Analysis of the sensitivity properties of a model of vector-borne bubonic plague 
Model sensitivity is a key to evaluation of mathematical models in ecology and evolution, especially in complex models with numerous parameters. In this paper, we use some recently developed methods for sensitivity analysis to study the parameter sensitivity of a model of vector-borne bubonic plague in a rodent population proposed by Keeling & Gilligan. The new sensitivity tools are based on a variational analysis involving the adjoint equation. The new approach provides a relatively inexpensive way to obtain derivative information about model output with respect to parameters. We use this approach to determine the sensitivity of a quantity of interest (the force of infection from rats and their fleas to humans) to various model parameters, determine a region over which linearization at a specific parameter reference point is valid, develop a global picture of the output surface, and search for maxima and minima in a given region in the parameter space.
PMCID: PMC2607428  PMID: 18270149
vector-borne disease; model sensitivity analysis; variational analysis
22.  Variations in arterial blood pressure are associated with parallel changes in FlowTrac/Vigileo®-derived cardiac output measurements: a prospective comparison study 
Critical Care  2009;13(6):R179.
The reliability of autocalibrated pressure waveform analysis by the FloTrac-Vigileo® (FTV) system for the determination of cardiac output in comparison with intermittent pulmonary arterial thermodilution (IPATD) is controversial. The present prospective comparison study was designed to determine the effects of variations in arterial blood pressure on the reliability of the FTV system in patients undergoing coronary artery bypass grafting (CABG).
Comparative measurements of cardiac output by FTV (derived from a femoral arterial line; software version 1.14) and IPATD were performed in 16 patients undergoing elective CABG in the period before institution of cardiopulmonary bypass. Measurements were performed after induction of anesthesia, after sternotomy, and during five time points during graft preparation. During graft preparation, arterial blood pressure was increased stepwise in intervals of 10 to 15 minutes by infusion of noradrenaline and lowered thereafter to baseline levels.
Mean arterial blood pressure was varied between 85 mmHg and 115 mmHg. IPATD cardiac output did not show significant changes during periods with increased arterial pressure either during sternotomy or after pharmacological manipulation. In contrast, FTV cardiac output paralleled changes in arterial blood pressure; i.e. increased significantly if blood pressure was raised and decreased upon return to baseline levels. Mean arterial blood pressure (MAP) and FTV cardiac output were closely correlated (r = 0.63 (95% confidence interval [CI]: 0.49 - 0.74), P < 0.0001) while no correlation between MAP and IPATD cardiac output was observed. Bland-Altman analyses for FTV versus IPATD cardiac output measurements revealed a bias of 0.4 l/min (8.5%) and limits of agreement from 2.1 to -1.3 l/min (42.2 to -25.3%).
Acute variations in arterial blood pressure alter the reliability of the FlowTrac/Vigileo® device with the second-generation software. This finding may help to explain the variable results of studies comparing the FTV system with other cardiac output monitoring techniques, questions the usefulness of this device for hemodynamic monitoring of patients undergoing rapid changes in arterial blood pressure, and should be kept in mind when using vasopressors during FTV-guided hemodynamic optimization.
PMCID: PMC2811929  PMID: 19900267
23.  A Computer Based File of X-Ray and Electron Beam Central Axis Depth Dose Data for Use in Radiation Therapy 
The central axis absorbed dose data for x-ray and electron beams generated by linear accelerators in the energy range 4 thru 25 MV are being compiled. The compilation includes specific x-ray beam parameters (surface doses, output factors, percent depth doses, tissue-phantom ratios, and wedge factors) as well as electron beam parameters (percent depth doses and output factors). The compilation includes published data sets of these parameters and those obtained directly from over 100 institutions participating in the study.
The data are grouped by accelerator model and input into computer files that provide a standard format suitable for intercomparisons. The software used to construct the computer files and to manipulate the data is discussed. Selected examples of the average values of parameters obtained to date with the standard deviations, the coefficients of variation, and the maximum and minimum values will be presented for several different linear accelerator models.
PMCID: PMC2203649
24.  Genetic and environmental influences on individual differences in cortisol level and circadian rhythm in middle childhood 
Hormones and Behavior  2012;62(1):36-42.
Individuals differ widely in cortisol output over the day, but the etiology of these individual differences remains poorly understood. Twin studies are useful for quantifying genetic and environmental influences on variation in cortisol output, lending insight into underlying influences on the components of Hypothalamic-Pituitary-Adrenal (HPA) axis functioning.
Salivary cortisol was assayed on 446 twin pairs (157 monozygotic, 289 dizygotic; ages 7–8). Parents helped youth collect saliva 30 min after waking, mid-afternoon, and 30 minutes prior to bedtime across 3 consecutive days. We used hierarchical linear modeling to extract predicted cortisol levels and to distinguish cortisol’s diurnal rhythm using a slopes-as-outcome piecewise growth curve model; two slopes captured the morning-to-afternoon and afternoon-to-evening rhythm, respectively. Separate genetic models were then fit to cortisol level at waking, mid-afternoon, and evening as well as the diurnal rhythm across morning-to-afternoon and afternoon-to-evening hours.
Three results from these analyses are striking. First, morning-to-afternoon cortisol level showed the highest additive genetic variance (heritability), consistent with prior research. Second, cortisol’s diurnal rhythm had an additive genetic component, particularly across the morning-to-afternoon hours. In contrast, additive genetic variation did not significantly contribute to variation in afternoon-to-evening slope. Third, the majority of variance in cortisol concentration was associated with shared family environments. In summary, both genetic and environmental factors influence cortisol’s circadian rhythm, and they do so differentially across the day.
PMCID: PMC3377812  PMID: 22583671
HPA axis; cortisol; diurnal rhythm; twins; behavior genetics
25.  Dendritic morphology of amygdala and hippocampal neurons in more and less predator stress responsive rats and more and less spontaneously anxious handled controls 
Behavioural brain research  2011;226(1):133-146.
We investigated the neurobiological bases of variation in response to predator stress (PS). Sixteen days after treatment (PS or handling), rats were grouped according to anxiety in the elevated plus maze (EPM). Acoustic startle was also measured. We examined the structure of dendritic trees of basolateral amygdala (BLA) output neurons (stellate and pyramidal cells) and of dorsal hippocampal (DHC) dentate granule cells of less anxious (LA) and more (extremely) anxious (MA) stressed animals (PSLA and PSMA). Handled controls (HC) which were less anxious (HCLA) and spontaneously more anxious (HCMA) equivalently to predator stressed subgroups were also studied. Golgi analysis revealed BLA output neurons of HCMA rats exhibited longer, more branched dendrites with higher spine density than the other groups of rats, which did not differ. Finally, spine density of DHC granule cells was equally depressed in HCMA and PSMA rats relative to HCLA and PSLA rats. Total dendritic length of BLA pyramidal and stellate cells (positive predictor) and DHC spine density (negative predictor) together accounted for 96% of the variance of anxiety of handled rats. DHC spine density was a negative predictor of PSMA and PSLA anxiety, accounting for 70% of the variance. Data are discussed in the context of morphological differences as phenotypic markers of a genetic predisposition to anxiety in handled controls, and a possible genetic vulnerability to predator stress expressed as reduced spine density in the DHC. Significance of findings for animal models of anxiety and hyperarousal comorbidities of PTSD are discussed.
PMCID: PMC3586250  PMID: 21925210 CAMSID: cams2783
Stress; Amygdala; Hippocampus; Morphology; Resilience; Vulnerability

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