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PubMed1996

Sensitive analysis of oxidative DNA damage in mammalian cells: use of the bacterial Fpg protein in combination with alkaline unwinding.

The measurement of oxidative DNA base modifications by different methods has received special attention in recent years. Here we describe a procedure to quantify DNA lesions recognized by the bacterial formamido-pyrimidine-DNA glycosylases (Fpg protein). These include 7,8-dihydro-8-oxoguanine (8-hydroxyguanine) as well as some other forms of imidazole ring-opened purines, which are converted into abasic sites and subsequently into DNA single-strand breaks by the associated endonuclease activity. The frequency of DNA strand breaks is determined by the alkaline unwinding technique. The procedure provides a fast and sensitive tool to assess the extent of spontaneous as well as induced oxidative DNA damage in mammalian cells.

Animals↗
PubMed1986

Sensitive analysis of asparagine and glutamine in physiological fluids and cells by precolumn derivatization with phenylisothiocyanate and reversed-phase high-performance liquid chromatography.

The analytical methodologies for the determination of free amino acids in plasma, serum, erythrocytes and leukemic cells are described. Deproteinization of the sample by methanol or organic acids is followed by derivatization with phenylisothiocyanate to form stable phenylthiocarbamylamino acid derivatives. The derivatives are separated by reversed-phase high-performance liquid chromatography in 80 min using a 5-microns C18 column (250 X 4 mm I.D.) and monitored by ultraviolet detection at 254 nm. Twenty physiological amino acids are resolved and quantified in plasma and erythrocyte samples. The resolution and sensitivity of the analytical method permitted unequivocal quantification of very low asparagine and glutamine levels in leukemic cells and growth media following treatment with asparaginase and glutaminase enzymes despite the presence of high aspartic and glutamic acid levels.

Amino Acids↗
PubMed2004

The pesticide module of the Root Zone Water Quality Model (RZWQM): testing and sensitivity analysis of selected algorithms for pesticide fate and surface runoff.

The Root Zone Water Quality Model (RZWQM) is a one-dimensional, numerical model for simulating water movement and chemical transport under a variety of management and weather scenarios at the field scale. The pesticide module of RZWQM includes detailed algorithms that describe the complex interactions between pesticides and the environment. We have simulated a range of situations with RZWQM, including foliar interception and washoff of a multiply applied insecticide (chlorpyrifos) to growing corn, and herbicides (alachlor, atrazine, flumetsulam) with pH-dependent soil sorption, to examine whether the model appears to generate reasonable results. The model was also tested using chlorpyrifos and flumetsulam for the sensitivity of its predictions of chemical fate and water and pesticide runoff to various input parameters. The model appears to generate reasonable representations of the fate and partitioning of surface- and foliar-applied chemicals, and the sorption of weakly acidic or basic pesticides, processes that are becoming increasingly important for describing adequately the environmental behavior of newer pesticides. However, the kinetic sorption algorithms for charged pesticides appear to be faulty. Of the 29 parameters and variables analyzed, chlorpyrifos half-life, the Freundlich adsorption exponent, the fraction of kinetic sorption sites, air temperature, soil bulk density, soil-water content at 33 kPa suction head and rainfall were most sensitive for predictions of chlorpyrifos residues in soil. The latter three inputs and the saturated hydraulic conductivity of the soil and surface crusts were most sensitive for predictions of surface water runoff and water-phase loss of chlorpyrifos. In addition, predictions of flumetsulam (a weak acid) runoff and dynamics in soil were sensitive to the Freundlich equilibrium adsorption constant, soil pH and its dissociation coefficient.

Algorithms↗
PubMed2006

Parameter identification and sedative sensitivity analysis of an agitation-sedation model.

Sedation administration and agitation management are fundamental activities in any intensive care unit. A lack of objective measures of agitation and sedation, as well as poor understanding of the underlying dynamics, contribute to inefficient outcomes and expensive healthcare. Recent models of agitation-sedation dynamics have enhanced understanding of the underlying dynamics and enable development of advanced protocols for semi-automated sedation administration. In this research, the agitation-sedation model parameters are identified using an integral-based fitting method developed in this work. Parameter variance is then analysed over 37 intensive care unit patients. The parameter identification method is shown to be effective and computationally inexpensive, making it suited to real-time clinical control applications. Sedative sensitivity, an important model parameter, is found to be both patient-specific and time-varying. However, while the variation between patients is observed to be as large as a factor 10, the observed variation in time is smaller, and varies slowly over a period of days rather than hours. The high fitted model performance across all patients show that the agitation-sedation model presented captures the fundamental dynamics of the agitation-sedation system. Overall, these results provide additional insight into the system and clinical dynamics of sedation management.

Computer Simulation↗
PubMed1989

A spherical source model for the thermal pulse decay method of measuring blood perfusion: a sensitivity analysis.

The thermal pulse-decay method, as developed and analyzed by Chen et al. [1-6], is a thermal clearance technique that uses a small thermistor probe for determining the blood perfusion and thermal conductivity of the tissue immediately surrounding the probe. They described the energy transfer of the probe/tissue system mathematically with a simple analytical model, the point source model, which assumes that the heating source is infinitely small. This paper introduces a new, more accurate analytical description that assumes the heating source is spherically symmetric with a finite radius. A numerical study of these two alternative mathematical models is presented in which the solutions of each model are compared to transient temperature decay data generated from a detailed finite difference simulation of the probe/tissue system. The accuracy and sensitivity of the predictions of each of these models to variations in tissue thermal conductivity and perfusion, probe characteristics, and heating time are presented. In all cases, the accuracy of the spherical source model was better than the point source model. It is also shown that the spherical source model can accurately predict low rates of perfusion (on the order of 1 kg/m3 s) unlike the point source model. The spherical source model allows for the possibility of the measurement probes to be calibrated for an "effective bead radius" which accounts for the nonideal characteristics of the probe, thereby giving even more accurate determinations of perfusion.

Blood Circulation↗
PubMed1989

Sensitive analysis of the mycotoxin zearalenone and its metabolites in biological fluids by high-performance liquid chromatography alpha.

A method is described for the analysis of zearalenone and its metabolites, alpha- and beta-zearalenol, in small volumes (0.5-2.0 ml) of biological fluids including milk, blood, plasma, urine and bile, using high-performance liquid chromatography with fluorescence detection. Isolation of the toxins from biological fluids was achieved using a series of pH-controlled solvent extractions. Detection limits for zearalenone and alpha-zearalenol were 1 ng/ml, and for beta-zearalenol ca. 5 ng/ml, both at a signal-to-noise ratio of 3. In bile, however, the detection was ca. five times less sensitive owing to interfering substances. Recoveries at low ng/ml concentrations were highest from urine (87-94%) and plasma (85-93%), slightly lower from whole blood (78-88%) and milk (75-84%), and lowest from bile (66-77%).

Animal Feed↗
PubMed1994

The global burden of disease in 1990: summary results, sensitivity analysis and future directions.

A basic requirement for evaluating the cost-effectiveness of health interventions is a comprehensive assessment of the amount of ill health (premature death and disability) attributable to specific diseases and injuries. A new indicator, the number of disability-adjusted life years (DALYs), was developed to assess the burden of disease and injury in 1990 for over 100 causes by age, sex and region. The DALY concept provides an integrative, comprehensive methodology to capture the entire amount of ill health which will, on average, be incurred during one's lifetime because of new cases of disease and injury in 1990. It differs in many respects from previous attempts at global and regional health situation assessment which have typically been much less comprehensive in scope, less detailed, and limited to a handful of causes. This paper summarizes the DALY estimates for 1990 by cause, age, sex and region. For the first time, those responsible for deciding priorities in the health sector have access to a disaggregated set of estimates which, in addition to facilitating cost-effectiveness analysis, can be used to monitor global and regional health progress for over a hundred conditions. The paper also shows how the estimates depend on particular values of the parameters involved in the calculation.

Adolescent↗
PubMed2000

A sensitivity analysis of the calculation of mechanical output through inverse dynamics: a computer simulation study.

The purpose of this study was to systematically determine the effect of experimental errors on the work output calculated using two different methods of inverse dynamics during vertical jumping: (a) the conventional (rotational) method and (b) the translational method. A two-dimensional musculoskeletal model was used to generate precisely known kinematics. Next, the location of each joint center (JC) and the location of each segment's center of mass (CM) were manipulated by +/-10% of segment length to simulate errors in the location of joint centers (delta JC) and errors in the location of segment's center of mass (delta CM), respectively. Work output was subsequently calculated by applying the two methods of inverse dynamics to the manipulated kinematic data. The results showed that the translational method of inverse dynamics was less sensitive (up to 13% error in total work output) to delta JC and delta CM than the rotational method (up to 28% error in total work output). The rotational method of inverse dynamics was particularly sensitive to simulated errors in JC.

Biomechanical Phenomena↗
PubMed1979

Sample-size estimation: a sensitivity analysis in the context of a clinical trial for treatment of mild hypertension.

The effectiveness of treatment for mild hypertension (diastolic pressures of 85 to 105 mm Hg) has not been conclusively demonstrated. Both the costs of a carefully designed clinical trial and the likelihood that it will produce definitive answers will depend importantly on the sample size. This paper presents sample-size estimates under a variety of assumptions regarding the characteristics of the population to be studied, the degree of blood pressure control to be achieved, and the health benefits to be expected. Under a central set of assumptions, the estimated sample size per group is 22,700 with death as an endpoint and 14,000 with morbid events (CHD and stroke) as endpoints. As individual assumptions are varied one at a time, required sample sizes range from 10,900 to 101,100 and from 6,800 to 63,100 for the respective endpoints. Results are most sensitive to the degree of blood pressure control actually achieved to the expected health benefits from blood pressure control. They are also highly sensitive to the sex composition of the population and to expected dropout rates. The choice of sample size will depend on the decision maker's assessment of the likelihood that each assumption will be fulfilled and on the degree of willingness to risk an inconclusive study result. By making explicit the effect of variation in each assumption, decision making is rendered more susceptible to critical examination by outside reviewers.

Adult↗
PubMed1991

A simulation model of AIDS in San Francisco: II. Simulations, therapy, and sensitivity analysis.

The HIV and AIDS incidences each year for homosexual men in San Francisco are estimated from data. A computer simulation model for HIV transmission dynamics and progression to AIDS is used to reconstruct the HIV epidemic. Using some a priori parameter estimates, simulations are found that give good fits to the incidence data. In the stimulations the populations is divided into risk groups whose sexual activities are found to be strongly connected. There is saturation in the high-risk group, but changes in sexual behavior are more important in obtaining adequate fits. The simulation modeling yields useful parameter estimates, but the remaining uncertainty in parameter values implies that the simulation forecasts are also uncertain. Changes in HIV incidence lead to changes in AIDS incidence about 6-10 years later. Simulation models with and without zidovudine treatment both fit the incidence data; thus the effects of therapy on AIDS incidence are unclear. The fits of the simulation model are most sensitive to the yearly migration rate, the number of stages in the progression to AIDS, and the average number of new sexual partners per month; thus better estimates of these parameters would be desirable.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Sensitive analysis of serum 3alpha, 7alpha, 12alpha,24-tetrahydroxy- 5beta-cholestan-26-oic acid diastereomers using gas chromatography-mass spectrometry and its application in peroxisomal D-bifunctional protein deficiency.

The final steps in bile acid biosynthesis take place in peroxisomes and involve oxidative cleavage of the side chain of C27-5beta-cholestanoic acids leading to the formation of the primary bile acids cholic acid and chenodeoxycholic acid. The enoyl-CoA hydratase and beta-hydroxy acyl-CoA dehydrogenase reactions involved in the chain shortening of C27-5beta-cholestanoic acids are catalyzed by the recently identified peroxisomal d-bifunctional protein. Deficiencies of d-bifunctional protein lead, among others, to an accumulation of 3alpha,7alpha,12alpha, 24-tetrahydroxy-5beta-cholest-26-oic acid (varanic acid). The ability to resolve the four C24, C25 diastereomers of varanic acid has, so far, only been carried out on biliary bile acids using p -bromophenacyl derivatives. Here, we describe a sensitive gas chromatography-mass spectrometry (GC/MS) method that enables good separation of the four varanic acid diastereomers by use of 2R-butylester-trimethylsilylether derivatives. This method showed the specific accumulation of (24R,25R)-varanic acid in the serum of a patient with isolated deficiency of the d-3-hydroxy acyl-CoA dehydrogenase part of peroxisomal d-bifunctional protein, whereas this diastereomer was absent in a serum sample from a patient suffering from complete d-bifunctional protein deficiency. In samples from both patients an accumulation of (24S,25S)-varanic acid was observed, most likely due to the action of l-bifunctional protein on Delta24E-THCA-CoA. This GC/MS method is applicable to serum samples, obviating the use of bile fluid, and is a helpful tool in the subclassification of patients with peroxisomal d-bifunctional protein deficiency.

17-Hydroxysteroid Dehydrogenases↗
PubMed1999

Highly sensitive analysis for N-myc amplification in neuroblastoma based on fluorescence in situ hybridization.

BACKGROUND/PURPOSE: The N-myc amplification status in neuroblastoma has been evaluated previously for the whole tumor by the Southern blot method. The aim of this study is to evaluate the effectiveness of the fluorescence in situ hybridization (FISH) method to analyze N-myc amplification in neuroblastoma and compare the findings with those using the Southern blot method. METHODS: In 26 neuroblastoma primary tumors and metastatic lesions, the N-myc amplification status was evaluated by both the Southern blot method and FISH method. RESULTS: Of the 22 samples with no N-myc amplification using Southern blot, no cells with N-myc amplification using FISH were present in 21 of the samples. However, one metastatic liver lesion showed 16% of the nuclei to display more than 10 copies of N-myc based on FISH analysis. In the 4 remaining samples with N-myc amplification using the Southern blot method (17 copies, 15 copies, 6 copies, and 3 copies), the rates of cells with more than 10 copies of N-myc based on a FISH analysis were 79%, 68%, 94%, and 9%, respectively. CONCLUSIONS: The FISH method can detect more accurately N-myc amplification than the Southern blot method either when the rate of cells with N-myc amplification is low or intratumor heterogeneity is present.

Blotting, Southern↗
PubMed1998

Treatment of acyclovir-resistant herpetic ulceration with topical foscarnet and antiviral sensitivity analysis.

BACKGROUND: Herpes simplex virus (HSV) can produce persistent mucocutaneous disease in patients with the acquired immunodeficiency syndrome (AIDS). In this case report, we evaluate the efficacy, safety and viral resistance after topical foscarnet in severe genital ulceration due to acyclovir-resistant HSV-2. CASE REPORT: A 45-year-old African woman was known for an HIV infection with severe immunosuppression (CD4 <100/mm3). She had received a long-term prophylaxis with acyclovir (400 mg b.i.d.) for a recurrent genital herpes. Few weeks after stopping this prophylaxis, she developed large genital ulcerations progressing despite valacyclovir treatment (1,000 mg t.i.d.). Cultures were positive for HSV-2, resistance to acyclovir was shown by the plaque reduction assay and topical foscarnet was tried. Treatment consisted of a 20-min application of topical foscarnet 2.4% twice a day. Dramatic improvement was observed with rapid antalgia, and cicatrization of the genital ulcerations was observed after 50 days. HSV could not be detected on the mucosal surface. Initially, HSV-2 was resistant to acyclovir but sensitive to foscarnet. After 1 month of topical treatment, HSV-2 became sensitive to acyclovir and was still sensitive to foscarnet. Finally, after 6 weeks of treatment, no virus could be detected by culture. CONCLUSION: Topical foscarnet (2.4%) is a convenient treatment for chronic genital herpes. Resistance to acyclovir disappears few weeks after stopping this drug and sensitivity to foscarnet persists during the 50 days of treatment.

Acyclovir↗
PubMed1996

Back-projection and sensitivity analysis of the HIV-AIDS epidemic in the Caribbean.

In this study we estimated past human immunodeficiency virus (HIV) incidence in 19 nations in the primarily English-speaking Caribbean and projected the course of the epidemic to the year 1999. We compared the results obtained from several different models of HIV incidence and different assumed incubation distributions. Linear and nonlinear optimization methods were used to fit several models (power, logistic, spline, and step) to adult (age 15 years or older) AIDS incidence data derived from our existing surveillance system. All four models tested gave good fits to the data, with estimates of cumulative HIV incidence in 1993 ranging from 16,504 to 21,732. An increase in the assumed median of the AIDS incubation distribution by one year increased the estimates of current cumulative adult HIV incidence by approximately 12%; these estimates varied by as much as 6% between models. An adjustment of the data for possible reporting delay increased the estimates by approximately 7% and for underreporting by 25%. Despite their sensitivity to underlying assumptions, back-projection estimates provide useful insights into the patterns of HIV and AIDS incidence. The models indicate that HIV and AIDS incidences in the English-speaking Caribbean have been rising steadily, with adult HIV prevalence in the general population still less than 1%.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Model misspecification sensitivity analysis in estimating causal effects of interventions with non-compliance.

Randomized trials often face complications in assessing the effect of treatment because of study participants' non-compliance. If compliance type is observed in both the treatment and control conditions, the causal effect of treatment can be estimated for a targeted subpopulation of interest based on compliance type. However, in practice, compliance type is not observed completely. Given this missing compliance information, the complier average causal effect (CACE) estimation approach provides a way to estimate differential effects of treatments by imposing the exclusion restriction for non-compliers. Under the exclusion restriction, the CACE approach estimates the effect of treatment assignment for compliers, but disallows the effect of treatment assignment for non-compliers. The exclusion restriction plays a key role in separating outcome distributions based on compliance type. However, the CACE estimate can be substantially biased if the assumption is violated. This study examines the bias mechanism in the estimation of CACE when the assumption of the exclusion restriction is violated. How covariate information affects the sensitivity of the CACE estimate to violation of the exclusion restriction assumption is also examined.

Algorithms↗
PubMed1987

Estimates of the population pharmacokinetic parameters and performance of Bayesian feedback: a sensitivity analysis.

We investigated the influence of bias in the estimates of the population pharmacokinetic parameters on the performance of Bayesian feedback in achieving a desired drug serum concentration. Three specific cases were considered (i) steady-state case, (ii) lidocaine example, and (iii) mexiletine example. Whereas in the first case both the feedback and the desired concentration represented steady-state values, in the lidocaine and mexiletine examples the feedback concentration was assumed to be sampled shortly after starting therapy. RMSE was used as a measure of predictive performance. For the simple steady-state case the relationship between RMSE and bias in the parameter estimates describing the prior distribution could be derived analytically. Monte Carlo simulations were used to explore the two non-steady-state situations. In general, the performance of Bayesian feedback to predict serum concentrations was relatively insensitive to bad population parameter estimates. However, large changes in RMSE could be observed with small changes in the true variance component parameters in particular in the intraindividual residual variance, sigma 2 epsilon, indicating that the prediction interval, in contrast to point prediction, is sensitive to bias in the estimates of the population parameters.

Bayes Theorem↗
PubMed2006

White petrolatum (Ph. Eur.) is virtually non-sensitizing. Analysis of IVDK data on 80 000 patients tested between 1992 and 2004 and short discussion of identification and designation of allergens.

UNLABELLED: Sporadic cases of contact allergy to white petrolatum, which is used as a vehicle in patch test preparations, have been reported. The quantitative relevance of the phenomenon remains yet to be elucidated. METHODS: Retrospective analysis of patch test data of the Information Network of Departments of Dermatology (IVDK, http://www.ivdk.org) between 1992 and 2004. RESULTS: Analysis of 79 365 patients patch tested with pure petrolatum yielded 27 '+' (0.03%) and 2 '+++' (0.003%) reactions. The majority of non-negative reactions (0.3%) was interpreted as doubtful (235) or mild irritant (32). The negative reaction index (RI) (-0.8), and the high positivity ratio (PR) (93%) especially a lack of concordance with patch test preparations containing > or=99% petrolatum indicate that many of the 'positive' (+) reactions have to be considered as irritant. There were 2 '+++' reactions. In 1 case, an 'angry back reaction' was confirmed. The other case is probably a reading or documentation error, as the majority of patch test reactions to preparations containing petrolatum remained negative in this case also. CONCLUSIONS: True allergic patch test reactions to white petrolatum are extremely rare and probably due to an individually increased susceptibility to allergens and/or irritants. This is in agreement with considering petrolatum as a non-sensitizer.

Allergens↗
PubMed1987

Model selection for ventricular mechanics: a sensitivity analysis approach.

Quantitative characterization of left ventricle pump properties has been recognized as being of great significance for both physiological and clinical purposes. Several descriptions have been proposed in the past to this end, where the ventricle is viewed as an isovolumic pressure generator coupled to an internal impedance, considered as either only viscous, only elastic or viscoelastic. Though these models have been used widely, the respective advantages and limits have not been fully elucidated. In this paper, six models for the left ventricular pumping function, of the viscoelastic type, are compared using both simulated and experimental data in a typical parameter estimation approach. Elastic and viscous parameters are estimated starting from ventricular pressure and aortic flow, together with the isovolumic pressure at the same preload. The basis for the comparison is the well-established criterion relating the fit obtained from collected data and the covariance matrix of the parameter estimates. The latter allows evaluation of the so-called indifference region in the parameter space, which is represented by an ellipse if both elastic and viscous elements are present. The properties of the indifference region are synthetically represented by two indices linked to the area and the eccentricity of the ellipse: the first represents the mean accuracy of the parameter estimate, the second gives information about the different sensitivities to variation of single parameters. This comparison, in both simulated and experimental cases, generally leads to preference for a model where elastance and viscosity vary with time in linear proportion to the isovolumically developed ventricular pressure. Appropriate description of the elastic effect reveals it to be very crucial while the viscous effect, though improving the fitting of data, is less critical.

Animals↗