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PubMed1998

Evidence of intra- and extracellular modifications of monoclonal IgG polypeptide chains generating charge heterogeneity.

The heavy and light chains of IgG monoclonal antibodies (mAbs) can be shown to be heterogeneous, with respect to isoelectric points, when analyzed by two-dimensional electrophoresis (2-DE). The molecular basis for this charge heterogeneity has not been clearly defined but it has been suggested that it could be due, in part, to differences in glycosylation. To investigate this possibility we have compared the 2-DE pattern of glycosylated and aglycosylated forms of the mouse IgG1 mAb (1B7-11), produced in vitro in the presence and absence of tunicamycin. Charge heterogeneity was shown not to be a consequence of glycosylation status. Intracellular and secreted IgG mAbs were also analyzed to investigate the time course of change in charge properties of the heavy and light chains. The charge heterogeneity was found to be generated intracellularly, and alterations in charge properties could be induced during incubation under physiological conditions. Semilogarithmic plots of the density of the principal heavy and light chain spots against incubation time showed linear relationships, suggesting that the charge shifts result from a first-order reaction. The semilogarithmic plot for the light chain correlated well with the time after IgG synthesis. These results suggest that the charge heterogeneity of an IgG mAb is due to intra- and extracellular modifications of the polypeptide chains which reflect "aging" of antibody molecules.

Animals↗
PubMed2005

Heterogeneity in the angiogenic response of a BT474 human breast cancer to a novel vascular endothelial growth factor-receptor tyrosine kinase inhibitor: assessment by voxel analysis of dynamic contrast-enhanced MRI.

PURPOSE: To investigate the heterogeneity in the angiogenic response of a human breast cancer xenograft to a novel vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor, AG-013736, using dynamic contrast-enhanced MR imaging (DCE-MRI). MATERIALS AND METHODS: Changes in pharmacokinetic parameters in a seven-day interval were compared between AG-treated and control groups, using Gd-DTPA and albumin-(Gd-DTPA)30. A voxel-by-voxel analysis was performed to produce parametric spatial pharmacokinetic parametric maps and histograms. Histogram segmentation was used to quantify the heterogeneity in tumor response to therapy, and compared with conventional descriptive measures of distribution in terms of their capacity to separate control from AG-treated tumors. RESULTS: The albumin-(Gd-DTPA)30 endothelial transfer constant, Kps, showed changes with AG-013736 treatment and tumor growth. The changes were highly heterogeneous for individual segments of the histogram with different Kps values, and the overall patterns in which the frequency distribution changed differed significantly between the two groups. A change in the number of voxels with Kps ranging from 0.03 to 0.14 mL/min/(100 mL tissue) was the most sensitive variable for separating control from AG-treated tumors (P = 0.0008). Parametric maps of the kinetic parameters also showed spatial heterogeneity in tumor response to treatment. The Kps maps depicted rapid development of central necrosis as a result of AG-013736 treatment. Maps of v(p) demonstrated a marked increase at peripheral regions of necrotic areas. Similar trends were noted in the Gd-DTPA rate constant Ktrans distribution. CONCLUSION: This study demonstrates the value of histogram analysis of maps of pharmacokinetic parameters for assessing heterogeneity in tumor response to antiangiogenic therapy. Changes in the number of voxels within certain segments of the Kps histogram were the most sensitive variable for separating control from AG-treated tumors.

Animals↗
PubMed2001

Approaches to heterogeneity in meta-analysis.

This paper reviews publications from January 1999 to March 2001 on reproductive health topics that were self-identified as meta-analysis or were indexed as meta-analysis in MEDLINE. It sought to assess whether tests of statistical heterogeneity were done, whether the results were reported, and how a finding of significance for a test of statistical heterogeneity was handled and the results interpreted. The review identified some concerns. Tests of statistical heterogeneity were not done universally even though virtually all writers on the topic emphasize their importance. Even when done, results of these tests were not universally reported. Although the consensus appears to be that heterogeneity tests are conservative for meta-analysis of studies and a probability value of 0.10 is preferred, many meta-analyses used the conventional value of 0.05 without providing a reason. The rationale for the choice of a random or fixed effects model was not generally evident. The review also provided some positive models and some recommendations for assessing, reporting and exploring heterogeneity are made considering these models and the published recommendations of experts.

Female↗
PubMed2005

Modelling clinical trials in heterogeneous samples.

Individual variation in genetic, phenotypic and environmental factors could lead to significant differences in rates of drug metabolism, in clinical responses to drugs, and in drug side effects. The impact of population heterogeneity on treatment effect estimation and on assessment and application of clinical trial findings has been less than fully studied. In this paper, we studied the properties of models that reflect population heterogeneity of clinical trial samples by unmeasured covariates such as genetic susceptibility. The impact of heterogeneity on the estimation of treatment effect in a two-armed placebo or active-controlled clinical trial was quantified using logistic regression models. We also proposed a two-stage clinical trial, where the effects of individual drug-response-related covariates were estimated in a 'training data set' in the first stage of the trial. In the second stage of the trial, a subgroup of individuals with enhanced (or reduced) sensitivity to drug treatments in a heterogeneous risk cohort was identified based on information about their drug-related characteristics. Only these 'responders' were included in the subsequent efficacy test. Our simulation results showed that population heterogeneity could lead to biased estimation of treatment effect not only in the contaminated groups but also in the uncontaminated groups. A two-stage trial could greatly increase the power of an efficacy test over a 'full trial' even with fewer individuals enrolled in the trial; results would apply to a more highly specified population. The bigger the covariate effects, the more efficient the two-stage trial is compared to a 'full trial'.

Biometry↗
PubMed2005

A Bayesian approach to jointly estimate centre and treatment by centre heterogeneity in a proportional hazards model.

When multicentre clinical trial data are analysed, it has become more and more popular to look for possible heterogeneity in outcome between centres. However, beyond the investigation of such heterogeneity, it is also interesting to consider heterogeneity in treatment effect over centres. For time-to-event outcomes, this may be investigated by including a random centre effect and a random treatment by centre interaction in a Cox proportional hazards model. Assuming independence between the random effects, we propose a Bayesian approach to fit our proposed model. The parameters of interest are the variance components sigma(0) (2) and sigma(1) (2) of these random effects, which can be interpreted as a measure of centre and treatment effect over centres heterogeneity of the hazard. These variance components are estimated from their marginal posterior density after integrating out the fixed treatment effect and the random effects. As this integration cannot be performed analytically, the marginal posterior density is approximated using the Laplace integration technique. Statistical inference is then based on the characteristics of the posterior marginal density, such as the mode and the standard deviation. We demonstrate the proposed technique using data from a pooled database of seven EORTC bladder cancer clinical trials. Substantial centre and treatment effect over centres heterogeneity in disease-free interval was found.

Bayes Theorem↗
PubMed1997

A Study on the Chemical Heterogeneity of Active Surface of Solid Catalysts

A method that can be used to characterize the chemical heterogeneity of active surface of solid catalyst is given. The chemical adsorption behavior of three adsorbates on Ni-W/F-Al2O3-SiO2 catalyst and supported Ni catalyst has been investigated. On the basis of fractal geometry, the roughness fractal dimension (Dr) and the chemisorption fractal dimension (Dc) of two kinds of catalyst are estimated. We use the difference between Dc and Dr to characterize the chemical heterogeneity of active sites on the catalytic surface. As a result, the chemical heterogeneity of the acid sites of Ni-W/F-Al2O3-SiO2 catalyst is very great. As for supported Ni catalyst, the chemical heterogeneity of active sites decreased when impregnating operation times in preparation of the catalyst increased. After impregnated four times, the chemical heterogeneity of its active surface of supported Ni catalyst is eliminated. Copyright 1997 Academic Press. Copyright 1997Academic Press

Journal Article↗
PubMed1998

Spatial structure, environmental heterogeneity, and population dynamics: analysis of the coupled logistic map.

Spatial extent can have two important consequences for population dynamics: It can generate spatial structure, in which individuals interact more intensely with neighbors than with more distant conspecifics, and it allows for environmental heterogeneity, in which habitat quality varies spatially. Studies of these features are difficult to interpret because the models are complex and sometimes idiosyncratic. Here we analyze one of the simplest possible spatial population models, to understand the mathematical basis for the observed patterns: two patches coupled by dispersal, with dynamics in each patch governed by the logistic map. With suitable choices of parameters, this model can represent spatial structure, environmental heterogeneity, or both in combination. We synthesize previous work and new analyses on this model, with two goals: to provide a comprehensive baseline to aid our understanding of more complex spatial models, and to generate predictions about the effects of spatial structure and environmental heterogeneity on population dynamics. Spatial structure alone can generate positive, negative, or zero spatial correlations between patches when dispersal rates are high, medium, or low relative to the complexity of the local dynamics. It can also lead to quasiperiodicity and hyperchaos, which are not present in the nonspatial model. With density-independent dispersal, spatial structure cannot destabilize equilibria or periodic orbits that would be stable in the absence of space. When densities in the two patches are uncorrelated, the probability that the population in a patch reaches extreme low densities is reduced relative to the same patch in isolation; this "rescue effect" would reduce the probability of metapopulation extinction beyond the simple effect of spreading of risk. Pure environmental heterogeneity always produces positive spatial correlations. The dynamics of the entire population is approximated by a nonspatial model with mean patch characteristics. This approximation worsens as the difference between the patches increases and the dispersal rate decreases: Under extreme conditions, destabilization of equilibria and periodic orbits occurs at mean parameter values lower than those predicted by the mean parameters. Apparent within-patch dynamics are distorted: The local population appears to have the wrong growth parameter and a constant number of immigrants (or emigrants) per generation. Adding environmental heterogeneity to spatial structure increases the occurrence of spatially correlated population dynamics, but the resulting temporal dynamics are more complex than would be predicted by the mean parameter values. The three classes of spatial pattern (positive, negative, and zero correlation), while still mathematically distinct, become increasingly similar phenomenologically.

Animals↗
PubMed2005

Plant cells: secondary metabolite heterogeneity and its manipulation.

This chapter proposes the concept of rational manipulation of secondary metabolite heterogeneity in plant cell cultures. The heterogeneity of plant secondary metabolites is a very interesting and important issue because these structure-similar natural products have different biological activities. Both taxoids and ginsenosides are two kinds of preeminent examples in the enormous reservoir of pharmacologically valuable heterogeneous molecules in the plant kingdom. They are derived from the five-carbon precursor isopentenyl diphosphate, produced via the mevalonate or the non-mevalonate pathway. The diterpenoid backbone of taxoids is synthesized by taxadiene synthase and the triterpenoid backbone of ginsenosides is synthesized by dammarenediol synthase or beta-amyrin synthase. After various chemical decorations (oxidation, substitution, acylation, glycosylation, benzoylation, and so on) mediated by P450-dependent monooxygenases, glycosyltransferases, acyltransferases, benzoyltransferases, and other enzymes, the terpenoid backbones are converted into heterogeneous taxoids and ginsenosides with different bioactivities. Although detailed information about accumulation and regulation of individual taxoids or ginsenosides in plant cells is still lacking, remarkable progress has recently been made in the structure and bioactivity identification, biosynthetic pathway, manipulation of their heterogeneity by various methodologies including environmental factors, biotransformation, and metabolic engineering in cell/tissue cultures or in plants. Perspectives on a more rational and efficient process to manipulate production of desired plant secondary metabolites by means of metabolic engineering and "omics"-based approaches (e.g., functional genomics) are also discussed.

Biotechnology↗
PubMed1990

The heterogeneity of the neuronal distribution of exogenous noradrenaline in the rat vas deferens.

After loading of the incubated rat vas deferens with 0.2 mumol/l 3H-noradrenaline (followed by 100 min of wash-out with amine-free solution), the efflux of endogenous and exogenous compounds was determined by HPLC with electrochemical detection and by column chromatography with scintillation counting. Two different types of heterogeneity of labelling were found. The first one is due to the preferential labelling of varicosities close to the surface of the tissue, the second one to the preferential labelling of vesicles close to the surface of loaded varicosities. As diffusion distances within the tissue and within varicosities are then longer for endogenous than for exogenous amine and metabolites, the composition of spontaneous efflux of exogenous compounds differed from that for endogenous compounds. Because of preferential neuronal and vesicular re-uptake of endogenous noradrenaline, the percentage contribution by noradrenaline to overall efflux was: endogenous less than exogenous. While 3H-DOPEG was the predominant exogenous metabolite, DOPEG and MOPEG equally contributed to the "endogenous" efflux. Desipramine abolished the consequences of the first heterogeneity of labelling, i.e., it increased the efflux more for endogenous than for exogenous noradrenaline; moreover it decreased the efflux of 3H-DOPEG, but increased that of 3H-MOPEG. The reserpine-like compound Ro 4-1284, on the other hand, abolished the consequences of the second type of heterogeneity; it reduced the specific activity of "total efflux" (i.e., of the sum of noradrenaline + DOPEG + MOPEG) to the specific activity of the tissue noradrenaline. The degree of heterogeneity of labelling was reduced after inhibition of monoamine oxidase and also when the tissues were loaded with 2 or 20 mumol/l 3H-noradrenaline. It is proposed that the various "compartments" and "pools" of noradrenaline described in the literature reflect the two heterogeneities described here.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1995

Heterogeneous activity of pulmonary vagal receptors during high-frequency oscillation ventilation.

The purpose of the study was to examine the response of vagal pulmonary slowly adapting stretch receptors (SAR) to high-frequency oscillation ventilation (HFO) in rabbits by analyzing the afferent activity recorded in vagal single-fiber preparations. The vagal afferent activity was recorded during short runs of HFO with a stroke volume of 2-3 ml/kg applied at oscillation frequencies (fosc) of 5, 10, 15, 20, and 25 Hz and each frequency at three levels of mean airway pressure (P(aw)), namely, 1, 3, and 8 cm H2O. The receptor discharge rates during HFO were compared with those during quiet spontaneous breathing as well as during static lung inflations and deflations. The majority of SAR was stimulated by HFO, however, the SAR discharge patterns during HFO were less homogeneous than during static lung inflations. The heterogeneity of SAR responses to HFO became pronounced with increasing P(aw) and fosc. From the results, we conclude that HFO elicits heterogeneous discharge patterns of SAR, but the previously reported heterogeneity of responses of rapidly adapting receptors was even greater. This heterogeneity of vagal activity is probably the result of heterogeneous mechanical conditions within the lungs during HFO and may, in turn, give rise to the various types of respiratory reflex responses to HFO.

Afferent Pathways↗
PubMed1994

Immunocytochemical and ultrastructural heterogeneities of normal and glibenclamide stimulated pancreatic beta cells in the rat.

When studied morphologically in semi-thin sections in the rat in vivo, pancreatic beta cells displayed heterogeneous immunoreactivities for insulin and amylin, depending on the islet size and the intra islet position of the beta cells. In larger islets, cortical beta cells (beta cells with contacts with all islet cell types and with the exocrine parenchyma) which are located in the periphery were more densely immunostained for insulin and amylin than medullary beta cells (beta cells with contacts only with other beta cells) which are located in the centre of the islet. Ultrastructurally, these findings were accompanied by differences in the number of secretory granules and mitochondria. Beta cells in small islets and at extra-islet sites exhibited a dense immunoreactivity. After administration of glibenclamide, immunoreactivities for insulin and amylin were diminished in a time-dependent manner, decreasing first in medullary and thereafter in cortical beta cells of larger islets. Ultrastructurally, the beta cells exhibited the typical signs of stimulation. A minority of beta cells in small islets and all beta cells in extra-islet locations remained unchanged. Thus pancreatic beta cells under basal and stimulatory conditions in vivo exhibit heterogeneity in hormone content and in ultrastructural features. These differences may represent the basis for a functional heterogeneity of the insulin secretory response of the individual beta cell both in vivo and in vitro in states of normal and impaired insulin secretion. As heterogeneity was observed only among beta cells in islets, while single beta cells surrounded by acinar cells exhibited no changes in insulin immunoreactivity, interactions between beta cells as well as between beta cells and other endocrine cells may be critical for expression of heterogeneity within the beta cell population.

Amyloid↗
PubMed1992

A region of heterogeneity adjacent to the 5s ribosomal RNA gene of cereal rusts.

Total genomic DNA was isolated from three cereal stem rusts, Puccinia graminis f. sp. tritici, f. sp. secalis, f. sp. avenae, and two cereal leaf rusts, P. recondita f. sp. tritici and P. coronata f. sp. avenae, and analyzed for the presence of heterogeneity in the intergenic region of the ribosomal DNA repeat unit. A 1 kb region of the repeat unit between the 26s and the 5s rRNA genes (IGR-1) was amplified by PCR and was found to be heterogeneous within each isolate and variable in size between races and species. The PCR results were confirmed by Southern blot analysis of native DNA. In an isolate of race C36(48), heterogeneity appeared to be due to variable numbers of 0.1 kb subrepeats in IGR-1. Nine wheat stem rust strains representing nine different races produced a unique pattern of heterogeneity while two different isolates of one race were identical, as were five of another. This may provide a rapid method for race identification in wheat stem rust. Heterogeneity and polymorphism in rye stem rust, oat stem rust, wheat leaf rust, and oat crown rust, was less pronounced than in wheat stem rust. In the course of this work, the 5s rRNA gene was located and its position and orientation within the ribosomal repeat unit was established.

Base Sequence↗
PubMed1991

Surface heterogeneity of bovine sperm revealed by aqueous two-phase partition.

Ejaculated, bovine sperm have been subjected to multiple partition in aqueous two-phase systems. This partition, carried out in a countercurrent fashion, reveals heterogeneity of the sperm population with respect to surface properties. The sperm, when partitioned in phase systems that detect non-change associated surface properties (change-insensitive) are largely distributed as two distinct populations. In charge-sensitive phase systems (which principally detect cell surface molecules carrying charge) the sperm do not show any obvious surface heterogeneity. Considerable heterogeneity is revealed in affinity-ligand phase systems containing palmitic acid coupled to one of the phase components-poly(ethylene glycol). There is a difference in surface heterogeneity between sperm which have been washed in buffer or left unwashed, direct from the ejaculate. This is indicative of weak adsorption of proteins to the sperm surface in seminal fluid. These results show that bovine ejaculated sperm is a heterogeneous cell population having unequal distributions of a number of different surface molecules.

Animals↗
PubMed1989

Homogeneous penetration but heterogeneous binding of antibodies to carcinoembryonic antigen in human colon carcinoma HT-29 spheroids.

The monoclonal antibodies 38S1, directed against the carcinoembryonic antigen (CEA), were tested for penetration and binding in human colon carcinoma HT-29 spheroids. Penetration was studied with a method which has not previously been used in immunological investigations. The method, which allows unbound substances to be visualized, is based on freeze drying, vapour fixation, dry sectioning and dry autoradiography. The antibodies penetrated easily and all parts of the HT-29 spheroids seemed to be reached within 15 min. The penetration was even faster than in control glioma U-118MG spheroids that did not express CEA. Binding of the 38S1 antibodies was demonstrated after processing with conventional histology and autoradiography. The binding in the HT-29 spheroids was, after a 1-h incubation period, extremely heterogeneous and occurred mainly in the peripheral parts. More cells were binding the antibodies after 8-h and 32-h incubations and these cells were arranged in peripheral clusters. No binding at all was seen in the CEA-negative glioma spheroids. The distribution of CEA antigens in monolayers and in frozen sections of spheroids of HT-29 cells was analysed with immunohistochemical staining using polyclonal CEA antibodies. The CEA antigens were heterogeneously distributed in both spheroids and monolayers and were as heterogenous as the binding of the monoclonal antibodies in the living spheroids. Thus, the heterogeneous binding in the living spheroids was not due to penetration barriers, but instead to the heterogeneity in the CEA antigen expression.

Adenocarcinoma↗
PubMed1994

Heterogeneity of monoamine oxidase activities in synaptic and non-synaptic mitochondria derived from three brain regions: some functional implications.

The heterogeneity of monoamine oxidase (MAO; EC 1.4.3.4) activities was studied in two fractions of synaptic mitochondria (SM & SM2) and one fraction of non-synaptic ("free") mitochondria (M) isolated from three rat brain regions (cerebral cortex, striatum, and pons & medulla) by the Lai and Clark (1979, 1989) method in order to elucidate the heterogeneity of MAO at the subcellular and brain regional levels. The activities toward serotonin (MAO-A), benzylamine (MAO-B), and dopamine (MAO-DA) in SM2 from all three regions were different from the corresponding values in SM. In addition, the various MAO activities in SM and SM2 showed heterogeneous distribution with respect to the three brain regions investigated. Both the distribution of MAO-A and MAO-B in non-synaptic mitochondria (M) did not show marked regional differences although MAO-DA in M varied depending on the region. These results clearly demonstrate that the distribution of MAO activities toward different substrates is heterogeneous both at the subcellular and the brain regional levels. The MAO-A:MAO-B ratios in the various mitochondrial fractions also showed trends that are consistent with this hypothesis. Furthermore, in fraction SM of synaptic mitochondria, this ratio was consistently higher than values in the other two mitochondrial fractions (SM2 & M) irrespective of the region from which they were isolated. In view of the functional importance of MAO in the regulation and compartmentation of amine metabolism, the heterogeneity of MAO at subcellular and regional levels may assume pathophysiological importance in neurological diseases (e.g., Parkinsonism) with which altered amine metabolism is associated.

Animals↗
PubMed2005

New aspects of vulnerability in heterogeneous models of ventricular wall and its modulation by loss of cardiac sodium channel function.

This numerical study quantified the vulnerable period (VP) in heterogeneous models of the cardiac ventricular wall and its modulation by loss of cardiac sodium channel function (NaLOF). According to several articles, NaLOF prolongs the VP and therefore increases the risk of re-entrant arrhythmias, but the studies used uniform models, neglecting spatial variation of action potential duration (APD). Here, physiological transmural heterogeneity was introduced into one-dimensional cables of the Luo-Rudy model cells. Based on the results with paired S1-S2 stimulation, a generalised formula for the VP was proposed that takes into account APD dispersion, and new phenomena pertaining to the VP are described that are not present in homogeneous excitable media. Under normal conditions, the vulnerable period in the heterogeneous cable with M cells was in the range of 0-21 ms, depending on S2 localisation, but only 2.4 ms throughout the uniform fibre. Unidirectional propagation induced during the VP could be antegrade or retrograde, depending on the localisation of the test stimulus and cable parameters, but, in a uniform model, it was always in the retrograde direction. Reduced sodium channel conductance from control 16 mS microF(-1) to 4 mS microF(-1) decreased the maximum VP to 11 ms in the heterogeneous cable, but increased the VP to 3 ms in the homogeneous model. It was concluded that realistic models of cardiac vulnerability should take into account spatial variations of cellular refractoriness. Several new qualitative and quantitative aspects of the VP were revealed, and the modulation of the VP by NaLOF differed significantly in heterogeneous and homogeneous models.

Action Potentials↗
PubMed2004

Heterogeneous UV/Fenton catalytic degradation of wastewater containing phenol with Fe-Cu-Mn-Y catalyst.

The heterogeneous UV/Fenton process with the appropriate amount of Fe-Mn-Cu-Y as catalyst was developed and various operation conditions for the degradation of phenol were evaluated. The results indicated that by using the heterogeneous UV/Fenton process, the COD(cr) removal rate reached almost 100% for wastewater containing phenol. Compared with the homogeneous process, the developed catalyst could be used at wider pH range in the UV/Fenton process. Comparison of various heterogeneous process showed that heterogeneous UV/Fenton process was best. The heterogeneous UV/Fenton process with Fe-Mn-Cu-Y catalyst is highly efficient in degrading various organic pollutants.

Computer Simulation↗
PubMed2005

Quantifying effects of soil heterogeneity on groundwater pollution at four sites in USA.

Four sites located in the north-eastern region of the United States of America have been chosen to investigate the impacts of soil heterogeneity in the transport of solutes (bromide and chloride) through the vadose zone (the zone in the soil that lies below the root zone and above the permanent saturated groundwater). A recently proposed mathematical model based on the cumulative beta distribution has been deployed to compare and contrast the regions' heterogeneity from multiple sample percolation experiments. Significant differences in patterns of solute leaching were observed even over a small spatial scale, indicating that traditional sampling methods for solute transport, for example the gravity pan or suction lysimeters, or more recent inventions such as the multiple sample percolation systems may not be effective in estimating solute fluxes in soils when a significant degree of soil heterogeneity is present. Consequently, ignoring soil heterogeneity in solute transport studies will likely result in under- or overprediction of leached fluxes and potentially lead to serious pollution of soils and/or groundwater. The cumulative beta distribution technique is found to be a versatile and simple technique of gaining valuable information regarding soil heterogeneity effects on solute transport. It is also an excellent tool for guiding future decisions of experimental designs particularly in regard to the number of samples within one site and the number of sampling locations between sites required to obtain a representative estimate of field solute or drainage flux.

Bromides↗