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PubMed2000

Chemical modification probes accessibility to organic phase: proteins on surfaces are more exposed than in lyophilized powders.

Chemical modification of myoglobin and cutinase suspended in n-hexane by acyl chlorides and iodine was monitored by electrospray mass spectrometry. The general rate of modification was always much faster for protein adsorbed to supports (silica or polypropylene) than for lyophilized powders. Modification rates were slower for larger acyl chlorides, particularly with lyophilized powders. About 20% of the protein molecules in lyophilized powders were modified much more quickly than the rest, a fraction consistent with those exposed on the surface of the solid. It appears that access to most of the molecules in lyophilized powders requires a very slow stage of solid-phase diffusion. This has been neglected in previous discussion of mass transfer limitation of lyophilized enzymes in organic media, and would not be revealed by the experimental evidence used to dismiss it. Studies of the effects of particle size and dilution with inactive protein are only sensitive to diffusion in liquid-filled pores, not through the solid phase. Slow solid-phase diffusion is not required for access to most support-adsorbed proteins, which is probably a major contributory factor to their enhanced catalytic efficiency in organic media. Hydration of lyophilized proteins accelerates chemical modification rates, as it does their catalytic activity. The main site of reaction of acyl chlorides in organic media is not amino groups (which are probably ion-paired), but is likely to be hydroxyl groups instead.

Journal Article↗
PubMed2001

Chemical modification probes accessibility to organic phase: proteins on surfaces are more exposed than in lyophilized powders.

Chemical modification of myoglobin and cutinase suspended in n-hexane by acyl chlorides and iodine was monitored by electrospray mass spectrometry. The general rate of modification was always much faster for protein adsorbed to supports (silica or polypropylene) than for lyophilized powders. Modification rates were slower for larger acyl chlorides, particularly with lyophilized powders. About 20% of the protein molecules in lyophilized powders were modified much more quickly than the rest, a fraction consistent with those exposed on the surface of the solid. It appears that access to most of the molecules in lyophilized powders requires a very slow stage of solid-phase diffusion. This has been neglected in previous discussion of mass transfer limitation of lyophilized enzymes in organic media, and would not be revealed by the experimental evidence used to dismiss it. Studies of the effects of particle size and dilution with inactive protein are only sensitive to diffusion in liquid-filled pores, not through the solid phase. Slow solid-phase diffusion is not required for access to most support-adsorbed proteins, which is probably a major contributory factor to their enhanced catalytic efficiency in organic media. Hydration of lyophilized proteins accelerates chemical modification rates, as it does their catalytic activity. The main site of reaction of acyl chlorides in organic media is not amino groups (which are probably ion-paired), but is likely to be hydroxyl groups instead.

Journal Article↗
PubMed2002

Superhydrophobic modification fails to improve the performance of small diameter expanded polytetrafluoroethylene vascular grafts.

To determine whether superhydrophobic modification of small diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts improves the performance of these grafts, we assessed neointima formation and platelet deposition in standard and superhydrophobic modified ePTFE grafts. Standard and superhydrophobic vascular grafts were implanted in the carotid arteries of two rabbits and two pigs. Furthermore, standard and superhydrophobic vascular patches were implanted in the carotid arteries of seven pigs. After 4 weeks of implantation all patches were removed and histomorphometric data were analyzed. The early thrombotic effect of superhydrophobic modification was examined by quantifying platelet glycoprotein receptor IIIa deposition onto each type of vascular graft after 15 min of in vitro circulation with human blood. All superhydrophobic and standard ePTFE vascular grafts occluded 15 min to 1 h after implantation in both rabbit and pig carotid arteries. All implanted patches remained patent and were completely covered by endothelium. Superhydrophobic modification of ePTFE vascular grafts did not lead to less neointima formation and resulted in significantly more platelet deposition than did standard ePTFE vascular grafts. Thus, superhydrophobic modification does not improve the performance of small diameter ePTFE vascular grafts.

Animals↗
PubMed1999

2'-carbohydrate modifications in antisense oligonucleotide therapy: importance of conformation, configuration and conjugation.

The 2'-position of the carbohydrate moiety has proven to be a fertile position for oligonucleotide modifications for antisense technology. The 2'-modifications exhibit high binding affinity to target RNA, enhanced chemical stability and nuclease resistance and increased lipophilicity. All high binding affinity 2'-modifications have C3'-endo sugar pucker. In addition to gauche effects, charge effects are also important in determining the level of their nuclease resistance. Pharmacokinetic properties of oligonucleotides are altered by 2'-conjugates. For certain modifications (e.g., 2'-F), the configuration at the 2'-position, arabino vs. ribo, determines their ability to activate the enzyme RNase H.

Alternative Splicing↗
PubMed2000

Kinetic characterization of Desulfovibrio gigas hydrogenase upon selective chemical modification of amino acid groups as a tool for structure-function relationships.

The effect of amino acid residues modification of Desulfovibrio gigas hydrogenase on different activity assays is reported. The first method consisted in the modification of glutamic and aspartic acid residues of the enzyme with ethylenediamine in order to change the polarity of certain regions of the protein surface. The second method consisted in the modification of histidine residues with a Ru complex in order to change the acid-base properties of the histidine residues. The implication of these modifications in the enzyme kinetics has been studied by measuring in parallel the activities of para/ortho hydrogen conversion, deuterium/hydrogen exchange and dyes reduction with hydrogen. Our experimental data support some hypothesis based on the three-dimensional structure of this enzyme: (a) electrostactic interactions between the hydrogenase and the redox partner play an essential role in the kinetics; (b) the histidine ligand and the surrounding acidic residues of the distal [4Fe4S] cluster form the recognition site of the redox partner of the hydrogenase; and (c) histidine residues are involved in the hydron transfer pathway of the hydrogenase.

Amino Acids↗
PubMed1997

Site-specific modification of rabbit muscle creatine kinase with sulfhydryl-specific fluorescence probe by use of hydrostatic pressure.

We investigated the effect of pressure on the reactivity of cysteine residues of rabbit muscle creatine kinase (CK). Performing the fluorescent modification under high pressure, a unique sulfhydryl group (Cys-253) of CK was labeled, in addition to Cys-282, which is known as a single reactive sulfhydryl under ambient conditions. CK is composed of two identical subunits, containing four cysteine residues in each subunit. Cys-282 plays an important role in enzymatic activity. In the pressure range from 0.1 MPa to 300 MPa, only one sulfhydryl group for each subunit of CK reacted with the reagents. However, at 400 MPa 2 sulfhydryl groups were modified. The 2-nitro-5-thiocyanobenzoic acid (NTCB) cleavage method revealed that both Cys-282 and Cys-253 were modified at 400 MPa. The chemical modification of Cys-282 induced a loss of enzymatic activity. By taking advantage of the modification under high pressure, selective modification of Cys-253 with 5-[N-(iodoacetamidoethyl)amino]-naphthalene-1-sulfonate (IAEDANS) was performed. A reversible blocking of Cys-282 at atmospheric pressure was followed by the reaction of Cys-253 with the fluorescent probe at 400 MPa. After the decompression, Cys-282 was unblocked, and obtained Cys-253-modified CK retained up to 64% of the catalytic activity of the intact CK. The fluorescent properties of IAEDANS covalently bound at Cys-253 were not significantly different from those of IAEDANS covalently bound at Cys-282.

Animals↗
PubMed1999

Optimising the signal peptide for glycosyl phosphatidylinositol modification of human acetylcholinesterase using mutational analysis and peptide-quantitative structure-activity relationships.

Glycosyl phosphatidylinositol (GPI)-modified proteins have a C-terminal signal peptide (GPIsp) that mediates the addition of a GPI-anchor to an amino acid residue at the cleavage and modification site (omega-site). Within the GPIsp, a stretch of hydrophilic amino acid residues are found which constitutes the spacer region that separates the omega-site residue from a hydrophobic C-terminus. Deletions and insertions into the spacer region of human acetylcholinesterase (AChE) show that the length of this spacer region is very important for efficient GPI-modification. Surprisingly, the natural length of the spacer region in human AChE was not optimal for the highest degree of GPI modification. The importance of the two adjacent residues downstream of the omega-site, the omega+1 and omega+2 residues, was investigated by peptide-quantitative structure-activity relationships (Peptide-QSAR). A model was made that predicts the efficiency of the GPI modification when these residues are substituted with others, and suggests important features for these residues. The most preferred omega+1 and omega+2 residues, predicted by the model, in combination with an ideal spacer length resulted in an optimised GPIsp. This mutant protein is more efficiently GPI-modified than any mutant AChE tested thus far.

Acetylcholinesterase↗
PubMed2003

On-line trajectory modifications of planar, goal-directed arm movements.

Sometimes a goal-directed arm movement has to be modified en route due to an unforeseen perturbation such as a target displacement or a hand displacement by an external force. In this paper several aspects of that modification process are addressed. Subjects had to perform a point-to-point movement task on a computer screen using a mouse-coupled pointer as the representation of the hand position. Trajectory modifications were imposed by unexpectedly changing the position of the target or by changing the relation between mouse and screen pointer. In the first series of experiments, we examined how often a trajectory is updated. Here, trajectory modifications were imposed by unexpectedly changing the normal relation between mouse and pointer to a shear-like relation, where a percentage of the forward/backward position of the hand was added to the pointer position in the left/right direction. Withdrawal of visual feedback during the movement revealed that trajectories were updated at interval times shorter than 200 ms. From the similarity with experiments where the original relation between mouse and pointer was restored during the movements, we conclude that motor plans are updated on-line to move the hand from its current perceived position to the target. In a second series of experiments, we studied whether a continuous change in target position yields similar trajectory modifications as a continuous hand displacement. To mimic the latter perturbation, we used the above-mentioned distortion of the mouse-pointer relation. We found that the resulting hand paths did not differ for the two visual perturbations and conclude that the perturbed, goal-directed movements are modified in a consistent way, irrespective of whether the position of the target or hand was perturbed. Simulations of the experimental data with a kinematic reaching model support this conclusion.

Acceleration↗
PubMed2003

Assembly of EcoKI DNA methyltransferase requires the C-terminal region of the HsdM modification subunit.

The methyltransferase component of type I DNA restriction and modification systems comprises three subunits, one DNA sequence specificity subunit and two DNA modification subunits. Limited proteolysis of the EcoKI methyltransferase shows that a 55-kDa N-terminal fragment of the 59-kDa modification subunit is resistant to degradation. We have purified this fragment and determined by mass spectrometry that proteolysis removes 43 or 44 amino acids from the C-terminus. The fragment fails to interact with the other subunits even though it still possesses secondary and tertiary structure and the ability to bind the S-adenosylmethionine cofactor. We conclude that the C-terminal region of the modification subunit of EcoKI is essential for the assembly of the EcoKI methyltransferase.

Amino Acid Sequence↗
PubMed2003

Modification of Gill-Thomas-Cosman frame for extracranial head-and-neck stereotactic radiotherapy.

PURPOSE: A modification of a commercially available, noninvasive, relocatable, stereotactic Gill-Thomas-Cosman (GTC) head frame is presented for treatment of extracranial lesions of the head and neck, base of the skull, and inferior nasopharyngeal region. METHODS AND MATERIALS: Skull-based and nasopharyngeal lesions cannot be treated with the GTC frame because it obstructs the beam path. To treat those lesions, the GTC frame was modified without compromising the integrity, flexibility, or use of the treatment software. The modification uses a set of aluminum extension rods of variable lengths and bevels to support a modified dental plate. The extension rods allow the dental tray and attached GTC frame to be lowered so that the more inferior regions may be treated. Ten patients underwent CT with the modified frame and CT localizer. For some patients, MRI was acquired without the frame. Image fusion of MRI and CT scans was used to delineate the target volume, and planning was done with the existing software for proper treatment. RESULTS: The modification of the GTC frame has been successful in imaging, planning, and extending the treatment domain for the base of the skull, nasopharyngeal regions, and other superior lesions of the head and neck. The reproducibility of the modified frame and the patient localization helmet technique was identical to that of the unmodified frame. CONCLUSION: The modification of the GTC frame is simple and accurate. It provides flexibility in treating an extended range of the base of the skull, nasopharyngeal region, and other superior lesions of the head and neck that otherwise could not be treated with the GTC frame.

Equipment Design↗
PubMed1997

Adaptive modification of treatment planning to minimize the deleterious effects of treatment setup errors.

PURPOSE: Using daily setup variation measured from an electronic portal imaging device (EPID), radiation treatment of the individual patient can be adaptively reoptimized during the course of therapy. In this study, daily portal images were retrospectively examined to: (a) determine the number of initial days of portal imaging required to give adequate prediction of the systematic and random setup errors; and (b) explore the potential of using the prediction as feedback to reoptimize the individual treatment part-way through the treatment course. METHODS AND MATERIALS: Daily portal images of 64 cancer patients, whose treatment position was not adjusted during the course of treatment, were obtained from two independent clinics with similar setup procedures. Systematic and random setup errors for each patient were predicted using different numbers of initial portal measurements. The statistical confidence of the predictions was tested to determine the number of daily portal measurements needed to give reasonable predictions. Two treatment processes were simulated to examine the potential opportunity for setup margin reduction and dose escalation. The first process mimicked a conventional treatment. A constant margin was assigned to each treatment field to compensate for the average setup error of the patient population. A treatment dose was then prescribed with reference to a fixed normal tissue tolerance, and then fixed in the entire course of treatment. In the second process, the same treatment fields and prescribed dose were used only for the initial plan and treatment. After several initial days of treatments, the treatment field shape and position were assumed to be adaptively modified using a computer-controlled multileaf collimator (MLC) in light of the predicted systematic and random setup errors. The prescribed dose was then escalated until the same normal tissue tolerance, as determined in the first treatment process, was reached. RESULTS: The systematic setup error and the random setup error were predicted to be within +/-1 mm for the former and +/-0.5 mm for the latter at a > or = 95% confidence level using < or = 9 initial daily portal measurements. In the study, a large number of patients could be treated using a smaller field margin if the adaptive modification process were used. Simulation of the adaptive modification process for prostate treatment demonstrates that additional treatment dose could be safely applied to 64% of patients. CONCLUSION: The adaptive modification process represents a different approach for use of on-line portal images. The portal imaging information from the initial treatments is used as feedback for reoptimization of the treatment plan, rather than adjustment of the treatment setup. Results from the retrospective study show that the treatment of individual patient can be improved with the adaptive modification process.

Algorithms↗
PubMed2002

Effects of mixed polyethyleneglycol modification on fixed aqueous layer thickness and antitumor activity of doxorubicin containing liposome.

Polyethyleneglycol (PEG) has often been used for the modification of liposomes, but it is difficult to insert PEG on the surface of liposomes, and the effects of modification are not marked enough. In this study, we examined the fixed aqueous layer thickness (FALT) of single or mixed PEG (molecular weight, 340, 500, 900, 2000)-modified doxorubicin (DOX) liposomes, and physical character and biological properties of these liposomes. On single PEG-modification, as the PEG-molecular weight increased, FALT also increased, but the ratio of the increase was reduced. While on modification by a mixture of PEG2000 and PEG with a short polyoxyethylene chain (PEG340 or PEG500), FALT increased compared with the single PEG2000-modified value. Moreover, when liposomes were modified by mixture of PEG2000 and PEG500, we recognized the most suitable mixed rate (PEG2000, 500=2:1), showed the maximum FALT. On the other hand, in vivo, as increase of FALT, DOX concentrations increased in the plasma and in the tumor, decreased in the liver. Furthermore, liposomes with remarkable increase of FALT showed enhancement of antitumor activity. As a result, the connection among increase of FALT and improvement of circulation in blood, the involvement of antitumor activity of DOX of these liposomes was suggested.

Algorithms↗
PubMed1999

Lipoprotein modification and atherosclerosis in aging.

The development of extensive atherosclerosis of major arteries of the heart, brain, and lower extremities is a particularly frequent problem in elderly individuals and is responsible for the majority of the cardiovascular morbidity and mortality in this population. Although the frequency and severity of this problem is well recognized, there has been relatively little investigation of the effects of aging on the development of atherosclerosis. Work by a number of investigators over the last 10-15 years has demonstrated that modifications of lipoproteins, resulting from oxidative stress, glycoxidation, formation of AGE, or other processes may play an important role in atherosclerosis. As described in this review, the aging process may enhance lipoprotein modification and atherosclerosis in several ways. Conditions such as hypertension, diabetes, and menopause all increase in frequency with advancing age and may contribute both directly and indirectly to lipoprotein modification and vascular injury.Additionally, in some studies of older animals and humans, there seems to be evidence for greater in vivo oxidative stress. Whether this is a specific consequence of aging and associated medical conditions, or related to differences in dietary fatty acid or antioxidant content or other lifestyle differences is currently unknown. One important consequence of this may be enhanced susceptibility of lipoproteins to oxidation. Additional study of lipoprotein modifications associated with aging is clearly needed, and may provide new insight and solutions to the common problem of atherosclerosis in the elderly.

Aging↗
PubMed1997

Long-term follow-up after radiofrequency modification of the atrioventricular node in patients with atrial fibrillation.

OBJECTIVES: The purpose of this study was to describe the long-term follow-up results in 62 patients with atrial fibrillation and an uncontrolled ventricular rate, who underwent radiofrequency modification of the atrioventricular (AV) node. BACKGROUND: Previous studies in small numbers of patients have suggested that radiofrequency modification may be effective in controlling the ventricular rate in patients with atrial fibrillation, but long-term follow-up data have been lacking. METHODS: The subjects of this study were 62 consecutive patients (mean age +/- SD 65 +/- 14 years; 43 with structural heart disease) who underwent an attempt at radiofrequency modification of the AV node because of symptomatic, drug-refractory atrial fibrillation with an uncontrolled ventricular rate. The atrial fibrillation was chronic in 46 patients and paroxysmal in 16. Radiofrequency energy was applied to the posteroseptal or mid-septal right atrium to lower the ventricular rate in atrial fibrillation to 120 to 130 beats/min during an infusion of 4 micrograms/min of isoproterenol. RESULTS: Short-term control of the ventricular rate was successfully achieved without the induction of pathologic AV block in 50 (81%) of 62 patients. Inadvertent high degree AV block occurred in 10 (16%) of 62 patients, with the AV block occurring at the time of the procedure in 6 patients and 36 to 72 h after the procedure in 4. During 19 +/- 8 months of follow-up (range 4 to 33), 5 (10%) of 50 patients had a symptomatic recurrence of an uncontrolled rate during atrial fibrillation. Overall, adequate rate control at rest and during exertion, without pathologic AV block, was achieved long term in 45 (73%) of 62 patients. Among 37 patients with a successful outcome, left ventricular ejection fraction increased from (mean +/- SD) 0.44 +/- 0.14 to 0.51 +/- 0.10 one year later (p < 0.001). Complications other than AV block included polymorphic ventricular tachycardia 10 to 24 h after the procedure in two patients who had a predisposing factor for ventricular tachycardia and sudden death 1 to 5 months after the procedure in two patients with idiopathic dilated cardiomyopathy, one of whom had a pacemaker for AV block. CONCLUSIONS: In approximately 70% of properly selected patients with atrial fibrillation and an uncontrolled ventricular rate, radiofrequency modification of the AV node results in excellent long-term control of the ventricular rate at rest and during exertion.

Aged↗
PubMed2003

Suicidal inactivation of the rabbit 15-lipoxygenase by 15S-HpETE is paralleled by covalent modification of active site peptides.

Lipoxygenases (LOXs) are multifunctional enzymes that catalyze the oxygenation of polyunsaturated fatty acids to hydroperoxy derivatives; they also convert hydroperoxy fatty acids to epoxy leukotrienes and other secondary products. LOXs undergo suicidal inactivation but the mechanism of this process is still unclear. We investigated the mechanism of suicidal inactivation of the rabbit 15-lipoxygenase by [1-(14)C]-(15S,5Z,8Z,11Z,13E)-15-hydroperoxyeicosa-5,8,11,13-tetraenoic acid (15-HpETE) and observed covalent modification of the enzyme protein. In contrast, nonlipoxygenase proteins (bovine serum albumin and human gamma-globulin) were not significantly modified. Under the conditions of complete enzyme inactivation we found that 1.3 +/- 0.2 moles (n = 10) of inactivator were bound per mole lipoxygenase, and this value did depend neither on the enzyme/inactivator ratio nor on the duration of the inactivation period. Covalent modification required active enzyme protein and proceeded to a similar extent under aerobic and anaerobic conditions. In contrast, [1-(14)C]-(15S,5Z,8Z,11Z,13E)-15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15-HETE), which is no substrate for epoxy-leukotriene formation, did not inactivate the enzyme and protein labeling was minimal. Separation of proteolytic cleavage peptides (Lys-C endoproteinase digestion) by tricine SDS-PAGE and isoelectric focusing in connection with N-terminal amino acid sequencing revealed covalent modification of several active site peptides. These data suggest that 15-lipoxygenase-catalyzed conversion of (15S,5Z,8Z,11Z,13E)-15-hydroperoxyeicosa-5,8,11,13-tetraenoic acid to 14,15-epoxy-leukotriene leads to the formation of reactive intermediate(s), which are covalently linked to the active site. Therefore, this protein modification contributes to suicidal inactivation.

Amino Acid Sequence↗
PubMed1997

Oleic acid rich diet protects against the oxidative modification of high density lipoprotein.

Oxidative modifications of lipoproteins could contribute to the development of atherosclerosis, but the influence of dietary fats on high density lipoprotein (HDL) oxidative modification is unknown. This study was designed to determine whether a diet rich in oleic acid could modulate the oxidative modification of HDL3. Twenty two healthy men were randomly placed on a 32-wk crossover study of an oleic acid rich diet supplied by a variant of sunflower oil vs a linoleic acid rich diet provided by conventional sunflower oil. Plasma HDL3 obtained after the diet rich in oleic acid showed a significantly higher oleic acid content in the phospholipid than lipoprotein isolated after the linoleic acid rich diet. HDL3 isolated after the oleic acid rich diet had lower values of thiobarbituric acid reactive substances (TBARS) than HDL3 obtained after the linoleic acid rich diet both for native (mean +/- SE; 0.24 +/- 0.02 vs 0.42 +/- 0.08 nmol MDA/mg protein; p < 0.01) and copper oxidized HDL3 (0.75 +/- 0.06 vs 0.95 +/- 0.07 nmol MDA/mg protein; p < 0.01). Indeed, TBARS for native HDL3 were negatively correlated with the oleic acid to linoleic acid ratio and positively with the percentage of linoleic acid in their phospholipids. Interestingly, HDL3 after both diets had similar antioxidant vitamins A and E content. HDL3 overall composition and fluidity were similar after the two diets. Moreover, HDL3 obtained after both diets produced identical [3H] free cholesterol efflux from human monocyte-derived macrophages (29%) and fibroblasts (26%). In conclusion, HDL3 rich in oleic acid was less easily oxidized regardless of the content of antioxidants such as vitamins A and E. Therefore, dietary monounsaturated fatty acid prevent the oxidative modification of lipoproteins.

Cholesterol↗
PubMed1999

Heme and apoprotein modification of cytochrome P450 2B4 during its oxidative inactivation in monooxygenase reconstituted system.

The mechanism of the cytochrome P450 2B4 modification by hydrogen peroxide (H2O2) formed as a result of partial coupling of NADPH-dependent monooxygenase reactions has been studied in the monooxygenase system reconstituted from the highly purified microsomal proteins: cytochrome P450 2B4 (P450) and NADPH-cytochrome P450 reductase in the presence of detergent Emulgen 913. It was found, that H2O2-mediated P450 self-inactivation during benzphetamine oxidation is accompanied by heme degradation and apoenzyme modification. The P450 heme modification involves the heme release from the enzyme under the action of H2O2 formed within P450s active center via the peroxycomplex decay. Additionally, the heme lost is destroyed by H2O2 localized outside of enzyme's active center. The modification of P450 apoenzyme includes protein aggregation that may be due to the change in the physico-chemical properties of the inactivated enzyme. The modified P450 changes the surface charge that is confirmed by the increasing retention time on the DEAE column. Oxidation of amino acid residues (at least cysteine) may lead to the alteration into the protein hydrophobicity. The appearance of the additional ionic and hydrophobic attractions may lead to the increase of the protein aggregation. Hydrogen peroxide can initiate formation of crosslinked P450 dimers, trimers, and even polymers, but the main role in this process plays nonspecific radical reactions. Evidence for the involvement of hydroxyl radical into the P450 crosslinking is carbonyl groups formation.

Animals↗
PubMedDate not supplied

Effect modification in epidemiologic studies of low-level neurotoxicant exposures and health outcomes.

Little attention has been invested in exploring the possibility that the nature or magnitude of a neurotoxicant's health impact on children depends on host characteristics (e.g., sex, age) or contextual factors (e.g., socioeconomic status, other chemical exposures). Such effect modification is a property of a true association, and should be distinguished from confounding. In epidemiologic studies of children, most efforts to identify effect modification have been unsystematic, pursued as part of data analysis rather than of study design. As a result, most samples have insufficient statistical power to characterize effect modification with adequate precision. This may contribute to an inconsistency in results across studies. Failure to assess effect modification adequately may also lead to invalid inferences. If the magnitude of an association between a neurotoxicant exposure and a particular end point varies across strata of a third factor, an estimate that summarizes the association across strata of this factor will be inappropriate, overestimating the association in a stratum in which the association is absent, and underestimating it in a stratum in which it is present. Until such dependencies are identified, our understanding of the mechanism(s) of a compound's neurotoxicity will remain incomplete, as will the knowledge base required to formulate public policy that adequately protects the most sensitive subgroups of the population.

Child↗