Greater Inter-individual Variation Research Articles

Associations Between Developmental Stability, Canalization, and Phenotypic Plasticity in Response to Heterogeneous Experience.

The processes of developmental stability, canalization, and phenotypic plasticity have ecological and evolutionary significance, and been studied extensively, but mostly separately and thus the relationships between them are not straightforward. Our objective was to better integrate these processes in the context of temporally heterogeneous environments. We did this by investigating the effects of early experience with temporal heterogeneity in water availability on associations between developmental stability, canalization, and phenotypic plasticity. We subjected eight plant species to a first round of alternating inundation and drought vs. constantly moderate water treatments (heterogeneous experience) and a second round of water conditions (to test plasticity). We measured fluctuating asymmetry (FA) in leaf size, intra- and inter-individual variation (CVintra and CVinter), and plasticity (PI) in traits and analyzed correlations between these variables across all species. Results showed little correlations between FA, CVintra and PI, several positive correlations between FA and CVinter in more stressful conditions, especially in as well as positive correlations between CVinter and PI initially and negative correlations between them later. These suggested the complexity of these relationships, which can depend on whether plasticity occurs. Greater inter-individual variation will more likely cooperate with plasticity before or during plastic response, whereas higher canalization may reflect phenotypic convergence. Both higher FA and CVintra can reflect faster growth, while CVintra may also reflect plant growth stage, and the two mechanisms should cooperate in response to environmental challenges. The complexity of these relationships suggests plants deal with environmental variation in elaborate and integrative ways which can be affected by many factors.

Resistant starch type 2 and whole grain maize flours enrich different intestinal bacteria and metatranscriptomes

The intestinal microbiota of Sprague-Dawley (SD) rats were investigated following consumption of diets containing refined high-amylose cornstarch (RS), waxy whole-grain flour from maize (WG), or high-amylose whole-grain flour (WG + RS) together with moderate (MF, 30% of energy) or high (HF, 42% of energy) levels of fat. Compared with control (CON) diets, RS reduced bacterial alpha-diversity and enriched Bacteroidetes and WG increased Lactobacillus proportions by three-fold. WG + RS conferred a combined effect, but the changes were attenuated and greater inter-individual variation was observed. Proportions of fiber-degrading bacterial taxa were inversely correlated with cecal pH. Notably, there was little influence of fat intake on the cecal microbiota. Examination of cecal metatranscriptomes showed that WG and CON diets resulted in similar microbiomes. RS consumption was associated with an increased abundance of either Bacteroides or Prevotella transcripts. Metatranscriptomes of RS-fed rats were consistently enriched in transcripts encoding chaperones, glutamate decarboxylases and glutaminases, and starch degradative enzymes.

Expression of cytochrome P450 isozyme transcripts and activities in human livers

Individual differences in cytochrome P450 (CYP) enzymes contribute to responses to drugs and environmental chemicals. The expression of CYPs is influenced by sex, age, and ethnicity. Human CYP studies are often conducted with human liver microsomes and liver cells to evaluate chemical induction and drug interactions. However, the basal or constitutive expression of CYP transcripts and enzyme activities in the intact liver are also important in our understanding of individual variation in CYPs. This study utilised 100 human liver samples to profile the constitutive expression of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A11 enzyme activity and transcript levels. The mRNA expression of the CYPs and xenobiotic receptors AhR, CAR, and PXR was examined via qPCR. Results showed that there was greater inter-individual variation in mRNA expression than in enzyme activities, except for CYP2C19. Females had higher CYP3A4 activity than males. Children had lower CYP4A14 activity, while elderly had lower P450 oxidoreductase activity. Compared to Caucasians, Hispanics had higher CYP2C8 activity and higher CYP2B6, CYP2C9, and CYP2C19 mRNA expression, whereas African Americans had lower CYP2D6 mRNA expression. These results add to our understanding of individual variations in xenobiotic metabolism and toxicology.

Stability-normalised walking speed: A new approach for human gait perturbation research

In gait stability research, neither self-selected walking speeds, nor the same prescribed walking speed for all participants, guarantee equivalent gait stability among participants. Furthermore, these options may differentially affect the response to different gait perturbations, which is problematic when comparing groups with different capacities. We present a method for decreasing inter-individual differences in gait stability by adjusting walking speed to equivalent margins of stability (MoS). Eighteen healthy adults walked on a split-belt treadmill for two-minute bouts at 0.4 m/s up to 1.8 m/s in 0.2 m/s intervals. The stability-normalised walking speed (MoS = 0.05 m) was calculated using the mean MoS at touchdown of the final 10 steps of each speed. Participants then walked for three minutes at this speed and were subsequently exposed to a treadmill belt acceleration perturbation. A further 12 healthy adults were exposed to the same perturbation while walking at 1.3 m/s: the average of the previous group. Large ranges in MoS were observed during the prescribed speeds (6–10 cm across speeds) and walking speed significantly (P < 0.001) affected MoS. The stability-normalised walking speeds resulted in MoS equal or very close to the desired 0.05 m and reduced between-participant variability in MoS. The second group of participants walking at 1.3 m/s had greater inter-individual variation in MoS during both unperturbed and perturbed walking compared to 12 sex, height and leg length-matched participants from the stability-normalised walking speed group. The current method decreases inter-individual differences in gait stability which may benefit gait perturbation and stability research, in particular studies on populations with different locomotor capacities. [Preprint: https://doi.org/10.1101/314757]

Transgenerational Effects of Extended Dauer Diapause on Starvation Survival and Gene Expression Plasticity in Caenorhabditis elegans.

Phenotypic plasticity is facilitated by epigenetic regulation, and remnants of such regulation may persist after plasticity-inducing cues are gone. However, the relationship between plasticity and transgenerational epigenetic memory is not understood. Dauer diapause in Caenorhabditis elegans provides an opportunity to determine how a plastic response to the early-life environment affects traits later in life and in subsequent generations. We report that, after extended diapause, postdauer worms initially exhibit reduced reproductive success and greater interindividual variation. In contrast, F3 progeny of postdauers display increased starvation resistance and lifespan, revealing potentially adaptive transgenerational effects. Transgenerational effects are dependent on the duration of diapause, indicating an effect of extended starvation. In agreement, RNA-seq demonstrates a transgenerational effect on nutrient-responsive genes. Further, postdauer F3 progeny exhibit reduced gene expression plasticity, suggesting a trade-off between plasticity and epigenetic memory. This work reveals complex effects of nutrient stress over different time scales in an animal that evolved to thrive in feast and famine.

Comparison of Performance-Based Observed Assessment, Self-Report, and Paper–Pencil Measures of Everyday Problem Solving in Chinese Older Adults

The study was to verify for older adults, the applicability of a recently developed measure of everyday problem solving, a performance-based observed assessment (the Chinese Version of Observed Tasks of Daily Living [OTDL-C]), by comparing with two other measures—a self-report questionnaire and a paper–pencil test. Totally 183 older adults (aged 60–84 years) completed demographic questionnaires and three everyday problem-solving assessments. All assessments measured the same instrumental domains of daily life (medication use, phone use, electric appliance use, and financial management). We observed significant differences in inter-individual variation, and found significant differences in the effects of age and education level on OTDL-C performance compared with self-report and paper–pencil measure performance. Additionally, the inter-individual variance was significantly greater for the OTDL-C and paper–pencil test than for the self-report questionnaire. Age remained a significant predictor of OTDL-C performance after controlling the scores of the self-report and the paper–pencil measures. Education level had more consistent effects on the total score and each domain score of the OTDL-C compared to the other two measures. Overall, our finding indicated that the OTDL-C had greater inter-individual variation, might be a more sensitive tool for examining age-related differences in the ability to solve everyday problem, and could be more applicable to older populations with diverse education levels compared to the self-report and the paper–pencil measures. In circumstances where a high sensitive assessment of everyday problem solving is needed to detect individual differences, the OTDL-C might be a more appropriate choice.

Circulating liver-specific microRNAs in cynomolgus monkeys.

Circulating microRNAs (miRNAs) can potentially be used as sensitive and specific biomarkers for tissue injury. However, the usefulness of circulating miRNAs as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific miRNAs. Therefore, a systematic investigation was performed to address this point. We identified organ-specific miRNAs from cynomolgus monkeys by next-generation sequencing analysis, which revealed that miR-122 was only abundant in the liver, whereas miR-192 was abundant in the liver, stomach, intestines, and kidney. The sequences of these miRNAs were identical to their human counterparts. Next, the absolute miR-122 and miR-192 levels were qualified by quantitative reverse transcription polymerase chain reaction (RT-qPCR) to determine the circulating levels of the miRNAs. No significant differences in the levels of circulating miRNAs between sexes were noted, and there was greater interindividual variation in miR-122 (20-fold variation) than in miR-192 (8-fold variation), based on their dynamic ranges. Finally, we evaluated the fluctuation in circulating liver-specific miRNAs in a monkey model of acetaminophen-induced hepatotoxicity. Acetaminophen with L-buthionine-(S,R)-sulfoximine induced hepatotoxicity in all the animals, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Circulating miR-122 and miR-192 levels increased more than ALT levels after 24 h, indicating that circulating miR-122 and miR-192 may serve as sensitive biomarkers for the detection of hepatotoxicity in cynomolgus monkeys. This review describes the fundamental profiles of circulating liver-specific miRNAs in cynomolgus monkeys and focusses on their organ specificity, circulating levels, and fluctuations in drug-induced hepatotoxicity.

Pastoral land-use of the Indus Civilization in Gujarat: faunal analyses and biogenic isotopes at Bagasra

The Indus Civilization (2600–1900 BC) in Gujarat is characterized by a series of small yet monumentally walled settlements located along trade and travel corridors. The manufacture and use of typically Harappan material culture at these settlements demonstrates that many residents of these sites participated in exchange and interaction networks that linked them to distant Indus cities. Less is known, however, regarding the ways in which the residents of these sites were situated into their local landscapes. Here we combine previously published faunal analyses from the small walled settlement of Bagasra in the Indian state of Gujarat, with a preliminary investigation of intra- and inter-individual variation in the ratios of biogenic isotopes of strontium (87Sr/86Sr), carbon (δ13C), and oxygen (δ18O) in the tooth enamel of domestic animals consumed at the site. 87Sr/86Sr ratios in the teeth of sheep and goats exhibit little intra- or inter-individual variation suggesting that most were raised locally while greater inter-individual variation in the teeth of cattle suggesting that nearly half of these animals were either raised further afield or were supplied with fodder raised elsewhere. δ13C values from these same samples in the teeth of sheep and goats exhibit considerable intra-individual variation suggesting of a seasonally variable diet incorporating significant wild forage while uniformly higher values in the teeth of cattle suggest that they consumed mostly agricultural produce throughout the year. δ18O values in the teeth of both sets of domestic livestock exhibit considerable intra-individual variation commensurate with the seasonal variation in temperature and rainfall characteristic of the region while variation between taxa is consistent with observed dietary differences. Taken together, our findings provide new information regarding the ways in which the domestic animals consumed at Bagasra were raised and obtained while establishing an empirical baseline necessary for further exploration of the land-use changes that may have accompanied the emergence and decline of South Asia's first urban civilization.

BEYOND COMPARING MEANS: THE USEFULNESS OF ANALYZING INTERINDIVIDUAL VARIATION IN GENE EXPRESSION FOR IDENTIFYING GENES ASSOCIATED WITH CANCER DEVELOPMENT

Identifying genes associated with cancer development is typically accomplished by comparing mean expression values in normal and tumor tissues, which identifies differentially expressed (DE) genes. Interindividual variation (IV) in gene expression is indirectly included in DE gene identification because given the same absolute differences in means, genes with lower variance tend to have lower p-values. We explored the direct use of IV in gene expression to identify candidate genes associated with cancer development. We focused on prostate (PCa) and lung (LC) cancers and compared IV in the expression level of genes shown to be cancer related with that in all other genes in the human genome. Compared with all those other genes, cancer-related genes tended to have greater IV in normal tissues and a greater increase in IV during the transition from normal to tumorous tissue. Genes without significantly different mean expression values between tumor and normal tissues but with greater IV in tumor than in normal tissue (note: the DE-based approach completely ignores those genes) had stronger associations with clinically important features like Gleason score in PCa or tumor histology in LC than all other genes were. Our results suggest that analyzing IV in gene expression level is useful in identifying novel candidate genes associated with cancer development.

Effect of Alcohol Consumption on CpG Methylation in the Differentially Methylated Regions of H19 and IG‐DMR in Male Gametes—Implications for Fetal Alcohol Spectrum Disorders

Exposure to alcohol in utero is the main attributable cause of fetal alcohol spectrum disorders (FASD) which in its most severe form is characterized by irreversible behavioral and cognitive disability. Paternal preconception drinking is not considered to be a significant risk factor, even though animal studies have demonstrated that chronic paternal alcohol consumption has a detrimental effect on the physical and mental development of offspring even in the absence of in utero alcohol exposure. It has been documented that alcohol can reduce the levels and activity of DNA methyltransferases resulting in DNA hypomethylation and that reduced methyltransferase activity can cause activation of normally silenced genes. The aim of this study was to establish a link between alcohol use in men and hypomethylation of paternally imprinted loci in sperm DNA in genomic regions critical for embryonic development, thus providing a mechanism for paternal effects in the aetiology of FASD. Sperm DNA from male volunteers was bisulfite treated and the methylation patterns of 2 differentially methylated regions (DMRs), H19 and IG-DMR, analyzed following sequencing of individual clones. The methylation patterns were correlated with the alcohol consumption levels of the volunteer males. There was a pattern of increased demethylation with alcohol consumption at the 2 imprinted loci with a significant difference observed at the IG-DMR between the nondrinking and heavy alcohol consuming groups. Greater inter-individual variation in average methylation was observed at the H19 DMR and individual clones were more extensively demethylated than those of the IG-DMR. CpG site #4 in the IG-DMR was preferentially demethylated among all individuals and along with the H19 DMR CpG site #7 located within the CTCF binding site 6 showed significant demethylation in the alcohol consuming groups compared with the control group. This study demonstrates a correlation between chronic alcohol use and demethylation of normally hypermethylated imprinted regions in sperm DNA. We hypothesize that, should these epigenetic changes in imprinted genes be transmitted through fertilization, they would alter the critical gene expression dosages required for normal prenatal development resulting in offspring with features of FASD.

Design issues in cross-sectional biomarkers studies: Urinary biomarkers of PAH exposure and oxidative stress

Cross-sectional biomarker studies can provide a snapshot of the frequency and characteristics of exposure/disease in a population at a particular point in time and, as a result, valuable insights for delineating the multi-step association between exposure and disease occurrence. Three major issues should be considered when designing biomarker studies: selection of appropriate biomarkers, the assay (laboratory validity), and the population validity of the selected biomarkers. Factors related to biomarker selection include biological relevance, specificity, sensitivity, biological half-life, stability, and so on. The assay attributes include limit of detection, reproducibility/reliability, inter-laboratory variation, specificity, time, and cost. Factors related to the population validity include the frequency or prevalence of markers, greater inter-individual variation than intra-individual variation, intra-class correlation coefficients (ICC), association with potential confounders, invasiveness of specimen collection, and subject selection. Three studies are selected to demonstrate different features of cross-sectional biomarker studies: (1) characterizing the determinants of the biomarkers (study I: urinary PAH metabolites and environmental particulate exposure), (2) relationship of multiple biomarkers of exposure and effect (study II: relationship between urinary PAH metabolites and oxidative stress), and (3) evaluating gene–environmental interaction (study III: effect of genetic polymorphisms of GSTM1 on the association of green tea consumption and urinary 1-OHPG levels in shipbuilding workers).

Ocular measurements throughout the adult life span of rhesus monkeys.

To examine the relationship of ocular components to refraction throughout the adult life span of the rhesus monkey (Macaca mulatta). Cycloplegic retinoscopy, A-scan ultrasonography, slit lamp examination, indirect ophthalmoscopy, and keratometry were performed in a cross-sectional study of 111 monkeys, aged 5 to 31 years. Lens thickness and anterior and vitreous chamber depths were measured from the echograms. The intercorrelations of these variables were analyzed, as well as their association with age and sex. In monkeys aged 5 to 15 years, the mean refractive value of +1.5 D with an SD of 1.7 D was maintained near the previously established developmental asymptote of +2 D. In monkeys older than 15 years, there was greater interindividual variation (SD = 4.5 D), including extreme myopia and hyperopia. The cornea became steeper with age. The axial length of the eyes increased up to 12 years of age and began to shorten after 20 years. Changes also occurred in the other individual components that constitute eye length. These age-related changes were decreased vitreous chamber depth, decreased anterior chamber depth, and increased lens thickness. In general, males had longer eyes than females. The eyes of old monkeys were more likely to exhibit cataract and drusen, but age-related changes in focal atrophy of the retinal pigment epithelium did not achieve statistical significance. The components of the monkey eye change with age in a pattern similar to that reported in humans. Age-related changes in individual ocular components that could be detrimental to refraction appear to be compensated for by changes in other components.

Comparison of the Pharmacokinetic Profiles of Soluble Aspirin and Solid Paracetamol Tablets in Fed and Fasted Volunteers

The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.

Comparison of the Pharmacokinetic Profiles of Soluble Aspirin and Solid Paracetamol Tablets in Fed and Fasted Volunteers

SummaryThe aim of this study was to investigate the absorption of popular preparations of two common analgesics – soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.

Evaluation of Grip Force Exertions in Dynamic Manual Work

An obstacle to the development of guidelines for reducing forceful hand movements is that manual force is not easily measured or estimated at the worksite, especially during highly dynamic activities. Grip force requirements during manual work are dependent not only on object weight, but also on the surface characteristics of the object and the task dynamics. In theory, it is possible to predict grip force requirements for manual tasks using Newtonian laws of physics; however few researchers have attempted to measure grip force during dynamic work, much less to compare actual grip force values to predicted levels. Therefore, a laboratory experiment was conducted to examine grip force exertions during two simulated industrial tasks. In each task, participants repetitively grasped and moved aluminum handles against varying levels of weight or resistance. Grip force was measured using a strain gauge mounted inside the handles. Results indicate that grip force varied continuously throughout each work cycle in response to changes in the motion of the hand/handle. The pattern of variation was consistent between subjects and could be approximated by a sinusoidal model. Greater interindividual variation in grip force exertion was observed when the task allowed greater flexibility in selecting a movement strategy. The results also indicate that subjects are more likely to “overshoot” the necessary grip force (i.e., apply more force than needed) at the initiation of movement, especially at lower weight levels. This study demonstrates that it is possible to predict variations in grip force during dynamic work, although further refinements in the procedure are needed. Use of modelling techniques will enable industrial designers to better estimate grip force requirements and to identify design strategies that will reduce the risk of musculoskeletal injury to the worker.

Intrinsic radiosensitivity of adult and cord blood lymphocytes as determined by the micronucleus assay

Predictive radiosensitivity testing necessitates rapid and reliable assays of radiosensitivity. We assessed the lymphocyte micronucleus assay as such an assay. We performed repeated experiments on lymphocytes from 10 healthy donors. Levels of radiation-induced micronuclei were measured following exposures of up to 4 Gy X-rays. When measuring the slope of the dose-response, we have found more variation between individuals than between repeated experiments on the same individual ( F value 12.31, P < 0.001). There is also greater interindividual variation in the data following a single dose of X-rays of 2 Gy ( F value 3.54, P < 0.01) and of 4 Gy ( F value 7.55, P < 0.005). We performed the micronucleus assay on five different samples of cord blood lymphocytes (CBLs). Their radiosensitivities were compared with the mean radiosensitivity of the lymphocytes from the normal group of donors. Comparing the level of micronuclei induced by 2 Gy, only CBL1 ( P < 0.01) and CBL2 ( P < 0.02) were more radiosensitive than the mean of the adult lymphocytes. At 4 Gy, CBL1 ( P < 0.001), CBL2 ( P < 0.05), CBL3 ( P < 0.01) and CBL5 ( P < 0.01) were more radiosensitive than the mean radiosensitivity of the adult lymphocytes. This was also shown when the slope of the dose-response curves were measured. We conclude that the lymphocyte micronucleus assay shows more variability when applied to lymphocytes from different individuals than when repeatedly applied to lymphocytes from the same individual, a requirement for the determination of individual radiosensitivity.

Pharmacokinetics of thio-TEPA and TEPA in the conventional dose-range and its correlation to myelosuppressive effects

A total of 13 patients with ovarian cancer were studied during the initial two courses of i.v. thio-TEPA treatment they underwent after primary surgery. Following an increase in the dose from 60 to 80 mg for the second course, no sign of saturation of thio-TEPA elimination processes or of formation of the metabolite TEPA occurred, indicating dose-independent pharmacokinetics. Myelosuppression after courses was registered by serial measurements of platelets and leukocytes. The time to platelet nadir was quite uniformly 3 weeks and tended to be longer than that of leukocytes, which averaged 2 weeks but showed greater interindividual variation. Linear regression analyses of pharmacokinetic parameters versus myelosuppression revealed statistically significant correlations between thio-TEPA pharmacokinetics and the percentage of reductions in leukocytes and platelets at their mean nadirs. In contrast, no such correlation could be demonstrated for TEPA despite its greater exposure to the body in terms of AUC. We advocate further investigation of this pharmacokinetic-pharmacodynamic relationship so as to establish individualized dosing of thio-TEPA.

Metabolism of methaqualone in geriatric patients.

The urinary excretion of five C-monohydroxy metabolites and the N-oxide of methaqualone has been measured in a group of eleven geriatric patients aged 71--90 years. The total excretion of the six metabolites in 24 h after the oral administration of a single dose was approximately one-half of that in a group of young healthy adults. The relative importance of the six metabolites was 4'-hydroxy greater than N-oxide greater than 2'-hydroxymethyl = 3'-hydroxy greater than 6-hydroxy = 2-hydroxymethyl which was the same order as that in young adults. The ratio of C-to N-oxidation was also the same in the two groups. There was no impairment of conjugation of the C-hydroxy metabolites with glucuronic acid in the geriatric group but there was greater interindividual variation in metabolite excretion. There was also evidence for delayed metabolism in the geriatric patients.