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PubMed1994

Variance of sensory threshold measurements: discrimination of feigners from trustworthy performers.

Sensory threshold measurements are criticized as subjective and therefore not to be relied upon in clinical diagnostic practice, particularly when deliberate deception by the patient is suspected. In an attempt to devise a method which permits dependable sensory threshold interpretation, individual variability of thresholds was examined in normal and neuropathic subjects. Normals were also instructed to feign sensory impairment resulting from hypothetical injury. For each subject, a number of threshold readings were averaged, yielding individual means and variances. Feigning normal subjects evidenced a larger variance compared to trustworthy normal and neuropathic subjects. Thus, alertness to variance reinforces the psychophysical analysis: small variance values suggest trustworthy normal or pathological results, whereas large variance calls the interpreter's attention to feigned results or inattentive test performance.

Cold Temperature↗

PubMed2003

Variables influencing the toxic response to organophosphates in humans.

Concerns and doubts associated with the predictable health effects in humans following exposure to xenobiotics is primarily due to the failure to consider the variables influencing the toxic response in each instance. Lack of correlation between laboratory data, animal experiments and clinical findings in man associated with exposure to organophosphates (OPs) is an example. We have reviewed the literature to identify the variables that need to be considered following exposure to OPs. These include factors related to the OP (physico-chemical properties, solvents, impurities), duration and routes of exposure, and factors related to the individual(s) exposed. Individual variables include variations in metabolic, sequestration and excretory processes and health status (age, gender, environmental factors, concurrent medications, cholinergic status). The assessment of ill-health following exposure is critical to the development and compliance with guidelines and to the adoption of the best instrumentation. We have suggested a schematic assessment that needs to be applied for each exposure associated with organophosphates and provided the reasons for the development of this format. Exposure to xenobiotics through the environment, occupation or following therapy is an unavoidable aspect of modern life. Application of the principles discussed to each xenobiotic exposure is necessary to provide accurate and adequate information to advance the prevention or minimising toxicity.

Age Factors↗

PubMedDate not supplied

Rocky Mountain spotted fever in Georgia, 1961-75: analysis of social and environmental factors affecting occurrence.

For the period of 1961 through 1975, 10 geographic and sociologic variables in each of the 159 counties of Georgia were analyzed to determine how they were correlated with the occurrence of Rocky Mountain spotted fever (RMSF). Combinations of variables were transformed into a smaller number of factors using principal-component analysis. Based upon the relative values of these factors, geographic areas of similarity were delineated by cluster analysis. It was found by use of these analyses that the counties of the State formed four similarity clusters, which we called south, central, lower north and upper north. When the incidence of RMSF was subsequently calculated for each of these regions of similarity, the regions had differing RMSF incidence; low in the south and upper north, moderate in the central, and high in the lower north. The four similarity clusters agreed closely with the incidence of RMSF when both were plotted on a map. Thus, when analyzed simultaneously, the 10 variables selected could be used to predict the occurrence of RMSF. The most important variables were those of climate and geography. Of secondary, but still major importance, were the changes over the 15-year period in variables associated with humans and their environmental alterations. Detailed examination of these factors has permitted quantitative evaluation of the simultaneous impacts of the geographic and sociologic variables on the occurrence of RMSF in Georgia. These analyses could be updated to reflect changes in the relevant variables and tested as a means of identifying new high risk areas for RMSF in the State. More generally, this method might be adapted to clarify our understanding of the relative importance of individual variables in the ecology of other diseases or environmental health problems.

Climate↗

PubMed1990

Genetic and environmental determinants of the lability of trait neuroticism and the symptoms of anxiety and depression.

A genetic analysis was conducted on trait neuroticism and symptoms of anxiety and depression in a five-wave study of 462 twin pairs. Models that assessed the relative importance of genetic and environmental factors to the lability (within-individual variability over time) of these measures were fitted to the data. Previous results concerning the substantial genetic involvement in the level of neuroticism and symptoms were confirmed. However, it was found that neither genes nor the shared environment of the twins was a significant cause of lability of these measures. An attempt was therefore made to identify aspects of individuals' environments that might be responsible for lability of neuroticism and symptoms. Adverse life events were found to predict variability of symptoms, but not of neuroticism. The availability of close social ties or having affectionless control in childhood did not contribute to lability.

Adult↗

PubMed2004

Variability in the structure of field 39 of the lower parietal area of the cortex in the left and right hemispheres of adult human brains.

The cytoarchitectonics of field 39 of the lower parietal area of the cortex in the left and right hemispheres were studied in normal individuals and professionally gifted world-famous people. Series of frontal sections were studied, stained by the Nissl cresyl violet method. The profile area of neurons was measured in layers III and V and the distribution of neurons in terms of this property was analyzed. Gifted people showed a significantly greater level of individual variability in the measures recorded here, especially in the right hemisphere, with larger proportions of very small and very large neurons.

Adult↗

PubMed2003

Monitoring sweat calcium using skin patches.

The purpose of this study was to determine whether a simple noninvasive sweat collection method using skin patches would be useful in monitoring sweat Ca and to determine changes in dermal Ca loss during a bed rest study testing a resistive exercise countermeasure. The study showed that the technique was highly reproducible: the mean intra-subject variation approached zero and the inter-individual variability (%CV) varied from 18% to 32% for the three anatomical regions (arm, chest, and back) tested. There was less than 10% difference in sweat Ca excretion from different skin regions within the same individual at a given time point. A calculated estimate of total body sweat excretion for 12 bed rest subjects was 35 +/- 4 mg/day (mean +/- SE), close to published whole body measurements. Bed rest testing showed no significant differences with or without exercise when conducted in a temperature-controlled environment. We conclude that the skin patch technique is useful for monitoring changes in sweat Ca.

Adult↗

PubMed1994

Regioselective biotransformation of midazolam by members of the human cytochrome P450 3A (CYP3A) subfamily.

The capabilities of cytochrome P4503A4 (CYP3A4), CYP3A5, and fetal hepatic microsomes containing CYP3A7 to metabolize midazolam were investigated using human hepatic microsomes and purified CYP3A4 and CYP3A5. Under initial rate conditions and high substrate concentration (400 microM midazolam), variability among eighteen human liver microsomal samples was 30- and 16- fold for 1'- and 4-hydroxylation of midazolam, respectively. Exclusion of two samples isolated from patients previously administered barbiturates reduced the inter-individual variability to 10.5- and 6.0-fold for 1'- and 4-hydroxylation, respectively. Six fetal hepatic microsomal samples showed 10-fold variation in both 1'-hydroxymidazolam and 4-hydroxymidazolam formation rates. The rates of formation of 4-hydroxymidazolam and 1'-hydroxymidazolam from midazolam by adult samples containing only CYP3A4 and by fetal liver samples were highly correlated (r2 = 0.99 and 0.97, P < 0.01, respectively). The rates of formation of 1'-hydroxymidazolam and 4-hydroxymidazolam from midazolam (400 microM) by adult samples that contained only CYP3A4 were correlated significantly (P < 0.01) with the ability of the samples to N-demethylate erythromycin (r2 = 0.95 and 0.92, respectively). 6 beta-hydroxylate testosterone (r2 = 0.96 and 0.96, respectively), and the CYP3A4 content of the samples (r2 = 0.89 and 0.86, respectively). Microsomal samples containing CYP3A5 in addition to CYP3A4 exhibited a significantly greater ratio of 1'-hydroxymidazolam to 4-hydroxymidazolam compared with samples containing only CYP3A4 or CYP3A7 (P < 0.001). Purified CYP3A5 in a reconstituted system, consisting of dilauroylphosphatidylcholine, cytochrome b5, and NADPH-cytochrome P450 reductase, and an NADPH-regenerating system displayed a 2-fold greater rate of 1'-hydroxymidazolam formation and a similar rate of 4-hydroxymidazolam formation compared with a reconstituted system with CYP3A4. In conclusion, CYP3A4, CYP3A5, and fetal microsomes containing CYP3A7 catalyze 1'- and 4-hydroxylation of midazolam with the ratio of these metabolites indicative of the CYP3A form.

Biotransformation↗

PubMed2006

Dynamics of interferon-specific gene expression in peripheral blood of interferon alfa-naïve patients with genotype 1 chronic hepatitis C infection treated with albumin-interferon alfa.

Albumin-interferon alfa (alb-IFN) is a novel recombinant protein derived from IFNalpha-2b genetically fused to human albumin, which combines in a single polypeptide the antiviral properties of IFNalpha with the long serum half-life of albumin. Interferon alfa (IFNalpha) mediated biological responses stem from the engagement of IFNalpha with its target receptor and subsequent modulation of interferon-specific gene (ISG) expression. The dynamics of ISG expression were evaluated in a Phase 2a study conducted in IFNalpha naïve patients with genotype 1 chronic hepatitis C (CHC) treated with alb-IFN. Whole blood was obtained pre-dose and on days 7 and 28 from 47 patients enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts ranging from 200 to1200mug. Gene expression of nine candidate genes including four ISGs was determined by a TaqMan Real-time PCR assay. There was sustained >5-fold median induction on days 7 and 28 of the ISG's- OAS1, IRF7, IFI44 and IFI27. While all subjects showed a molecular response to alb-IFN, individual variability in pre-treatment gene expression levels and fold of modulation during treatment was observed. At days 7 and 28, induction of OAS1, IFI44 and IRF7 showed significant pair-wise correlation in individual patients (r>0.7 and P<0.001). There was no correlation of baseline expression or induction of gene expression with antiviral response. In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the molecular response associated with an IFNalpha.

Journal Article↗

PubMed1992

A longitudinal approach to modeling outcomes in a nursing home study.

Recent developments in longitudinal statistical methodology have improved our ability to model dynamic processes such as adaptation to nursing homes. Longitudinal observations provide information on individual patterns of change and factors affecting them. However, longitudinal analyses are often complicated by unequal periods of observation and individual variability in patterns of change. This paper demonstrates the use of a linear mixed-effects model to study adaptation in a longitudinal nursing home study with different numbers of repeated measurements for each individual because of discharges, transfers, and mortality.

Adaptation, Psychological↗

PubMed1994

Pattern of characteristics in cataract patients.

Cataract extraction was performed in 1261 eyes. The relevant information was complete in 826 cases and thus only these were included in this study. Eleven variables describing clinical history, preoperative findings, operative problems and one variable representing visual acuity 4 months postoperatively were entered into a factor analysis model. Three factors were extracted by factor analysis, and these factors may be considered to be the underlying causes embracing the individual variables. Factor 1: the maculopathy factor; explained 23.3% of the total variance. Sixteen percent of the variance was attributable to Factor 2: the miosis factor. Lastly, Factor 3: operative problems; was responsible for 13.4% of the variance. The maculopathy factor was significantly associated with postoperative visual acuity (p < 0.001). Slight significant association was also found between the factor for operative problems and visual outcome, whereas no association was seen between the miosis factor and the final vision.

Adult↗

PubMed2005

Association of Kir6.2 and INS VNTR variants with glucose homeostasis in young obese.

Although insulin secretion is commonly increased and glucose tolerance decreased in young obese patients, there is a wide individual variability of these parameters. We investigated whether common variants at the Kir6.2 (KCNJ11) and insulin variable number of tandem repeat (INS VNTR) loci are associated with insulin or glucose levels in 388 obese children. The E23K and INS VNTR alleles showed no significant association when each locus was examined individually but a clear effect when the two loci were combined for analysis. In obese children with Kir6.2 KK and class III VNTR alleles, fasting glucose was slightly but consistently greater (4.76 +/- 0.05 mM) than in those with Kir6.2 EE and class I/I VNTR alleles (4.63 +/- 0.06 mM, P = 6.10(-4)) or other genotypes (4.64 +/- 0.03 mM, P = 1.10(-3)). Obese children with KK and class III VNTR genotypes also had an early response to oral glucose diminished by approximately 36% [insulinogenic index (IGI) = 50 +/- 4] compared with Kir6.2 EE and class I/I (IGI = 78 +/- 7, P = 0.026) or other genotypes (IGI = 69 +/- 3, P = 0.001). In young European obese, the polymorphisms of Kir6.2 and INS VNTR are thus associated with a trend for lower insulin and higher glucose levels, which may reveal a possible epistatic genetic effect that may influence a prediabetic trait in young obese children.

Adolescent↗

PubMed1999

Neural network analysis of preoperative variables and outcome in epilepsy surgery.

OBJECT: Because appropriate patient selection is essential for achieving successful outcomes after epilepsy surgery, the need for more robust methods of predicting postoperative seizure control has been created. Standard multivariate techniques have been only 75 to 80% accurate in this regard. Recent use of artificial intelligence techniques, including neural networks, for analyzing multivariate clinical data has been successful in predicting medical outcome. METHODS: The authors applied neural network techniques to 80 consecutive patients undergoing epilepsy surgery in whom data on demographic, seizure, operative, and clinical variables to predict postoperative seizures were collected. Neural networks could be used to predict postoperative seizures in up to 98% of cases. Student's t-tests or chi-square analysis performed on individual variables revealed that only the preoperative medication index was significantly different (p = 0.02) between the two outcome groups. Six different combinations of input variables were used to train the networks. Neural network accuracies differed in their ability to predict seizures: using all data (96%); all data minus electroencephalography concordance and operative side (93%); all data except intra- or postoperative variables such as tissue pathological category (98%); all data excluding pathological category, intelligence quotient (IQ) data, and Wada results (84%); only demographics and tissue pathological category (65%); and only IQ data (63%). CONCLUSIONS: Analysis of the results reveals that several networks that are trained with the usual accepted variables characterizing the typical evaluation of epilepsy patients can predict postoperative seizures with greater than 95% accuracy.

Anticonvulsants↗

PubMed1998

Antibody response of elk immunized with porcine zona pellucida.

Immunocontraception using porcine zona pellucida (PZP) vaccines is being explored as a nonlethal method of solving the problems of locally overabundant wildlife populations. This study characterized the immunological response of captive elk (Cervus elaphus nelsoni) to PZP challenge using 18 3-yr-old cows and was conducted from 14 September 1994 to 13 December 1995. All animals were given a single PZP inoculation and 1 mo later six of these animals were randomly chosen and received a booster inoculation. Blood samples were drawn from all animals at the time of the initial inoculation and 1, 2, 4, 6, 10, and 15 mo later. Immunological response was assessed by measuring anti-PZP antibody levels in serum. All animals demonstrated a strong immune response with no evidence that the booster enhanced antibody levels. Antibody levels rose from between 0 and 4 at the time of the initial injection to peak levels of 85 to 163 within 2 to 6 mo, followed by a noticeable decline by 15 mo post-vaccination. Limited data suggest that antibody levels > 100 may be required to effect contraception. High individual variability in immune response observed in this study suggests it may be difficult to predict the proportion of animals effectively treated. Disruption of seasonal synchrony in calving also could occur if antibody levels in individuals fall below effective levels while animals are still cycling. These results indicate that immunocontraception using PZP vaccines is possible for elk. However, carefully controlled population experiments will be required in order to assess the potential and limitations for management applications of this technique.

Animals↗

PubMed1987

Effect of egg cholesterol and dietary fats on plasma lipids, lipoproteins, and apoproteins of normal women consuming natural diets.

Nine normal women, 22 to 37 years old, consumed controlled quantities of natural foods to test their responses to dietary cholesterol and saturated fat. All diets contained, as percentage of calories, 14% protein, 31% fat, and 55% carbohydrate. The main sources of polyunsaturated and saturated fats were corn oil and lard, respectively, and egg yolk was used for cholesterol supplementation. All subjects participated in four diet protocols of 15 days duration, and each diet period was separated by 3 weeks without diet control. The first diet (corn) was based on corn oil, had a polyunsaturated to saturated fat ratio (P/S) of 2.14, and contained 130 mg of cholesterol. The second diet (corn+) was identical to the first but contained a total of 875 mg of cholesterol. The third diet (lard) was based on lard, had a P/S ratio of 0.64, and contained 130 mg of cholesterol. The fourth diet (lard+) was identical to the third, but contained 875 mg of cholesterol per day. Changes of the plasma lipid, lipoprotein and apoprotein parameters relative to the corn diet were as follows: the corn+ diet significantly increased total plasma cholesterol, HDL-cholesterol, LDL-cholesterol, and apoB levels; the lard diet significantly increased total cholesterol, HDL-cholesterol, and apoB; and the lard+ diet significantly increased the total cholesterol, HDL-cholesterol, LDL-cholesterol, and apoA-I and apoB levels. There were no significant variations in VLDL-cholesterol, triglyceride, or apoE levels with these diets. The diets affected both the number of lipoprotein particles as well as the composition of LDL and HDL. Compared to the corn diet, cholesterol and saturated fat each increased the number of LDL particles by 17% and 9%, respectively, and the cholesterol per particle by 9%. The combination of saturated fat and cholesterol increased particle number by 18% and particle size by 24%. Switching from lard+ to lard, corn+, or corn diets reduced LDL-cholesterol of the group by 18%, 11%, and 28%, respectively, while a large inter-individual variability was noted. In summary, dietary fat and cholesterol affect lipid and lipoprotein levels as well as the particle number and chemical composition of both LDL and HDL. There is, however, considerable inter-individual heterogeneity in response to diet.

Adult↗

PubMed1984

Variability in serologically detected male antigen titer and some resulting problems: a critical review.

Seroologically detected male antigen" (also called H-Y antigen) was first described in normal male mammals but now appears to occur in normal female mammals as well. "Serologically detected male predominant" (SDMP) antigen is a more appropriate name since the titer in normal males usually exceeds that of normal females. As we show, in each sex there is a considerable inter-individual variability in SDMP antigen titer, and in moderate-to-large size samples the low end of the male range of titers usually coincides with the high end of the female range. Several major problems arise from failure to recognize and/or to deal adequately with this normal variation in SDMP antigen titer. The chief problem is that the "controls" used (often a single individual) may be inadequate and misleading, leading to unjustified designation of samples as "positive", "negative", or even "deviant" ("intermediate", "reduced") for SDMP antigen titer. Other problems include deficiencies in technique and lack of statistical control for test and sample variability. Adequate attention to these problems, especially to the normal variability in SDMP antigen titer, could reduce the contradictions and inconsistencies which have troubled this field.

Animals↗

PubMed2006

Population pharmacokinetics of high-dose methotrexate in children with acute lymphoblastic leukaemia.

OBJECTIVE: To develop and a priori validate a methotrexate population pharmacokinetic model in children with acute lymphoblastic leukaemia (ALL), receiving high-dose methotrexate followed by folinic acid rescue, identifying the covariates that could explain part of the pharmacokinetic variability of methotrexate. METHODS: The study was carried out in 49 children (aged 6 months to 17 years) who received high-dose methotrexate (3 g/m(2) per course) in long-term treatment. In an index group (37 individuals; 1236 methotrexate plasma concentrations), a population pharmacokinetic model was developed using a nonlinear mixed-effects model. The remaining patients' data (12 individuals; 278 methotrexate plasma concentrations) were used for model validation. Age, sex, total bodyweight (TBW), height, body surface area, lowest urine pH during infusion, serum creatinine, ALT, AST, folinic acid dose and length of rescue were analysed as possible covariates. The final predictive performance of the pharmacokinetic model was tested using standardised mean prediction errors. RESULTS: The final population pharmacokinetic model (two-compartmental) included only age and total bodyweight as influencing clearance (CL) and volume of distribution of central compartment (V(1)). For children aged < or =10 years: CL (L/h) = 0.287 . TBW(0.876); V(1) (L) = 0.465 . TBW, and for children aged >10 years: CL (L/h) = 0.149 . TBW; V(1) (L) = 0.437 . TBW. From the base to the final model, the inter-individual variabilities for CL and V(1) were significantly reduced in both age groups (30-50%). The coefficients of variation of the pharmacokinetic parameters were <30%, while residual and inter-occasional coefficients maintained values close to 40%. Validation of the proposed model revealed the suitability of the model. CONCLUSION: A methotrexate population pharmacokinetic model has been developed for ALL children. The proposed model could be used in Bayesian algorithms with a limited sampling strategy to estimate the systemic exposure of individual patients to methotrexate and adapt both folinic acid rescue and methotrexate dosing accordingly.

Adolescent↗

PubMed1976

Erythromycin and clindamycin absorption and elimination in pregnant women.

Thirty-nine pregnant women admitted for therapeutic abortions during early or mid pregnancy were given erythromycin estolate, erythromycin base, or clindamycin hydrochloride orally in single or multiple doses. Peak serum levels of clindamycin were 3.4 to 9.0 mug/ml following a single dose of 450 mg, whereas peak serum levels of erythromycin were 0.29 to 7.2 mug/ml following 500 mg in a single dose. The individual variability of serum concentrations of erythromycin was greater than that reported in normal men and nonpregnant women, whereas the serum levels of clindamycin were rather uniform, and similar to what has been reported in nonpregnant individuals. Following multiple doses of each antibiotic, high serum levels were obtained in virtually all subjects, and urine levels were also higher. Following single doses the mean urinary recovery was 2% for erythromycin and 16.8% for clindamycin.

Abortion, Therapeutic↗

PubMed1991

Pharmacokinetically determined cyclosporine dosage in young children.

To account for the individual variability in cyclosporine pharmacokinetics and the non-existence of dosing recommendations in young children, we studied the pharmacokinetics of cyclosporine before renal transplantation in ten children aged 1.1-2.5 years, to determine the appropriate individual dose. Our aim was to reach a steady-state cyclosporine blood level of 200-300 micrograms/l, 8 h after a dose in the first days after renal transplantation. Cyclosporine was given as a single oral dose (10 mg/kg) or as a 4-h i.v. infusion (3 mg/kg), and the blood concentration was determined for 24 h by a specific monoclonal radioimmunoassay. The mean terminal cyclosporine half-life (t1/2) was 9.3 h (range 2.8-20.4), blood clearance 10.8 ml/min per kilogram (range 6.8-22.7) and volume of distribution 2.8 l/kg (range 1.4-4.7). The bioavailability of oral cyclosporine was low; the mean amount absorbed was 21.8% of the administered dose (range 11-35). The mean calculated dose needed to attain the intended predose blood cyclosporine level of 200-300 micrograms/l at steady-state was 5 mg/kg per day for i.v. and 21 mg/kg per day for oral administration. In view of the short t1/2, we used three doses/day. The validity of the predicted doses is shown by the mean cyclosporine doses used during the first 10 days after transplantation, which were 93.5% of the calculated oral and 96.6% of the calculated i.v. doses. The observed mean cyclosporine concentration during the same period was 196 micrograms/l.

Cyclosporins↗