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PubMed2006

Chemokine receptors as biomarkers in multiple sclerosis.

Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.

Adult↗
PubMed1973

Accelerated triglyceride secretion. A metabolic consequence of obesity.

A new animal model was developed to determine the effect of obesity upon endogenous triglyceride secretion. Desert sand rats (Psammomys obesus), rodents which become spontaneously obese and hyperinsulinemic when given ad lib. chow, were given intravenous Triton to allow in vivo measurement of triglyceride secretion rates (TGSR). In a group of 18 fasted animals of varying body weight and degrees of obesity, TGSR correlated significantly with body weight (r=0.68, P < 0.01) indicating that obesity was associated with accelerated endogenous release of triglyceride. In these same animals, basal plasma insulin levels correlated significantly with body weight (r=0.78, P < 0.001) and TGSR correlated significantly with mean plasma insulin levels (r=0.73, P < 0.001), suggesting that hyperinsulinemia may have been the mechanism through which obesity enhanced TGSR. No correlation was found between basal triglyceride level and either body weight, basal insulin, or TGSR which suggested that individual triglyceride removal rates among the animals may have been variable. To test this hypothesis, seven animals were studied prospectively before and after induction of obesity. There were significant increases (P < 0.02) in all parameters, i.e., weight, plasma insulin level, TGSR, and basal triglyceride level. Thus, when each animal was used as its own control, thereby minimizing the postulated factor of variable individual triglyceride removal, increments in basal triglyceride were shown to accompany the development of obesity, hyperinsulinemia, and accelerated triglyceride secretion. These data from studies in the sand rat offer in vivo evidence that obesity leads to accelerated triglyceride secretion, an effect which may be mediated by hyperinsulinemai, and which can be invoked as one possible mechanism to explain hypertriglyceridemia associated with obesity in man.

Animals↗
PubMed1992

Graphical displays: implications for divided attention, focused attention, and problem solving.

When completing tasks in complex, dynamic domains observers must consider the relationships among many variables (e.g., integrated tasks) as well as the values of individual variables (e.g., focused tasks). A critical issue in display design is whether or not a single display format can achieve the dual design goals of supporting performance at both types of tasks. We consider this issue from a variety of perspectives. One relevant perspective is the basic research on attention and object perception, which concentrates on the interaction between visual features and processing capabilities. The principles of configurality are discussed, with the conclusion that they support the possibility of achieving the dual design goals. These considerations are necessary but not sufficient for effective display design. Graphic displays map information from a domain into visual features; the tasks to be completed are defined in terms of the domain, not in terms of the visual features alone. The implications of this subtle but extremely important difference are discussed. The laboratory research investigating alternative display formats is reviewed. Much like the attention literature, the results do not rule out the possibility that the dual design goals can be achieved.

Attention↗
PubMed2006

Accuracy and biological variation of human serum paraoxonase 1 activity and polymorphism (Q192R) by kinetic enzyme assay.

BACKGROUND: Paraoxonase 1 (PON1) phenotype is a better predictor of atherosclerosis risk than are PON1 genetic polymorphisms alone. Larger studies are required to determine the role of PON1 and there is a need for standardized PON1 assays between laboratories. METHODS: We have adapted 5 enzyme kinetic assays for high-throughput automated analysis of PON1 activity. Using different substrates and reaction conditions, we measured PON1 activity and used activity ratios to identify the PON1 Q192R genetic polymorphisms and assessed the accuracy of the genotype assignments in 79 adult study participants by comparing them with genotypes determined by AlwI restriction enzyme digestion of a 176-bp PCR amplification product from genomic DNA. Imprecision was determined using pooled serum and purified enzyme preparations. Biological variability was estimated by analysis of serial samples from 17 individuals. Variability parameters were compared with total cholesterol as a point of reference to a recognized biomarker of coronary heart disease risk. RESULTS: Salt stimulation and inhibition ratios were 97.4% and 94.7% correct in assigning Q192R genotype, respectively. Analytical imprecision (CV) was 1.0%-3.0% for phenylacetate and paraoxon substrate assays and 3.0%-8.0% for the para-nitrophenylacetate substrate assays. Combination of the 2 ratios into a double ratio resulted in 100% correct genotype classification. CONCLUSION: The described methods for measurement of PON1 activity and accurate genotype assignment are rapid and have potential to facilitate the efficient investigation of PON1 status in clinical and epidemiological studies.

Adult↗
PubMed1988

Estimation of urinary 24-hr creatinine excretion by body size and dietary protein level: a field survey based on seasonally repeated measurements for residents living in Akita, Japan.

We aimed to investigate the modifying effect of dietary protein level on the estimation of 24-hr creatinine excretion using anthropometric measurements, in a group of 40 healthy Japanese adults, during usual daily life. To evaluate the variability of each measurement during non-restrictive life, we assayed 24-hr urinary excretions of creatinine and urea-N and measured heights and weights once in every three months in a total of 4 times during a year. Urinary urea-N was used as a marker of dietary protein level. Seasonal variability of anthropometrics and urinary excretions was observed on the individual basis. In comparison to the rather small individual variability of weight (mean of CV = 1.2 for males, 1.7 for females), variability of urinary creatinine (CV = 11.7, 8.4) and urea-N (CV = 18.9, 17.3) took larger values. The creatinine excretion was estimated by the following two sets of predictor variables; (I) age, height and weight, (II) age, height, weight and urea-N. Although, a statistically significant estimation was obtained by (I), estimation (II) resulted higher regression coefficient than (I), and contribution of urea-N to the estimation of creatinine was shown. Average level of seasonal variability of each predictor variable was further applied to the regression equation (II). Therefore, the possible difference of 24-hr creatinine excretion caused by the seasonal variability of dietary protein level was estimated to be 9.2% for males and 3.6% for females in the given population. Thus, when one predicting formula of 24-hr creatinine by the use of anthropometrics is applied to other populations, the difference of protein nutritional status should be carefully considered.

Adult↗
PubMed2004

Pharmacogenetics of antipsychoatics.

Although a number of antipsychotics have been introduced for the treatment of schizophrenia, inter-individual differences of in antipsychotic response and the number of refractory schizophrenic patients have become two of the most challenging problems in clinical psychiatry. Thus, the pharmacogenetics of antipsychotics have been aimed at providing genetic components of this inter-individual variability in antipsychotic response in order to establish an individually-based pharmacotherapy for schizophrenia and to elucidate the mechanism of antipsychotic response so as to solve the refractoriness of schizophrenia. Pharmacogenetics, which is defined as the science of pharmacological response and its modification by hereditary influence can be divided into two categories: the genetic background of pharmacokinetics, i.e. the absorption, distribution, tissue localization, biotransformation and excretion of drugs, and pharmacodynamics, i.e. the biochemical and physiological consequences of a drug and its mechanism of action. Pharmacokinetics of antipsychotics has been focused mainly on the association between genetic polymorphisms in CYP genes, including CYP2D6, and the metabolism of these drugs. Polymorphism in CYP2D6 enables a division of individuals within a given population into at least two groups, i.e. poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) of certain drugs. PMs have higher plasma concentrations of and more adverse effects from antipsychotics. UMs could be one of the important factors that induce treatment-refractoriness to antipsychotics. Genetic polymorphisms in serotonin and dopamine receptors that have a high affinity for antipsychotics have so far been extensively investigated in the pharmacodynamics of this type of drug. Not just one gene but multiple genes play a role in complex phenotypes, including the clinical response to medication. Thus, a multiple candidate genes approach has recently been adopted in the pharmacogenetics of antipsychotics. The new field of pharmacogenomics using DNA microarray analysis, which focuses on the genetic determinants of drug response at the level of the entire human genome, is important for development and prescription of safer and more effective individually-tailored antipsychotics.

Alleles↗
PubMedDate not supplied

[The cytogenetic damage, radiosensitivity and adaptive response in children living in the different districts of Moscow].

The spontaneous level of blood lymphocytes with micronuclei (MN), the sensitivity to 1.0 Gy irradiation and adaptive response (AR) after adaptive irradiation with a dose of 0.05 Gy 5 hr later have been studied in children population living in different districts of Moscow. It was shown that spontaneous frequency of cells with MN, the sensitivity to 1.0 Gy acute irradiation and the AR manifestation have significant differences in samples taken from children living in different districts. The individual variability is significant also. In each group of children the individuals with the enhanced radiosensitivity after adaptive irradiation have been observed. In conformance with the data of radioecological inspection the radiation situation in different Moscow districts is quite safe on overage but in some districts the spontaneous level of lymphocytes with MN, and radiosensitivity after 0.05 Gy irradiation were enhanced, the AR was not found.

Adaptation, Physiological↗
PubMed1990

Heat intolerance: predisposing factor or residual injury?

Great individual variability exists in the ability to sustain heat stress. Some individuals are more susceptible to heat than others. Those individuals, among the young active population (athletes, military recruits, laborers), are at risk to contract exertional heat stroke. Low tolerance to heat results from either functional factors, or from congenital or acquired disturbances. In most cases heat intolerance can be foreseen. Cases of dehydration, overweight, low physical fitness, lack of acclimatization, febrile or infectious diseases, and skin disorders should be regarded a priori as predisposing factors for heat intolerance. Special attention should be paid to subjects with previous heat stroke episodes since it might reflect an underlying cause for heat susceptibility. The heat tolerance of these subjects should be tested 8-12 wk postepisode to detect a possible residual injury in the ability to thermoregulate adequately in the heat.

Acclimatization↗
PubMed1996

Variability of clinical and pressure-flow study variables after 6 months of watchful waiting in patients with lower urinary tract symptoms and benign prostatic enlargement.

PURPOSE: We quantified the physiological variability of clinical and pressure-flow study variables in patients with symptomatic benign prostatic enlargement. MATERIALS AND METHODS: Symptom scores were measured, and advanced urodynamic studies with pressure-flow analysis were performed in 178 patients before and 6 months after a period a watchful waiting. RESULTS: Patients without bladder outlet obstruction experienced significant symptomatic improvement. Symptoms in patients with obvious bladder outlet obstruction did not improve significantly. The reproducibility of mean pressure-flow variables was evident. However, there was an important intra-individual variability. Patients with obvious bladder outlet obstruction showed a significant decreases in detrusor pressure at maximal flow of 14cm. water, a significant decrease in the urethral resistance factor of 7 cm. water and a significant decrease of 1 obstruction class on the linear passive urethral resistance relation nomogram, indicating less severe bladder outlet obstruction. CONCLUSIONS: Mean differences among therapy groups must be regarded critically, especially when the difference are slight and possibly within physiological variability.

Aged↗
PubMed1992

Clinical implications of variable antiarrhythmic drug metabolism.

Due to their narrow therapeutic indices, antiarrhythmic drugs have a great potential for adverse outcome. This is amplified by extreme inter-individual variability in their disposition and their pharmacological actions. Genetically determined inter-individual differences in metabolism account for a great deal of this variability. However, because of active metabolites, chirally-specific actions and chirally-specific metabolism, it is not possible to generalize about the outcome of phenotypic differences in the metabolism of a given drug. Careful study of these factors can enable physicians to understand the spectrum of potential responses to a drug. Newly developed molecular biology techniques now make it possible to determine the genotype for the CYP2D6 gene that controls metabolism of many antiarrhythmic drugs. This information, combined with a full understanding of the drugs' clinical pharmacology now makes it possible to predict the clinical outcome for drugs such as encainide, flecainide, mexiletine, propafenone and combinations of these drugs with quinidine.

Anti-Arrhythmia Agents↗
PubMed1977

The use of public transportation in urban areas: toward a causal model.

In this study, using the statistical models recently introduced by Goodman, we analyze the reasons why individuals choose the car or public transportation for the journey to work and draw out some of the implications of our analysis for public policy. Building on the work of Schnore, we develop a model in which both structural and individual variables are interrelated and show that the structural contexts within which individuals make decisions about their choice are crucial. We also show that, while status differentials are largely accounted for by income differences, male preferences for the automobile tend not to be due either to the structural variables or to income differences. Our findings suggest that present policies designed to induce people to shift to public transportation for the journey to work are not likely to be effective, since they do nothing to alter present cost differentials between the two modes.

Automobiles↗
PubMed2005

Temporal relationships of 21 physiological variables in horse and sheep.

Daily or circadian oscillation has been documented in a variety of physiological and behavioral processes. Although individual variables have been studied in great detail, very few studies have been conducted on the temporal relationships between the rhythms of different variables. It is not known whether the circadian pacemaker generates each and every rhythm individually or whether most rhythms are simply derived from a few clock-controlled rhythms. As a first step in elucidating this issue, 21 physiological variables were recorded simultaneously in horse and sheep. The results indicated that, in both species, different variables exhibit different degrees of daily rhythmicity and reach their daily peaks at different times of the day. The variables exhibiting strongest rhythmicity were locomotor activity, rectal temperature, and plasma concentrations of melatonin and glucose. Comparison of rhythmicity and acrophase in the various rhythms allowed inferences to be made about mechanisms of causation.

Animals↗
PubMed2006

Response to chemotherapy in patients with lung metastases: how many nodules should be measured?

OBJECTIVE: With the introduction of cross-sectional imaging methods the number of lesions per patient that can be evaluated is frequently large and most oncologists and study protocols use only one lesion or a few 'representative' lesions to evaluate chemotherapy response. Intra-patient response variability can therefore affect evaluation reproducibility. This study evaluates intra-individual variation in response to chemotherapy in patients with multiple lung metastases. METHODS: We prospectively studied chest CT images of patients with solid tumors and pulmonary metastases under systemic chemotherapy being evaluated for tumor response. The response of 566 pulmonary nodules in 41 evaluations was determined by both WHO and RECIST criteria in order to determine intra-individual tumor response variation. RESULTS: There was almost perfect agreement between the WHO and the RECIST criteria for the evaluation of tumor response. High intra-individual variability of tumor response was observed in a significant proportion of the evaluations. A new nodule was the main criterion for determination of disease progression. A mean of 35% of the total number of nodules of a patient have a response evaluation different from that calculated with all the nodules together. CONCLUSIONS: Intra-individual variation in tumor response of pulmonary metastases is elevated in some patients. Selecting any or some nodules for response evaluation could significantly influence therapeutic response perception.

Adolescent↗
PubMed1995

[Variability of blood pressure. Clinical and therapeutic implications].

The high degree of the intra-individual variability of blood pressure (BP) is related both to biological and technological factors: the biological components of variability are either linked to sympathetic system and respiratory movements or induced by physical and psycho-sensorial stresses; the technological sources of variability are the apparatus and the doctor. The consequences of this high variability can be quantified: the risk for a between-visit change of 35 mmHg for systolic BP (and 17 mmHg for diastolic BP) to be due to the spontaneous BP variability, is as high as 95%. Moreover, according to the regression to the mean, in selected patients with a mean SBP as high as 160 mmHg, a mean spontaneous decrease of 9 mmHg is expected to occur, at the next visit. The physician has then to manage the lack of accuracy of clinic BP measurements. For this purpose, three strategies have to be used: thoroughly examining the patient (if associated with an organ damage, the high BP undoubtedly requires to be treated); rigorously taking into account the published recommendations of BP measurements (the sources of error are now well known and may be easily corrected); finally, using the most sophisticated methods of BP measurements (elf BP measurement), semi-ambulatory or ambulatory BP monitoring, exercise testing), which in some circumstances, may provide useful additional information.

Adult↗
PubMed1998

Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals.

In the present study, we investigated whether the negative feedback action of glucocorticoids (GCs) on the hypothalamo-pituitary-adrenal (HPA) axis changes with age. We performed a 1-mg dexamethasone (DEX) suppression test in 216 healthy elderly individuals. To investigate individual variability of feedback sensitivity in more detail, 2.5 yr later a 0.25-mg DEX suppression test was carried out in 164 of the same individuals. We investigated whether there was an effect of age or gender on both basal and post-DEX cortisol levels, as well as on the concentration of DEX. Furthermore, we examined whether the reactions to the two doses of DEX differed, and whether indications for an intraperson stability of baseline cortisol levels could be found. Neither the pre- nor the post-1-mg DEX plasma cortisol concentrations showed a correlation with age, and there were no differences between men and women. The same was true for the pre- and post-0.25-mg DEX cortisol concentrations. In reaction to 1 mg DEX, over 90% of the subjects investigated showed a cortisol suppression to levels below 50 nmol/L. After the administration of 0.25 mg DEX, there was a much wider range in post-DEX cortisol concentrations. After the administration of 1 mg DEX, there was a significant correlation between liver function parameters and plasma DEX concentrations in males, and there was a correlation between body mass index and plasma DEX concentration in females. Plasma DEX concentrations after the administration of 1 mg and 0.25 mg DEX were closely correlated within subjects (P < 0.001). There was an intraindividual stability of serum cortisol levels determined at an interval of 2.5 yr. Furthermore, the individuals with the highest baseline cortisol concentrations also had the highest post-0.25-mg DEX cortisol concentrations, indicating a close relationship between basal cortisol levels and the feedback sensitivity of the HPA axis to a low dose of DEX. These observations suggest a genetic influence on the set point of the HPA axis. Aging does not seem to lead to a change in HPA activity as measured by early morning total cortisol levels. Also, no changes in the sensitivity of the feedback system to DEX were observed with age. DEX metabolism is influenced by liver function (in males) and by body mass index (in females).

Adult↗
PubMed2006

A brief conceptual tutorial of multilevel analysis in social epidemiology: using measures of clustering in multilevel logistic regression to investigate contextual phenomena.

STUDY OBJECTIVE: In social epidemiology, it is easy to compute and interpret measures of variation in multilevel linear regression, but technical difficulties exist in the case of logistic regression. The aim of this study was to present measures of variation appropriate for the logistic case in a didactic rather than a mathematical way. DESIGN AND PARTICIPANTS: Data were used from the health survey conducted in 2000 in the county of Scania, Sweden, that comprised 10 723 persons aged 18-80 years living in 60 areas. Conducting multilevel logistic regression different techniques were applied to investigate whether the individual propensity to consult private physicians was statistically dependent on the area of residence (that is, intraclass correlation (ICC), median odds ratio (MOR)), the 80% interval odds ratio (IOR-80), and the sorting out index). RESULTS: The MOR provided more interpretable information than the ICC on the relevance of the residential area for understanding the individual propensity of consulting private physicians. The MOR showed that the unexplained heterogeneity between areas was of greater relevance than the individual variables considered in the analysis (age, sex, and education) for understanding the individual propensity of visiting private physicians. Residing in a high education area increased the probability of visiting a private physician. However, the IOR showed that the unexplained variability between areas did not allow to clearly distinguishing low from high propensity areas with the area educational level. The sorting out index was equal to 82%. CONCLUSION: Measures of variation in logistic regression should be promoted in social epidemiological and public health research as efficient means of quantifying the importance of the context of residence for understanding disparities in health and health related behaviour.

Adolescent↗
PubMed1995

Impact of access and social context on breast cancer stage at diagnosis.

This study examined the impact of individual demographic characteristics (age, race/ethnicity, and type of reporting hospital), together with measures of social context, including area of residence socioeconomic status (SES), change in SES, and access to screening (area mammography capacity), on breast cancer stage at diagnosis among New York City residents diagnosed between 1980 and 1985. Three logistic regression models evaluated the impact of individual variables, social context variables, and both classes of variables combined on the outcome of having late-stage (regional or distant) compared to early-stage (local) cancer. The logistic regression models indicated that women aged 50 to 64 years were independently more likely to have late-stage cancer than those younger or older. Controlling for individual and social context variables, African American women were 25 percent more likely than White women to have late-stage breast cancer (p < 0.0001); higher odds seen in the individual model for Hispanic women disappeared after controlling for area SES. In the combined model, women diagnosed from public hospitals were 44 percent more likely to have late-stage disease than those diagnosed in nonpublic settings (p < 0.0001). In both the social context and combined models, area mammography capacity was a significant independent predictor of stage (p = 0.016); area-level SES, but not change in SES, was independently related to late-stage disease (p = 0.002). These data suggest that breast cancer control activities should more actively ensure adequate access to screening, particularly for minorities, populations living in socioeconomically disadvantaged areas, and those cared for in the public sector.

Adult↗
PubMed1997

Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking.

AIMS: Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking. METHODS: Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal nicotine, 15 mg/day; (3) nicotine nasal spray, 24-1 mg doses/day; (4) placebo nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of nicotine and cotinine were determined via infusion of deuterium-labeled nicotine and continine. Plasma levels of nicotine, cotinine, and 3'-hydroxycotinine and daily intake of nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma nicotine and continine levels. RESULTS: There was considerable individual variation in plasma nicotine and cotinine levels and in the daily of nicotine absorbed from various delivery systems, with most variability with nicotine nasal spray (fivefold) and least for transdermal nicotine (two-to threefold). Plasma nicotine levels were determined most strongly by nicotine clearance. Continine levels were determined most strongly by dose of nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of nicotine to continine. CONCLUSIONS: Plasma levels of nicotine and cotinine produced by nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of nicotine dosing based on therapeutic drug monitoring with comparison to nicotine or continine levels during cigarette smoking prior to treatment may be necessary to optimize nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3'-hydroxycotinine in people.

Administration, Cutaneous↗