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PubMed1989

Variability of the adaptive response to ionizing radiations in humans.

Human lymphocytes exposed to low doses of ionizing radiations from incorporated tritiated thymidine ([3H]dThd) or from X-rays become less susceptible to the induction of chromatid aberrations by high doses of X-rays. This indicates that low doses of ionizing radiation can produce an effect similar to the adaptive response observed with alkylating agents in prokaryotes, animal and plant cells. To determine whether there is individual variability in the adaptive response to ionizing radiations we exposed human lymphocytes from 18 different healthy donors to 'adapting' doses of [3H]dThd (0.01 microCi/ml) or X-rays (0.01 Gy) and subsequently to a 'challenge' treatment of 0.75 Gy of X-rays delivered 2 h before fixation. Four of the 18 donors did not show an adaptive response; in some cases in these individuals a synergistic response of increased, rather than decreased, damage was found. Two of these 4 donors showed no adaptive response in 3 subsequent experiments separated by 4-month intervals. This suggests that the human population exhibits a heterogeneity in the adaptive response to ionizing radiations which might be, at least in part, genetically determined.

Adult↗
PubMed1990

The problem of obtaining reproducible quantitative data of the olivocochlear pathway as exemplified in the guinea pig.

We have tried to quantify the number of efferent neurons comprising the olivocochlear bundle in the guinea pig by using the retrogradely transported fluorescent dye, true blue. The dye was injected into numerous regions of the cochlea for various distances. The data from 14 complete experiments have been evaluated. The majority of the labelled cells were found ipsilaterally, with the lateral superior olive containing 59.2% and showing cochleotopicity. Of the 28.9% found contralaterally, the nucleus of the ventral lateral lemniscus had 16.9%, and the trapezoid body nucleus 8.0%, differing significantly from the other nuclei of the superior olivary complex. Although the distribution of the labelling was consistent, there was great variability in actual numbers. Calculations based on cell density showed no differences along the length of the basilar membrane, and resulted in a total of around 2500 efferent neurones. This figure agrees closely with the maximum counts found by other workers. However, the cause of the individual variability remains unanswered.

Animals↗
PubMed1977

Thermally induced conformational transitions of Bence-Jones protein IVA and its proteolytic fragments.

The thermally induced conformational transitions of the kappa-type Bence-Jones protein IVA and its proteolytic fragments (variable and constant halves) were studied by differential adiabatic scanning microcalorimetry, circular dichroism and thermal differential spectroscopy. The striking feature of the results is the good agreement between the experimental heat of thermal denaturation of intact Bence-Jones protein and the heat calculated from the individual variable and constant halves. The results suggested that the variable and constant halves have independent secondary and tertiary structures. It is likely that in the intact light chain, the variable and constant domains have weak non-covalent interactions between themselves. It was shown that at pH values from 7.4 to 2.0 the variable halves exist in the dimeric form. Evidence was obtained that two relatively independent regions of strong non-covalent interactions stabilize the dimers of variable and constant domains.

Bence Jones Protein↗
PubMedDate not supplied

Rapid optimization of antibotulinum toxin antibody fragment production by an integral approach utilizing RC-SELDI mass spectrometry and statistical design.

A process for the rapid development and optimization of the fermentation process for an antibotulinum neurotoxin antibody fragment (bt-Fab) production expressed in Escherichia coli was achieved via a high-throughput process proteomics and statistical experimental design. This process, using retentate chromatography-surface enhanced laser desorption/ionization mass spectrometry (RC-SELDI MS), was employed for identifying and quantifying bt-Fab antibody in complex biological samples for the optimization of microbial fermentation conditions. Five variables (type of culture media, glycerol concentration, post-induction temperature, IPTG concentration, and incubation time after induction) were statistically combined using an experimental 2(5)(-1) fractional factorial design and tested for their effects on maximal bt-Fab antibody production. When the effects of individual variables and their interactions were assessed, type of media and post-induction temperature showed statistically significant increase in yield of the fermentation process for the maximal bt-Fab antibody production. This study establishes an integral approach as a valuable tool for the rapid development of manufacturing processes for producing various biological materials. To verify the RC-SELDI MS method, a Fab-specific immuno-affinity HPLC assay developed here was also employed for the quantification of the bt-Fab antibody in crude lysate samples obtained during the fermentation optimization process. Similar results were obtained.

Botulinum Toxins↗
PubMed2002

Factors affecting health related quality of life of patients with inflammatory bowel disease.

UNLABELLED: Using a disease specific instrument to measure the health related quality of life (HRQOL) of patients with inflammatory bowel disease (IBD), it has been shown that their perceived HRQOL worsens during active disease. The precise factors involved in HRQOL changes reported by these patients are largely unknown. Our aim was to elucidate which socio-demographic and health status variables are related with HRQOL in IBD patients. To this end, 354 patients with IBD were interviewed. To quantify the impairment in the HRQOL, the 36-item version of the inflammatory bowel disease questionnaire (IBDQ) was administered to all patients. To explore the relation of each individual variable on the HRQOL an univariate analysis by using the Spearman correlation, the Mann-Whitney or the Kruskal-Wallis test was performed when necessary. Factors significant at the univariate analysis were assessed using multiple linear regression modeling with global IBDQ score as the dependent factor. RESULTS: Disease type did not predict IBDQ score in the univariate nor in the multivariate analysis. Consequently, statistical analysis was performed in the global group of 354 patients independently of the type of disease. Lower recurrence/year index, longer disease duration, higher level of education, symptom activity, male gender and non-necessity of hospitalization all predict a better HRQOL (p < 0.05). Factors which remained significant (p < 0.05) in the multiple regression modeling were gender, need of hospitalization, symptomatic activity, recurrence/year index and education level. CONCLUSIONS: Symptomatic activity and socio-demographic variables such as gender and education are the most important factors involved in the impairment of HRQOL in patients with IBD.

Adult↗
PubMed1990

Evidence for involvement of multiple forms of cytochrome P-450 in aflatoxin B1 metabolism in human liver.

Liver cancer is a major cause of premature death in many areas of Africa and Asia and its incidence is strongly correlated with exposure to aflatoxin B1 (AFB1). Because AFB1 requires metabolic activation to achieve a biological response, there is a need for detailed knowledge of the mechanism of activation to assess individual risk. We have carried out an extensive study using a total of 19 human liver samples to determine the individual variability in the metabolism of the toxin to mutagenic or detoxification products and to identify the specific cytochrome P-450 forms involved in these processes. Metabolism to the toxic 8,9-epoxide or to products mutagenic in the Ames test was found to exhibit very large individual variation. The rates of metabolic activation were highly correlated with both the level of proteins of the P450IIIA gene family and with the total cytochrome P-450 content of the microsomes. In agreement with this, antibodies reacting with P450IIIA proteins were strong inhibitors of both the metabolism and mutagenicity in the majority of the samples. However, the inhibition varied between 50% and 100%. The expression of a protein in the P450IIC gene family also correlated with AFB1 metabolism and mutagenicity. This result therefore indicated the involvement of cytochromes other than P450IIIA in the activation of AFB1 by human liver microsomes. This hypothesis was strongly supported by the finding that antibodies to P450IA2 and P450IIA1 were also effective inhibitors of metabolism in many of the samples. These data demonstrate that, although P450IIIA probably plays an important role in AFB1 activation, several other cytochrome P-450 forms have the capacity to activate the toxin. Similar considerations apply to detoxifying metabolism to aflatoxin Q1 and aflatoxin M1. The levels of expression of many of the forms of cytochrome P-450 involved in AFB1 metabolism are known to be highly sensitive to environmental factors. This indicates that such factors will be an important determinant in individual susceptibility to the tumorigenic action of AFB1.

Aflatoxin B1↗
PubMed1989

Correction for gravity in isokinetic dynamometry of knee extensors in below knee amputees.

In isokinetic dynamometry of the knee extensors the influence of gravity on the lower limb is often neglected. The aim of this study was to assess the shape, the quantity and reproducibility of the gravity correction curve (GCC). Eight amputees participated in this study. The GCC was produced on an isokinetic dynamometer (QD) throughout the range of motion on the amputated side with prosthesis and on the non-amputated side. The results were compared with the GCC calculated according to the Cybex data reduction computer procedure. The isokinetic torque registration of the QD is, in a mathematical way, a straight line (Pearson correlation coefficient greater than 0.99). The other GCC is shaped like a cosinus curve. The intra-individual reproducibility is high, the inter-individual variability substantial. An explanation for the difference between the two methods is discussed. For an ideal measurement of the muscular torque, one should not only correct for the effect of gravity but for all factors counteracting the effect of the knee extensors. In that case an individual GCC should be made directly with the dynamometer.

Adolescent↗
PubMed2003

American and Japanese women use different coping strategies during normal pregnancy.

In this longitudinal study, pregnant women in Japan and the United States reported on three coping strategies. Two are individually phrased: personal influence over outcomes and acceptance of outcomes. The third, social assurance, is grounded in relationships, noting that close others can influence outcomes. A European American sample rated acceptance highest as a strategy, whereas Japanese women rated social assurance highest. For Americans, acceptance correlated with better pregnancy outcomes (less distress over time, better prenatal care, and less weight gain). For Japanese women, social assurance predicted a more positive maternal relationship. Acceptance correlated with less Time 1 distress in both samples. Surprisingly, personal influence generally did not predict positive outcomes in either sample, perhaps because normal pregnancy is a time-limited event with a positive prognosis. The findings are consistent with the view that well-being is related to individual variables in the United States but also to features of social relationships in Japan.

Adaptation, Psychological↗
PubMed1996

Empirical techniques for determining the reliability, magnitude, and pattern of neuropsychological change after epilepsy surgery.

PURPOSE: We assessed test-retest neuropsychological performance in patients with complex partial seizures to derive reliable change indices (RCIs) and regression-based norms for change, indices that may be helpful in assessing cognitive outcome after anterior temporal lobectomy. METHODS: Forty patients with complex partial seizures (CPS) who did not undergo epilepsy surgery were administered a comprehensive neuropsychological battery on two occasions. Their test-retest data were used to compute both RCIs and regression-based norms for change for each neuropsychological index. RCIs corrected for practice effects provide a confidence interval (CI) indicating the degree of performance change required to exceed the variability attributable to sources of error (e.g., practice, test-retest reliability). Regression-based norms for change also correct for several sources of measurement error and examine observed versus expected test-retest changes on a common metric, thereby facilitating determination of the degree and relative magnitude of change across cognitive domains. RESULTS: Mean changes in test-retest performance were generally modest, but were evident across several test measures. Our data indicate a considerable degree of individual variability in test-retest performance. CONCLUSIONS: RCIs and regression-based norms are complementary indexes and can be particularly useful in examining the test-retest performance of individual patients who undergo epilepsy surgery as well as in the more general investigation of cognitive outcome after epilepsy surgery.

Adult↗
PubMed1987

Growth direction in the mandibular condyle of pre-pubertal and pubertal monkeys (Macaca fascicularis) studied by morphometry and radioautography.

Eight male monkeys with prepubertal or pubertal skeletal maturity were used to assess age-related changes in anterior-posterior gradients of parameters which characterize growth velocity. The animals received single intravenous doses of 1 mCi/kg body weight of [3H]-proline at 24 h, and of 0.5 mCi/kg body weight [3H]-thymidine, 3 h before death. Four perichondral and chondral layers, and the subchondral zone of erosion of each condyle, were analysed morphometrically and radioautographically at 12 sampling sites distributed systematically over the joint surface. Values for cell density, cell proliferation, extracellular cartilaginous matrix production, cartilage resorption and subchondral bone formation produced characteristic curves which generally peaked in the central joint region. These peaks did not shift, either in relation to age or growth velocity, suggesting a uniform posterior-superior growth direction. Individual variability in both shape and prominence of the curves usually prevailed over the group effects attributable to skeletal maturity or growth velocity. Thus the gradual age-dependent shift in human condylar growth direction may be revealed only in longitudinal studies and would be masked by pronounced individual variation in cross-sectional studies of small samples.

Animals↗
PubMed2005

Determination of ankle external fixation stiffness by expedited interactive finite element analysis.

Interactive finite element analysis holds the potential to quickly and accurately determine the mechanical stiffness of alternative external fixator frame configurations. Using as an example Ilizarov distraction of the ankle, a finite element model and graphical user interface were developed that provided rapid, construct-specific information on fixation rigidity. After input of specific construct variables, the finite element software determined the resulting tibial displacement for a given configuration in typically 15s. The formulation was employed to investigate constructs used to treat end-stage arthritis, both in a parametric series and for five specific clinical distraction cases. Parametric testing of 15 individual variables revealed that tibial half-pins were much more effective than transfixion wires in limiting axial tibial displacement. Factors most strongly contributing to stiffening the construct included placing the tibia closer to the fixator rings, and mounting the pins to the rings at the nearest circumferential location to the bone. Benchtop mechanical validation results differed inappreciably from the finite element computations.

Ankle↗
PubMed1992

An automated flow cytometric micronucleus assay for human lymphocytes.

A new flow cytometric method is presented for scoring micronuclei (MN) in human lymphocytes after in vitro gamma-irradiation. Fifty to fifty-five hours after PHA-stimulation, the frequency of micronuclei per nucleus and the fraction of cells in the second cell cycle were measured using flow cytometry. All data were automatically analysed using our DAS-software package. Eight individual linear-quadratic dose response curves derived from five donors revealed inter- and intra-individual variabilities of all curve parameters. Since also an age dependence was found for spontaneous MN-frequencies and for the linear curve parameter, a combined linear-quadratic age-dose-effect model was used to fit the data. The 90% prediction intervals show that a reliable individual dose estimation for donors aged between 23 and 54 years cannot be achieved for exposures below 1 Gy.

Adult↗
PubMed2002

No evidence for an influence of the human platelet antigen-1 polymorphism on the antiplatelet effects of glycoprotein IIb/IIIa inhibitors.

This study investigated the hypothesis that the human platelet antigen-1 (HPA-1) polymorphism may influence the antiplatelet effects of glycoprotein (GP)IIb/IIIa inhibitors. Adenosine diphosphate (30 micro mol)-induced fibrinogen binding was measured by flow cytometry. Abciximab (0.03-3 micro g/ml), tirofiban (0.3-30 nmol/l) or eptifibatide (0.01-1 micro g/ml) were incubated for 15 min with the samples prior to stimulation. IC(50) values for the inhibition of fibrinogen binding were determined from each experiment. All subjects were genotyped by GALIOS and automated fluorescence correlation spectroscopy. Although a marked variability in the inhibitory effects of all three GPIIb/IIIa inhibitors was confirmed, there were no significant differences between the genotypes with respect to the inhibition of fibrinogen binding. Thus, the present study does not provide evidence for an effect of HPA-1 polymorphism on the inter-individual variability in the platelet inhibitory effects of the three GPIIb/IIIa inhibitors approved for clinical use.

Abciximab↗
PubMed2004

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function.

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.

Adult↗
PubMed2001

Selection and validation of biomarkers for chemoprevention: the contribution of epidemiology.

This chapter considers the epidemiological contribution of DNA adducts as an example of markers for use in chemoprevention studies, and highlights the potential biases inherent in the conduct of epidemiological studies with molecular markers. Although adducts have been interpreted mainly as biomarkers of exposure, 'bulky' DNA adducts such as those measured by 32P-postlabelling or ELISA in white blood cells are more correctly interpretable as markers of cumulative unrepaired DNA damage. The latter concept can prove useful in cancer epidemiology, since it is consistent with existing knowledge on the importance of duration of exposure in the etiology of chemically-induced cancers. Increasing evidence suggests that in addition to prolonged exposure to genotoxic chemicals, inter-individual variability in carcinogen metabolism and DNA repair is predictive of cancer risk. Also from this point of view, measurements of 'bulky' DNA adducts can be useful as biomarkers for studies in populations, since they express the amount of carcinogen linked to DNA after repair, taking into account individual repair capacity. Finally, we suggest a theory of causality based on the work of Wesley Salmon and the concept of 'propagating mark', which is particularly attractive for molecular epidemiologists.

Biomarkers, Tumor↗
PubMed2002

TNFalpha production in whole blood cultures from healthy individuals.

Tumor necrosis factor alpha (TNFalpha) is a major mediator of inflammatory responses and also plays a prominent role in bridging the innate and adaptive phases of immunity. In the present work we attempted to study TNFalpha production in endotoxin-stimulated blood of healthy individuals, and the inter-individual variability in TNFalpha production. For this study, we used diluted whole blood stimulated with lipopolysaccharide (LPS). The levels of the pro-inflammatory cytokine TNFalpha were measured by ELISA and by the L929 cytotoxicity bioassay in 16 and 18 healthy donors, respectively. There were highly significant inter-individual variations in the induced TNFalpha production. It is worth noting that there was no difference in sensitivity between ELISA and the cytotoxicity L929 bioassay. We concluded that whole blood culture is a sensitive method to determine the pro-inflammatory cytokine production in response to endotoxin stimuli in a relevant physiologic milieu. Our data indicate that this method provides appropriate information about the state of cellular immunity of the individual.

Animals↗
PubMed1989

The role of individual difference in determining the nature of comprehension defects in aphasia.

This study was concerned with the relationship between locus of lesion and subtypes of language comprehension defect in aphasia. Previous studies had indicated that performance in sound recognition identified two subtypes of aural comprehension deficit and that performance in pantomime recognition identified two subtypes of reading comprehension defect. Defects in sound recognition and pantomime recognition were found in association with a variety of lesion loci. However, comprehension defective aphasics with normal sound recognition or pantomime recognition had lesions closely similar in location and size to those of aphasics who performed poorly on these tests. Findings suggest that whether an aphasic with a language comprehension defect is impaired in sound recognition or pantomime recognition depends, at least in part, on individually variable predisposing factors. It would appear possible that this phenomenon reflects a separate dimension of hemispheric cerebral dominance.

Adult↗
PubMed1995

Inter-individual variation in half-life of infused recombinant factor VIII is related to pre-infusion von Willebrand factor antigen levels.

In an attempt to explain the substantial inter-individual variability in half-life of infused factor VIII (FVIII) among haemophilia A patients, we studied the correlation of pre-infusion von Willebrand factor antigen (vWFAg) levels and the half-life of a recombinant-DNA-derived FVIII (r-VIII SQ. Pharmacia, Sweden). Intra-individual variation in half-life was small (range of variation 0-2.1 h) in 12 severely affected haemophiliacs who received two doses of FVIII concentrate. In contrast, inter-individual variation in half-life was large (range of half-lives 6-28.8 h). A strong correlation between half-life and pre-infusion vWFAg levels was present (r = 0.87, P = 0.0003). We conclude that the half-life of infused recombinant FVIII is related to pre-infusion vWFAg levels in severely affected haemophilia A patients.

Adult↗