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PubMed2006

What is the meaning of non-linear dose-response relationships between blood lead concentrations and IQ?

Recent literature [e.g. Canfield RL, Henderson CR, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. Intellectual impairment in children with blood lead concentrations below 10mg per deciliter. New Engl J Med 2003;348(16):1517-1526; Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, Canfield RL, Dietrich KN, Bornschein R, Greene T, Rothenberg SJ, Needleman HL, Schnaas L, Wasserman G, Graziano J, Roberts R. Low-level environmental lead exposure and children's intellectual function: an international pooled analysis. Environ Health Perspect 2005;113(7):894-899] has suggested the existence of a supra-linear dose-response relationship between environmental measures such as blood lead concentrations and IQ. This communication explores the mathematical requirements placed on such dose-response relationships when the environmental measure, or independent variable, is lognormally distributed and the effect, or dependent variable, is normally distributed. Results of the analyses show that a supra-linear slope is a required outcome of correlations between data distributions where one is lognormally distributed and the other is normally distributed. The analysis shows that caution should be taken in assigning biological significance to supra-linear dose-response relationships in these instances. Detailed analyses of such data sets should be conducted to determine if the magnitude of supra-linear slopes are more or less than mathematically required, and from there to consider biological significance.

Dose-Response Relationship, Drug↗

PubMed1995

Assessment of data sets containing a considerable number of values below the detection limits.

Using real examples it is demonstrated that the concentrations of non-essential substances in biological systems always follow a statistical log-normal distribution. This is based on the assumption that in a first-order approximation the rate of excretion of the quantity of unwanted molecules or atoms in the biological system is only dependent on their concentration. Applying a natural logarithmic transformation, the resulting log-normal distribution always has a standard deviation of about 1, as shown by statistical analysis of more than 680 clusters of analytical results. Assuming a log-normal distribution with a standard deviation of 1, it is possible to derive factors for the estimation of percentiles, such as the median, even when this percentile is below the detection limit; quantifiable and higher percentiles only must be multiplied by a specific factor. This new method has the advantage that no arbitrary assumptions must be made about artificial parameters such as the numerical treatment of non-detectable analytical data. The assumptions used for the calculation of the factors are justified by proof with experimental data. The applicability of the new method is demonstrated for various contaminants in various plants and animals.

Animals↗

PubMed1996

N-Acetylated domains in heparan sulfates revealed by a monoclonal antibody against the Escherichia coli K5 capsular polysaccharide. Distribution of the cognate epitope in normal human kidney and transplant kidney with chronic vascular rejection.

The Escherichia coli K5 capsular polysaccharide has the same (GlcUA-->GlcNAc)n structure as the nonsulfated heparan sulfate/heparin precursor polysaccharide. A monoclonal antibody (mAb 865) against the K5 polysaccharide has been described (Peters, H., Jürs, M., Jann, B., Jann, K., Timmis, K. N., and Bitter-Sauermann, D. (1985) Infect. Immun. 50, 459-466). In this report, we demonstrate the binding of anti-K5 mAb 865 to N-acetylated sequences in heparan sulfates and heparan sulfate proteoglycans but not to heparin. This is shown by direct binding and fluid phase inhibition of mAb 865 in an enzyme-linked immunosorbent assay. In this system we found that the binding of the mAb decreased with increasing sulfate content of the polysaccharide. By testing chemically modified K5 and heparin polysaccharides, we found that each of the modifications that occur during heparan sulfate (HS) synthesis (N-sulfation, C-5 epimerization, and O-sulfation) prevents recognition by mAb 865. Samples of heparan sulfate from human aorta (HS-II) were selectively degraded so as to allow the separate isolation of N-sulfated and N-acetylated block structures. N-Sulfated oligosaccharides (obtained after N-deacetylation by hydrazinolysis followed by nitrous acid deamination at pH 3.9) were not recognized by mAb 865, in contrast to N-acetylated oligosaccharides (obtained after nitrous acid deamination at pH 1.5), although the reactivity was lower than for intact HS-II. Analysis of the latter's pH 1.5 deamination products by gel filtration indicated that a minimal size of 18 saccharide units was necessary for antibody binding. These results lead us to propose bivalent antibody-heparan sulfate interaction, in which both F(ab) domains of the mAb interact with their epitopes, both of which are present in a single large (>/=18 saccharide units) N-acetylated domain and additionally with single epitopes present in two N-acetylated sequences (each <18 saccharide units) bridged by a short N-sulfated domain. Immunohistochemistry with mAb 865 on cryostat sections of normal human kidney tissue, revealed its binding to most but not all renal basement membranes. However, all renal basement membranes contain heparan sulfate, as shown by a mAb against heparitinase-digested heparan sulfate stubs (mAb 3G10). This finding indicates that not all heparan sulfate chains present in basement membranes express the mAb 865 epitopes. Besides the normal distribution, mAb 865 staining was found in fibrotic and sclerotic lesions in vessels, interstitium, and mesangium in transplant kidneys with chronic vascular rejection. Occasionally, a decrease of staining was observed within tubulo-interstitium and glomeruli. These findings show that N-acetylated sequences in heparan sulfates can be demonstrated by anti-K5 mAb 865 in normal and diseased kidneys.

Acetylation↗

PubMed1985

Phenylbutazone and its metabolites in plasma and urine of thoroughbred horses: population distributions and effects of urinary pH.

A survey of plasma and urinary concentrations of phenylbutazone and its metabolites in thoroughbred horses racing in Kentucky was carried out. Post-race blood samples from more than 200 horses running at Latonia Racetrack and Keeneland in the Spring of 1983 were analysed. The modal plasma concentration of phenylbutazone was between 1 and 2 micrograms/ml, the mean concentration was 3.5 micrograms/ml and the range was up to 15 micrograms/ml. Oxyphenbutazone had a modal plasma concentration between 1 and 2 micrograms/ml, a mean concentration of 2.07 micrograms/ml and a range of up to 13 micrograms/ml. gamma OH-phenylbutazone had a modal plasma concentration of less than 1 microgram/ml, a mean level of 1.39 micrograms/ml and a range of up to 7.32 micrograms/ml. All plasma concentration frequency distributions were well fitted by log normal distributions. Urinary concentrations of phenylbutazone yielded modal concentrations of less than 1 microgram/ml, a mean urinary concentration of 2.9 micrograms/ml, with a range of up to 30.5 micrograms/ml. This population fitted a log-normal distribution. For oxyphenbutazone the modal concentration was less than 3 micrograms/ml, the mean concentration was 15.26 micrograms/ml, with a range to 81.5 micrograms/ml. The frequency distribution of these samples was apparently bimodal. For gamma OH-phenylbutazone, the modal concentration was less than 4 micrograms/ml, the mean concentration 21.23 micrograms/ml, with a range of up to 122 micrograms/ml. The population frequency distribution for gamma OH-phenylbutazone was indeterminate. Analysis of the pH of these post-race urine samples showed a bimodal frequency distribution. The pH values observed ranged from 4.9 to 8.7, with peaks at about pH 5.25 and 7.25. This bimodal pattern of urinary pH values is consistent with observations made in England and Japan. Urinary pH influenced the concentrations of phenylbutazone, oxyphenbutazone and gamma OH-phenylbutazone found in the urine samples. The concentration of these metabolites found in alkaline urines were from 32 to 225 times greater than those found in acidic urines. Plasma concentrations of phenylbutazone and its metabolites, however, were unaffected by urinary pH. In interlaboratory experiments, horses running at Hollywood Park were dosed with phenylbutazone at about 2 g/1000 lbs 24 and 48 h before racing, and a mean dose of 0.6 g/1000 lbs at 72 h prior to racing. Post-race plasma samples from these horses showed phenylbutazone concentrations ranging from 0.44 to 9.97 micrograms/ml, with a mean concentration of 4.09 micrograms/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1996

[Normal cerebral perfusion of 99mTc-ECD brain SPECT--evaluation by an anatomical standardization technique].

A single photon emitter labeled tracer, 99mTc-ethyl cysteinate dimer (99mTc-ECD), has now been used for rCBF studies with SPECT. However, normal distribution pattern of this agent in the brain still remains unclear. Therefore, the specific purpose of this study was to investigate the normal distribution pattern of 99mTc-ECD SPECT image. Regional cerebral distribution was measured with SPECT and 984 +/- 17 MBq of 99mTc-ECD in ten normal subjects. During the SPECT measurement, subjects were placed comfortably in a supine position with their eyes closed. Each SPECT image was anatomically standardized using a computerized brain atlas system of Roland et al. (HBA: Human Brain Atlas) and X-CT image. Anatomically standardized SPECT images were globally normalized to 100 count/voxel. Then, the mean and SD images of brain SPECT were calculated voxel-by-voxel basis. The highest radioactivity was found in the medial aspect of the occipital lobe. The results indicate that the normal distribution pattern of 99mTc-ECD in the human brain may be not simply reflect the regional cerebral blood flow.

Adult↗

PubMed1978

Thyroid hormone concentrations in a large scale community survey. Effect of age, sex, illness and medication.

Total thyroid hormone concentrations have been measured in the course of a large scale community survey to determine the distribution of these variables in the normal population and to assess the effect of age, sex, previously undectected thyroid disease and medication upon these parameters. 2779 subjects were studied. Serum T4 concentrations were normally distributed. A progressive increase in T4 levels with age was noted in the males, and a smaller increase in females which was concealed by the raised T4 values secondary to oral contraceptive therapy in females under the age of 45. Serum T3 levels were also normally distributed. There was a small reduction in T3 with age in the males but this fall was not seen in the females. T3 values were relatively higher in females under the age of 45 but this increase was not noted after exclusion of subjects taking an oral contraceptive. The changes in thyroid hormone concentrations with age are relatively minor (particularly with respect to T3) in a randomly selected sample from an English town. It is suggested that the changes reported by other authors reflect the process of selection used, and the high frequency of undetected thyroid disease, other illness and medication in hospital-based communities.

Adolescent↗

PubMed1975

Iodoamino acid content and distribution in normal and abnormal human thyroids.

Iodoamino acid content and distribution were measured in adenomas, nodular goiters, thyroiditis and carcinomas and compared to thyroids from patients who died suddenly and normal thyroid tissues originally adjacent to diseased tissue. Tissues were hydrolyzed with Pronase, derivatized and analyzed by gas chromatography as had previously been reported for rat thyroids. Considerable overlap in values was found among adenomas, nodular goiters and papillary and follicular carcinomas as compared to values in normal thyroid tissue, but low values were also found in several diseased tissues. MIT/DIT and T3/T4 ratios were essentially constant in most tissues, even when T4 values were low. MIT/DIT ratios were, however, high and iodothyronines undetectable in all Hurthle cell neoplasms, clearly differentiating them from other thyroid conditions.

Adenoma↗

PubMed1989

Standing pressure distribution for normal and below-knee amputee children.

Below-knee (BK) amputee children have a different morphology from normal children and amputees may thus have atypical limb loading during standing. The purpose of this investigation was to examine differences in standing ground-shoe pressure distribution between BK and normal children. A pressure plate was used to measure the ground-shoe weight distribution of three BK children and ten normal children during standing. Results indicated that the weight distribution between prosthetic and non-prosthetic limbs of BK children was not significantly different from the feet of normal children. The anterior-posterior weight distribution for the prosthetic and non-prosthetic feet was significantly different from that of the normal children. Further quantification of weight distribution and analysis of more subjects is necessary to determine the benefits, detriments, or irrelevance of these results.

Amputation, Surgical↗

PubMed1984

Mechanics and gas distribution in normal and obstructed lungs during tidal breathing.

Quantitative characteristics of the dynamic mechanical and gas distribution behavior in 6 normal subjects and 5 subjects with COPD were compared during tidal breathing. Transpulmonary pressure, total lung volume, flow, and N2 fraction at the mouth were measured while N2 was washed out from the lung. The washouts were performed at several frequencies and lung volumes. As an index of nonuniform mechanical behavior, we calculated the frequency variation in dynamic pulmonary compliance (CLdyn). Based on a moment analysis of the multibreath N2 washout, we calculated a mean dilution number (MDN) as an index of the inhomogeneity of alveolar gas distribution and mixing. At FRC or above FRC the CLdyn decreased much more with frequency for the COPD subjects than for the normal subjects. The MDN was also much greater in the presence of COPD. However, the frequency dependence of the MDN was small for both the normal and COPD subjects and uncorrelated with the frequency dependence of CLdyn. Because the multibreath N2 washout and the frequency dependence of CLdyn reflect different aspects of ventilation inhomogeneity, these two responses are unique.

Adolescent↗

PubMed2004

Three-dimensional structure of the Lagrangian acceleration in turbulent flows.

We report experimental results on the three-dimensional Lagrangian acceleration in highly turbulent flows. Tracer particles are tracked optically using four silicon strip detectors from high energy physics that provide high temporal and spatial resolution. The components of the acceleration are shown to be statistically dependent. The probability density function of the acceleration magnitude is comparable to a log-normal distribution. Assuming isotropy, a log-normal distribution of the magnitude can account for the observed dependency of the components. The time dynamics of the acceleration components is found to be typical of the dissipation scales, whereas the magnitude evolves over longer times, possibly close to the integral time scale.

Journal Article↗

PubMed2004

Statistical characteristics of mechanical heart valve cavitation in accelerated testing.

BACKGROUND AND AIM OF THE STUDY: Cavitation damage has been observed on mechanical heart valves (MHVs) undergoing accelerated testing. Cavitation itself can be modeled as a stochastic process, as it varies from beat to beat of the testing machine. This in-vitro study was undertaken to investigate the statistical characteristics of MHV cavitation. METHODS: A 25-mm St. Jude Medical bileaflet MHV (SJM 25) was tested in an accelerated tester at various pulse rates, ranging from 300 to 1,000 bpm, with stepwise increments of 100 bpm. A miniature pressure transducer was placed near a leaflet tip on the inflow side of the valve, to monitor regional transient pressure fluctuations at instants of valve closure. The pressure trace associated with each beat was passed through a 70 kHz high-pass digital filter to extract the high-frequency oscillation (HFO) components resulting from the collapse of cavitation bubbles. Three intensity-related measures were calculated for each HFO burst: its time span; its local root-mean-square (LRMS) value; and the area enveloped by the absolute value of the HFO pressure trace and the time axis, referred to as cavitation impulse. These were treated as stochastic processes, of which the first-order probability density functions (PDFs) were estimated for each test rate. RESULTS: Both the LRMS value and cavitation impulse were log-normal distributed, and the time span was normal distributed. These distribution laws were consistent at different test rates. CONCLUSION: The present investigation was directed at understanding MHV cavitation as a stochastic process. The results provide a basis for establishing further the statistical relationship between cavitation intensity and time-evolving cavitation damage on MHV surfaces. These data are required to assess and compare the performance of MHVs of different designs.

Acceleration↗

PubMed1982

[On the importance of new test of HDL-cholesterol in lipoid diagnostics with geriatric patients (author's transl)].

1. By introducing a HDL-cholesteroltest in the multiple screening we have the chance to valuate the diagnostical validity of the test value of triglycerides, total cholesterol and HDL-Cholesterol and of the calculated value of LDL-cholesterol and ratio HDL/LDL-cholesterol. 2. We studied the incidence of lipoid findings of 210 patients by graphical statistics. 3. The test values of triglycerides, total cholesterol and HDL-cholesterol manifest a mixed collection with a graph having different maximums whereby statistically a "normal" population can be differentiated from a "pathological" population. 4. The calculated value LDL-cholesterol is normal distributed, the ratio HDL/LDL-cholesterol is logarithmic normal distributed. The causes therefore are statistic effects.

Aged↗

PubMed1993

[Evaluation of detecting 9 tumor markers in serum for diagnosis of primary liver cancer].

Nine tumor markers in serum including alpha-fetoprotein (AFP), r-glutamyltranspeptidase (GGT), lactate dehydrogenase (LDH), alpha 1-antitrypsin (alpha 1-AT), total sialic acid (TSA), ferritin (Ft), ceruloplasmin (CP), LDH isoenzymes and GGT isoenzymes were used for differential diagnosis of primary liver cancer. Of 5 measurement data tested by statistics, CP and TSA were close to normal distribution (P > 0.1), GGT, LDH and alpha 1-AT showed skewness distribution or to be close to normal distribution with in transformation (P > 0.1). The results indicated that the determination of the cut-off value should depend on the statistical distribution of data. Analysis of single and dual-combination tests as well as triple analysis with sequential progressive screening had been performed to evaluate the predictive value of clinical diagnosis, i.e. the sensitivity, the specificity and the correct diagnosis efficiency. Three predictive values of a single test were lower than what clinical diagnosis raqvest. The dual-combination tests had higher specificity but a lower sensitivity. For triple analysis with sequential progressive screening among the liver cancer group (n = 23), the related disease group (n = 44) and the healthy individuals group (n = 40), the correct diagnosis efficiency was 95%, 97.3% and 100%, respectively. This suggests that the method described here has potential value in clinical practice.

Biomarkers, Tumor↗

PubMed1999

Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or low factor XIII specific activity.

Factor XIII is a transglutaminase essential for normal hemostasis. We have studied the plasma FXIII levels and FXIII activity in 71 individuals and found these to be normally distributed. FXIII specific activity is also normally distributed. However, we show that FXIII activity is not directly dependent on FXIII levels, and individuals with low FXIII levels may have high FXIII activity and vice versa. We have determined the FXIIIA genotype in these individuals to assess whether the variation observed in FXIII specific activity is dependent on specific polymorphisms in the FXIIIA gene. Our data show that the Leu34 and Leu564 variants give rise to increased FXIII specific activity, while the Phe204 variant results in lower FXIII specific activity. We also report preliminary evidence that the Phe204 polymorphism may be associated with recurrent miscarriage. Overall, we have identified 23 unique FXIIIA genotypes. Certain specific FXIIIA genotypes consistently give rise to high, low, or median FXIII specific activity levels, while others appear to have little or no consistent influence on the FXIII phenotype. These genotype to phenotype relationships are discussed in light of the growing interest in the role of FXIII in clinical problems involving an increased thrombotic tendency.

Abortion, Habitual↗

PubMed1997

Cortisol concentrations in post competition horse urine: a French and British survey.

The purpose of the present report was to estimate the population parameters of cortisol concentrations in urine, an endogenous hormone used as a 'doping' agent and for which an international threshold (1.0 micrograms/ml) has been proposed. Two data bases (French and UK) corresponding to 112 and 142 samples, respectively were considered. Urine was collected under specific post competition conditions. Cortisol concentrations were obtained by validated methods (HPLC for the French samples, and GC-MS for UK samples). No difference was observed between the 2 data sets and statistical analyses were carried out on the two merged files. The overall geometric mean cortisol concentration was 48 ng/ml. Distribution was not Gaussian. A log-normal distribution was not rejected (for P > 0.05). Using the log-normal distribution, it was calculated that the probability of exceeding a cortisol concentration in urine of 1.0 micrograms/ml was 1.1 x 10(-4). It was concluded that the actual international threshold is specific i.e. robust with regard to the risk of erroneously declaring an unmedicated horse as positive.

Animals↗

PubMed1992

Bivariate distributions for height and weight of men and women in the United States.

For the U.S. population, we fit bivariate distributions to estimated numbers of men and women aged 18-74 years in cells representing 1 in. intervals in height and 10 lb intervals in weight. For each sex separately, the marginal histogram of height is well fit by a normal distribution. For men and women, respectively, the marginal histogram of weight is well fit and satisfactorily fit by a lognormal distribution. For men, the bivariate histogram is satisfactorily fit by a normal distribution between the height and the natural logarithm of weight. For women, the bivariate histogram is satisfactorily fit by two superposed normal distributions between the height and the natural logarithm of weight. The resulting distributions are suitable for use in public health risk assessments.

Adolescent↗

PubMed1979

Cytophotometric studies of the nuclear DNA content in cartilaginous tumors.

The histopathological differentiation between chondromas and low-grade malignant chondrosarcomas can be difficult. For this reason we studied in 37 different cartilaginous tumors the mitotic index and the Feulgen DNA content using a scanning-integration cytophotometric technique. In 23 chondromas the Feulgen DNA content was diploid and showed a unimodal normal distribution. The number of mitoses was 0--0, 5%. The nuclei of a chondroblastoma were also diploid and the Feulgen DNA content was normally distributed. The mitotic index was 1% and few tetraploid nuclei, which were probably G2 nuclei, were observed. In two chondromyxoid fibromas, the average Feulgen DNA content was diploid and normally distributed. Several tetraploid nuclei were noted. The mitotic index was respectively 0.25% and 1.75%. Recurrence was noted in the first case. The Feulgen DNA content and mitotic index were clearly different in the chondrosarcomas. The distribution of the DNA content was bimodal or unimodal in low-grade chondrosarcomas. The mitotic index was less than 3%. In high-grade malignant chondrosarcomas, the histograms were broad unimodal or aneuploid. The mitotic index was above 5%.

Adolescent↗

PubMed1983

Information processing in the system from light to horizontal cell response of the carp retina.

In this paper, two types of experiments in the carp retina are presented. One is the analysis of responses to white-noise-modulated light at different average mean intensity levels recorded from L-type horizontal cells. For weak light, the responses fluctuated symmetrically around mean values. For brighter light, however, the distribution of amplitude of the response departed from the normal distribution. The deviation from the normal distribution was characterized in terms of symmetry rather than peakedness. The deviation also implies the existence of a nonlinearity in the system. The other type is with barium ion. Ba2+ produced dramatic effects on the spectral response patterns of horizontal cells; the depolarizing response to long wavelength light of the R/G cell and the hyperpolarizing response to deep red light of the Y/RB cell were eliminated in Ba2+-containing solutions. The response of the L cell to white-noise-modulated light was also changed by application of Ba2+. In Ba2+-containing solution, the response became larger as well as slower than that in normal solution. The results of Ba2+ are discussed in relation to the interactions between cone and horizontal cells.

Animals↗