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Hyperleptinemia in women with Cushing's disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion.

The episodicity of 24 h leptin release was studied in seven women (mean age 39 years, range 22-56 years) with pituitary-dependent hypercortisolism and in seven age- and body mass index (BMI)-matched female controls. Pulsatile leptin release was quantified by model-free cluster analysis and deconvolution, the orderliness of leptin patterns by the approximate entropy statistic (ApEn), and nyctohemeral leptin rhythmicity by cosinor analysis. Blood samples were taken at 10 min intervals for 24 h. Both cluster and deconvolution analysis revealed 2.4-fold increased leptin secretion in patients, caused by combined and equal amplification of basal and pulsatile secretion. Cluster analysis identified 7.1+/-1.5 peaks per 24 h in patients and 6.0+/-0.5 in controls (not significant). The statistical distribution of the individual sample secretory rates was similarly skewed in patients and controls (0.55+/-0.12 vs 0.52+/-0.07). The acrophase (timing of the nyctohemeral leptin peak) in patients occurred at 2314 h (+/-76 min) and at 0058 h (+/-18 min) in controls (not significant). The approximate entropy of leptin release was equivalent in patients and controls (1.67+/-0.03 vs 1.61+/-0.05). The approximate entropy (ApEn) for cortisol in patients was 1.53+/-0.09 and in controls was 0.93+/-0.07 (P<0.0005). Cross-ApEn showed significant pattern synchrony between leptin and cortisol release, which (unexpectedly) was not disrupted by the cortisol excess (patients, 2.02+/-0.04; controls, 1.88+/-0.09; P=0.233). Insulin levels in fasting patients ('fasting insulin') were 27+/-5.7 mU/l vs 14+/-1.6 mU/l in controls (P=0.035). Leptin secretion correlated with fasting insulin levels (R(2)=0.34, P=0.028) and with the cortisol production rate (R(2)=0.33, P=0.033) when patients and controls were combined. In summary, Cushing's disease in women increases leptin production about twofold in an amplitude-specific way. The pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern the 24 h leptin release are not altered. The increased secretion is not explained by BMI and is probably only partly explained by increased insulin production, suggesting a cortisol-dependent change in adipose leptin secretion.

Adult↗

The coupon collector and the suppressor mutation: estimating the number of compensatory mutations by maximum likelihood.

Compensatory mutation occurs when a loss of fitness caused by a deleterious mutation is restored by its epistatic interaction with a second mutation at a different site in the genome. How many different compensatory mutations can act on a given deleterious mutation? Although this quantity is fundamentally important to understanding the evolutionary consequence of mutation and the genetic complexity of adaptation, it remains poorly understood. To determine the shape of the statistical distribution for the number of compensatory mutations per deleterious mutation, we have performed a maximum-likelihood analysis of experimental data collected from the suppressor mutation literature. Suppressor mutations are used widely to assess protein interactions and are under certain conditions equivalent to compensatory mutations. By comparing the maximum likelihood of a variety of candidate distribution functions, we established that an L-shaped gamma distribution (alpha=0.564, theta=21.01) is the most successful at explaining the collected data. This distribution predicts an average of 11.8 compensatory mutations per deleterious mutation. Furthermore, the success of the L-shaped gamma distribution is robust to variation in mutation rates among sites. We have detected significant differences among viral, prokaryotic, and eukaryotic data subsets in the number of compensatory mutations and also in the proportion of compensatory mutations that are intragenic. This is the first attempt to characterize the overall diversity of compensatory mutations, identifying a consistent and accurate prior distribution of compensatory mutation diversity for theoretical evolutionary models.

Epistasis, Genetic↗

On the quantitative genetics of mixture characters.

Finite mixture models are helpful for uncovering heterogeneity due to hidden structure. Quantitative genetics issues of continuous characters having a finite mixture of Gaussian components as statistical distribution are explored in this article. The partition of variance in a mixture, the covariance between relatives under the supposition of an additive genetic model, and the offspring-parent regression are derived. Formulas for assessing the effect of mass selection operating on a mixture are given. Expressions for the genetic and phenotypic correlations between mixture and Gaussian traits and between two mixture traits are presented. It is found that, if there is heterogeneity in a population at the genetic or environmental level, then genetic parameters based on theory treating distributions as homogeneous can lead to misleading interpretations. Some peculiarities of mixture characters are: heritability depends on the mean values of the component distributions, the offspring-parent regression is nonlinear, and genetic or phenotypic correlations cannot be interpreted devoid of the mixture proportions and of the parameters of the distributions mixed.

Environment↗

[Assessment of occupational exposures to industrial hazardous substances. I. A proposed method based on interday fluctuation of contaminant concentrations for evaluating employee's exposure averages (TWAs)].

Occupational exposures to potentially hazardous substances may vary considerably because of factors such as sampling and analytical errors, and intraday and interday environmental fluctuations in contaminant concentration. Of these factors, day-to-day environmental fluctuations most likely affect daily exposure averages over days, weeks, months or years. A new method based on day-to-day fluctuations of daily exposure averages (geometric standard deviation) was developed for making reliable assessment of the employee's exposure situation. It is assumed that daily exposure averages of a worker are lognormally and independently distributed statistically. Finally, a classification scheme on the basis of n days measurements is presented. 95% upper limit or arithmetic mean of individual exposure averages (8-h TWAs) can be evaluated in comparison with an established standard. The method may provide an approximate estimate because of statistical premise, but it can be utilized for practical purposes, particularly, in case where only one or two days are being monitored. An action level concept based on random sampling and analytical errors and interday variations developed by OSHA/NIOSH, and a sampling and decision scheme based on one-sided tolerance limits proposed by Tuggle (1982) are also discussed.

Data Interpretation, Statistical↗

Variation of enzyme activities at a branched pathway involved in the utilization of gluconate in Escherichia coli.

Twenty-four strains of Escherichia coli from the ECOR collection were characterized for growth rate in gluconate minimal salts medium and for Vmax and Km of the three enzymes (gluconokinase, 6-phosphogluconate dehydrogenase, and 6-phosphogluconate dehydratase) that form a branch point for the utilization of gluconate. A total of 11 characters--growth rate, three Vmax values, four Km values, and three Vmax/Km values--were determined for these 24 ECOR strains. Most of the characters were normally distributed. Statistical tests showed that growth rate is significantly less variable than enzyme activities. Also, analyses of variance showed significant differences among strains and among the extant five genetic groups of E. coli for the characters measured. A Mantel test showed that, for some characters, closely related strains shared similar character values. Two hypotheses regarding the relationships between growth rate and enzyme activity and between various enzyme activities were tested. None of the expected correlations between growth rate and enzyme activity or between enzyme activities was detected. The results were discussed in terms of metabolic control analysis and neutral theory.

Biological Evolution↗

Spectral tuning of photoactive yellow protein.

We report a theoretical study on the optical properties of a small, water-soluble photosensory receptor, photoactive yellow protein (PYP). A hierarchical ab initio molecular orbital calculation accurately evaluated the optical absorption maximum of the wild-type, as well as the lambda(max) values of 12 mutants. Electronic excitation of the chromophore directly affects the electronic state of nearby atoms in the protein environment. This effect is explicitly considered in the present study. Furthermore, the spectral tuning mechanism of PYP was investigated at the atomic level. The static disorder of a protein molecule is intimately related to the complex nature of its energy landscape. By using molecular dynamics simulation and quantum mechanical structure optimization, we obtained multiple minimum energy conformations of PYP. The statistical distribution of electronic excitation energies of these minima was compared with the hole-burning experiment (Masciangioli, T. [2000] Photochem. Photobiol. 72, 639), a direct observation of the distribution of excitation energies.

Amino Acid Substitution↗

[Lymphocyte subpopulations in the cerebrospinal fluid: III. Normal values].

For cerebrospinal fluid (CSF) samples from 50 subjects previously selected to represent suitably a normal control group and for a methodology that may be actually used for CSF samples even with normal cell count, it is possible to characterize lymphocyte subpopulations with normal statistical distribution and low dispersion of results for all lines considered. Data (mean +/- standard deviation) here estimated were (%): for B-lymphocyte subpopulation 7.0 +/- 1.44; for T lymphocyte subpopulation 76.0 +/- 2.92; for T-active lymphocytes 53.7 +/- 3.26; for T-avid lymphocytes 19.2 +/- 4.32 when all T subpopulation is considered, and 11.1 +/- 2.04 when only T-active subpopulation is studied; for T-sensitized or actually activated 22.3 +/- 3.95. These data may suggest that lymphocytes actually related to immunological activation will be properly represented by the difference between T-lymphocytes and its T-active line in each case. In every samples T and T-active lymphocytes are different subpopulations when surface receptor density is considered, by evidence of avidity for sheep erythrocytes. It is also possible that killer lymphocytes, or antibody mediated cytotoxic cells, may be related to modified lymphoid cells identified in the CSF normal cytomorphological profile.

Adolescent↗

[Reference values for carboxyhemoglobin].

INTRODUCTION: The reference values (RV) of biological indicators are used in the interpretation of the results of such indicators in individuals occupationally exposed to chemical agents. The Brazilian Group for the Establishment of Reference Values has worked on these definitions for the purpose of establishing RVs for several bioindicators in various regions of the country. In the present study, the RV for carboxyhemoglobin (COHb) was determined for the South of Minas Gerais. MATERIAL AND METHOD: The COHb was analyzed by the Beutler and West (1984) spectrophotometric method, optimized in our laboratory. In all the samples, analyses of some biochemical and hematological parameters were made to evaluate the health condition of a population of 200 volunteer non-smokers occupationally not exposed to CO. Each individual answered a questionnaire to obtain data pertinent to the interpretation of the results. The reference values were expressed as mean values +/- standard deviation, with a 95% confidence interval, and an upper reference value. The statistical distribution of the results was made so as to enable comparisons between the results of groups of workers, rather than individual evaluations, to be made. RESULTS AND CONCLUSIONS: The mean value +/- standard deviation was 1.0% +/- 0.75; the 95% confidence interval was 0.9-1.1% and the upper reference value was 2.5%. By the t Student test (p < or = 0.05), no difference was detected between the values related to sex, age or ingestion of alcoholic beverages. The reference values obtained were close to those reported for others countries.

Adolescent↗

[Trends in mortality due to respiratory diseases in elderly, Brazil, 1980 to 1998].

INTRODUCTION: The increase in life expectancy and the decline in mortality rates in Brazil have an impact on social programs to the elderly, especially related to health care. The objective of the study isto analyze the mortality trends for respiratory diseases in elderly. METHODS: An ecological time series was carried out and mortality data was obtained from the Mortality Information System of the Ministry of Health (SIM/MS-DATA-SUS). it was analyzed the time trends of standardized mortality rates according to age groups (60 to 69, 70 to 79 and 80 years old and more) and gender, using linear regression models. The proportional mortality for this disease group compared to all causes of death was also studied. RESULTS: There were increasing trends for mortality rates in both sexes, especially among males. The proportion of deaths due to respiratory diseases was higher among older ages. CONCLUSION: Respiratory diseases are one of the main causes of hospitalization and death in the elderly population. Prevention and care for elderly, as well as further etiology studies should be a priority in Brazil.

Age Distribution↗

Virtual screening for environmental pollutants: structure-activity relationships applied to a database of industrial chemicals.

The current risk paradigm calls for individual consideration and evaluation of each separate environmental pollutant, but this does not reflect accurately the cumulative impact of anthropogenic chemicals. In the present study, previously validated structure-activity relationships were used to estimate simultaneously the baseline toxicity and atmospheric persistence of approximately 50,000 compounds. The results from this virtual screening indicate fairly stable statistical distributions among small anthropogenic compounds. The baseline toxicity was not changed much by halogen substitution, but a distinct increase seemed to occur in the environmental persistence with increased halogenation. The ratio of the atmospheric half-lives to the median lethal concentrations provides a continuous scale with which to rank and summarize the incremental environmental impacts in a mixture-exposure situation. Halogenated compounds as a group obtained a high ranking in this data set, with well-known pollutants at the very top: DDT metabolites and derivatives, polychlorinated biphenyls, diphenyl ethers and dibenzofurans, chlorinated paraffins, chlorinated benzenes and derivatives, hydrochlorofluorocarbons, and dichlorononylphenol. Environmentally friendly chemicals that obtained the lowest rank are nearly all hydroxylated and water-soluble. Virtual screening can assist with "green chemistry" in designing safe and degradable products and enable assessment of the efficiency in chemicals risk management.

Chemical Industry↗

User subjectivity in Monte Carlo modeling of pesticide exposure.

Monte Carlo techniques are increasingly used in pesticide exposure modeling to evaluate the uncertainty in predictions arising from uncertainty in input parameters and to estimate the confidence that should be assigned to the modeling results. The approach typically involves running a deterministic model repeatedly for a large number of input values sampled from statistical distributions. In the present study, six modelers made choices regarding the type and parameterization of distributions assigned to degradation and sorption data for an example pesticide, the correlation between the parameters, the tool and method used for sampling, and the number of samples generated. A leaching assessment was carried out using a single model and scenario and all data for sorption and degradation generated by the six modelers. The distributions of sampled parameters differed between the modelers, and the agreement with the measured data was variable. Large differences were found between the upper percentiles of simulated concentrations in leachate. The probability of exceeding 0.1 microg/L ranged from 0 to 35.7%. The present study demonstrated that subjective choices made in Monte Carlo modeling introduce variability into probabilistic modeling and that the results need to be interpreted with care.

Monte Carlo Method↗

Operant control of response latency in monkeys: evidence for a central explantation.

Two monkeys (M. mulatta) were trained to press a telegraph key after onset of a tone and release it quickly in response to a subsequent light or click stimulus occurring after a variable interval. After training first with a fixed time limit on response latency for key release and then with a continuously adjusting limit, reaction time to click was 160 msec and to light, about 200 msec. Temporal contingencies or "payoff bands" were then introduced which reinforced only responses with latencies which fell between two limits 50 msec apart. Feedback was given as to whether each latency was too slow, within the band, or too fast. A trained monkey could precisely center its latency distribution on any 50 msec-wide payoff band located from 200 to 600 msec after the stimulus, with from 60 to 80% of its responses achieving reinforcement. Distribution statistics were comparable to those of trained human subjects. Because such precise timing might be accomplished by a peripheral adjustment, such as changing the manner of holding the key, latency of electromyographic activation was measured in participating arm muscles in one monkey. Electromyographic activation preceded key release by a constant interval, regardless of response latency, indicating a more central mechanism for timing of brief intervals.

Animals↗

Application of bioinformatics in search for cleavable peptides of SARS-CoV M(pro) and chemical modification of octapeptides.

According to the "distorted key" theory as elaborated in a review article years ago (Chou, K.C.: Analytical Biochemistry, 1996, 233, 1-14), the knowledge of the cleavable peptides by SARS-CoV M(pro) (severe acute respiratory syndrome coronavirus main proteinase) can provide very useful insights on developing drugs against SARS. In view of this, the softwares, ZCURVE_CoV 1.0 and ZCURVE_CoV 2.0 (http://tubic.tju.edu.cn/sars/), developed recently for SARS-Coronavirus are used to analyze the 36 complete SARS-Coronavirus RNA sequences in the gene bank NCBI (http://www.ncbi.nlm.nih.gov/) from different sources for protein coding genes, and to search for the cleavage sites of SARS-CoV M(pro) in polyproteins pp1a and pp1ab. A total of 396 cleavage points are found in the 36 SARS-Coronavirus and 11 cleavable octapeptides abstracted from the 396 cleavage sites. The statistical distributions of amino acids for the cleavable octapeptides at the subsites R4, R3, R2, R1, R1', R2', R3' and R4' are calculated. The cleavage-specific positions are on R2, R1 and R1', and the positions R3 and R4 are featured by some certain specificity for SARS-CoV M(pro). The structural characters of amino acid residues around the cleavage-specific positions are discussed. Two most promising octapeptides, i.e., NH(2)-ATLQ downward arrowAIAS-COOH and NH(2)-ATLQ downward arrowAENV-COOH, are selected to be the candidates for chemical modification, converting into the inhibitors of SARS-CoV M(pro). A possible strategy to convert a cleavable octapeptide by SARS enzyme into a drug candidate against SARS is elucidated.

Amino Acid Sequence↗

Correlation of biparietal and fetal body diameters: 12--26 weeks gestation.

One hundred thirty-four obstetrical diagnostic sonographic examinations were performed on patients of 12--26 gestational weeks. The following abdominal diameter measurements were obtained: (1) anteroposterior transverse diameter; (2) right-to-left transverse diameter; (3) average of (1) and (2); and (4) greatest longitudinal diameter. These measurements were plotted against the respective biparietal diameters, and normal statistical distribution curves were developed. These curves have proven helpful in cases with a questionable disproportionate relation between the fetal head and body size in early pregnancy. The data have facilitated identification of fetal abnormalities sufficiently early in the pregnancies to permit advising therapeutic abortion. Five cases outside the normal range are discussed and compared to normal. In several cases, the sonographic results played a major role in the decision-making process of the patient involved.

Adult↗

The mean filtration pressure of leukocyte suspensions and its relation to the passage of leukocytes through nuclepore filters and capillary networks.

OBJECTIVE: To quantitatively evaluate the deformability of bulk suspensions of leukocytes (WBCs), account for the variance of individual cell mechanical properties, and deduce the potential for WBC entrapment within the capillary network in response to alterations in cell properties. METHODS: The transient washout of WBCs initially trapped under low perfusion pressure in 5-microns pores of Nuclepore filters was analyzed for a 0.2-ml bolus of WBCs (derived from hamsters) with equal numbers of filter pores and cells, to characterize the statistical distribution of pressures, Pyield, required to dislodge the cells. Contributions of the variance in WBC diameter, pore diameter, and cremaster muscle capillary diameter to Pyield were estimated with a WBC cortical shell model and an analysis of the probability function of the ratio of WBC to pore diameter, lambda. RESULTS: For normal WBCs, Pyield exhibited a log-normal distribution with mean (Pyield) of 0.59 cmH2O. Incubation of cells in cytochalasin-B reduced (Pyield) almost 50%, whereas phorbol myristate acetate increased (Pyield) twofold. Incubation in N-formyl-methiolnyl-leucyl-phenylalanine had no significant effect on (Pyield), as polymorphonuclear cells became permanently trapped in the filter. The fluorescent dyes acridine orange, acridine red, and tetramethylrhodamine isothiocyanate increased (Pyield) as much as 10-fold, whereas steady-flow filtration methods showed no alteration. Analysis of the distribution of lambda revealed that due to their smaller pore diameters, in vitro filtration methods may overestimate in vivo values of (Pyield) by almost twofold. CONCLUSIONS: The transient filtration of WBC suspensions appears to be much more sensitive to subtle alterations in WBC deformability than steady-flow methods and may provide greater insight into the determinants of capillary perfusion. Estimates of (Pyield) are comparable to those obtained with micropipettes and permit analysis of substantially greater numbers of cells within a sample. Fluorescence labeling techniques should be used with caution, as they may dramatically alter cell properties to an extent undetectable by direct in vivo observations.

Animals↗

Comparison of bubble release from various types of oxygenators.

A comparative study of microbubble release from various types of oxygenators was performed using ultrasonic Doppler techniques. Bubble count versus amplitude histograms were calculated to derive the statistical distribution of the relative microbubble sizes. To compare the different oxygenators with respect to differences in microbubble releases, several key parameters as, temperature, liquid flow rate, gas to flow relationship, liquid level within the oxygenator, were altered one at a time to indicate different and oxygenator related sensitivities with respect to variations of the key parameters.

Extracorporeal Circulation↗

Theory of filtration of mixed blood suspensions.

A theory is developed for the flow of suspensions of blood cells through filters in which the properties of the cells are defined by statistical distributions. It is shown that conditions are generally transient, and computational procedures are developed to compute the pressure drop and the fraction of the pores of the filter containing cells of various types as a function of time. The computations show a large influence of very small concentrations of stiff cells which gradually collect in the filter and effectively plug the filter during the time of a typical test. It is also shown that the mean value of the resistance offered by a cell population with a limited distribution of resistances is more important than dispersion of resistances about the mean in determining the observable pressure curve. Experimental data are presented demonstrating that the drug pentoxifylline reduces the stiffness of leukocytes.

Blood Flow Velocity↗

Electrosyntheses from aromatic aldehydes in a flow cell. Part II. The cross-coupling of benzaldehydes to unsymmetrical diols.

It is demonstrated that the reduction of mixtures of two benzaldehydes in acidic water-methanol in a membrane flow cell with a lead cathode can lead to a mixture of diols including the unsymmetrical diol, e.g. 4-F-C6H4-CH(OH)-CH(OH)-C6H5. In the conditions employed, the ratio of the three diol products follows the statistical distribution expected for the coupling of two different radical intermediates produced in the same ratio as the concentrations of their precursors. The yield and current efficiency for the diols are excellent when the pH and potential are selected so that a le- reduction of both benzaldehydes occurs. The yield of unsymmetrical dimer based on one reactant can be increased substantially by using the other carbonyl compound as a sacrificial reagent.

Acetophenones↗