COMPUTATION OF MODEL-DEPENDENT TOLERANCE BANDS FOR AMBULATORILY MONITORED BLOOD PRESSURE

The construction of time-specified reference limits requires systematic sampling in clinical health, particularly for those variables characterized by a circadian rhythm of large amplitude, as it is the case for blood pressure (BP). For the detection of false negatives, tolerance intervals (limits that will include at least a specified proportion of the population with a stated confidence) are important and should substitute when possible for prediction limits. We have previously described a nonparametric method for the computation of model-independent tolerance intervals that are constructed by first dividing the sampling range in several time spans in which no appreciable changes in population characteristics (namely, mean and variance) take place. The tolerance interval is then computed for each of the time spans. The limits thus computed, as well as results of any comparison of a given individual's profile against such tolerance intervals, are highly dependent on the sampling scheme of both the reference individuals and the test subject. To avoid this problem, we have developed an alternative method that allows the computation of model-dependent tolerance bands for hybrid time series. Assuming that a set X of longitudinal series monitored from a given group of reference individuals can be fitted with the same individual model, a population model C(X,t) can be also determined, as well as the deviation S(X,t) of each individual curve from the population model. The tolerance band will then have the form C(X,t) ± kS(X,t), where k is here estimated following a nonparametric approach based on bootstrap techniques. Alternatively, two different values of k can be estimated (for the lower and upper limits of the tolerance interval, respectively) in cases for which we cannot assume symmetry. The method is generally applicable for any population model describing the reference population (including the fit of multiple significant components, nonsinusoidal waveforms, and/or trends). The method was used to establish time-specified tolerance bands for time series of blood pressure monitored automatically in healthy individuals of both genders. Model-dependent intervals are preferred to the model-independent limits when reliance on a specified sampling rate needs to be avoided. These limits may serve for an objective and positive definition of health, for the screening and diagnosis of disease, and for gauging the subject's response to treatment. (Chronobiology International, 17(4), 567–582, 2000)     

Circadian time-qualified tolerance intervals for ambulatory blood pressure monitoring in the diagnosis of hypertension

The large-amplitude circadian pattern in blood pressure of healthy subjects of both genders suggests that the constant threshold currently used to diagnose hypertension should be replaced by a time-specified reference limit reflecting the mostly predictable blood pressure variability during the 24 h. Accordingly, we derived circadian time-specified reference standards for blood pressure as a function of gender. We studied 743 normotensive Caucasian volunteers (400 men and 343 women), 45.7 ± 16.5 (mean ± SD) years of age. Blood pressure was measured by ambulatory monitoring at 20-min intervals during the day and at 30-min intervals at night for 48 consecutive hours. Data from each blood pressure series were synchronized according to the rest-activity cycle of each individual in order to avoid differences among subjects in actual times of daily activity. Data were then used to compute 90% circadian tolerance intervals for each gender separately. The method, derived on the basis of bootstrap techniques, does not need to assume normality or symmetry in the data and, therefore, it is highly appropriate to describe the circadian pattern of blood pressure variability. Results reflect expected changes in the tolerance limits as a function of gender and circadian sampling time, as well as upper blood pressure limits below the thresholds currently used for diagnosing hypertension, especially for women. The use of these time-dependent tolerance limits for the computation of a hyperbaric index as a measure of blood pressure excess has already been shown to provide a reproducible and high-sensitivity test for the diagnosis of hypertension, which can also be used to evaluate treatment efficacy.     

A practical kinetic model for efficient isolation of useful antibodies from phage display libraries

To isolate phages displaying a practical and useful antibody with a high k_on value and/or a low k_off value from phage display antibody libraries, we developed a rational strategy based on a kinetic model. In the model, the recovery of a phage displaying an antibody after a round of biopanning is expressed as a function of five parameters, the apparent association rate constant of the phage antibody to the immobilized antigen (k_on′), the apparent dissociation rate constant of the phage antibody from the immobilized antigen (k_off′), the effective antigen concentration (C), the time for the binding process (t_b) and the time for the washing process (t_w). An optimum set of operating parameters (C, t_b and t_w) for isolating phages displaying an antibody with a high k_on value was designed based on the model. Three rounds of biopanning were carried out under the designed conditions, against a phage library in which the hypervariable regions of an original antibody were randomized. All isolated phages displayed an antibody with a higher k_on value and one displayed an antibody with a 30-fold greater k_on value than that of the original antibody. Experimental conditions which improve the efficiency of conventional off-rate selections are also described.     

Circadian Time-Qualified Tolerance Intervals for Ambulatory Blood Pressure Monitoring in the Diagnosis of Hypertension

The large-amplitude circadian pattern in blood pressure of healthy subjects of both genders suggests that the constant threshold currently used to diagnose hypertension should be replaced by a time-specified reference limit reflecting the mostly predictable blood pressure variability during the 24 h. Accordingly, we derived circadian time-specified reference standards for blood pressure as a function of gender. We studied 743 normotensive Caucasian volunteers (400 men and 343 women), 45.7 ± 16.5 (mean ± SD) years of age. Blood pressure was measured by ambulatory monitoring at 20-min intervals during the day and at 30-min intervals at night for 48 consecutive hours. Data from each blood pressure series were synchronized according to the rest-activity cycle of each individual in order to avoid differences among subjects in actual times of daily activity. Data were then used to compute 90% circadian tolerance intervals for each gender separately. The method, derived on the basis of bootstrap techniques, does not need to assume normality or symmetry in the data and, therefore, it is highly appropriate to describe the circadian pattern of blood pressure variability. Results reflect expected changes in the tolerance limits as a function of gender and circadian sampling time, as well as upper blood pressure limits below the thresholds currently used for diagnosing hypertension, especially for women. The use of these time-dependent tolerance limits for the computation of a hyperbaric index as a measure of blood pressure excess has already been shown to provide a reproducible and high-sensitivity test for the diagnosis of hypertension, which can also be used to evaluate treatment efficacy.     

The tolerance-hyperbaric test: a chronobiologic approach for improved diagnosis of hypertension

Blood pressure (BP) displays predictable large-amplitude circadian variability. Thus, the identification and the proper definition of hypertension are highly ambiguous when based on single time-unspecified measurements. One way to deal with such variability in the diagnosis of hypertension is to replace the commonly used constant limits of BP by a time-specified reference interval based on the normal circadian BP rhythm assessed by ambulatory BP monitoring (ABPM). A proper reference limit can be constructed, for instance, as a tolerance interval computed for every specific time interval throughout the 24 h. Once such a threshold (given by the upper limit of the tolerance interval) is constructed, a hyperbaric index (HBI) can be computed by numerical integration of the total area of any given patient's BP profile above threshold. The HBI plus the duration of excess within the 24h day serves as nonparametric endpoints for assessing hypertension. Both retrospective and prospective evaluation of this tolerance-hyperbaric test validate its high sensitivity and specificity in the diagnosis of hypertension. We describe the theory of the HBI as well as a newly created dedicated software program that automatically derives the tolerance intervals from a reference database of normotensive subjects and calculates the HBI and other potentially valuable parameters based on data obtained by ABPM. The establishment of time-qualified tolerance limits and the assessment of the extent and timing of BP elevation represents a valuable tool for the more accurate diagnosis of hypertension as well as means of gauging response to treatment.     

THE TOLERANCE-HYPERBARIC TEST: A CHRONOBIOLOGIC APPROACH FOR IMPROVED DIAGNOSIS OF HYPERTENSION

Blood pressure (BP) displays predictable large-amplitude circadian variability. Thus, the identification and the proper definition of hypertension are highly ambiguous when based on single time-unspecified measurements. One way to deal with such variability in the diagnosis of hypertension is to replace the commonly used constant limits of BP by a time-specified reference interval based on the normal circadian BP rhythm assessed by ambulatory BP monitoring (ABPM). A proper reference limit can be constructed, for instance, as a tolerance interval computed for every specific time interval throughout the 24 h. Once such a threshold (given by the upper limit of the tolerance interval) is constructed, a hyperbaric index (HBI) can be computed by numerical integration of the total area of any given patient's BP profile above threshold. The HBI plus the duration of excess within the 24h day serves as nonparametric endpoints for assessing hypertension. Both retrospective and prospective evaluation of this tolerance-hyperbaric test validate its high sensitivity and specificity in the diagnosis of hypertension. We describe the theory of the HBI as well as a newly created dedicated software program that automatically derives the tolerance intervals from a reference database of normotensive subjects and calculates the HBI and other potentially valuable parameters based on data obtained by ABPM. The establishment of time-qualified tolerance limits and the assessment of the extent and timing of BP elevation represents a valuable tool for the more accurate diagnosis of hypertension as well as means of gauging response to treatment.     

Algorithm for application of Fourier analysis for biorhythmic baselines of pharmacodynamic indirect response models

The change of an indirect pharmacological response R(t) can be described by a periodic time-dependent production rate k_in (t) and a first-order loss constant k_out. If k_in(t) follows some biological rhythm (e.g., circadian), then the response R(t) also displays a periodic behavior. A new approach for describing the input function in indirect response models with biorhythmic baselines of physiologic substances is introduced. The present approach uses the baseline (placebo) response R_b(t) to recover the equation for k_in(t). Fourier analysis provides an approximate equation for R_b(t) that consists of terms (usually two or three) of the Fourier series (harmonics) that contribute most to the overall sum. The model differential equation is solved backward for k_in(t), yielding the equation involving R_b(t). A computer program was developed to perform the square L²-norm approximation technique. Fourier analysis was also performed based on nonlinear regression. Cortisol suppression after inhalation of fluticasone propionate (FP) was modeled based on the inhibition of the secretion rate k_in(t) using ADAPT II. The pharmacodynamic parameters k_out and IC₅₀ were estimated from the model equation with k_in(t) derived by the new approach. The proposed method of describing the input function needs no assumption about the behavior of k_in(t), is as efficient as methods used previously, and is more flexible in describing the baseline data than the nonlinear regression method. (Chronobiology International, 17(1), 77-93, 2000)     

Plasticity of response to equal quantities of endurance training separated by non-training in humans

1. 1. The pattern of elevation of several serum biochemical indices (BI) of training stress (creatine kinase, CK; lactate dehydrogenase, LDH; aspartate aminotransferase, AST, Ca²⁺; urate, UR; urea, U; total protein, Prot; cholesterol, C) were measured serially through two extended periods of training, including taper (50 days each) separated by a period of complete non-training (90 days) in two male subjects.

2. 2. The patterns of variation in BI were compared with similar variation in elements of a two compartment model predicting performance from training.

3. 3. These elements arbitrarily described as Fitness [g(t)] and Fatigue [h(t)] were estimated daily from a daily training impulse [w(t)] defined from the duration time and heart rate elevation of an individual in a training session.

4. 4. g(t) and h(t) were used to predict performance [p(t)] which might be expected from the training undertaken. So that: p(t) = k₁g(t) — k₂h(t) where k₁ and k₂ are arbitrary constants.

5. 5. Performance p(t) when iteratively modelled against a Criterion running Performance, Cp(t) measured serially throughout training, over a standard distance, then defines the pattern of variation in the elements g(t) and h(t) (Morton et al., 1990).

6. 6. Hard training for 28 days and a succeeding 22 days of taper in each training period produced a rise and fall in elevated serum enzyme activity, ESEA, (CK, LDH and AST) which mirrored the time-course pattern of h(t), the fatigue element of the dose/response model of training, with a slight phase delay.

7. 7. Thus ESEA was already declining during hard training.

8. 8. During the taper period ESEA declined rapidly to base line. This response was remarkably symmetrical in each, separate training period.

9. 9. The Criterion running performance (CP) declined during hard training and rebounded throughout the taper period reaching an asymptote before beginning to decline again as training fitness [g(t)] was lost, although the fatigue [h(t)] state was now minimal.

10. 10. Serum Prot, U, Ur respectively were also elevated throughout hard training, first following the hypothesized h(t) curve but showing a biphasic response, declining during the latter phase of hard training, and rising again during taper.

11. 11. The symmetry of response of these indices in each period was less evident than the ESEA response. None of the BI patterns measured was in phase with g(t), all, seemingly, reflected the catabolic rather than the anabolic process of hard training.

外生菌根真菌土生空团菌种群遗传多样性与结构研究

土生空团菌Cenococcum geophilum是生态系统中广泛分布的外生菌根真菌,具有丰富的遗传多样性和重要的生态功能.为揭示土生空团菌的种群遗传多样性和结构,本研究对采集自中国10个森林地点的桦木科Betulaceae、壳斗科Fagaceae和松科Pinaceae植物根系219份样品高通量测序的土生空团菌ITS2...     

Critical exponents for sol–gel transition in aqueous alginate solutions induced by cupric cations

The sol–gel transition in aqueous alginate solutions of four alginate samples having different molecular weights (M_W) and M/G ratios induced by cupric cations was monitored by rheology measurements. The gel point f_gel and the relaxation critical exponent n were determined using the Winter’s criterion over the alginate concentration C_Alg of 1–4 wt%. The scaling for the zero shear viscosity η₀ before the gel point and the equilibrium modulus G_e after the gel point was established against the relative distance ε from the gel point at the concentration of C_Alg = 1 wt%, giving the critical exponents k and z. The results indicated that f_gel was almost independent of the alginate concentration and became higher for the sample with lower molecular weight. The critical exponent n decreased with the increase in C_Alg for these four Cu-alginate samples and the fractal dimension d_f estimated from n suggested a denser structure in the critical gel with high G content. The critical exponent n evaluated from k and z agreed well with n determined from the Winter’s criterion.     

Computation of Time-Specified Tolerance Intervals for Hybrid Time Series with Nonequidistant Sampling,Illustrated for Plasma Growth Hormone

The ideal reference interval for a variable of clinical interest would be specific for all deterministic factors affecting that variable, including the time of sampling in relation to biological rhythms. In particular, growth hormone is characterized in children by circadian and ultradian variability, with high peaks of secretion occurring mainly during sleep. For clinical applications, the use of tolerance intervals has been recommended, and they should substitute, whenever possible, for prediction limits. In the case of hybrid data (time series of data collected from a group of subjects), such a tolerance interval could be very difficult to determine following a parametric approach similar to the procedure used for the computation of prediction intervals, especially when consideration of both within-subjects and among-subjects variances is wanted. Accordingly, we have developed a nonparametric method for the computation of such tolerance intervals. Because the method is based on bootstrap techniques, it does not require the assumption of normality or symmetry in the data and is also more appropriate when dealing with small samples. The method was used to establish time-qualified reference limits for a series of growth hormone sampled around the clock in groups of prepubertal children differentiated according to stature. The use of these tolerance intervals may eliminate many false-positive and false-negative diagnoses that might be obtained when relying on time-unspecified single samples. The provision of such tolerance limits introduces time-specification and time-structure evaluation into prevention, diagnosis, and treatment of growth disorders. (Chronobiology International, 14(4), 409–425, 1997)     

大围山樱属植物群落结构及物种多样性

研究大围山樱属植物群落结构特征和物种多样性,为野生樱属植物保护和利用提供科学依据.结果 表明:大围山樱属植物有钟花樱桃群落、尾叶樱桃群落、华中樱桃群落和雪落樱桃群落,生活型结构以高位芽植物为主,植物区系组成以泛热带植物成分为主.物种多样性为灌木层＞乔木层,尾叶樱桃群落＞华中樱桃群落＞钟花樱桃群落＞雪落樱桃群落.种群以中...     

鮸形态性状与体质量的关系

为了研究鮸的形态性状与体质量之间的关系,测量了524尾12月龄左右鮸的体质量(Y, g)和8个形态性状(cm),包括全长(X₁)、体长(X₂)、头长(X₃)、躯干长(X₄)、尾长(X₅)、尾柄长(X₆)、尾柄高(X₇)和体高(X₈).采用相关分析、回归分析、通径分析以及模型拟合等方法对其进行分析.结果表明: 鮸所有性状两两之间存在极显著正相关关系,相关系数在0.834～0.941.经共线性诊断排除了体长这一具有严重共线性的性状后,采用逐步引入-剔除法进行多元回归并进行显著性检验,成功筛选出全长(X₁)、躯干长(X₄)、尾柄高(X₇)和体高(X₈)4个统计检验极显著的形态性状,并建立多元回归方程:Y ＝-444.188 +7.943X₁ +12.861X₄ +38.254X₇ + 42.722X₈.通径分析结果显示,4个形态性状中,体高对体质量的直接作用最大(通径系数=0.351),全长次之(通径系数=0.335).对全长和体高与体质量之间的函数关系进行曲线模型拟合得出,在6个拟合模型中,幂函数模型拟合效果最好,方程为:y=0.013 x^2.891(全长); y=2.028 x^2.751(体高).经适合性检验得知,全长比体高通过幂函数对体质量的预测效果更好.研究结果可为鮸的形态性状在选择育种中的有效利用提供重要参考.     

Mechanistic study on the reaction of boronic acids with H-resorcinol

Kinetics for the reaction of m-nitrophenyl- (m-NO₂Ph-), phenyl- (Ph-), methyl(Me-), and n-butyl- (n-Bu-) boronic acids with H-resorcinol has been studied at various temperatures and pressures. The pseudo first-order rate constant (k_obs) exhibited saturation in the plot of k_obs against the total boronic acid concentration (C_B) for the reactions of m-NO₂PhB(OH)₂ and PhB(OH)₂, while the plot was linear for the reactions of MeB(OH)₂ and n-BuB(OH)₂, which leads to the following equations, respectively: k_obs=k*KC_B/(1+KC_B) and k_obs=k*KC_B=k_fC_B. It was experimentally shown that the reaction of boronic acids with H-resorcinol proceeds with rate determining second chelate-ring closure.     

The effect of exogenous factors on morphology and asexual reproduction in laboratory cultures of the intertidal sea anemone, Haliplanella luciae (Verrill) (Anthozoa: Actiniaria) from Delaware

Temperature in combination with different feeding frequencies caused rapid changes in the morphology of experimental culture populations of Haliplanella luciae (Verrill) due to exogenous effects on fission rate (k). A temperature of 15°C permitted few fissions, and only when the anemones were fed at frequent intervals. Conditions which maximized k caused significant decreases in diameter, numbers of septa, and numbers of tentacles after only 26 days in culture. Anemones fed every two days at 15°C showed the least morphological change over the culture period, remaining morphologically similar to field specimens. Asexual reproduction in H. luciae is not as well integrated with organismal growth as in hydroids. The importance of k and environmental regulators of k in determining both morphological structure and population size of H. luciae is discussed. In this study H. luciae were of a previously undescribed color variant, with light longitudinal bands.     

锁阳ITS序列遗传多样性分析

为阐明锁阳(Cynomorium songaricum)的遗传结构与遗传多样性, 以甘肃省河西走廊地区及青海省共18个居群的188个锁阳个体为研究对象, 利用现代分子生物学技术, 采用序列分析方法从核-质基因方面对遗传结构进行了分析。结果显示, 锁阳ITS序列总长度为687 bp, 含有7个变异位点, 定义9个单倍型, 整体单倍型多态性H_d=0.294 20, 核苷酸多样性π=0.000 49。在整个单倍型网络中介图中, 单倍型H1位于中心位置, 并在所有的居群中均有分布, 为核心的古老单倍型。分子方差分析结果显示, 锁阳种群变异主要来源于种群内。根据ITS序列得到的群体间遗传分化系数以及Mantel检验结果, 锁阳种群间的遗传距离与地理距离之间不存在相关性, 表明现存的锁阳居群是相对近期发生生境片段化的产物。中性检验结果表明, 锁阳拒绝中性进化, 群体历经扩张或者基因座位受到负选择作用, 其中性零假说不能被排除。该研究为锁阳的系统分类、资源鉴定以及保护措施的制定提供了分子证据。     

Benzo(a)pyrene diolepoxide-haemoglobin and albumin adducts at low levels of benzo(a)pyrene exposure

A biomonitoring study was conducted to simultaneously measure individual benzo(a)pyrene (BaP) exposure in 50 office employees, not occupationally exposed to polycyclic aromatic hydrocarbons (PAH), using personal samplers and the formation of (+) r-7, t-8-dihyroxy-t-9,t-10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE) adducts to haemoglobin (BPDE-Hb) and serum albumin (BPDE-SA). The population enrolled was exposed to an average of 0.58 ± 0.46 ng BaP m^-3 (mean ± SD). The concentration of BaP collected from smokers' samples was double that from non-smokers (P = 0.007). BPDE adducts to Hb and SA were quantified as BaP tetrols released from hydrolysis of macromolecules and measured by high-resolution gas chromatography-negative ion chemical ionization-mass spectrometry. BPDE-Hb adducts were detected in 16% of the population and BPDE-SA adducts in 28%. Smoking did not affect adduct formation. When BaP personal monitoring data were used as the criterion of exposure, no correlation was found with the presence and the levels of BPDE-Hb and BPDE-SA adducts. Undetected sources of PAH, such as the diet, might markedly alter the exposure profile depicted by individual air sampling and affect the frequency and levels of protein biomarkers. This is the first comparative analysis of BPDE-Hb and BPDE-SA adducts, providing reference values for these biomarkers in a general urban population. However it is difficult to establish which biomarkers would be the more relevant in assessing low BaP exposure, due to undetectable factors such as dietary PAHs, that might have influenced the results to some degree.     

多鳞四须鲃耗氧率、排氨率和窒息点的初步研究

控制水温在(20±0.5)℃条件下,采用Winkler法和奈氏试剂法分别测定水中的溶氧含量和氨氮含量,通过比较流水呼吸室进、出口水中的溶解氧和氨氮含量之差以确定多鳞四须鲃(Barbodes schwanenfeldi)的耗氧率、排氨率及窒息点.结果表明,多鳞四须鲃耗氧率随体重增加而减小,关系式为Y=0.24X^-0.09(R²=0.9028);随放养密度的增大而减小,关系式为Y=-0.029X+0.3301 (R²=0.9291).排氨率随体重的增加而减小,关系式为Y=-0.0008X+0.2433 (R²=0.9817);随放养密度的增大而增加,关系式为Y=-0.050X+0.4979 (R²=0.9889).多鳞四须隹巴晚间(18:00～4:00)的耗氧率明显高于白天(6:00-1:00),排氨率则相反,白天的排氨率相对较高,表明多鳞四须鲃巴属于"昼伏夜出"型鱼类.多鳞四须啬巴的窒息点为1.2572mg·L^-1,耐氧性较差.     

Population structure and spatial pattern of Caragana tibetica communities in Nei Mongol shrub-encroached grassland

Aims The community structure and function of the shrub-encroached grassland, as well as its formation mechanism, is one of hot scientific problems in vegetation science. The spatial pattern analysis is an important means for studying plant population interactions and the relationships between plant population and environment. The shrub-encroached grassland is one major vegetation type in Nei Mongol. Knowledge on the spatial pattern of shrub can improve our understanding on adaptive characteristics of shrub to steppe environment.
Methods We chose Caragana tibetica encroached grassland distributed in Ordos City as research objects. The spatial position of each C. tibetica individual in 64 m × 64 m study plot was determined by a method of “three-distance location method”, and then the spatial pattern and intraspecific associations of C. tibetica individuals was analyzed with the point pattern analysis.
Important findings The results showed that C. tibetica population was at the rising stage. The mature individuals showed a uniform distribution at the scale of less than 3.7 m, subsequently exhibiting a random distribution with an increased scale. The juvenile individuals showed an aggregation distribution at the scale of 0.3-20.4 m, but a uniform distribution at other scales. The dead C. tibetica individuals were distributed aggregately at the scale from 0.7 to 1.4 m, but randomly at other scales. An indistinctive positive association was found for live C. tibetica individuals to dead individuals at the scale of less than 9.9 m, but no associations was found between them at other scales. The mature individuals negatively interacted with juveniles at the scale of larger than 2.2 m, but unassociated at the other scales.