Uric acid and renal function in multiple sclerosis.

OBJECTIVE: The purpose of this study was to examine the circadian distribution of creatinine and uric acid clearances in subjects with Multiple Sclerosis. MATERIALS AND METHODS: Eleven subjects with MS, 6 women (48+/-7y) and 5 men (58+/-5y) volunteered for this circadian study. Thirteen healthy females (39+/-11y) served as controls. Data of seven healthy male controls (64+/-8 y) were extracted from a similar circadian study conducted previously. Each MS patient, and each male control had blood samples drawn around the clock, at 3h intervals (8/24h), and each collected urines over 3h periods (8/24h). Each female control contributed only one blood sample and one complete 24h urine collection. Blood and urine samples were analyzed for a number of relevant analytes: ELAM, IL-6, NO, insulin, ACTH, aldosterone, cortisol, electrolytes, lymphocytes, monocytes including creatinine and uric acid clearances. Those were standardized to an average body surface area of 1.73 m2. RESULTS: The relevant analytes demonstrated increased synthesis of insulin, IL-6, ELAM, monocytes, and reduced concentrations of serum NO. The creatinine clearances were significantly lower in MS females than in female controls, 63+/-22 vs.108+/-18 ml/min. They were also lower than those of MS males and male controls, 107.8+/-17, 97.5+/-8.2 ml/min. Uric acid clearances in MS females were also lower 6.9+/-2.4 vs. 10.5+/-4.4 ml/min. The uric acid clearance in MS males was higher than in male controls, 7.0+/-4.5 vs. 4.0+/-1.0 ml/min. CONCLUSIONS: The alterations in selected relevant analytes and the reduced creatinine and uric acid clearances in females but not in males, suggest a renal dysfunction in MS females. These observations may contribute to understanding better the mechanism of renal dysfunction in female patients and perhaps this may be an additional factor contributing to greater frequency of MS in females than in male subjects.

Chronotherapy of ovarian cancer: effect on blood variables and serum cytokines. A case report.

A 7-year-old patient with Stage III-c ovarian cancer was subjected to 8 cycles, approximately four weeks apart, of chronobiologically-optimized treatments with combination of three anti-cancer agents: Four cycles at AM, Cytoxan and PM, cis-Platinum; four cycles at AM, Adriamycin and PM, cis-Platinum. A second look laporoscopy revealed clean intestines, no definite masses in the pelvis area although there was an apparent mass in the right upper pelvis and several slightly enlarged lymph nodes in the base of mesentery. Six cycles of Taxol were administered at about Noon. Seven months remission appeared evident as judged by no changes in monthly examinations, in blood work or in CA-125 marker levels which remained below 12 U/ml. During the eight month the CA-125 marker began to rise, 36 then to 52 U/ml. A second 6 cycle series of Taxol was initiated but the CA-125 marker continued to rise, 57, 65, 72, 86, and 87 U/ml level. The patient declined in spirit, in well-being and expired 2 weeks later, 31 months after the initial diagnosis of cancer. Blood hematology, chemistry, and cytokines variables were analyzed at about weekly intervals. Significant reductions in total WBC, neutrophiles and platelet levels were evident during the second week of all cycle treatments, while increases were noted in serum levels of IL-2, IL-6 and IL-10 following Cytoxan-cis-Platinum-Adriamycin, but not Taxol. After each infusion moderate and temporary increases in RBC levels were noted. The treatments impact on hematology, chemistry, cytokine variables and on the integrity of the patient, are presented and briefly discussed.

Circadian distribution of hematology variables in subjects with multiple sclerosis.

Hematology variables were measured in blood samples obtained every 3h (8/24h) from 10 multiple sclerosis (MS) patients and 34 healthy subjects and analyzed for circadian characteristics using the population multiple-components method. Red blood cell (RBC) and hemoglobin levels as well as hematocrits exhibited circadian rhythms with minimal amplitudes in healthy individuals and insignificant variability in the smaller group of MS patients. In contrast the total white blood cell (WBC) and platelet counts for MS patients and healthy individuals both showed significant circadian characteristics while the mean 24h WBC and platelet levels did not significantly differ between the two groups. When the different WBC subsets were examined independently, statistically significant circadian rhythms were seen for lymphocytes and eosinophils for both MS patients and healthy individuals and for neutrophils only in the latter. Moreover, the 24h mean levels of lymphocytes, basophils, and eosinophils were significantly higher for the healthy controls while those of monocytes were higher for the MS patients. However, of all the variables tested with significant circadian rhythms in both groups of individuals, only those of lymphocyte numbers exhibited different patterns with somewhat higher amplitude in healthy individuals and a peak level occurring over an hour after that of MS patients. These changes may be the reflection of a disturbance in the regulation of patterns of lymphocyte activity and migration in MS patients. In addition, the elevation in circulating monocytes in MS patients is consistent with the inflammatory nature of the disease.

Circadian variability of blood pressure in liver transplant recipients without antihypertensive therapy.

Hypertension is a frequent cardiovascular risk factor in liver transplant recipients. The usefulness of ambulatory blood pressure monitoring (ABPM) in these patients is unknown. This study was aimed at evaluating the circadian rhythms of blood pressure in liver allograft recipients. In 53 liver transplant patients blood pressure was measured with the Spacelabs device program. No patient received antihypertensive therapy for at least 15 days beforehand. Clinical blood pressure measurement showed 26 patients to be hypertensive. Of these, ABPM verified the diagnosis in 23. Overall, 72% of the patients were hypertensive, and 39.5% showed a nondipper pattern. Diastolic hypertension was more frequent than systolic hypertension. No differences were found in renal function, immunosuppressive therapy, or corticosteroids.

Diagnosing gestational hypertension and preeclampsia with the 24-hour mean of blood pressure.

The use of ambulatory blood pressure monitoring has provided a method of blood pressure assessment that may compensate for some of the limitations of isolated measurements. Here we aim to examine prospectively the effectiveness of the commonly used 24-hour mean as a potential screening test for the identification of gestational hypertension and preeclampsia. We analyzed 503 blood pressure series from 71 healthy pregnant women and 256 series from 42 women who developed gestational hypertension or preeclampsia. Forty-eight-hour blood pressure monitoring was done once every 4 weeks after the first obstetric consultation. Sensitivity and specificity of the 24-hour mean of blood pressure were computed for each trimester of pregnancy by comparing distributions of values obtained for healthy and complicated pregnancies, without assuming an a priori threshold for diagnosing gestational hypertension on the basis of mean blood pressure. Sensitivity ranges from 31.8% for diastolic blood pressure in the second trimester to 84.1% for systolic blood pressure in the third trimester. However, specificity is as low as 6.9% for diastolic blood pressure in the first trimester. The positive predictive value does not reach 55% for any variable in any trimester. The higher relative risk was consistently obtained for systolic blood pressure (4.9 in the third trimester). Despite the highly statistically significant differences in blood pressure found between healthy and complicated pregnancies in all trimesters, the daily mean of blood pressure does not provide a proper and stable individualized test for diagnosing hypertensive complications in pregnancy. Other indexes obtained from the blood pressure series have been shown, however, to identify early in pregnancy those women who subsequently will develop gestational hypertension or preeclampsia, rendering ambulatory blood pressure monitoring a useful, but still costly, technique in pregnancy.

Reproducibility of the hyperbaric index as a measure of blood pressure excess.

The approach of establishing a time-specified tolerance limit reflecting the circadian variability in blood pressure and then determining the hyperbaric index, the area of blood pressure excess above the upper limit of the tolerance interval, has been proposed for diagnosing hypertension as well as for evaluating the patient's response to treatment. The retrospective evaluation of this test provided high sensitivity and specificity in the diagnosis of hypertension, with a threshold value for the hyperbaric index of 15 mm Hg. h. To evaluate the stability and reproducibility of this tolerance-hyperbaric test, we studied 332 previously untreated subjects (218 men) who underwent sequential 48-hour ambulatory blood pressure monitoring for 2 years, providing a total of 1337 blood pressure profiles. Diagnosis of hypertension was established for each subject on the restricted basis of presenting at least 1 blood pressure profile with a hyperbaric index above the previously defined threshold. Sensitivity of this tolerance-hyperbaric test was 98.6%, with a negative predictive value of 99.7%. For the same subjects, the blood pressure load (percentage of values >140/110/90 mm Hg for systolic/mean arterial/diastolic blood pressure during activity or >120/95/80 mm Hg during resting hours) had a sensitivity of 49% and specificity of 25%. The 24-hour mean, still the most common approach for diagnosing hypertension on the basis of ambulatory monitoring, had sensitivities of 40% and 31% for systolic and diastolic blood pressure, respectively. Despite the limitations of ambulatory blood pressure monitoring, the tolerance-hyperbaric test represents a reproducible, noninvasive, and high-sensitivity test for the identification of subjects in need of prophylactic or therapeutic intervention.

Circadian blood pressure variability in healthy and complicated pregnancies.

With the aim to describe the circadian pattern of noninvasive ambulatorily monitored blood pressure during the trimesters of pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia, we analyzed 759 blood pressure series sampled by ambulatory monitoring for about 48 hours every 4 weeks after the first obstetric visit in 71 women with uncomplicated pregnancies, 28 with gestational hypertension, and 14 with preeclampsia. The circadian pattern of blood pressure variation for each group (complicated versus uncomplicated pregnancies) and trimester of gestation was established by linear least-squares methods. A highly statistically circadian pattern is demonstrated for systolic and diastolic blood pressure for both groups of pregnant women in all trimesters (P<.001 in all cases). Blood pressure decreases from the first trimester to the second and rises again in the third for healthy pregnant women. For women who developed gestational hypertension or preeclampsia, blood pressure is stable during the first half of pregnancy and then continuously increases until delivery. The differences in circadian rhythm-adjusted mean between complicated and uncomplicated pregnancies are highly statistically significant in all trimesters (always P<.001). This study confirms and extends to ambulatory everyday life conditions the predictable circadian variability in blood pressure during gestation. The differences in blood pressure between healthy and complicated pregnancies can be observed as early as the first trimester of pregnancy. Those differences are found when both systolic and diastolic blood pressures for women with a later diagnosis of gestational hypertension or preeclampsia are well within the accepted normal physiological range of blood pressure variability.

Nocturnal rise of leptin in normal prepubertal and pubertal children and in patients with perinatal stalk-transection syndrome.

We studied 24-h profiles of circulating leptin levels using a sensitive and specific radioimmunoassay in healthy pre- (Tanner 1) and pubertal boys and girls (Tanner 3-4) as well as in a group of patients with perinatal stalk-transection syndrome. Similar nyctohemeral rhythm in serum leptin levels were found in prepubertal (MESOR: 2.34 +/- 0.2 ng/ml; amplitude 0.32 +/- 0.1 ng/ml) and pubertal boys (MESOR 2.2 +/- 0.2 ng/ml; amplitude 0.38 +/- 0.07 ng/ml). Likewise, no differences were found between prepubertal (MESOR 6.6 +/- 1.07 ng/ml; amplitude 1.67 +/- 0.4 ng/ml) and pubertal girls (MESOR 4.05 +/- 0.5 ng/ml; amplitude 0.95 +/- 0.2 ng/ml). In contrast, higher MESOR (p < 0.002) and amplitude values (p < 0.005) were found in prepubertal and pubertal girls than in prepubertal and pubertal boys. Finally a significant nyctohemeral rhythm in serum leptin levels was found in patients with perinatal stalk-transection syndrome (MESOR: 9.3 +/- 2.3 ng/ml; amplitude 1.46 +/- 0.4 ng/ml). This data shows the existence of sexual dimorphism in the nyctohemeral rhythm in serum leptin levels that are not influenced by the pubertal stage or by pulsatile anterior pituitary hormone secretion.

Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women.

This study investigated the effects of low-dose acetylsalicylic acid (aspirin) on blood pressure in pregnant women who were at risk of developing gestational hypertension or preeclampsia and who received aspirin at different times of the day according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 100 pregnant women. Blood pressure for each subject was automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery. Women were randomly assigned to one of six groups according to treatment (placebo, 50 subjects or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Results indicated that there was (1) no effect on blood pressure from placebo at any time (P>.212) and (2) a highly statistically significant (P<.001) time-dependent effect on blood pressure from aspirin. There was no effect of aspirin on blood pressure at time 1 (compared with placebo), but the blood pressure reduction was highly statistically significant after time 2 and, to a greater extent, after time 3 (mean reduction of 12 and 8 mm Hg in 24 hours for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). These time-dependent effects of aspirin on blood pressure should be taken into account for the optimization of long-term aspirin administration at low doses for prevention of preeclampsia. In any meta-analysis of aspirin effects, inquiries about the time when the subjects took the drug are indicated and may account for discrepancies in the literature.

Blood pressure variability during gestation in healthy and complicated pregnancies.

The evaluation of predictable variability in blood pressure by the use of ambulatory devices, and the proper processing of the time series thus obtained, can be useful for the early assessment of hypertensive complications in pregnancy. We have used this approach to quantify a predictable pattern of blood pressure and heart rate throughout pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia. We analyzed 503 blood pressure series from 71 healthy pregnant women and 256 series from 42 women who developed gestational hypertension or preeclampsia. Blood pressure monitoring (48-hour) was done once every 4 weeks after the first obstetric consultation. The pattern of variation along gestation of the 24-hour mean of blood pressure for groups of normotensive and hypertensive pregnant women was established by polynomial regression analysis. This method revealed predictable patterns of variation of 24-hour means with gestational age: for normotensive pregnant women, results indicate a steady decrease in blood pressure up to the 21st week of pregnancy, followed by an increase in blood pressure up to the day of delivery. This pattern of variation is not found in pregnancies complicated with gestational hypertension or even preeclampsia: the 24-hour mean of blood pressure is stable until the 22nd week of pregnancy and then correlated with gestational age, indicating a significant linear increase of blood pressure in the second half of pregnancy. For both healthy and complicated pregnancies, heart rate slightly increases until the end of the second trimester, and it is stable thereafter. This study confirms and extends to ambulatory everyday life conditions the predictable pregnancy-associated variability in blood pressure. The differences between uncomplicated and complicated pregnancies offer new end points for an early identification of gestational hypertension and preeclampsia.

Blood pressure patterns in normal pregnancy, gestational hypertension, and preeclampsia.

With the aim to describe the daily pattern of blood pressure during the trimesters of pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia, we analyzed 1494 blood pressure series systematically sampled by ambulatory monitoring for 48 hours every 4 weeks after the first obstetric visit in 124 women with uncomplicated pregnancies, 55 with gestational hypertension, and 23 with a final diagnosis of preeclampsia. The circadian pattern of blood pressure variation for each group and trimester of gestation was established by population multiple-component analysis. A highly statistically significant circadian pattern represented by a linear model that includes components with periods of 24 and 12 hours is demonstrated for systolic and diastolic blood pressure for all groups of pregnant women in all trimesters (P:<0.001 in all cases). The differences in circadian rhythm-adjusted mean between complicated and uncomplicated pregnancies are highly statistically significant in all trimesters (always P:<0.001). There is also a statistically significant difference in circadian amplitude (extent of daily change) of blood pressure between healthy and complicated pregnancies in all trimesters (always P:<0.004). Results further indicate similar circadian characteristics between women who later developed gestational hypertension or preeclampsia in the first trimester of pregnancy. The difference between these 2 groups in circadian mean is statistically significant in the second trimester for systolic (P:=0.022) but not for diastolic blood pressure (P:=0.986). In the third trimester, the difference in circadian mean is highly statistically significant for both variables (P:<0.001). The differences in blood pressure between healthy and complicated pregnancies can be observed as early as in the first trimester of pregnancy. Those highly significant differences are found when both systolic and diastolic blood pressure for women with a later diagnosis of gestational hypertension or preeclampsia are well within the accepted normal physiological range of blood pressure variability. These differing changes in the circadian pattern of blood pressure with advancing gestational age between healthy and complicated pregnancies offer new end points that may lead to an early identification of hypertensive complications in pregnancy as well as to the establishment of prophylactic intervention.

Blood pressure excess for the early identification of gestational hypertension and preeclampsia.

We have examined prospectively whether the combined approach of establishing tolerance intervals for the circadian variability of blood pressure (BP) as a function of gestational age, and then determining the so-called hyperbaric index (area of BP excess above the upper limit of the tolerance interval) by comparison of any patient's BP profile (obtained by ambulatory monitoring) with those intervals provides a high sensitivity test for the early detection of pregnant women who subsequently will develop gestational hypertension or preeclampsia. We analyzed 657 BP series from 92 women with uncomplicated pregnancies and 378 series from 60 women who developed gestational hypertension or preeclampsia. BP was sampled for about 48 hours once every 4 weeks after the first obstetric consultation. Circadian 90% tolerance limits were determined as a function of trimester of gestation from 497 series previously sampled from a reference group of 189 normotensive pregnant women. The hyperbaric index was then determined for each individual BP series in the validation sample. Sensitivity of this test for diagnosing gestational hypertension was 93% for women sampled during the first trimester of gestation and increased up to 99% in the third trimester. The positive and negative predictive values were above 96% in all trimesters. Despite the limitations of ambulatory monitoring, the approach presented here, now validated prospectively, represents a reproducible, noninvasive, and high sensitivity test for the very early identification of subsequent gestational hypertension and preeclampsia, on the average, 23 weeks before the clinical confirmation of the disease.

Administration time-dependent effects of aspirin in women at differing risk for preeclampsia.

This study extends previous results on the effects of low-dose aspirin on blood pressure in pregnant women at differing risk of developing hypertension in pregnancy and who received aspirin at different times according to their rest-activity cycle. A double-blind, randomized, placebo-controlled trial was conducted in 240 pregnant women randomly assigned to 1 of 6 groups according to treatment (placebo or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Blood pressure and heart rate for each subject were automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery, as well as at puerperium (6 to 8 weeks after delivery). Subjects were further divided for comparative purposes according to the results of the tolerance-hyperbaric test for early identification of those with a higher risk for developing hypertensive complications in pregnancy. Results indicated that there was no effect of aspirin on blood pressure at time 1 (compared with placebo). A blood pressure reduction was, however, highly statistically significant at time 2 and, to a greater extent, at time 3 (mean reductions of 14.2 and 9.6 mm Hg in 24-hour means for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). Effects of aspirin on blood pressure were significantly larger for women with a positive test at the time of recruitment (P<0.001). Differences in blood pressure among pregnant women receiving aspirin at different times in the circadian cycle disappeared at puerperium (P>0.212). There was no effect of aspirin or placebo on heart rate. This study corroborates the statistically significant, time-dependent effect of low-dose aspirin on blood pressure in pregnant women with differing risk of developing hypertensive complications in pregnancy. Although the mechanism involved in the administration-time-dependent responsiveness of blood pressure to aspirin still remains uncertain, the use of doses of aspirin <80 mg/d that do not affect placental thromboxane, initiation of the use of aspirin after 16 weeks' gestation, and the lack of circadian timing for aspirin administration could all explain the lack of positive results in previous clinical trials.

Circadian interleukin-6 secretion and quantity and depth of sleep.

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the post-deprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime under-secretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep.

Circadian rhythm of serum total homocysteine in men.

Serum homocysteine levels were examined in a 24-hour study of 7 healthy and 5 diabetic men, revealing a statistically significant circadian rhythm (p = 0.030), normal concentrations of 11.83 +/- 1.2 vs 12.99 +/- 1.2 micromol/L, with peak values occurring during the evening (10:37 P.M.) and lowest levels occurring during the morning. These findings imply that increased atherosclerotic risk in insulin-resistant diabetics during morning hours does not appear to be explained by differences in homocysteine levels in the normal population.

Ultradian rhythms in gross motor activity of adult humans.

During waking h, the existence of ultradian rhythms in gross motor activity has been described in nonprimates, nonhuman primates and newborn humans, but not in adult humans. Some of the previous studies suggested that the appearance of these rhythms could be favored by conditions of isolation and low environmental demands. To confirm the existence of ultradian rhythmicity in the gross motor activity of adult humans and to describe their characteristics, an actimeter was used to record the mobility of 13 adults who remained alone and isolated for 5 h (15:00-20:00) in a monotonous environment with nothing to do. Least squares rhythmometry analysis showed that the gross motor activity of 12 out of 13 subjects had significant rhythms (p < 0.05) within the ultradian band, with periods of between 0.5 and 2.5 h. There were important individual differences between the dominant periods and the same subject might show more than one significant period. These rhythms were stable and they tended to appear immediately the experiment began. The results suggest that a philogenetically old mechanism that organizes gross motor activity in ultradian rhythms exists in adult humans.

Reproducible and predictable yearly pattern in the incidence of uterine cervical cancer.

A yearly pattern in the occurrence of uterine cervical cancer (UCC), obtained from cytological examinations reported as type V (cases concluding a malignant alteration), has been previously shown for data obtained in the Monterrey Metropolitan Area (state of Nuevo Leon, Mexico) for a span of 10 years (1978-1987), with a peak of relative incidence in the month of February being high stable for consecutive years. With the aim of extending and validating those results, we analyzed the monthly totals of positive detected cases of UCC in the states of Nuevo Leon, Chihuahua, Coahuila, and Tamaulipas (covering most of Northern Mexico) during the same period. To eliminate bias due to the seasonal variation in the number of screening smears, data were first expressed in relation to the number of cytological examinations done the same month. The least-squares fit of a 1-year cosine curve to the data of relative incidence in the four states reveals a statistically significant yearly pattern (p = .008), with a maximum of relative incidence in February almost double that during the rest of the year. Results indicate that the relative incidence of UCC is higher than the yearly average during the winter, with secondary peaks in May and October. In view of the nonsinusoidal waveform in the incidence of UCC, we undertook a multiple-component analysis, allowing several cosine functions to be simultaneously fitted to the data. Results indicate that the yearly pattern in the relative incidence of UCC can be represented by a model that includes two components with periods of 12 and 4 months (p = .004). The same model can be documented as statistically significant independently for each of the four states. These results, summarizing over 2200 positive cases of UCC detected in more than 1,100,000 screening smears, are in full agreement with those found previously for part of the state of Nuevo Leon and reveal a highly stable and predictable yearly pattern of variation in the relative incidence of UCC in Northern Mexico.

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.

Circadian time structure of cardiovascular characteristics in human pregnancy.

Conventional time-unspecified single measurements of blood pressure and heart rate may be misleading because they may be influenced, among other factors, by the patient's emotional state, position, diet, and external stimuli. All of these effects depend on the stages of a (mathematical) spectrum of rhythms and trends with age. The evaluation of predictable variability in blood pressure and heart rate by (a) the use of fully ambulatory devices, and (b) chronobiologic data processing, assesses early cardiovascular disease risk, e.g., in pregnancy. We have used this approach to quantify changes in 24-h synchronized (circadian) characteristics of cardiovascular variables in two consecutive pregnancies of a clinically healthy woman. Blood pressure and heart rate were automatically monitored, with few interruptions, at 1-h intervals, each time for at least 48 consecutive h, and for a total of 76 days of monitoring in each pregnancy. Circadian parameters of those circulatory variables were computed for each single day of measurement by the least-squares fit of a 24-h cosine curve. Regression analysis of parameters thus obtained revealed patterns of variation of circadian-rhythm-adjusted means and amplitudes with gestational age. In both pregnancies, the predictable variability of the circadian-rhythm-adjusted mean of blood pressure can be approximated by a second-order polynomial model on gestational age: a steady linear decrease in systolic, diastolic, and mean arterial blood pressure up to the 22nd week of pregnancy is followed by an increase in blood pressure up to the day of delivery. This longitudinal study confirms and extends to ambulatory everyday life conditions the predictable pregnancy-associated variability in blood pressure and heart rate and also allows the establishment of prediction and confidence limits for cardiovascular parameters in a healthy pregnancy.

Inferential statistical method for analysis of nonsinusoidal hybrid time series with unequidistant observations.

Most variables of interest in laboratory medicine show predictable changes with several frequencies in the span of time investigated. The waveform of such nonsinusoidal rhythms can be well described by the use of multiple components rhythmometry, a method that allows fitting a linear model with several cosine functions. The method, originally described for analysis of longitudinal time series, is here extended to allow analysis of hybrid data (time series sampled from a group of subjects, each represented by an individual series). Given k individual series, we can fit the same linear model with m different frequencies (harmonics or not from one fundamental period) to each series. This fit will provide estimations for 2m + 1 parameters, namely, the amplitude and acrophase of each component, as well as the rhythm-adjusted mean. Assuming that the set of parameters obtained for each individual is a random sample from a multivariate normal population, the corresponding population parameter estimates can be based on the means of estimates obtained from individuals in the sample. Their confidence intervals depend on the variability among individual parameter estimates. The variance-covariance matrix can then be estimated on the basis of the sample covariances. Confidence intervals for the rhythm-adjusted mean, as well as for the amplitude-acrophase pair, of each component can then be computed using the estimated covariance matrix. The p-values for testing the zero-amplitude assumption for each component, as well as for the global model, can finally be derived using those confidence intervals and the t and F distributions. The method, validated by a simulation study and illustrated by an example of modeling the circadian variation of heart rate, represents a new step in the development of statistical procedures in chronobiology.