Standardisation of minimal erythematous dose reading and assessment: a new system.

BACKGROUND/PURPOSE: Sunscreen efficacy is usually expressed by the sun protection factor (SPF) which is calculated by establishing the minimum erythematous dose (MED), i.e. the smallest amount of energy required to trigger erythema. Efforts have been made to harmonise SPF testing but in vivo SPF methodology could still be improved to reduce its variability. This article proposes a means of standardising MED evaluations through the development and validation of an MED assessment system based on image analysis. METHODS: The MED assessment system comprises a camera combined with a black tube for acquiring pictures of the skin surface. Specific software was then developed to analyse these pictures to determine the MED based on the shape, size and colour of the exposed zones. The MED assessment system was validated through two studies. The first study was designed to assess the correlation between three expert graders who visually determined the MEDs in five subjects on whom three different suncare products (SPF 6, SPF 30 and SPF 50+) were tested. The second study correlated results obtained from one expert grader with those from a grader assisted by the new MED assessment system. RESULTS: Results of the first study showed substantial variation between graders, with kappa agreement as low as 0.59 (percentage error 19.7%). Results of the study assessing correlation between the expert grader and the grader facilitated by the new MED assessment device showed better correlation, with a kappa value of 0.75 and percentage error of 9.61%. CONCLUSION: A high degree of inter-grader variability was seen when MED was assessed by expert graders. The new MED assessment system provides background colour correction and standardisation to enable accurate MED determination. A high level of correlation was seen between the expert grader and the new MED assessment system, thus demonstrating its potential utility in more accurate and homogenous MED evaluations. Future multicentre studies are required to improve and validate the standardised MED determination for suncare products and to further evaluate the role of this new MED assessment system. However, these preliminary results are encouraging and may set the scene for this new MED assessment system to become the standard of the future.

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.

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.

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.

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.

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.

Chronolab: an interactive software package for chronobiologic time series analysis written for the Macintosh computer.

Methods based on periodic regression have been designed for the detection of periodic components in short, noisy, and nonequidistant time series (as they are usually present in medicine and biology). The procedure consists of fitting a set of (cosine) curves to the data, with the analyst choosing the domain of trial periods to be analyzed and the distance between consecutive trial periods. We here describe an interactive program for least-squares rhythmometry written in C language for the Macintosh computer. For any given number of time series to be analyzed at once, the program is able to perform two different kinds of analyses: (a) linear in time, for the sequential fit of trial periods; and (b) linear in frequency, for the sequential fit of harmonic components from an initial fundamental period. For each series and for each trial period fitted to the data, the program gives the following information: fitted period; percent rhythm; p value from testing the assumption of zero amplitude; rhythm-adjusted mean or mesor, amplitude, and acrophase, each with corresponding standard errors and 95% confidence intervals when the component is statistically significant; and (when required by the analyst) p values from tests of sinusoidality, normality of residuals, and homogeneity of variance. Additionally, the program provides a summary report for each time series analyzed, including descriptive statistics such as the number of data analyzed for that series, minimum, maximum, arithmetic mean, standard deviation, standard error, 90% range, and 50% range. The analyst is also able to transform the data before doing any rhythmometric analysis. Transformations already integrated in the program include square root, logarithm, inverse, data as percentage of mean, data as percentage of mesor, and elimination of values outside +/- 3 SD from the mean. When several periods are suspected to be statistically significant, a multiple-component analysis can be also used by the concomitant least-squares fit of several harmonics. The program allows the simultaneous analysis of several periods in several variables from several individuals, with limitations depending solely on internal memory availability and speed requirements from the user. When series from different subjects or different variables in the same subject are available for analysis, a parameter test also included in the program can be used for comparison of rhythm characteristics at any given period. All information required in a single analysis is given by the analyst in the form of self-explanatory commands grouped in different "menus."(ABSTRACT TRUNCATED AT 400 WORDS)

Circadian rhythm of double (rate-pressure) product in healthy normotensive young subjects.

The double product (DP), systolic blood pressure multiplied by heart rate, is a surrogate measure of myocardial oxygen demand and cardiac workload used increasingly today in medicine. The double product is more strongly correlated with left ventricular mass than the daily blood pressure mean. The purpose of this study was to describe the normative circadian pattern of the double product in healthy normotensive young adults. We studied 125 men and 75 women, 23.0+/-3.3 (mean +/- SD) years of age, without medical history of hypertension and 24h ambulatory systolic/diastolic blood pressure mean consistently below 135/85 mm Hg. Subjects underwent ambulatory blood pressure monitoring at 30-minute intervals for 48 consecutive hours once each season of the year, yielding 930 protocol-correct blood pressure and heart rate time series. Subjects maintained their usual routine of diurnal activity and nocturnal sleep and avoided use of over-the-counter and other medication. Circadian rhythmicity in the double product was established by population multiple-component analysis. The double product rose rapidly from the lowest value, attained 3h before awaking from sleep at night, to a markedly elevated level at the commencement of morning activity. The double product was highest in the afternoon, roughly 7h after the commencement of diurnal activity. In both men and women, the shape of the high-amplitude circadian rhythm in the double product was best described by a complex model composed of three cosine curves having periods of 24h, 12h, and 6h. The 24h mean in the double product of 8092.51+/-42.76 (mean +/- SD) in men was significantly lower than that of 8353.17+/-37.48 in women (P < .001). The circadian double amplitude of the rhythm was statistically significantly greater (P < .001) in men (50% of the 24h mean) than women (44% of the 24h mean). The double product did not differ between seasons in women, but it did in men (P = .017) due to reduced heart rate in summer. The circadian pattern of large amplitude in the double product and its gender differences must be taken into account when using this variable to assess cardiac workload, risk of left ventricular hypertrophy, and efficiency of antihypertensive therapy.

Influence of aspirin usage on blood pressure: dose and administration-time dependencies.

This study investigates the possible effects of acetylsalicylic acid (ASA; aspirin) on systolic (S) and diastolic (D) blood pressure (BP) in healthy and mildly hypertensive subjects receiving ASA at different times according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 73 healthy young adult volunteers and 18 previously untreated subjects with mild hypertension. The BP of each subject was automatically monitored every 30 minutes for 48h before the trial and at the end of a one-week course of placebo and a one-week course of ASA. Healthy volunteers were randomly assigned to one of six groups, defined according to the dose of ASA (either 500 mg/day, the usual commercial dose; or 100 mg/day) and timing of ASA and placebo (within 2h after awakening, Time 1; 7h to 9h after awakening, Time 2; or within 2h of bedtime, Time 3). Subjects with mild hypertension received the low dose of 100 mg/day ASA, as well as one week of placebo, and were randomly assigned to one of the same three groups defined above according to the time of treatment. A small (approximately 2 mmHg in the 24h mean of SBP), but statistically significant, BP reduction was found when 500 mg/day ASA was given to healthy volunteers at Time 2. With 100 mg/day, the effect of ASA in healthy subjects was comparable to the BP reduction found with the higher dose for Time 2; there was again no effect on BP at Time 1, but we found a statistically significant effect at Time 3 (2.3 mmHg reduction in the 24h mean of SBP), larger than for Time 2. For hypertensive patients, the BP reduction was again statistically significant for Time 2 and, to a greater extent, for Time 3 (approximately 4.5 mmHg for both SBP and DBP); all patients in these two groups showed a BP reduction after one week of ASA. The effect was about three times as large as the BP reduction obtained in healthy subjects treated with 100 mg/day ASA. Results indicate a statistically significant time- and dose-dependent effect of ASA on BP. In any meta-analysis of ASA effects, inquiries about the time when subjects took the drug are indicated and may account for discrepancies in the literature. Moreover, the influence of ASA on BP demonstrated here indicates the need to identify and control for ASA effects in patients using ASA before and during their participation in antihypertension medication trials.

Reanalysis of filter-feeding behavior of caddis fly (Brachycentrus) larvae reveals masking and circadian rhythmicity.

Data published on the subjectively determined presence or absence of circadian periodicity in feeding of Brachycentrus occidentalis Banks, an aquatic insect belonging to the order Trichoptera, were reanalyzed by statistical methods based on the cosine model. The 4h data for 5 days of synchronized environmental conditions followed by 5 days of constant conditions (using original values and purified values after removal of an 8h component attributed to the feeding schedule) were quantified for rhythm characteristics by the least-squares fit of cosines. A circadian rhythm was highly significant during synchronized conditions (light-dark and cycling water temperature) and in continuous light when water temperature continued to cycle. A circadian rhythm in the percentage of larvae feeding during continuous light and constant water temperature, which had not been observed by visual inspection in the original data, was detected in the unmasked data with a "free-running" period not overlapping 24.0h (95% confidence limits from 18.95h to 21.66h). Effects of masking brought about by manually feeding the larvae every 8h were statistically significant under both synchronized and constant environmental conditions.

Neonatal cardiovascular dynamics in relation to matroclinous and patroclinous history of high blood pressure.

Genetic risk is a primary contributing factor to the predisposition of a newborn child to elevated blood pressure later in life. An index of this factor is needed to assess in the neonate the success or failure of preventive interventions instituted for the pregnant women. This index could be based on characteristics of blood pressure and heart rate variability measured during the first 2 days after birth. In the search for such an index, the systolic and diastolic blood pressures and heart rates of 127 newborn babies were automatically monitored at about 30-min intervals for 48 h with a Nippon Colin device, starting early after birth. Circadian parameters (obtained by the linear least-squares fit of a 24-h cosine curve to each individual series) and descriptive statistics for the three circulatory variables were used in a multiple regression analysis to compute a linear prediction function for the cardiovascular risk score. This score was obtained for each neonate on the basis of the presence or absence of overt cardiovascular disease, elevated blood pressure, or obesity across two generations, those of the newborn's parents and grandparents. Results from regression indicate that the best model includes the circadian amplitudes of systolic and diastolic blood pressure and the circadian ranges of systolic blood pressure and heart rate. The contributions from patroclinous versus matroclinous family history were then compared. Results show that linear prediction models include the same variables for both paternal and maternal cardiovascular risk score. These results provide a neonatal index of cardiovascular risk, to be used later for the evaluation of the effects on the newborn of intervention for the pregnant women.

Time-specified reference limits for ambulatorily monitored blood pressure in clinical health.

For the study of blood pressure, the use of automatic fully ambulatory recording systems greatly facilitates data collection and, in combination with proper software, the interpretation of results. Hardware for automatic long-term measurement is here wedded to a set of software modules to assess the circadian variability of human blood pressure. To evaluate changes in blood pressure within a day, the authors analyzed 150 series of systolic and diastolic blood pressures and heart rates automatically monitored every 30 minutes for at least 48 hours. Subjects were clinically healthy men and women 19-23 years of age. Individual circadian-rhythm parameters computed for each time series by least-squares rhythmometry were used to assess rhythm characteristics of all subjects and for each gender separately. Those individual parameters were also used for the computation of a so-called paradesm, a (here 90%) time-specified prediction region for the amplitude-acrophase pair. The limits thus obtained for the circadian amplitude (an index of within-day variability) of blood pressure were exceeded in cases of amplitude-hypertension. Additionally, the original data were used to compute time-specified prediction limits for blood pressure and heart rate in clinical health. Such reference limits may serve for an objective and positive definition of health, for the screening and diagnosis of disease, and for gauging a subject's response to treatment. The combined hardware-software method for the establishment of time-qualified reference limits presented allows the assessment of the extent and timing of rhythmic change and can be used for the interpretation of single values obtained at specified times.

Computer-based medical system for the computation of blood pressure excess in the diagnosis of hypertension.

A computer-based system for assessing hypertension was designed by combining hardware for automatic, long-term blood pressure (BP) measurement with a set of software modules for computing time-specified tolerance intervals and evaluating measures of BP excess. BP is so variable that the identification and proper definition of hypertension are highly ambiguous when based on single measurements. One first step in dealing with such variability is to replace the constant limits for BP frequently used in the assessment of hypertension by a time-specified reference interval. Once such a threshold is available, a hyperbaric index can be computed by numerical integration as the total area (within one cycle) of any given patient's BP above the threshold. In order to examine the extent of normal physiologic excess, a series of 266 systolic and diastolic BP and heart rate (HR) measurements were automatically monitored every 30 minutes for at least 48 hours from clinically healthy subjects, aged 19 to 25 years. Original data were used to obtain 90% tolerance intervals for each gender separately. The hyperbaric index was then computed for each individual BP profile. The distribution of the maximum hyperbaric index (maximum of the values computed for systolic, mean arterial, and diastolic BP levels shows a highest value of 14.839 mmHg x hr for the men and of 10.229 mmHg x hr for the women. These values represent a testable threshold for assessing hypertension based on the proposed approach. The tolerance intervals obtained from the reference population were also used to compute hyperbaric indices for a series of 175 BP measurements sampled from clinically healthy people, as well as a series of 60 measurements sampled from patients with mild hypertension. Sensitivity and specificity in the diagnosis of hypertension based on the hyperbaric index were both 100%, as opposed to values obtained from computing the BP load, the average of the BP series, or the circadian amplitude, all of which provided a much poorer diagnostic test. The software system developed for automatically establishing time-qualified tolerance limits from a reference population and assessing the extent and timing of BP elevation for a test subject may help to establish a prognosis and diagnosis, with a correspondingly better assessment of health status, to initiate treatment if needed, to time treatment when it is most desirable and least harmful in terms of undesired effects, and to gauge the patient's response to treatment.

Sleep-time ambulatory blood pressure as a novel therapeutic target for cardiovascular risk reduction.

Diagnosis of hypertension and clinical decisions regarding its treatment are typically based upon daytime clinic blood pressure (BP) measurements, occasionally supplemented by wake-time patient self-assessment. Yet, correlation between BP level and target organ damage, cardiovascular disease (CVD) risk, and long-term prognosis is higher for ambulatory BP monitoring (ABPM) measurements. Numerous studies consistently reveal CVD events are better predicted by the asleep than awake or 24 h BP means. In addition, when the asleep BP mean is adjusted by the awake mean, only the former is a significant independent predictor of outcome. Endogenous circadian rhythms explain statistically and clinically significant ingestion time differences in efficacy, duration of action, safety and/or effects on the daily BP pattern of most hypertension medications and their combinations. Bedtime versus morning-time ingestion of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, independent of drug terminal half-life, both better reduces asleep BP and normalizes the daily BP profile into a more normal dipper pattern. The recently completed prospective outcome MAPEC Study verifies therapeutic restoration of the normal sleep-time BP decline, a novel therapeutic goal most effectively achieved by ingestion of the entire daily dose of ⩾ 1 conventional hypertension medications at bedtime, best decreases CVD morbidity and mortality. Our findings indicate around-the-clock ABPM is a clinical necessity to accurately detect abnormal sleep-time BP and assess CVD risk, and that hypertension ought to be managed by a bedtime therapeutic strategy, preferably one including medication that antagonizes the activities and actions of the renin-angiotensin-aldosterone system.

Chronobiological analysis techniques. Application to blood pressure.

Most variables of clinical interest show predictable changes with different frequencies, mainly, but not exclusively, along the rest-activity cycle (circadian variation). Methods of linear least-squares estimation have been designed for the detection of periodic components in sparse and noisy time series (as they are usually present in clinical situations). They include the single and population-mean cosinor methods. In cases where more than one period is statistically significant over the span of time investigated, or when the waveform is non-sinusoidal, the use of multiple components analysis to fit a model consisting of several cosine functions (harmonics or not from a given fundamental period) is recommended. We describe these methods, from the characterization of the underlying models to the process of parameter estimation. As an application example, we describe the modelling of the circadian variation of blood pressure (BP). In most individuals, BP presents a morning increase, a small postprandial valley and a deeper descent during nocturnal rest. This pattern can be easily modelled by means of a model with periods of 24 and 12 hours. Individuals that differ from this model might be considered to present increased cardiovascular risk.

High sensitivity test for the early diagnosis of gestational hypertension and preeclampsia. III. Computation of time-specified tolerance intervals as reference for blood pressure excess in the diagnosis of gestational hypertension.

According to classic embryological testbooks intervillous circulation is established early in the first trimester. This process starts with trophoblastic invasion of the decidua in which proteolytic enzymes facilitate the penetration and erosion of the adjacent maternal capillaries with formation of the lacunae. After the lacunar or previllous stage trophoblast invades deeper portions of endometrium with belonging spiral arteries. This gradual process finishes with direct opening of the spiral arteries in the intervillous space under the fully developed placenta. This classic concept of establishment of the intervillous circulation was challenged in 1987 and 1988 by the experiments of Hustin and Shaaps. The authors believed that blood flow in the intervillous space is absent in incompletely development before 12 weeks of gestation. After the introduction of the generation of far more sensitive color Doppler devices in the last few years, our group and several others reported a positive finding of intervillous circulation during the first trimester of pregnancy.