Cugini's syndrome in statu nascendi. Oratio contra morem prevalentem et pro chronobiologica ratione ad pressione sanguinis curandam. A plea against the prevailing custom and in favor of a chronobiological approach to treating blood pressure.

An increase in the circadian amplitude (A) of blood pressure (BP) had been reported to precede a rise in the circadian BP average (MESOR, M), as pre-hypertension in the stroke-prone Okamoto rat. In humans, children with a positive family history of high BP and/or related cardiovascular disease had, on average, a larger BP-A than children with a negative family history, and an elevated BP-A was associated with intermediate values of the left ventricular mass index (LVMI), whereas an elevation in BP-M was only observed for larger LVMI values. Against this background, with 24-hour ambulatory monitoring (ABPM) interpreted chronobiologically, Pietro Cugini (University La Sapienza of Rome, Italy) has reported an elevation of both the circadian BP-M and BP-A as occurring with a minimal change (hypertensive) retinopathy. He determined by cosinor the extent of predictable BP change within a day as BP-2A, estimated by the least squares fit of a 24-hour cosine curve to the data. As compared to controls without retinopathy, he found a retinal end-organ involvement associated with average systolic (S) / diastolic (D) BP-Ms of 124/76 vs. 112/72 mmHg, with corresponding SBP/DBP-As of 12/10 vs. 8/7 mmHg. We refer to "Cugini's syndrome", suggesting the need for clarification, preferably in longitudinal studies, of any generalizable sequence in end-organ involvement, that may occur in the course of the development of some human Vascular Variability Disorders (VVDs) of unknown etiology, that include an elevation of the circadian BP-A and/or BP-M, concomitantly or separately in a sequence with the BP-A increase preceding that in BP-M, as in models of high BP in the rat or vice versa. Seven-day half-hourly or hourly around-the-clock monitoring of BP and HR variability interpreted chronobiologically, C-ABPM, as a minimum, is recommended for routine medical care to detect VVDs consisting of 1. MESOR-hypertension, MH; 2. Circadian Hyper-Amplitude-Tension, CHAT (BP overswing); 3. odd timing of the circadian rhythm of BP but not that of HR; 4. above-threshold pulse pressure; and/or 5. below-threshold HR variability. All conditions are best determined by 24-hour/7-day or, when abnormality is detected, longer C-ABPM. Eventually, all conditions will need to be assessed in the light of reference values from gender- and age-matched peers, as is now the case for the fi rst three VVDs listed above. When C-ABPM is not practicable, a 7-day series of 3-hourly manual self-measurements during waking (and one measurement about mid-sleep) (C-MBPM) is recommended. When continuous monitoring becomes possible, as it is within the state of the science, detecting Cugini's syndrome will also become possible with the clarification as to whether any change in BP-M and/or BP-A occurs concomitantly or sequentially, with changes in BP-A anticipated to precede changes in BP-M.

Chronomics.

Several international meetings have revealed an accumulating body of reference values for well-established about-daily and about-yearly rhythms of photic origin and evidence also for about-7-day, -27-day, -half-yearly, -10.5- and -21-yearly, and even -50-yearly rhythmicities in us as well as around us, as invisible non-photic heliogeophysical signatures possibly built into individuals and/or populations, complementing the biological year and day. In time series (biological or other) that are dense and sufficiently long, the characteristics of rhythms, chaos (deterministic and other) and trends can all be quantified as elements of structures called chronomes. Chronobiological methodology assesses uncertainties in comparisons of endpoints in all elements of chronomes, before and after: 1) changes in lifestyle, such as meal quality, quantity, timing and salting of the food; 2) preventive non-drug interventions to limit the risk of vascular disease; or 3) drug treatments for high-risk subjects as well as for those with actual vascular disease, all on a practicable, individualized and also a general population basis. A collateral hierarchy characterizes molecular to psychosocial aspects of living beings that are exposed to their socio-ecological environs and thus are synchronizable and/or otherwise manipulable by society, meals, lighting, heating, and non-photic, non-thermic environmental variations that become predictable to the extent that they appear to constitute cycles, yet adhere only to a statistical, rather than a deterministic causality. With this qualification, chronome mapping with outcomes could eventually serve an individualized optimization of lifestyle, for chronoprevention and chronotherapy as well as for inquiries into the evolution and future of life, a budding chronoastrobiology, in keeping with the original title of the conference.

Safe handling of agricultural pesticides in Minnesota: results of a county-wide educational intervention.

Safe pesticide handling in a group of Minnesota farmers, aged 40 years and older, was influenced through the use of a multifaceted, countywide educational intervention. Two intervention counties and two control counties were involved in this effort. The intervention consisted of mailed pesticide information to farm households, educational programs on pesticides for county physicians, elementary school training modules on pesticides and the use of safe pesticide handling displays in key business areas by agricultural extension agents. Five hundred eight farmers were identified as pesticide users (186 in the intervention counties and 322 in the control counties). The use of gloves and other protective clothing while handling pesticides increased in the intervention group. Improvement was greater in those who had used protective equipment the least before the intervention. From these results, it appears that a broad-based educational intervention might have a modest impact in how farmers protect themselves when using pesticides.

Mammogram utilization among farm women.

Utilization of preventive health care services is lower in rural populations than in urban populations, possibly as a result of barriers to preventive health care that are characteristic of rural settings. This study was conducted to identify factors associated with mammogram utilization among farm women. Mammogram utilization among farm women from six southern Minnesota counties was examined as part of a larger community-based cancer intervention study. Farm women aged 40 and older were randomly selected from a list of farm households and interviewed by telephone to determine mammogram utilization and factors related to utilization. Of the 606 respondents, 78 percent reported ever having a mammogram and 49 percent reported a mammogram within the past year. Physician recommendation for a screening mammogram and family history of breast cancer were found to be associated with ever having a mammogram. Correct knowledge of mammogram screening guidelines was associated with a mammogram within the past 12 months. Overall, physician recommendation was the most influential determinant of utilization. As more emphasis is placed on prevention, patient education by physicians can have the greatest impact on mammogram utilization.

Factors associated with safe use of agricultural pesticides in Minnesota.

How farmers protect themselves against pesticide exposure has important public health consequences. To obtain insights into pesticide self-protection, this study obtained data on chemically resistant glove and other protective equipment use as they relate to the type of farming practice, demographic characteristics of farmers and their farming operations, farmers' preventive health beliefs and behaviors, and factors related to their health care. Data were obtained by telephone interviews conducted in six rural Minnesota counties. Survey respondents totaled 1, 327 (87% response rate), with 502 reporting pesticide use. Ninety-five percent of the latter respondents believed in the effectiveness of protective equipment and 88 percent believed that pesticide exposures are harmful. Fifty-six percent of the subjects wore chemically resistant gloves and 22 percent wore other protective clothing 75 percent of the time or more when using pesticides. Glove use and certification to use restricted pesticides was less frequent for women. The use of protective equipment in this group of Minnesota farmers was weakly related to being certified to apply restricted pesticides, believing in the effectiveness of protective clothing, believing that smoking causes serious health problems, using crop insecticides, and distance to a health care facility.

Spectral differences between epitopes in the cronomes of salivary CA130 and CA125.

Ovarian tumor markers CA125 and CA130 are here investigated in the search for harbingers of an elevated cancer risk or pre-cancer. A circadian rhythm of large amplitude is demonstrated for salivary CA125 and CA130 of a clinically healthy 28-year-old woman (AP). The circadian rhythms of both markers found in AP have a pattern similar to that of a patient (EH) with a müllerian cancer involving the ovary, with high values in the early morning and low values in the afternoon. Whereas acrophases occur approximately at the same circadian stage in both AP and EH, the MESOR and circadian amplitude are higher in EH as compared to AP. The circadian rhythm of salivary CA130 of AP is similar to that of other clinically healthy women. CA130 concentrations are lower than CA125 concentrations in unstimulated saliva (before rinsing of the mouth) in this clinically healthy woman (AP), and in other women studied herein. This difference between CA130 and CA125 concentrations is observed irrespective of circadian stage and irrespective of the concentration range of CA125 at the outset. After rinsing of the mouth, a statistically significant decrease in both CA130 and CA125 concentration is observed in AP and in another healty woman (GC) who collected saliva both before and after rinsing of the mouth.

Metachronanalysis of circannual and circasemiannual characteristics of human suprachiasmatic vasopressin-containing neurons.

We here test for and detect anticipated about-yearly (circannual) changes in the volume and number of vasopressin-containing neurons in the human suprachiasmatic nucleus. We then resolve inferential statistical parameters quantifying the extent and timing (the amplitude and acrophase) of the circannual rhythm previously missed by data inspection and classical biometry. We parametrize about-half-yearly changes previously validated by non-parametric statistical tests. New dynamic circannual and circasemiannual endpoints thus become available for basic investigation and the assessment of disease risk elevation and/or chronoprotopathology. It was earlier demonstrated that the circannual rhythms of prolactin and TSH are prominent classifiers of individuals at high versus low familial and other risk for developing breast or prostate cancer. Any neurocrine or neural mechanisms contributing to this classification are now amenable to study, on a population basis, with the dynamic hypothalamic rhythm characteristics yielded by this metachronanalysis.

Chronobiology: a frontier in biology and medicine.

On the occasion of Franz Halberg's 70th birthday, some of his many achievements are reviewed. We provide a historical background to the development of chronobiology; offer insight into the current state of this new science; and sketch the promise of this discipline for health care and cure. As a tribute to Franz Halberg, in an era of fast-growing technology, an attempt is made to describe his perspective of tomorrow's medicine and biology. The many students he trained throughout his productive career face the challenge of deserving the trust he placed in them and of further implementing his vision. A leader in social pediatrics put it aptly: it will take several generations of researchers to study and master his life's work.

Further steps toward a neonatal chronocardiology.

The study of 53 series of blood pressures at half-hour intervals from clinically healthy full-term newborns during the first days of life reveals various classifiers correlating with a history of high blood pressure: the circadian amplitude of diastolic blood pressure, the 50% range of systolic blood pressure and the standard deviation of heart rate.

Chronobiologic monitoring and analysis for anesthesiologists: another look at a chronoanesthetic index.

A circadian rhythm in anesthetic index is quantified by the single cosinor method in data published earlier. Although the double circadian amplitude, a measure of the extent of predictable change, is only 14%, the assumption of no rhythm (zero amplitude) is rejected at the 1% level of statistical significance. It seems likely that, in the absence of noise, the amplitude of the rhythmic change in the response to the anesthetic will be larger. The broader importance of chronobiology for anesthesiologists is also indicated. Hardware and software for the monitoring of a patient's vital signs before, during, and after surgery provide refined dynamic endpoints from the analysis of data series and lead to time-specified reference values that improve even the interpretation of time-specified single values.

Variability of human blood pressure with reference mostly to the non-chronobiologic literature.

The voluminous literature on the variability encountered in 24-h recordings of human blood pressure in health is here presented by reference to selected clinical articles. Most references are cited by number for the sake of brevity, with a few cited by author when this appears to be of particular interest. Reports of work on laboratory animals are included when the findings are directly pertinent as background to studies on human beings. Results from semiautomatic and automatic direct and indirect measurements are briefly reviewed and aligned with results from work in which blood pressure was self-measured or measured conventionally by staff. The considerable and not generally recognized range of human blood pressure variability is thus extracted from the literature. An apparently limited extent of variation is shown to result mostly from the averaging of data from individuals constituting the groups investigated. Once variation is overwhelmingly documented and recognized as a fact, the different ways in which variations are presented and utilized by different author-investigators gain in importance. In a number of studies, methods of time series analysis are used. Thus, major attention can be paid to the extent to which predictable changes, so-called rhythms, characterize the data. Circadian rhythms are found to be quite prominent. By the assessment of these rhythms and about-yearly (circannual) ones, one quantifies health and individualized risk as well as disease. Otherwise 'unmanageable' variability, reviewed herein, can be resolved by relatively simple inferential statistical procedures as a set of new endpoints. A formidable foe thus becomes a powerful friend: the rhythm characteristics can be used in cardiovascular physiology and epidemiology, and preventive and curative medicine. Long-term blood pressure monitoring is no longer a mere research tool and a curiosity for the practitioner of medicine. Results from such monitoring should immediately be used in the clinic, in the school and at home. Automatic blood pressure monitoring, cost-effectively used in combination with self-measurement, as needed, may become a routine procedure if data collection can be wedded to appropriate analyses yielding new endpoints as sensitive gauges of health.

Chronobiology of human blood pressure in the light of static (room-restricted) automatic monitoring.

Systematic 24-h automatic physiologic monitoring has obvious merits, even without rhythmometry. It can lead more readily to the recognition of odd-hour blood pressure elevation (e.g., of 'evening' or 'morning' hypertension). Such a condition can constitute an initial diagnosis or it may be found under treatment that may seem to be satisfactory if its effects are assessed only on the basis of a conventional check at a casual, possibly 'wrong' time. The mere inspection of a 24-h record, however, does not necessarily allow one to make objective quantitative global statements as to a change in pattern, e.g., after a given intervention. This paper illustrates how by rhythmometry, some of the uncertainties of a subjective interpretation of a record may be removed by practitioners of medicine, as well as basic scientists interested in mechanisms of blood pressure variability. This is possible since a large part of blood pressure variability can be accounted for by its circadian periodic behavior. We herein present a methodology for data collection and analysis that allows the objective quantification of blood pressure rhythm parameters in health and disease and the derivation of reference standards for such parameters. The chronobiologic approach thus makes it possible to define 'hypertension' objectively, and to distinguish between 'mesor-' and 'amplitude-hypertension', i.e., between an elevation in overall mean and one in the predictable extent of variability. Moreover, chronobiology has shown that mesor-hypertension may be preceded by an elevation in circadian amplitude only (amplitude-hypertension). Parameter tests readily allow the assessment, in relation to an objective reference standard, of these conditions, with a defined probability. Similarly, response to drug or non-drug therapy can be established and a given intervention optimized by timing treatment. Using chronobiologic tools in cardiovascular research provides new insights into possible mechanisms underlying mesor- and amplitude-hypertension. The teaching of the chronobiology of blood pressure and autorhythmometry in schools has been proven to be feasible and has been recommended as a step toward self-help for health care.

Comparative effects of meal timing on circadian rhythms of plasma insulin and skin surface temperature in non-human primates.

Circadian rhythms of plasma immunoreactive insulin and skin surface temperature were demonstrated in a group of African green vervets. Alteration in the timing of a single daily meal of fixed calorie content resulted in an acrophase shift of plasma immunoreactive insulin for the group of animals and in an acrophase shift of skin surface temperature in 7 or the 8 animals studied. The acrophase shift of skin surface temperature was considerably less then the shift of acrophase of plasma immunoreactive insulin, which closely approximated the shift in meal timing. The results of this study are compared with results of similar studies in human beings.

Changes with age characterize circadian rhythm in telemetered core temperature of stroke-prone rats.

In a stroke-prone (SP) strain of laboratory rats, aging is associated with quantifiable changes of the circadian rhythm in body core temperature: (1) its timing becomes less tight, as revealed by a larger standard error of the acrophase (the peak in the 24-hour cosine function best approximating all data) and (2) the acrophase in old SPs occurs earlier than in young ones--quite apart from (3) a decrease in circadian amplitude reported earlier. These results gain particularly in interest in the context of the recent finding that a large (approximately 90 degrees) acrophase-advance is associated with bilateral lesions of the suprachiasmatic nuclei in inbred (non-SP) Fischer rats. These observations may be of interest to those developing models of aging functions in disorders with blood pressure elevation.