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Biomedical subjects

F Halberg

Publications and source records attributed to F Halberg.

At least 415 records · Page 23Linked to original sources
PubMedDate not supplied

From experimental units to unique experiments: chronobiologic pilots complement large trials.

The timing of treatment affects outcome. For mapping multi-frequency rhythm spectra first to optimize chronochemotherapy, 1000 marker determinations on the subject are more informative than a few determinations on each of hundreds of patients. N-of-6 subgroups should follow, with one subject assigned to each of 6 marker rhythm stages, 60 (e.g. 4 hours on a 24-hour scale) apart. Once the time structure has been mapped, minimal sampling requirements determined, and guidelines for treatment established, the information gained from chronobiologic n-of-1 and n-of-6 test pilot designs can be built cost-effectively into randomized controlled trials to benefit large patient populations. Sequential tests combined with marker rhythmometry and cosinor analysis on single test subjects, small groups and eventually on each patient are powerful tools that can extract information otherwise unattainable even at great cost and bring the P-value from publications to the patients.

Antineoplastic Agents↗
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Usefulness of circadian amplitude of blood pressure in predicting hypertensive cardiac involvement.

Twenty-four-hour blood pressure (BP) profiles of 56 patients diagnosed as 'hypertensive' by WHO criteria were analyzed by the fit of a 24-hour cosine curve according to the single cosinor method. A left ventricular mass index (LVMI) was also assessed by two-dimensional echocardiography on each patient as a gauge of target organ involvement. LVMI and the BP MESOR correlates positively for systolic, S (r = 0.324), mean arterial, MA (r = 0.334) and diastolic, D (r = 0.267) BP (P less than 0.05), yet no statistically significant linear correlation between LVMI and the circadian BP amplitude (one-half of predictable change) was found. When a second-degree polynomial regression was fitted to the circadian BP amplitudes, an association was found (SBP: R2 = 0.138, P = 0.02; MAP: R2 = 0.167, P = 0.01; DBP: R2 = 0.128, P less than 0.01). The corresponding curves were characterized by peaks in the circadian amplitudes of SBP, MAP and DBP around a value of LVMI between 110 and 120 g/m2. For further scrutiny, three subgroups had been formed on the basis of literature, a priori with respect to the LVMI (group 1: LVMI less than 100); group 2: 100 less than LVMI less than 130; group 3: 130 less than LVMI). For MESORs, there was no difference between groups 1 and 2, whereas the MESOR of group 3 were larger than the other two groups. The circadian BP amplitudes of group 2 were larger than those of the other two groups for SBP, MAP and DBP. An increasing LVMI precedes a definitive increase of BP MESOR and coincides with an increase in the circadian BP amplitude; thus an increase in extent of circadian changes can alert the self-monitoring population of a target organ involvement.

Adolescent↗
PubMedDate not supplied

Circadian variation in multiple sclerosis of oxidative stress marker of DNA damage. A potential cancer marker?

OBJECTIVE: To investigate circadian rhythm (CR) of urinary creatinine and 8-hydroxy-2-deoxyguanosine (8-OHdG) in patients with Multiple Sclerosis (MS) and to present concentrations of this DNA damage marker, 5 years prior to mastectomy, in one MS study subject, and 2 years prior to biopsy confirmed a carcinoma (CA) of the prostate in one non-MS subject. MATERIALS AND METHODS: Eleven subjects with MS (6 women 36-52 years of age and 5 men 51-68 years) volunteered for this study, carried out at Edward Hines Jr., Medical Center. Subjects were offered a general hospital diet (2400 cal in total/24h) at 16:30h, 07:30h and 13:00h. The dark (sleep) phase of the light-dark cycle extended from 22:30h to 06:30h with brief awakening for sampling at 01:00h, and 04:00h. Urine samples were collected for consecutive 3h spans beginning at 16:00-19:00h and were analyzed for creatinine and 8-OHdG. Twelve men (including 3 with type 2 diabetes) provided 21 profiles according to the same protocol used for comparison. In addition, 10 healthy women provided 24h urine samples. Statistical analysis of data was performed using the Single-Cosinor and Population-Mean Cosinor. RESULTS: A CR was detected for creatinine in healthy men (p < 0.001) but not for MS patients. Urinary creatinine concentrations were lower in MS women than in healthy women (p = 0.015) and were lower in MS women than in men healthy or with MS (p < 0.001): Women; MS 655 +/- 76; H 1381 +/- 316; Men, MS 1830 +/- 285; H 1532 +/- 265 mg/24h vol. A CR was evident in 8-OHdG in MS (p = 0.007) and in non-MS subjects (p < 0.001) with highest values occurring at about 16:45h. The average concentrations of 8-OHdG in MS patients were similar to those in healthy subjects: Women, MS 589 +/- 125; H 794 +/- 318; Men, MS 504 +/- 156; H 591 +/- 134 picomoles/kg bw/24h vol. The 8-OHdG concentrations of a MS patient, later diagnosed with breast cancer, were found to exceed the upper 95% prediction limit in health. An increased 8-OHdG level was also noted in a non-MS subject who 2 years later received a biopsy-confirmed diagnosis of prostate CA. CONCLUSIONS: Despite the small number of subjects in this study, a statistically significant CR was documented for 8-OHdG in urine of subjects with MS. Interestingly, the increased concentrations of DNA damage marker, the 8-OHdG, 5 years prior to mastectomy and the 2 years prior to affirmative diagnosis of prostate CA, could be the most significant clinical observations of this study. Follow-up studies of a larger population of subjects would, thus, be required to ascertain the predictive validity of such challenging observation.

8-Hydroxy-2'-Deoxyguanosine↗
PubMedDate not supplied

Marker rhythmometry with macrophage-colony stimulating factor (M-CSF).

In a patient with a debulked müllerian adenocarcinoma involving the ovary, an elevated serum concentration of macrophage-colony stimulating factor (M-CSF) (5.3 ng/ml) was lowered into the range of the age- and gender-matched controls by a 24-hour infusion of 135 mg/m2 of taxol, as was a Ca125 of 1480 U/ml by three such taxol courses given at 3-week intervals (to 14 U/ml). A downward trend of M-CSF in serum with an about-14-hour ultradian modulation during the first chemotherapy course resembles that of the concomitantly assessed Ca125. A decreasing trend modulated by an about-half-weekly component is found in M-CSF of fractionated urines collected at spontaneous voidings around the clock for 5 days. M-CSF may serve as a chronobiologic marker for optimizing, on an individualized basis, 1) the infradian scheduling of chemotherapy courses and 2) the ultradian-circadian within-course time patterns. Timing based on markers of the anticancer effect aims at teh as-yet unattained transfer from rodent to human of cancer cures that were not previously feasible without chronobiologic considerations. This goal can be pursued with M-CSF as well as Ca125 and UGP as possibly complementary chronobiologic markers in a chronotherapy trial with taxol in humans.

Aged↗
PubMedDate not supplied

Chronobiology meets the need for integration in a reductionist climate of biology and medicine.

One of us introduces a chronobiology course to students at the University of Milan, Italy, with a succinct statement that may well serve to summarize the foregoing 24 points. Its few lines distill the preceding details and formulate the raison d'être of Chronobiology: Chronobiology is: not only a science in its own right; not only a methodology; not only a new kind of statistical analysis; not just an aspect of biology, but a new way of invariably approaching any problem in biology, notably medicine.

Animals↗
PubMedDate not supplied

The blood pressure and heart rate chronome of centenarians.

Rhythm characteristics of blood pressure (BP) and heart rate (Hr) of 11 healthy centenarians and 66 medical students are described. Each subject ambulatorily monitored measured BP and HR around the clock at 15-min intervals for 48 hours. Least-squares spectra were obtained by the fit of cosine curves (cosinor) and compared between the two populations. Confounding by geographic differences seems to be ruled out by comparisons with results from international data bases. A shift in prominence from the circadian domain to higher frequency harmonics was found for the BP but not for the HR of centenarians. In clinically mostly healthy centenarians, markers of primary aging may consist of a relatively low circadian BP and HR amplitude and a tendency toward internal and external desynchronization. Whether these chronobiologic changes with age are desirable, indifferent or undesirable can now be elucidated by outcome studies, in the light of the reference standards provided herein.

Activity Cycles↗
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Human mesor-hypertensive chronorisk.

Twelve endocrine variables in blood from a small number of clinically healthy adult women were sampled systematically around the clock and the seasons. Pattern discrimination methods singled out certain hormone values in certain seasons as classifiers for a high vs low risk of developing diseases associated with a high blood pressure. Further evidence in support of such classifiers is obtained on data from adolescent, menstrually cycling young adults and post-menopausal women, here analyzed as pool of series, with the scope of the data from any one age group greatly extended by a resampling procedure, namely, by bootstrapping. This mathematical approach was carried out on data series around the clock and seasons on several hormones as well as systolic and diastolic blood pressure. Classifier roles were strongly supported for plasma aldosterone and thyroid stimulating hormone, originally by an analysis of variance and, in the case of aldosterone, by circannual cosinor analysis and by numerical resampling. Circannual bootstrapping, a procedure recommended for broad routine use as a safeguard for hypothesis testing, was also done for plasma cortisol, dehydro-epi-androsterone sulfate and prolactin, variables for which (parametric) analyses of variance and cosinors did not reveal any difference between groups at high and low cardiovascular risk. In these instances, bootstrapping results are tentative and await further analyses. Results show the ability of circannual bootstrapping to detect outliers. Identification of classifiers provides cost-effective endocrine checks complementing the targeted automatic monitoring of blood pressure. Circannual indices for risk evaluation are, however, costly in several ways since it takes at least a year and quite a few samples to estimate them reliably. Accordingly, we also extended the scope of previous results by the application of an added procedure for circadian bootstrapping. With circadian as well as circannual bootstrapping, we here illustrate a major potential component of a system of chrono-engineering for health maintenance. This system should start with focus on the newborn. The results on adults here analyzed are likely to be more prominent in the neonate, to the extent that they are genetic in origin, yet amenable to modification by the extra-uterine environment.

Adolescent↗
PubMedDate not supplied

Gender, age and circadian blood pressure variation of apparently healthy rural vs metropolitan Japanese.

Interim chronobiologic cardiovascular reference data have been described; 353 clinically healthy Japanese subjects were monitored every 15 min for 24h on 2 occasions. Special attention was paid to the difference between metropolitan and rural areas. Not only the MESORs of SBP and DBP, but also the circadian amplitudes, were higher in the Tokyo than in a rural area (Komaki, Aichi Prefecture). Age-related alterations in the circadian profile of cardiovascular variables were noted for women but not for men. The average MESOR remained similar for SBP in men, whereas in women the average MESOR increased with advancing age in both urban and rural areas. The average circadian amplitude of SBP also increased with age in women, but not in men. No significant deviations of acrophase with age were found for SBP and DBP in men, whereas in rural women the acrophase tended to occur earlier with increasing age.

Adolescent↗
PubMedDate not supplied

Ambulatory blood pressure monitor and 'analyzer'.

Earlier, we described the format provided by an ambulatory blood pressure monitor, the ABPM-630 with a data handler (AA-200), manufactured by Colin Medical Instruments. A detailed procedure for data transfer from the memory cassette into the analyzer and into an IBM PC in a format compatible with programs in the Chronobiology Laboratories is provided with a brief description of the hardware used. Among several instruments available for ambulatory blood pressure and heart rate monitoring, the ABPM-630 has several advantages: it does not require electrodes (a merit it shares with other instruments); it is portable, even if there are smaller ones; it functions silently, being activated by a CO2 cartridge; and it provides data obtained by two methods, by auscultation and by oscillometry, in part as a backup for one another, depending on whether auditory or movement noise are within limits acceptable to the instrumentation. This feature renders it more likely that some record will be obtained. In our earlier publication, we had referred to and then briefly described a special program which converts the format of the data handler into a format acceptable for analyses with programs from the University of Minnesota Chronobiology Laboratories. Herein, the operation of transferring data from the ABPM-630 memory cassette to an IBM-compatible personal computer (PC) is described, with an indication further of the programs used in the Chronobiology Laboratories.

Ambulatory Care↗
PubMedDate not supplied

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.

Animals↗
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Magnetic resonance spectroscopy and ambulatory cardiovascular monitoring noninvasively gauge timing of phosphate metabolism and circulation.

Circadian changes in high-energy phosphate metabolism of the human forearm and the relative independence of these metabolic changes from the circulation were noninvasively demonstrated and quantified by combining nuclear magnetic resonance spectroscopy (MRS), ambulatory blood pressure and heart rate monitoring and chronobiologic time series analysis.

Adenosine Diphosphate↗
PubMedDate not supplied

Chronobiological study of several enzymes of lysosomal origin in human plasma.

The possible occurrence of circadian and circannual rhythms in the plasma concentrations of the following enzymes of lysosomal origin was assessed: beta-D-N-acetylglucosaminidase (EC 3.2.1.30) beta-D-glucuronidase (EC 3.2.1.31), beta-D-glucosidase (EC 3.2.1.21), beta-D-galactosidase (EC 3.2.1.22), alpha-D-galactosidase (EC 3.2.1.23), alpha-L-fucosidase (EC 3.2.1) and alpha-D-mannosidase (EC 3.2.1.24). The circadian rhythm was studied in 16 women (aged: 17-24 years) and 13 men (age: 23 years) volunteers; the circannual rhythm, in 10 women and 8 men (age: 20-25 years). The circadian rhythm was detected in all the tested enzymes of women, and only in alpha-D-galactosidase, beta-D-glucosidase, alpha-D-mannosidase and beta-D-acetylglucosaminidase of men. A statistically significant difference between genders in the circadian rhythm was exhibited by beta-D-galactosidase (MESOR; amplitude) beta-D-glucosidase (MESOR; amplitude; acrophase) beta-D-N-acetylglucosaminidase, beta-D-glucuronidase and alpha-D-galactosidase (MESOR) and alpha-L-fucosidase (amplitude, acrophase). A circannual rhythm was detected in all the tested enzymes with the exception of beta-D-glucuronidase and beta-D-N-acetylglucosaminidase; no statistically significant difference between genders was detected. The group rhythms of some of the enzymes (alpha-D-galactosidase, beta-D-glucosidase, beta-D-galactosidase) showed similar values of both circadian and circannual acrophases, suggesting that they may subjected as a group to the same chronobiological coordination, possibly mediated by hormones. The chronobiological rhythms of lysosomal enzymes were different from those of lactate dehydrogenase and alpha 1-antitrypsin, indicating that these rhythms are not merely reflecting fluctuations of the water content of plasma. No in-phase relationship was observed between the circadian and circannual rhythms of plasma cortisol and those of the tested lysosomal enzymes, excluding a direct chronobiological and possibly functional relationship between this hormone and lysosomal enzymes.

Adult↗