Creatinine clearance and blood pressure: a 34-year circadian study.

BACKGROUND AND OBJECTIVE: The first circadian study of the 361st Medical Laboratory, USAR, was conducted in May 1969 during the Annual Military Training at Brook Army Hospital, Fort Sam Houston, Texas. The study was approved by the Surgeon General, 5th US Army, and was designed to establish a circadian database for 63 medically relevant variables of 13 young members of the Unit. The subsequent studies, all in the month of May, in 1979, 1988, 1993,1998, and 2003, followed the same protocol and were conducted at Edward Hines Jr., Veterans Administration Hospital, after approval by Human Studies Subcommittees. Since a reduction in Creatinine Clearance (CrCl) to the level of 60 ml/min/1.73m2 signals the onset of kidney malfunction and since a concurrent increase in blood pressure (BP) >140/90 mm Hg, contributes greatly to an unfavorable cardiovascular prognosis, it seemed prudent to examine possible changes in these and in other relevant variables in a group of young Army men, which may have developed over a 34 year period of time. MATERIAL AND METHODS: Thirteen US Army male volunteers (23-27y of age) served as subjects in the 1969 study. A majority of these men, two additional Army men and two non-military subjects, participated in subsequent studies: 1979 (7,2,1), 1988 (8,2,1), 1993 (5,4,1), 1998 (7,2,2), 2003 (7,2,1). In each study, subjects were admitted to a hospital ward, were given medical examination including a 12-lead electrocardiogram and followed the same Protocol. Lights "OUT" at 22:30h and "ON" at 06:30h. The meals, hospital 2400-calorie diets, were served at 17:30, 07:30 and at 13:30h. Vital signs were measured immediately after each 3h urine collections, around the clock, and bloods were collected every 3h. Blood, plasma, serum, saliva and urines were analyzed for numerous analytes including creatinine, using automated laboratory systems. Kidney functions were assessed using the measured and estimated glomerular filtration rates. RESULTS: Over the 34y study span, 16 men provided sixty-one 24h profiles for CrCl-related variables (urine volume, creatinine, and serum creatinine) and fifty-eight profiles for BP. Using all normalized data, a significant circadian rhythm was found for each of these variables. Significant circadian variations in SBP, DBP, serum and urine creatinine, and urine volume, were evident with peak levels, on average, occurring in the evening hours. CONCLUSIONS: In healthy subjects, age was associated with an increase in SBP and urine volume and with a decrease in urine creatinine. In diabetic subjects, aging was associated with increases in both blood pressure and Creatinine Clearance. It is interesting to note that for the 3 subjects who at a later date developed diabetes, the CrCl levels were higher than the 5 age-matched controls during each study year, over the entire 34y observation span, including the period prior to diagnosis. Clin Ter 2008; 159(6):409-417.

Why continued surveillance? Intermittent blood pressure and heart rate abnormality under treatment.

Several opinion leaders have monitored their blood pressure systematically a sufficient number of times a day for chronomic (time structural) analyses, from the time of encountering chronobiology until their death; they set an example for others who also may not wish to base treatment on single spotchecks in a health care office. Such self-measurements, while extremely helpful, were not readily feasible without a noteworthy interruption of activities during waking as well as of sleep. New, relatively unobtrusive instrumentation now makes monitoring possible and cost-effective and will save lives. Illustrative results and problems encountered in an as-one-goes self-survey by GSK, a physician-scientist, are presented herein. Both MESOR-hypertension and CHAT (circadian hyper-amplitude-tension) can be intermittent conditions even under treatment, and treatment is best adjusted based on monitoring, rather than "flying blind".

Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer.

BACKGROUND: Circadian rhythms in plasma concentrations of many hormones and cytokines determine their effects on target cells. METHODS: Circadian variations were studied in cortisol, melatonin, cytokines (basic fibroblast growth factor IbFGF], EGF, insulin-like growth factor-1 [IGF-1]), and a cytokine receptor (insulin-like growth factor binding protein-3 [IGFBP-3]) in the plasma of 28 patients with metastatic breast cancer. All patients followed a diurnal activity pattern. Blood was drawn at 3h intervals during waking hours and once during the night, at 03:00. The plasma levels obtained by enzyme-linked immunoassay (ELISA) or radioimmunoassay (RIA) were evaluated by population mean cosinor (using local midnight as the phase reference) and by one-way analysis of variance (ANOVA). RESULTS: Cortisol and melatonin showed a high-amplitude circadian rhythm and a superimposed 12h frequency. bFGF showed a circadian rhythm with an acrophase around 13:00 with a peak-to-trough interval (double amplitude) of 18.2% and a superimposed 12h frequency. EGF showed a circadian rhythm with an acrophase around 14:20, a peak-to-trough interval of 25.8%, and a superimposed 12h frequency. IGF-1 showed a high value in the morning, which is statistically different (t test) from the low value at 10:00, but a regular circadian or ultradian rhythm was not recognizable as a group phenomenon. IGFBP-3 showed a low-amplitude (peak-to-trough difference 8.4%) circadian rhythm with the acrophase around 11:00 and low values during the night. CONCLUSIONS: (1) Circadian periodicity is maintained in hospitalized patients with metastatic breast cancer. (2) Ultradian (12h) variations were superimposed on the circadian rhythms of the hormones and several of the cytokines measured. (3) Studies of hormones and cytokines in cancer patients have to take their biologic rhythms into consideration. (4) The circadian periodicity of tumor growth stimulating or restraining factors raises questions about circadian and/or ultradian variations in the pathophysiology of breast cancer.

Circadian rhythms and clinical medicine with applications to hypertension.

Circadian (24-h) rhythms are important to the practice of medicine. The phasing and amplitude of key physiologic and biochemical circadian rhythms contribute to predictable-in-time patterns in the manifestation and exacerbation of most medical conditions. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and medications. Rhythmicity in the pathophysiology of medical conditions is the rationale for chronotherapeutics--that is purposeful variance of the concentration of medicines in synchrony with biologic rhythm determinants of disease activity--to optimize treatment outcomes. This article discusses the concept of biologic time structure and its relevance to the practice of medicine, with a focus on hypertension and cardiovascular issues.

A multicenter comparison of isoflurane and propofol as adjuncts to remifentanil-based anesthesia.

STUDY OBJECTIVE: To compare recovery, hemodynamics, and side effects of remifentanil-based anesthesia with hypnotic concentrations of isoflurane or propofol. DESIGN: Multicenter, prospective, randomized, two-group study. SETTING: 15 university and 5 municipal hospitals. PATIENTS: 249 ASA physical status I, II, and III adult patients scheduled for elective gynecological laparoscopy, varicose vein, or arthroscopic surgery of at least 30 minutes' duration. INTERVENTIONS: Anesthesia was induced in the same manner in both groups: remifentanil-bolus (1 microg/kg), start of remifentanil-infusion (0. 5 microg/kg/min), followed by propofol as needed for induction. Five minutes after intubation, remifentanil was reduced to 0.25 microg/kg/min, and it was combined with either a propofol-infusion (0.1 mg/kg/min) or with isoflurane (0.6 vol% end-tidal) in O(2)/air. Adverse hemodynamic responses of heart rate and systolic blood pressure were recorded and treated according to a predefined protocol. With termination of surgery, anesthetic delivery was discontinued simultaneously without tapering, and recovery times were recorded. MEASUREMENTS AND MAIN RESULTS: No significant differences were observed between the remifentanil-isoflurane or remifentanil-propofol treatment regimens. Recovery times (means +/- SD) were similar for spontaneous ventilation (5.8 +/- 3.2 min vs. 6. 3 +/- 3.7 min), extubation (7.6 +/- 3.5 vs. 8.5 +/- 4.2 min), eye opening (6.8 +/- 3.2 vs. 7.5 +/- 3.8 min), and arrival to the postanesthesia care unit (16.5 +/- 7.0 vs.18.0 +/- 7.2 min). There were no significant differences in adverse hemodynamic responses, postoperative shivering, nausea, or vomiting between the groups. CONCLUSIONS: Emergence after remifentanil-based anesthesia with 0.6 vol% of isoflurane is at least as rapid as with 0.1 mg/kg/min propofol. Both isoflurane and propofol are suitable adjuncts to remifentanil, and the applied dosages are clinically equivalent with respect to emergence and recovery. Therefore, both combinations should be appropriate, particularly in settings in which rapid recovery from anesthesia is desirable, such as fast tracking and/or ambulatory surgery.

Melatonin levels in women with fibromyalgia and chronic fatigue syndrome.

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are stress associated disorders mainly affecting women. FM is characterized primarily by widespread musculoskeletal pain, and CFS by profound debilitating fatigue, but there is considerable overlap of clinical symptoms between these 2 syndromes. Neuroendocrine abnormalities have been noted in both FM and CFS and desynchronization of circadian systems has been postulated in their etiology. The pineal hormone melatonin is involved in synchronizing circadian systems and the use of exogenous melatonin has become widespread in patients with FM and CFS. METHODS: We examined the characteristics and relationship of melatonin and cortisol levels in premenopausal women with FM (n = 9) or CFS (n = 8), compared to age and menstrual cycle phase matched controls. Blood was collected from an indwelling intravenous catheter every 10 min over 24 h, and plasma melatonin and cortisol were determined by radioimmunoassay at 60 and 10 min intervals, respectively. RESULTS: Night time (23:00-06:50) plasma melatonin levels were significantly higher in FM patients compared to controls (p<0.05), but there was no significant difference in melatonin levels between CFS patients and controls. No differences in the timing of cortisol and melatonin secretory patterns and no internal desynchronization of the 2 rhythms were found in either patient group, compared to controls. CONCLUSION: Raised plasma melatonin concentrations have been documented in several other conditions that are associated with dysregulation of neuroendocrine axes. Increased melatonin levels may represent a marker of increased susceptibility to stress induced hypothalamic disruptions. These data indicate that there is no rationale for melatonin replacement therapy in patients with FM and CFS.

Clinical chronobiology and chronotherapeutics with applications to asthma.

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24 h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24 h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.

Biologic rhythms in the immune system.

In all of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies; the circadian (about 24 h) rhythms are the best explored. The circadian variations in immunocompetent cells circulating in the peripheral blood are of a magnitude to require attention in medical diagnostics. Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. The response of the immune system to introduction of an antigen and to challenge of the sensitized organism varies in extent in the circadian frequency range and also in lower frequencies, for example, of about a week (circaseptan) or seasonally (circannual). The medical application of the biologic rhythms of the immune system extends to diagnostic measures, as well as treatment.

The chronobiology of prostate-specific antigen (PSA): case report and chrono-metaanalysis.

The circadian profiles of circulating PSA of a 72-year-old man (FH) and of 11 other clinically relatively healthy men are compared. The time course of FH's PSA was also followed longitudinally with single samples for over 3 years. A transient peak in PSA exceeding the upper time-unspecified age-corrected reference limit prompted a retrospectively premature biopsy which indicated prostatitis. Watchful waiting and additional PSA determinations may be the preferred approach before biopsy, notably in the elderly, for reasons of cost and invasiveness of the procedure. The load associated with a biopsy is also evaluated by a cardiovascular response.

[The origin of the biological week from data on the rhythm of cardiac contractions in people during the solar activity cycle]. / O probleme proiskhozhdeniia biologicheskoi nedeli po dannym o variatsiiakh ritma chastoty serdechnykh sokrashchenii u liudei v tsikle solnechnoi aktivnosti.

A human biologic week in the heart rate variations was compared with the variations of the sunspot area and geomagnetic activity over the solar cycle. The low ratio of amplitude of circaseptan rhythm to that of circadian rhythm in the heart rate of several clinically healthy men who did around-the-clock self-measurements in a number of years coincides with the period of anomalously low amplitude of circaseptan rhythm of the solar activity. Results herein suggest that physiologic circaseptan rhythms are built into the genome being adapted evolutionary to the original heliogeomagnetic environmental circaseptans.

Urinary tract infections in the homebound elderly.

The incidence of bacteriuria is widespread in the elderly. Because home care nurses serve elderly clients with multiple problems, bacteriuria is often encountered in the home care setting. The elderly may present with typical signs and symptoms of infection. However, the indications are often vague and nonspecific. Bacteria in the urine often presents with no symptoms and is best left untreated. The responsibilities of the nurse include evaluating signs and symptoms presented by their clients and overseeing therapeutic plans, specimen collection, infection control practices, catheter care, education, and prevention. It is important that prevention always receive top priority.

Time-dependent variations of the skin barrier function in humans: transepidermal water loss, stratum corneum hydration, skin surface pH, and skin temperature.

Although circadian rhythms have been described for many human functions, there are minimal data on circadian rhythms related to skin physiology. This study investigated the circadian rhythmicity of skin variables related to skin barrier function in humans. We measured transepidermal water loss, stratum corneum moisture, skin surface pH, and skin temperature in 16 healthy volunteers (nine men and seven women, aged 23-53 y). Subjects were sampled every 2 h in two sessions over a 24 h span. Twelve samples were obtained for each variable in the following sites: forehead, forearm, upper back, and shin. We used cosinor analysis and ANOVA to validate observed differences. Time-dependent rhythms were detected in most skin variables except in stratum corneum hydration. We found a statistically significant circadian rhythmicity characterized by cosinor analysis in transepidermal water loss, skin surface pH, and skin temperature on the forearm, forehead, and shin. Peak-trough differences occurred in all locations. The values of the same variables measured at different sites correlated positively, whereas the values of the different variables did not. These results suggest that skin permeability is higher in the evening and night than in the morning. These data may be clinically relevant in several aspects applied to skin physiology and topical drug application.

Circannual variation of cell proliferation in lymphoid organs and bone marrow of BDF1 male mice on three lighting regimens.

BDF1 male mice, which had been raised for several generations on a lighting regimen of LD 12:12, were studied. Experiments were conducted over 24 h spans during winter, spring, summer, and fall. For 3-4 weeks prior to each study, one-third of the animals were kept on a lighting regimen of 8 h of light alternating with 16 h of darkness (LD 8:16), one-third was kept on a regimen of LD 12:12, and one-third was kept on a regimen of LD 16:8. Subgroups of mice on all three lighting regimens were killed at 4 h intervals over a 24 h span. At 20 minutes prior to sacrifice, the animals received 5 microCi of 3H-thymidine/0.2 ml/20 gm body weight intraperitoneally. The thymidine uptake in DNA (DPM[3H]/microgram DNA) was studied as an index of cell proliferation in the thymus, inguinal lymph node, spleen, femur, and a segment of the lumbar vertebral column. A circannual variation of 3H-thymidine uptake in DNA was found in all organs irrespective of the lighting regimen under which the animals were kept. The timing of the circannual variation, however, varied among the organs. In the thymus, the lowest thymidine uptake occurred during summer, with higher thymidine uptake during the other three seasons. In the inguinal lymph node, the peak in thymidine uptake was in the spring, with lower values during the other three seasons, the lowest during summer. In the spleen, the highest thymidine uptake occurred in the mice on all three lighting regimens during fall, with lower uptake during winter, spring, and summer. In the bone marrow of both the femur and the vertebral column, the thymidine uptake was high in winter and fall and low in spring and summer. Serum corticosterone measurements were available in winter, spring, and fall, and they showed statistically significant lower values in winter and fall than in spring. The conclusion was drawn that circannual rhythms of 3H-thymidine uptake in the DNA of the thymus, spleen, lymph nodes, and bone marrow are found in mice reared for generations under a LD 12:12 lighting regimen and persist if the animals are kept under a regimen of LD 8:16 or LD 16:8 for 3-4 weeks prior to sacrifice.

Modifications of circadian and circannual rhythms with aging.

Whereas biological rhythms are now fairly well documented in young healthy adults, reports in elderly are relatively few for obvious reasons, including the difficulty of setting groups matched in age, sociological and professional background, medical history, and not in need of specific medication. Aging may modify one or several parameters characterizing biological rhythms. The modifications are different from one function to the next, and great care should be given not to mistake changes attributable to the aging process with those resulting from physical and physiological impairment caused by passed environmental aggressions and diseases. Nevertheless, the increasing number of subjects reaching the age of 65 or older, thanks to medical progress, makes necessary establishing time-qualified references values in the aged, as this kind of investigation should lead to an improvement of the conditions and quality of life of elderly subjects.

Resonance of about-weekly human heart rate rhythm with solar activity change.

In several human adults, certain solar activity rhythms may influence an about 7-day rhythm in heart rate. When no about-weekly feature was found in the rate of change in sunspot area, a measure of solar activity, the double amplitude of a circadian heart rate rhythm, approximated by the fit of a 7-day cosine curve, was lower, as was heart rate corresponds to about-weekly features in solar activity and/or relates to a sunspot cycle.

Clinical relevance of about-yearly changes in blood pressure and the environment.

Changes identified by inferential statistics from summer to winter of high to low arterial blood pressures (BP) have been quantified as a large predictable about-yearly BP swing. This condition of a large annual BP amplitude (LABPA) raises concern about hypotension as well as hypertension and raises new questions regarding appropriate guidelines for diagnosis and treatment. Recommendations made in the fall on the basis of data collected in the summer may be totally inadequate in dealing with the patient's condition in the winter. In order to avoid such mistakes, it is imperative to implement a systematic surveillance of BP in the light of current chronobiological limits. Patients with a large circannual BP amplitude are particularly suited for a study of the underlying hormonal mechanisms. The longitudinal monitoring of their BP is also amenable to the study of environmental influences from near and far.

Changes in human blood pressure with season, age and solar cycles: a 26 year record.

The record was studied of a 71-year-old, diurnally active (0700-2200 hours) male psychiatrist (G.N.) who self-measured systolic and diastolic blood pressure (BPS and BPD) mostly but not exclusively on Sunday mornings, from 1969 to 1994. A large about-yearly change was revealed which increased with age and was accompanied by a decreasing trend in the yearly rhythm-adjusted mean (MESOR; P < 0.01). According to conventional criteria that specify only upper limits of acceptability, G.N. was hypertensive in summer and normotensive in other seasons. Since changes in both MESOR and circannual amplitude occurred, a systematic surveillance of BP is the chronobiological recommendation.