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.

Cancer marker assessment: case report on salivary and urinary CEA.

A circadian rhythm is demonstrated for salivary CEA in a clinically healthy man who collected unstimulated saliva samples around the clock for 4 days. Its acrophase occurs around 07:00, slightly later than for patients with colon cancer. A circadian rhythm of borderline statistical significance is found for the urinary excretion rate of CEA determined during the same span by this patient. It has an acrophase occurring around 15:00, differing from that of salivary CEA. Although CEA may have only limited value to assess tumor burden, even when determined in blood, rhythm characteristics of tumor markers such as CEA await applications for guiding treatment timing and for detecting earliest chronome alterations not only in the case of an overt cancer but as a feature of predisease and/or disease risk elevation.

Comparison of gentamicin pharmacokinetic parameters determined by fluorescence polarization immunoassay and latex agglutination methods.

Fluorescence polarization immunoassay (FPIA) (TDx, Abbott Laboratories Diagnostics, Irvin, TX, U.S.A.) is commonly utilized for quantitative determination of gentamicin serum concentrations. Recently, automated homogeneous latex agglutination (LA) (Technicon Immuno-1, Miles Diagnostics Division, Tarrytown, NY, U.S.A.) for the quantitative determination of gentamicin serum concentrations has been approved for commercial use. The purpose of this study was to determine whether gentamicin serum concentration-time data from the same patients assayed by FPIA and LA would produce the same estimates for half-life, elimination rate constant, distribution volume, drug clearance, dosage interval, and dose. A total of 70 pre- and postinfusion serum samples were obtained from 19 patients. Each sample was divided into two aliquots; one was assayed by FPIA and the other by LA. The correlation coefficient between the two assay methods was 0.99 (y = 1.03x - 0.05). The mean differences for half-life, volume of distribution, elimination rate constant, total body clearance, and gentamicin dosage were 0.13, 0.32, 0.66, -0.99, and 0.03%, respectively. No statistically significant differences were seen in calculated gentamicin pharmacokinetic parameters (p < 0.05). Pharmacokinetic parameters and dosage recommendations derived from FPIA and the LA assay using pre- and postinfusion serum concentration-time data appear interchangeable and do not result in differences between gentamicin dosing regimens.

Chronobiology in laboratory medicine.

A critical amount of information has accumulated over the last decades to allow the application of chronobiology to clinical and laboratory medicine. The tasks faced in laboratory medicine include the quantitative measurement of the multifrequency human time structure in health and disease. For this purpose, it is essential to choose an adequate sample size in order to obtain meaningful results and quantitative endpoints which can be interpreted by inferential statistical techniques. No statistical technique is applicable for all purposes and it is essential that the assumptions underlying each technique and its limitation are well known to the investigator. The multifrequency nature of the human time structure has to be kept in mind in order to avoid erroneous results. Time qualified reference ranges have to be established for high amplitude rhythms. Circadian and/or circannual rhythm alterations have been described as group phenomenon in subjects with epidemiologically determined risk states for common diseases, but will require much further studies for the application to individual subjects. Rhythm parameters are new endpoints in the evaluation of the human time structure in health. Alterations of these parameters may occur as cause or as consequence of disease. Recognition of rhythm abnormalities in disease are critical for a meaningful application of chronopharmacology. Time dependent changes in pharmacokinetics and pharmacodynamics have to be taken into account in the interpretation of drug level determinations. A considerable degree of individuality of timing has been documented in some frequencies. This individuality and the rhythm abnormalities found in disease require the study of reference or marker rhythms. If the complexity of the human time structure is clearly understood and its study pursued in a critical manner with quantitative endpoints, chronobiology opens a new dimension in laboratory and clinical medicine.

Circadian rhythm parameters of endocrine functions in elderly subjects during the seventh to the ninth decade of life.

The circadian rhythm of 17 endocrine parameters (ACTH, aldosterone, cortisol, C-peptide, DHEA-S, FSH, growth hormone, insulin, LH, 17-OH progesterone, prolactin, testosterone, total T3, total T4 and TSH and estradiol and progesterone in women only) were studied in 63 clinically apparently healthy men (124 profiles) and 86 women (154 profiles) during the 7th to 9th decade of life. The subjects lived under very uniform conditions in a home for the aged with their daily schedule standardized by institutional routine with rest at night on the average from 21:30 to 06:30 local time and 3 daily meals at 08:30, 13:00 and 18:30. Blood was drawn over a 24-h span at 4-h intervals. Circadian periodicity was ascertained and the rhythm parameters quantified by cosinor analysis. In clinically healthy elderly subjects, circadian periodicity persisted in most parameters studied well into the 9th decade of life. The timing of the circadian rhythm was comparable between subjects in their 7th decade and 9th decade of life with the exception of cortisol and DHEA-S, which showed a phase advance with advancing age. A decrease in circadian amplitude is limited during this part of the human life span to only a few of the functions investigated and with the exception of prolactin in the women, a decrease in amplitude did accompany a decrease in MESOR.

Circadian and seasonal variations in iodine excretion in children with and without endemic goiter.

The urinary iodine excretion was measured in 193 children 11 +/- 1.5 years of age living in the endemic goiter area of Dîmbovita, Romania. One hundred and thirty four of the children showed some degree of endemic goiter, 59 showed none. All children followed a diurnal activity pattern with rest during the night. They received their usual iodine supplement of 1 gm potassium iodide once a week during the school year (which included the time of all measurements made). Urine was collected in six 4-hour samples over a 24-hour span. The examinations were conducted during the months of March, June, September and December. Iodine was determined by an automated ceric ion arsenic acid method using a Technicon Autoanalyzer. Circadian and seasonal variations of urine volume and iodine excretion were statistically verified by the cosinor technique and the seasonal variations also by one way analysis of variance using the circadian means as input. A comparable circadian rhythm of iodine excretion was found in the children with and without endemic goiter, with an acrophase during the evening (20:16 with a 95% C.I., from 19:32 to 21:04). The circadian rhythm in iodine excretion has to be taken into account whenever an estimate of the 24-hour excretion is attempted from a sample covering less than the entire 24-hour span. There was a statistically significant seasonal variation of the 24-hour iodine excretion in the boys with and without endemic goiter and in the group as a whole. The 24-hour iodine excretion during March was 102 +/- 6 mcg, during June 81 +/- 4 mcg, during September 79 +/- 3 mcg and during December 102 +/- 7 mcg. The average 24-hour iodine excretion pooled over all seasons was 91 +/- 3 mcg/24 hrs in the children with and 91 +/- 5 mcg/24 hrs in the children without endemic goiter. During March and December the iodine excretion indicates an iodine intake not usually associated with a high prevalence of endemic goiter. However, during the months of June and September (and presumably even more during the months of July and August when during summer vacation no iodine supplementation was given in school) the 24-hour iodine excretion indicates some degree of iodine deficiency. The seasonal variation in urinary iodine excretion thus points to a time when increased iodine prophylaxis may be of value.

Circadian hematologic time structure in the elderly.

Twenty-three clinically healthy, diurnally active elderly subjects, 71 +/- 5 years of age were studied over a 24-hr span (six samples). Complete blood counts and differential counts were done (Ortho ELT-8, Wright stained smears). The circadian rhythm parameters of the hematologic variables in the elderly subjects were compared with reference values obtained from a larger group of clinically healthy young adult and adult subjects studied independently. The data were analyzed by cosinor and the Bingham test. Circadian rhythms in the number of circulating formed elements in the peripheral blood persist in the aged. In comparison with the young adult, the elderly subjects show differences in the timing (phase advance) of the circadian rhythms in circulating neutrophil leukocytes and lymphocytes, a decrease in the circadian amplitude of circulating platelets, a decrease in circadian rhythm adjusted mean (mesor) in the red cell count, and in the neutrophil band forms.

Non-immune fetal hydrops with hepatic hemangioendothelioma and Kasabach-Merritt syndrome: a case report.

A premature infant presented with non-immune hydrops fetalis, a liver mass, thrombocytopenia, and hypofibrinogenemia. Histologic examination of the liver tumor showed an infantile hemangioendothelioma. The clinical features of this case can be explained by anemia, hypoalbuminemia, and coagulopathy. The association with Kasabach-Merritt syndrome, the pathophysiology of non-immune hydrops fetalis, and primary hepatic neoplasms of the neonate are discussed.

Plasma and urinary catecholamines in salt-sensitive idiopathic hypertension.

Nineteen patients with normal renin idiopathic hypertension were arbitrarily classified as salt-sensitive or salt-resistant depending on whether their mean arterial pressure did or did not increase by 8% or more when sodium intake was increased. The responses of the two subsets and of five normal subjects to sodium intakes of 9, 109, and 249 mEq/day given for 7 days were as follows: The salt-sensitive subjects retained more sodium than normal and plasma or urinary norepinephrine did not decrease when they were given a high sodium intake; urinary dopamine was normal but did not increase normally when sodium intake was increased. The salt-resistant subjects excreted sodium normally and plasma and urinary norepinephrine was decreased by 30 and 37%, respectively, when they were given a high sodium intake; urinary dopamine was supernormal and did not increase further when sodium intake was increased. Cumulative sodium retention during the high sodium intake was directly related to the percentage of change in plasma norepinephrine in the hypertensive subjects, suggesting that renal adrenergic activity was a factor in the impaired sodium excretion in the salt-sensitive patients. Cumulative sodium retention and the percentage of change in plasma norepinephrine were inversely related to urinary dopamine in the hypertensive subjects, suggesting that increased formation of dopamine in renal and neural tissue in the salt-resistant subjects may have been responsible for the differences between the subsets in renal and adrenergic responses to a high sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular function in malnutrition.

Twenty-one dogs were chronically instrumented with ultrasonic left ventricular dimension transducers and micromanometers to elucidate the effects of acute protein-calorie malnutrition on cardiac function. Ten dogs received a regular diet for 3 wk, whereas 11 dogs received a protein-calorie-deficient diet designed to achieve a mean weight loss of 20-25% over a 3-wk period. Studies of cardiac function were performed in awake intact animals at base line (1 wk postoperatively) and after 3 wk. In the malnourished dogs, cardiac mass was lost in proportion to total body mass loss. Mean cardiac mass fell from 115 to 91 g. This was largely due to wall thinning in this group. Heart rate dropped from 125 to 79 beats/min with malnutrition and ejection fraction increased from 29.8 to 34.6%. Cardiac output fell from 2.98 to 2.38 l/min, but cardiac index normalized to body surface area was unchanged. No significant changes in hemodynamics were observed in the control group. In the malnutrition group, global ventricular contractility, as measured by the load-independent index of systolic function or the slope of linear relationship between end-systolic pressure and end-systolic volume (EmaxPV), decreased slightly from 3.56 to 2.81 mmHg/ml (P = 0.07). However, Emax calculated from circumferential stress and strain data was unchanged. This indicates that depressed contractility was due to loss of cardiac muscle mass rather than any change in the myocardium per se. Response to beta-adrenergic stimulation was unchanged with starvation. Acute protein-calorie malnutrition causes significant cardiac atrophy that is reflected in decreased cardiac output and slightly reduced contractility but not in intrinsic properties of the myocardium.

Chronobiology of serum iron concentration in subjects of different ages at different geographic locations.

The circadian rhythm in serum iron concentration was studied in 61 elderly men (74 +/- 6 years of age) and 93 women (78 +/- 8 years of age) in Bucharest, Romania, in 81 clinically healthy boys and 103 girls (11 +/- 1.5 years of age) in Tîrgoviste, Romania, in 4 elderly men and 19 women (71 +/- 5 years of age) and in 75 young-adult men (24 +/- 11 years of age) and 52 women (24 +/- 9 years of age) in St. Paul, Minnesota, USA. Six samples were obtained from each subject around a 24-hour span. The sampling sessions in the elderly subjects in Romania and in the children extended over all four seasons. A circadian rhythm statistically verified by Cosinor analysis was evident in all groups in both locations. A statistically significant sex difference with lower circadian mean (mesor) and a lower amplitude in the women was found in the Romanian elderly subjects. The children in Romania showed no sex difference in any circadian rhythm parameters. The young adult subjects in Minnesota showed a significantly higher mesor and a phase delay in the men as compared with the women. The elderly subjects of both sexes at both geographic locations had a lower circadian mesor than the young adults and the children. In the Romanian elderly subjects also the circadian amplitude was lower, which was not the case in the Minnesotans. While the acrophase in the elderly subjects and in the children in Romania was comparable (0928 and 0932 local time resp.), the young adults in Minnesota showed in comparison to the Romanians a phase delay (1132 local time) and the elderly in Minnesota showed a phase advance (0732 local time) in comparison to all other groups. The latter finding will have to be confirmed by more extensive studies. In the elderly subjects in Romania the circadian rhythm in serum iron concentration was in phase with the circadian rhythms in total serum bilirubin and alkaline phosphatase but showed significant phase differences from the circadian rhythms in serum albumin, urea nitrogen (BUN), gammaglutamyl transferase (Gamma-GT), serum globulins, glucose, insulin and total serum proteins. The elderly subjects in Romania showed a statistically significant circadian phase delay in summer as compared to fall but showed no seasonal variation of the mesor. The children showed a circadian phase advance in fall as compared to the other seasons and a seasonal variation of their mesor with higher values in spring and summer as compared with winter and fall.(ABSTRACT TRUNCATED AT 400 WORDS)

Circadian and circannual variations of thyroid function in children 11 +/- 1.5 years of age with and without endemic goiter.

A group of 194 children 11 +/- 1.5 years of age from Tirgoviste, Romania, an endemic goiter area, were studied over a 24-hr span (six blood samples at 4-hr intervals) during all four seasons. One hundred thirty-four of the children had some clinical evidence of endemic goiter, and 60 had none. Total and free T3 and T4, reverse T3, thyroglobulin, thyroxin-binding globulin (TBG; three seasons only), and TSH were studied. The circadian rhythms were analyzed by cosinor and the circannual variations by ANOVA. Children with and without endemic goiter showed circadian rhythms in all functions studied except free T4 for which no statistically significant rhythm was detected in the children with goiter. There were differences in the acrophase of total T3, free T3, and TBG, with phase advance in the children with goiter in total T3 and free T3 and a phase delay in TBG. Mesor and amplitude showed no differences except in total T4 for which the amplitude in the children with goiter was statistically significantly lower than in the children without goiter. Children with and without endemic goiter showed seasonal variations in total T4 and free T4 as well as total T3, free T3, and reverse T3, with the highest values in the fall; in thyroxin-binding globulin the highest values were in the winter; and in TSH the highest values were in the summer. There was no significant seasonal variation in thyroglobulin. There was no difference in the circannual variation between children with and without endemic goiter.

Circannual variations in blood pressure, urinary catecholamine excretion, plasma aldosterone, and serum sodium, potassium, calcium, and magnesium in children 11 +/- 1.5 years of age.

A total of 194 clinically healthy children 11 +/- 1.5 years of age were studied during different seasons. Systolic and diastolic blood pressure were determined by auscultatory endpoints, and blood and urine were collected at 4-hr intervals over a 24-hr span. Urinary norepinephrine, epinephrine, and dopamine were determined by HPLC, plasma aldosterone by RIA, serum sodium and potassium by ion-specific electrode, and calcium and magnesium by colorimetry. The circadian means showed statistically significant circannual variations in all variables except epinephrine. The highest circadian means of systolic and diastolic blood pressure and of urinary norepinephrine occurred during winter; the highest values of plasma aldosterone, serum potassium, and urinary dopamine were found in fall, those of serum calcium and magnesium during the summer, and that of serum sodium in spring. Circannual rhythms characterize functions related to blood pressure regulation in children. The circannual elevation of blood pressure (within the usual range) and of norepinephrine were both found to occur in winter. This time relation may have a functional significance, although a causal relationship is not proven by the temporal coincidence of two rhythms.

Chronobiology of catecholamine excretion in different age groups.

Urine was collected at 4-hr intervals over a 24-hr span in 87 boys and 106 girls 11 +/- 1.5 years of age and over one or several 24-hr spans in 62 elderly men and in 85 elderly women 77 +/- 8 years of age. Epinephrine, norepinephrine, and dopamine were determined by HPLC. The data were analyzed by cosinor and by one-, two-, and three-way ANOVA. Children and elderly subjects showed circadian rhythms of urine volume and of the excretion of norepinephrine, epinephrine, and dopamine. While the urine volume was higher in the elderly subjects than in the children, norepinephrine, epinephrine, and dopamine excretion in the girls and epinephrine in the boys showed a statistically significantly higher mesor than in the elderly subjects of the same sex. There was a sex difference, with lower values in all variables in the girls and women compared to their male counterparts; the circadian amplitudes of norepinephrine, epinephrine, and dopamine in the girls and of epinephrine in the boys were higher than the circadian amplitudes in the elderly subjects. The circadian timing in urinary excretion between the elderly subjects and the children was different, with a consistent phase delay; the acrophase of the circadian rhythm in the elderly subjects moved in the night hours. In contrast, there was no age difference in the acrophase of norepinephrine and epinephrine excretion or in dopamine in the females. In the males, the circadian rhythm in dopamine excretion in the elderly subjects did not quite reach statistical significance at the P less than 0.05 level. Circannual variations with high values in winter and low values in spring and summer were found in norepinephrine excretion in boys, girls, and elderly women, but not in elderly men. In neither age group was there a statistically significant seasonal variation in epinephrine. Only in girls was a statistically significant circannual rhythm in dopamine excretion found, with highest dopamine values in the fall and lowest values in winter and spring.

Circannual rhythms of laboratory measurements in serum of elderly subjects.

A total of 160 elderly subjects 77 +/- 8 years of age were studied in 201 24-hr profiles consisting of six blood samples collected at 4-hr intervals. The sampling sessions were spread over all four seasons. The circadian means were analyzed (one-way ANOVA) for the presence of circannual variations. Statistically significant circannual variations were found in the serum concentrations of albumin, bilirubin, calcium, chloride, CPK, globulin (calculated), glucose, LDH, potassium, sodium, triglycerides, uric acid, and total protein. The data presented indicate that many chemical constituents commonly measured in human serum and urine show seasonal variations in elderly subjects, some of which are large enough to present potential diagnostic problems. Others may not pose diagnostic problems in today's practice of laboratory medicine, but indicate seasonal changes in metabolic functions or, if endogenous in nature, circannual rhythms that may be of physiologic and pathobiologic importance. There is a need to quantify certain of these rhythms as a predictable portion of variability in laboratory values and presumably as an indicator of human health.

Endocrine factors of blood pressure regulation in different age groups.

Systolic and diastolic blood pressures were measured and blood and urine were collected at 4-hr intervals over a 24-hr span in 194 diurnally active children 11 +/- 1.5 years of age and in 278 elderly subjects 77 +/- 8 years of age. Plasma aldosterone and cortisol were determined by radioimmunoassay, serum calcium and magnesium on a Dupont ACA, and urinary epinephrine and norepinephrine by high-pressure liquid chromatography. In the children, there was a slight but statistically significant positive correlation between the circadian means in systolic blood pressure and norepinephrine excretion and serum calcium, and between diastolic blood pressure and norepinephrine excretion and serum calcium and magnesium. In the elderly subjects, there was a positive correlation between the circadian mean in diastolic blood pressure and aldosterone. In contrast to the findings in the children, however, the elderly subjects showed a negative correlation between the circadian means in norepinephrine excretion and in systolic and diastolic blood pressures. These investigations indicate differences in the regulation of the blood pressure within the "usual range" between children and elderly subjects. This has to be kept in mind in the study of essential hypertension, a syndrome that may be caused by different mechanisms in different age groups.