Twenty-nine year study on circadian distribution of urinary zinc levels of same male subjects.

OBJECTIVES: To examine the circadian distribution and total 24h levels of urinary zinc (Zn) in same male subjects over an extended period of time in order to ascertain their relationship with aging. MATERIALS AND METHODS: Eight young army volunteers served as subjects over a period of 29 years: 1969, 1979, 1988, 1998. By 1979 three of them became latent diabetics. Complete physical examination, anthropometric measurements and same procedural protocol was followed in each study. Samples were collected over 3 hour periods for 24 hours in the middle of each month of May. Urine aliquots were analyzed for creatinine, using conventional laboratory procedure. Zn was analyzed using Atomic Absorption Spectrophotometry in 1969, and 1979 and by Inductively Coupled Plasma, in 1988 and 1998. RESULTS: Over the course of 29 years the circadian distribution of Zn was altered by decrease in amplitude in Zn levels, while the 24h concentrations of Zn decreased progressively with increasing age in healthy and diabetic subjects: Healthy; 966+/-130 microg at age of 29; 666+/-14 microg at 39; 511+/-80 microg at 48; and 555+/-71 microg at age of 58y; Diabetics exhibited similar trend; 1757+/-60 microg at age 28; 1253+/-40 microg at age 38, 1132+/-31 microg at 47, and 1025+/-11 microg at the age of 57. Anthropometric measurements in each study period revealed significant increases in diabetic subjects for body weight, body surface area, BMI and significant decrease in body heights of both groups. CONCLUSIONS: The daily excretion of urinary Zn over the 29 years period decreased by 42% in healthy and diabetic subjects. Although there appears to be a lack of a reliable index of intracellular Zn status to accurately monitor and control zinc deficiency in younger and older populations, the present data suggest that depletions of Zn are also evident in healthy aging subjects whose daily diet was not deficient in zinc.

Circadian distribution of serum cytokines in multiple sclerosis.

AIMS: The purpose of this study was to examine circadian distribution of selected cytokine levels (IL-2, IL-10, GM-CSF, TNF-alpha, and IFN-gamma) in serum of subjects with active Multiple Sclerosis (MS) and non-MS subjects. MATERIALS AND METHODS: Six females (36-56y) and five males (52-68y) with active MS volunteered and consented for the study conducted at Special Diagnostic Ward of this hospital. All subjects gave their medical history and were given complete physical examination. Low purine meals were served at 16:30, 07:30 and 13:00 h. Lights were "OFF' at 22:30 hr and "ON" at 06:30h. Blood collections were made at 3h intervals over a 24h period of time. Six healthy male subjects (53-76y) subjects' data were obtained from a study conducted 3 years previously using the same procedural protocol. Cytokine assays were assessed using commercial enzyme-linked immuno-absorbent procedure. Time series of average data and the range of change between the highest and lowest concentrations are presented for MS subjects along with data from non-MS subjects. RESULTS: IL-2, IL-10, and GM-CSF levels were significantly reduced in females with MS when compared with levels of healthy subjects while their IL-6 levels were increased. The IL-6, GM-CSF and TNF-alpha levels in males with MS were below detection limits. The TNF-alpha levels were essentially similar in MS females and healthy subjects. CONCLUSIONS: These preliminary studies, although with very small number of patients and healthy male controls appear to suggest that the circadian analysis of cytokines and other markers of immunity may have utility in understanding the pathogenesis of diseases like MS.

Relationships between 24h observations in intraocular pressure vs blood pressure, heart rate, nitric oxide and age in the medical chronobiology aging project.

OBJECTIVE: To evaluate associations between intraocular pressure (IOP) and blood pressure (BP), heart rate (HR), serum nitric oxide (NO), diurnal variations, diabetes and aging in data collected during 24h studies of men conducted over 34y. MATERIALS AND METHODS: As part of the Medical Chronobiology Aging Project, male Army veterans, ages 22 to 81y, without a history of eye disease, were studied around-the-clock in May 1969 (n = 13), 1979 (n = 11), 1988 (n = 11), 1993 (n = 11), 1998 (n =12) and 2003 (n = 10). Measurements of IOP (R & L eyes, supine position), BP and HR (sitting position), and collection of blood were obtained every 3h (8 readings/24h) from 19:00h to 16:00h the next day. Individual time series were analyzed for circadian characteristics by the least-squares fit of a 24& 12h cosine. After normalizing all data to percent of mean to reduce inter-subject variability in levels, grouped data were analyzed for time-effect by ANOVA and for circadian rhythm by multiple component (24h&12h) cosine fitting. Individual 24h averages were analyzed by simple and multiple regression for relationships between IOP and systemic variables, diabetic status and age. RESULTS: Over the 34y study span, 22 men provided sixty-three 24h profiles for IOP & HR, 61 for BP, and 21 for NO. Using all normalized data, a significant circadian rhythm was found for each variable at p <0.001. Circadian peaks (orthophases) are located in the late morning for IOP-R (10:20h) and IOP-L (10:52h), and in the evening for HR (18:52h), NO (20:00h), SBP (20:40h) and DBP (21:44h). An out-of-phase relationship of about 10h is noted on a group basis between IOP vs BP, HR and NO. The locations of individual circadian peaks for IOP-R were found around the clock, but with a significant predominance between 10:00 and 16:00h (day type), and 04:00-10:00h (morning type). In contrast, BP, HR and NO showed a significant clustering of evening type or night type peaks. The overall mean IOP for the right eye was slightly, but not significantly, higher than the left eye (17.60+/-0.21 vs 17.34+/-0.18 mmHg; p = 0.385), with a strong positive correlation between both eyes (R = 0.952, p <0.0001). IOP showed a significant positive correlation with SBP (R = 0.49, p <0.001), diabetic status (R = 0.47, p <0.001), age (R = 0.32, p = 0.011), and HR (R = 0.28, p = 0.031). A multiple regression using SBP, DBP, HR, age and diabetic status (5 men became diabetic over the 34y study span) as independent variables resulted in SBP being the strongest predictor of IOP (p = 0.0001), followed by DBP (p = 0.0103). After adjustment for BP, independent effects of age (p = 0.187), HR (p = 0.789) and diabetic status (p = 0.153) were eliminated from the prediction equation. CONCLUSIONS: The results of these studies reveal significant circadian variations in IOP, BP, HR and NO, with peak levels, on average, near noon for IOP and in the evening for BP, HR and NO. An increase in SBP was associated with an increase in IOP. While SBP and DBP are significant predictors of IOP levels, single measurements during regular clinic hours may not reveal the full functional relationship between the variables measured in our studies. Therefore, circadian information on total 24h patterns may contribute to the reliability of diagnosis and guide proper individualized timing of optimal patient management (e.g., for glaucoma, hypertension, diabetes, among other conditions).

Circadian distribution of hematology variables in subjects with multiple sclerosis.

Hematology variables were measured in blood samples obtained every 3h (8/24h) from 10 multiple sclerosis (MS) patients and 34 healthy subjects and analyzed for circadian characteristics using the population multiple-components method. Red blood cell (RBC) and hemoglobin levels as well as hematocrits exhibited circadian rhythms with minimal amplitudes in healthy individuals and insignificant variability in the smaller group of MS patients. In contrast the total white blood cell (WBC) and platelet counts for MS patients and healthy individuals both showed significant circadian characteristics while the mean 24h WBC and platelet levels did not significantly differ between the two groups. When the different WBC subsets were examined independently, statistically significant circadian rhythms were seen for lymphocytes and eosinophils for both MS patients and healthy individuals and for neutrophils only in the latter. Moreover, the 24h mean levels of lymphocytes, basophils, and eosinophils were significantly higher for the healthy controls while those of monocytes were higher for the MS patients. However, of all the variables tested with significant circadian rhythms in both groups of individuals, only those of lymphocyte numbers exhibited different patterns with somewhat higher amplitude in healthy individuals and a peak level occurring over an hour after that of MS patients. These changes may be the reflection of a disturbance in the regulation of patterns of lymphocyte activity and migration in MS patients. In addition, the elevation in circulating monocytes in MS patients is consistent with the inflammatory nature of the disease.

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.

Normal-appearing captopril MAG-3 renal scintigraphy in hemodynamically significant renal artery stenosis. A case report.

The finding from a normal-appearing angiotensin converting enzyme (ACE)-inhibitor renal scan is generally reassuring to the physician screening for renovascular hypertension. In fact, the false-negative rate for captopril scintigraphy is very low. Possible reasons for false-negative scans have not been well documented. A fifty-two-year-old man was evaluated and found to have renovascular hypertension on two occasions, at initial presentation and again eight months later (restenosis had occurred). Renovascular hypertension was present on both occasions as judged by decline of blood pressure following angioplasty of right renal artery stenosis (approximately 80% and approximately 70% stenosis on the two occasions, respectively). However, ACE-inhibitor renal scanning with 99mTc MAG-3 gave disparate results on the two occasions. The first study using oral captopril (25 mg) indicated a low probability of renal artery stenosis, whereas the second study done with the patient regularly taking lisinopril (10 mg daily) was markedly positive. Possible reasons for the initial negative study include poor absorption of oral captopril or inadequate inhibition of the renin-angiotensin system by the 25 mg dose.

Leptomeningeal metastasis: MR imaging.

Seven patients with central nervous system neoplasia and leptomeningeal metastases, proved either at initial diagnosis or on follow-up with contrast material-enhanced computed tomography (CT), were evaluated with magnetic resonance (MR) imaging. In two patients, diffuse sulcal enhancement on CT scans was inapparent on T1- or T2-weighted MR images. Likewise, in four patients diffuse cisternal enhancement on CT scans was not identifiable with MR. Nodular or focal cisternal masses were identified with both CT and MR imaging in three patients; in two, however, MR imaging provided less information. Ependymal and subependymal metastases identified with CT (two patients) were indistinguishable on MR images from periventricular abnormalities of radiation therapy and/or hydrocephalus. These findings suggest that leptomeningeal metastasis may be so subtle or inapparent as to be overlooked with MR imaging alone. Thus, CT and MR imaging should be considered complementary techniques for initial diagnosis and follow-up of tumors with a propensity for leptomeningeal metastasis.