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Biomedical subjects

D Lakatua

Publications and source records attributed to D Lakatua.

At least 19 recordsLinked to original sources
PubMed1992

Chronobiology of pituitary-thyroid functions.

One hundred ninety four children, 11 +/- 1.5 years of age and 166 elderly men and women, 77 +/- 8 years of age were studied over one or (in the case of some of the elderly subjects) over several (up to 4) 24-hours spans. All subjects were diurnally active and rested at night and followed their regular three meal pattern. The subjects were studied in subgroups of 20-25 during all four seasons of the year. During each study, blood was collected at 4 hour intervals over one 24-hour span (6 samples). Circadian and circannual variations were found and described by cosinor analysis in the children as well as in the elderly subjects. The children with endemic goiter (134) as compared to those without endemic goiter (60) showed a slight circadian phase advance in plasma total and free T3, a lower circadian amplitude of total T4 concentrations and the absence of a detectable circadian rhythm in free T4. The children with goiter showed a phase delay in serum TBG. There was no difference between the children with and without goiter in the circadian MESOR of any thyroid parameter or of TSH. The children with endemic goiter in the region of Dimboviţa, Romania, are in clinical and biochemically euthyroid condition with some slight poral abnormalities of thyroid function. Seasonal variations in children and elderly patients showed the highest values of TSH during summer and fall, while the highest values in the plasma concentrations of thyroid hormones were found during the cold season of the years. Thyroglobulin in the children showed a circadian rhythm but no seasonal variation.

Aged↗
PubMed1989

Chronobiology, growth hormone and healthy and malignant growth.

Chronobiology, the computer-aided science (logos) of life (bios) in time (chronos), provides novel concepts, tools and facts for those concerned with mitosis, growth and growth hormone (GH). GH concentrations in human plasma demonstrate a statistically significant circadian rhythm on a 6h as well as on a 24h rest-activity cycle. On a 24h routine of light (L) and darkness (D), alternating at 12h intervals, and in continuous D, circadian mitotic rhythms in mice persist as a feature of growth or regeneration. A circadian cell cycle commences with an increase in phospholipid labeling, followed by an increase in cytoplasmic RNA formation, preceding, in regular sequences, an increase in nuclear DNA formation and the next mitotic peak in those cells that are dividing in a growing or regenerating (reversibly "post-mitotic') rodent liver. About 5-day (presumably estral) and about 7-day (circaseptan) components as well as circadians are resolved as a spectrum of mitotic rhythms in rodent cornea. The effects of hormones such as GH or a synthetic ACTH analogue, ACTH 1-17, depend upon the circadian cell cycle stages when the agent is administered. No effect or statistically significant effect can be the result only of 1) the timing of a fixed dose of GH or 2) of the timing of the samples taken to investigate any effect. For both the timing of administration and the assessment of effects, a multifrequency spectrum of rhythms, if taken into account, can provide (in lieu of a considerable and often formidable source of variation) a new critical dimension of growth and development.

Adolescent↗
PubMed1988

Natural killer cell activity: age, estrous- and circadian-stage dependence and inverse correlation with metastatic potential.

The timing within the estrous cycle of surgical removal of a transplanted murine mammary tumor profoundly influences the frequency of pulmonary metastases. We investigated the potential role of the immune response in this phenomenon by measuring splenic natural killer (NK) cell activity and interleukin-2 (IL-2) production in syngeneic tumor-free mice of two age groups at each of two circadian times and in each of four estrous stages. Estrous stage was determined by assessment of vaginal smear cellularity immediately prior to killing and spleen harvest. In a single-cell splenocyte preparation, NK cytotoxicity against a standard tumor cell target was assessed using a radiolabeled chromium release assay while IL-2 activity was determined in a bioassay utilizing the IL-2-dependent CTLL-2 cell line. Mice from the younger group were found to have eight-fold higher NK activity and 35% greater IL-2 production. After normalization of NK and IL-2 values for age, a highly statistically significant difference in NK activity was found among the four estrous and between the two circadian stages of sacrifice. NK activity was greater during the daily resting span across every estrous stage. IL-2 values were highest in diestrus and proestrus when sampled in the light span and in estrus-metestrus when sampled in the dark. The stages within the fertility cycle associated with lowest metastatic potential (proestrus/estrus) correspond precisely with those of highest splenocyte NK activity. These results indicate that an important component of the cellular immune response varies rhythmically both during the fertility and circadian cycles of the host. The rhythmic changes in NK activity may be in part responsible for the similarly rhythmic frequency of postsurgical metastatic dissemination.

Age Factors↗
PubMed1988

[Blood levels of dehydroepiandrosterone sulfate (DHEA-S) and the risk of breast cancer].

In North American women at low or high risk of developing breast cancer, as assessed by an epidemiologic questionnaire, the plasma concentration of dehydroepiandrosterone sulfate shows a statistically significant circannual variation. In adolescents, in all seasons, circulating dehydroepiandrosterone sulfate is a classifier of the risk of developing breast cancer, a relatively low concentration of this hormone being associated with an increased risk.

Adolescent↗
PubMed1988

Splenocyte natural killer cell activity and metastatic potential are inversely dependent on estrous stage.

We have previously shown that the timing of surgical removal of an estrogen-receptor-bearing mammary adenocarcinoma within the estrous cycle of the female C3HeB/FeJ mouse profoundly influences the frequency of subsequent tumor cell metastasis. In order to investigate the role of the immune response in this phenomenon, we measured splenic natural killer (NK) cell activity and interleukin-2 (IL-2) production in 80 female cycling mice, 16 to 18 weeks old, assigned to one of four estrous stages as determined by relative quantity of vaginal cellularity; proestrus, estrus, metestrus, and diestrus. After prolonged synchronization on 12-hours-on, 12-hours-off light-dark circadian schedules, daily vaginal smears were obtained for 2 weeks to characterize estrous cycling. On the day the animals were killed, vaginal smears were performed and single-cell suspensions were prepared from the harvested spleens. Direct cytotoxicity of spleen cells against the YAC tumor target was assessed immediately in a 3 1/2 hour 51Cr release assay and expressed as NK activity in lytic units (LU 20%). IL-2 production was determined in a bioassay with the IL-2-dependent CTLL-2 cell line. Significant differences in NK activity among estrous stages mimicking the variation found in frequency of surgical cure from mammary adenocarcinoma were observed (p = 0.035; one-way analysis of variance), with the time of lowest metastatic potential corresponding precisely with the time of highest splenocyte NK activity. These both occurred during the proestrus and estrus stages, characterized by high fertility, ovulation, and peak FSH, LH, and estrogen concentrations. In addition, NK activity was found to correlate significantly with IL-2 production (r = 0.4, p less than 0.0005). These results indicate that important components of the cellular immune response to cancer vary rhythmically with hormonal changes in the host and may represent one of the factors affecting the delicate balance between host and tumor that alters the frequency of postsurgical metastatic dissemination.

Animals↗
PubMed1987

Rhythmic pineal-hypophyseal-adrenal intermodulations ex vivo.

To assess circadian and circaseptan rhythmic intermodulation, female mice, kept on regimens of 12 hr light (L) alternating with 12 hr of darkness (D) (LD 12:12) were sampled for 1-13 days at six circadian stages. Pineals were removed and homogenized with 0.9% NaCl. Adenohypophyses were bisected and incubated in Krebs-Ringer buffer (KRb) and/or with 10(-7) M melatonin (Mt). Adrenals were bisected and incubated with KRb, with 10(-7) M Mt, with 0.05 IU of ACTH 1-17 (Sy; Hoechst, Italy), or with Sy + 0.025 ml of the aqueous pineal homogenate (APH). ACTH and prolactin (PRL) in adenohypophysis incubation fluid were determined by radioimmunoassay (RIA), and corticosterone in adrenal incubation fluid was determined by RIA or by a fluorometric method. By this chronobiologic approach, time series were collected systematically in the search for predictable variability. Once these series reveal an algorithmically formulatable pattern, with a waveform validated by inferential statistical means, they are graded in terms of complexity as alpha, beta, gamma, and delta rhythms. Spontaneously (alpha-) rhythmic along the 24-h scale is the corticosterone produced by bisected adrenal glands incubated with KRb only, and the Mt content of the APH, in keeping with earlier work. Reactively (beta-) rhythmic is the response, again along the 24-hr scale, of the adrenal to Sy or Mt and the response of the anterior pituitary to Mt at different circadian times. Modulatory (gamma and delta) rhythms characterize the Mt effect on the (beta-rhythmic) adrenal stimulation by Sy. Chronomodulations thus emerge as more or less complete sequences of a decrease, no effect and/or increase; or, rather, as an attenuation, no effect and/or amplification by the pineal, of the pituitary effect upon the adrenal. Linear least-squares rhythmometry, mostly single cosinors, describes and quantifies circadian (alpha, beta, and gamma) and infradian (delta) rhythms in the original series and in the differences in responses [beta - alpha] and [gamma - beta] (P less than 0.001 in each case). These spontaneous alpha, response beta, modulatory gamma, and frequency-divided delta rhythms reveal a collateral neuroendocrine hierarchy, characterized by the pineal feedsideward phenomenon, as a feature of interactions recurring with circadian and infradian frequencies.

Adrenocorticotropic Hormone↗
PubMed1987

Individualized principal component analysis of endocrine circannual variability.

The technique of principal component (PC) analysis (PCA) of multivariate observations is a method that allows dimension reduction of multivariate data for further analysis. It is here introduced as a means of selecting chronobiologically important variables that can be further studied by an analysis of variance. The use of PCA is illustrated for a study of major temporal sources of human endocrine variability. Contributions to temporal variability by seven steroidal and six nonsteroidal hormones are compared in samples available at 100-min intervals for 24 hr in three seasons for each of three clinically healthy individuals: an adolescent woman, a menstrually cycling woman, and a postmenopausal woman. On an individualized basis, it is ascertained that the first principal component, a new variable, is primarily determined by steroids and that PCA can single out variables displaying interseasonal (circannual) differences validated as statistically significant by a subsequent analysis of variance. The variables here scrutinized and identified as contributing to the PC, however, need not all differ with statistical significance along the scale of the seasons. The steroids contributing the first principal component are DHEA-S and an estrogen in all three individuals studied, cortisol and aldosterone in two of them, and 17-OH progesterone in one case.

Adolescent↗
PubMed1986

Cisplatin chronotherapy and disulfiram rescue reduce toxicity without interfering with anticancer activity: animal findings and preliminary clinical experiences.

Cisplatin-induced mortality and nephrotoxicity are each predictably worse when the drug is given at certain points within the circadian schedule. Oral disulfiram protects rats from toxic effects at some circadian stages but not others. This manuever does not diminish the anticancer activity of cisplatin in these rats. Human beings given 2 g of oral disulfiram and high doses of cisplatin at the circadian stage associated with least cisplatin nephrotoxicity (prospectively determined potassium excretion acrophase) suffer little or no kidney damage. Disulfiram administration apparently does not interfere with the antineoplastic activity of cisplatin in humans. This is the first demonstration of the feasibility of assignment of treatment time according to a measure of the patient's 'internal clock' as assessed by pretreatment marker rhythmometry. It also establishes the feasibility of giving disulfiram to human beings.

Aged↗
PubMed1984

Circadian and circannual rhythms of hormonal variables in elderly men and women.

A group of fourteen men (73 +/- 5 yr of age), and eighteen women (77 +/- 7 yr of age) institutionalized at the Berceni Clinical Hospital, Bucharest, Romania, were studied over a 24-hr span once during each season (winter, spring, summer and fall). All subjects followed a diurnal activity pattern with rest at night and ate three meals per day with breakfast at about 0830, lunch at about 1300 and dinner at about 1830. The meals were similar, although not identical for all subjects during all seasons. On each day of sampling blood was collected at 4-hr intervals over a 24-hr span. Seventeen hormonal variables were determined by radioimmunoassay. Statistically significant circadian rhythms were detected and quantitated by population mean cosinor analysis in pooled data from all four seasons in both sexes for ACTH, aldosterone, cortisol, C-peptide, dehydroepiandrosterone-sulfate (DHEA-S), immunoreactive insulin, prolactin, 17-OH progesterone, testosterone, total T4 and TSH. In women, estradiol and progesterone also were determined and showed a circadian rhythm during all seasons. Total T3 and FSH showed circadian rhythm detection by cosinor analysis in the men only; LH showed no consistent circadian rhythm as group phenomenon in men or women. A circannual rhythm was detected using the circadian means of each subject at each season as input for the population mean cosinor in the women for ACTH, C-peptide, DHEA-S, FSH, LH, progesterone, 17-OH progesterone and TSH. In the men, a circannual rhythm was detected for ACTH, FSH, insulin, LH, testosterone and T3. There were phase differences between men and women in ACTH, FSH and LH. In those functions in which both the circadian and circannual rhythms were statistically significant, a comparison of the amplitudes showed in the women a higher circannual rather than circadian amplitude for DHEA-S. In 17-OH progesterone, TSH and C-peptide, the circadian amplitude in women was larger. In men, the circannual amplitude of T3 was larger than the circadian amplitude and in insulin the circadian amplitude was larger than the circannual amplitude. There was no statistically significant difference between the circadian and circannual amplitudes in the women in ACTH and progesterone and in the men in ACTH and testosterone.

Aged↗
PubMed1983

Circadian as well as circannual rhythms of circulating aldosterone have decreased amplitude in aging women.

Age differences in the characteristics of the circadian rhythm in circulating radioimmunoassayable aldosterone were studied on nine 20 to 26 year-old and ten 70 to 78 year-old women and ten 23 to 26 year old and ten 70 to 80 year old men in Würzburg, West Germany. These diurnally active-nocturnally resting subjects were sampled every 3 hours for 15 hours. A classical analysis of variance and a multivariate analysis of rhythm characteristics revealed major effects of age exerted on the circadian aldosterone amplitude in women (p = 0.003) but not in concomitantly sampled men. These observations complement the study of circadian and circannual rhythms in 8 young adults (15-21 years), 10 mature adults (29-36 years) and 10 post-menopausal (44-59 years) North American women, sampled at 100 minute intervals for 24 hours, once in each season, and document that the adrenocortical aldosterone-producing system remains rhythmic with at least two frequencies up to the late decades of human life, although in women it may be characterized by a reduction in the extent of spectral change after 70 years of age.

Adult↗
PubMed1983

Circadian pineal modulation of pituitary effect on murine corticosterone in vitro.

An old controversy is resolved as a novel effect: In a rhythmic fashion, aqueous pineal homogenate (APH) enhances, attenuates or leaves unaffected the production of corticosterone by mouse adrenals incubated with pituitary media. All glands stem from the same circadian stage in these (isophasic) studies on 72 female CD2F1 mice, standardized for two weeks in L 0600-1800 and D 1800-0600. Every 4 hours during a 24-hour span, 12 mice were killed. Pineals were removed for the preparation of APH and stored at 4 degrees C. Hypothalami, pituitaries and adrenals were removed, bisected and placed in wells containing 1 ml Krebs-Ringer buffer (K), at 4 degrees C, until incubation. At each circadian stage, bisected adrenals were incubated with 95% O2 and 5% CO2 at 37 +/- 1 degree C for 5 hours, with K only or with the addition of 0.05 IU ACTH 1-17 or APH or with isophasic pituitary or hypothalamic preincubation media with and without APH or muscle. Media were stored at -20 degrees C until corticosterone RIA. A circadian rhythm (p less than 0.05) characterized corticosterone production after stimulation by the pituitary alone or with APH. The overall modulatory effect of APH is an increased circadian amplitude of adrenal corticosterone production, in response to the isophasic pituitary.

Adrenal Glands↗
PubMed1982

Ethylene oxide induced sister chromatid exchange in human lymphocytes using a membrane dosimetry system.

In an earlier study, we demonstrated that human exposure to ethylene oxide (EO) during sterilization procedures was associated with increased sister chromatid exchanges (SCE) in cultured peripheral blood. To study further toxic and mutagenic properties of EO in vitro, we devised a membrane dosimetry system which can be used to expose lymphocytes in peripheral blood to specified amounts of EO. The system consists of an exposure chamber, cell culture dishes to which are applied plastic membranes of varying diameters and an infrared analyzer used to monitor ambient EO concentrations in the system. Aliquots of EO-exposed media were subjected to gas chromatography for quantitation. Our preliminary analyses of the cultured cells indicate that the membrane dosimetry system we developed is capable of reproducibly delivering quantities of EO to target cells. Elevated SCEs were observed at as little as 10 micrograms/ml (in media) during a 20-min exposure period. A significant dose-response relationship between SCE and EO dose was recorded up to 35 micrograms/ml, the highest dose tested. Lymphocytes at 35 micrograms/ml showed a fourfold increase in SCE compared to control cultures. We conclude that the membrane dosimetry system provides a reproducible method to investigate EO mutagenesis in human cells in vitro and may prove applicable to a wide range of mutagenic gases.

Chromatography, Gas↗
PubMed1981

Circadian host and tumor rhythms in Balb/C mice, rhythm induction in Harding-passey Melanoma.

The Harding-Passey melanoma in Bal/C or CD2F1 female mice shows, in light synchronized (LD12:12) undisturbed animals, no detectable circadian rhythm in cell proliferation as gauged by 3H-thymidine uptake in DNA. Manipulation of the animals and saline injection (.2 ml/20 gm), hydroxyurea injection (10 mg/ .2 ml/20 gm), and ACTH-17 (HOE 433) (.4 IU/ .2 ml/20 gm) induced a statistically significant circadian variation detected in several studies 4-24 and 16-36 hours after the treatment, only if the injection is given at the beginning of the light phase (LD12:12). Thus, tumor synchronization in this model is critically dependent upon the circadian stage of administration of the synchronizing agent. Endogenous and exogenous ACTH seem to be the synchronizing agent. Hydroxyurea in the dose given shows no additional effect.

Animals↗