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Biomedical subjects

A Reinberg

Publications and source records attributed to A Reinberg.

At least 19 recordsLinked to original sources

Circadian changes in psychologic effects of ethanol.

Six healthy human males (aged 22 to 26 years) synchronized with diurnal activity from 0700 hours to midnight and nocturnal rest, volunteered to document changes in psychologic variables resulting from ethylalcohol ingestion (ethanol 0.67 g/kg of body weight). For each subject four separate tests were performed at least 1 week apart at 0700, 1100, 1900, and 2300 hours in randomized order, with measurements taken before and 15, 30, 60, 90, 120, 140 minutes postingestion and thereafter at 4-hour intervals during a 24- to 36-hour period. Subjects fasted for 12 hours preceding ethanol ingestion time and for 8 hours thereafter. Self-rated inebreity (visual analogue scale) was greatest after ingestion at 2300 hours and lowest after ingestion at 1100 hours. Both speed to perform random number addition and eye-hand skill tests were slowest after ingestion at 2300 hours. However, changes observed for self-rated physical vigor, tempo, hand-grip strength, and systolic blood pressure did not appear to be ethanol ingestion time dependent. Validated ethanol ingestion time-dependent effects including those of oral temperature were not related to changes in the drug pharmacokinetics.

Adult

Diurnal changes in psychophysiological variables of school girls: comparison with regard to age and teacher's appreciation of learning.

Ninety-five nonresident girls of a private school volunteered for the study with the teachers' help as well as parental consent. Ages were approximately 8, 9, and 10 years. They were synchronized with diurnal activity from 0730 to 2100 h and nocturnal rest. Fatigue, drowsiness, and attention were self-rated using visual analogue scales; oral temperature was self-measured and a letter cancellation test was performed. Each of these variables was measured at school at 0900, 1100, 1400, and 1600 h on Mondays, Thursdays, Fridays, and Saturdays for two consecutive weeks in 1987 (March 30-April 11) and again in 1989 (March 13-25) when the youngest group had become 10 years old. According to conventional teacher evaluation of learning (learning performance) within each group, three subgroups were formed: top third, middle third, and bottom third. Time series (more than 50,000 data) were analyzed according to several statistical methods, but mainly chronograms with ANOVA. Similar diurnal changes in oral temperature were validated for each group and subgroups. The occurrence of a diurnal change in self-rated variables (fatigue and drowsiness) and score in letter cancellation was age related: no detection in the 8-year-old group (and subgroups) and validation (p less than 0.002) in 9- and 10-year-old groups (and respective subgroups). A good learning performance was associated with a reduced drowsiness in school girls of 9 and 10 years. Age-related, time-of-day differences in drowsiness (when detected) as well as learning performance effect were not associated with observed duration of sleep. Validated changes in self-rated fatigue were close to that of drowsiness. At 0900 h, girls of 9 and 10 years were more tired when belonging to the bottom third than top third subgroup. Whatever the time of day, self-rated attention was greater in the top than in the bottom third for these girls. Differences related to learning performance were validated in each grade. However, best scores were recorded for the bottom third in the 8-year-old group, while best scores were provided by top third subgroups in 10-year-old girls. It seems that in girls around 8 years of age, critical changes can be detected with regard to the (ontogenic?) occurrence of time-of-day differences in a set of psychophysiologic variables as well as influential effects of learning performance on the same variables. Reported finding are compatible with the hypothesis of circadian oscillators working at the level of the cortex of the human brain.

Age Factors

Growth hormone (GH) and GH-releasing hormone response to ACTH 1-17 at different times of day. Evidence of a circadian stage dependence.

The effect of injection of ACTH 1-17 on the secretion of GH has been examined at three different circadian stages (07, 14 and 21 h) in the winter. Each week for six consecutive weeks the subjects were investigated before and after I.M. injection either of saline (controls) or 100 micrograms ACTH 1-17. Each subject was his own control. The peak plasma concentration of GH was always found 40 min after the injection. The larger absolute increase and the greater AUC curve were seen following the injections at 14.00 h and 21.00 h. The findings could not be attributed to an effect on GH-RH, since secretion of it remained unchanged during the test.

Adolescent

Effect of shift work on the night-time secretory patterns of melatonin, prolactin, cortisol and testosterone.

In a study of the internal desynchronization of circadian rhythms in 12 shift workers, 4 of them, aged 25-34 years, agreed to be sampled every 2 h during their night shift (0000 hours to 0800 hours). They were oil refinery operators with a fast rotating shift system (every 3-4 days). We found marked changes in the secretory profiles of melatonin, prolactin and testosterone. Melatonin had higher peak-values resulting in a four-times higher amplitude than in controls. With respect to prolactin and testosterone, peak and trough times were erratic and the serum concentrations were significantly decreased in shift workers. Serum cortisol presented a decreased rhythm amplitude together with higher concentrations at 0000 hours in shift workers. This study clearly shows that fast rotating shift-work modifies peak or trough values and rhythm amplitudes of melatonin, prolactin, testosterone and cortisol without any apparent phase shift of these hormones. Whether the large rhythm amplitude of melatonin may be considered as a marker of tolerance to shift work, as reported for body temperature and hand grip strength, since it would help the subjects to maintain their internal synchronization, needs further investigation.

Adult

Chemotherapy of advanced ovarian cancer with 4'-O-tetrahydropyranyl doxorubicin and cisplatin: a randomized phase II trial with an evaluation of circadian timing and dose-intensity.

The efficacy and toxicity of the new anthracycline, 4'-0-tetrahydropyranyl doxorubicin (THP) (50 mg/m2 intravenous [IV] bolus) in association with cisplatin (100 mg/m2 IV as a 4-hour infusion) was assessed in 31 patients with advanced ovarian carcinoma. Twenty-eight patients were assessable for toxicity among whom 25 were assessable for response (International Federation of Gynecology and Obstetrics [FIGO] stage IIIa, four patients; IIIb, 15 patients; IV, six patients). Nine patients had received prior treatment. Patients were randomized to receive schedule (sch) A (THP at 6 hours, then cisplatin from 16 to 20 hours) or sch B (THP at 18 hours, then cisplatin from 4 to 8 hours). Sch A was hypothesized as less toxic since THP was best tolerated in the late rest span and cisplatin near the middle of the activity span in experimental studies. The rate of clinical complete response (CR) was 52%, that of partial response (PR) was 12%, and the overall clinical response rate (CR plus PR) was 64% (sch A, 73%; sch B, 57%). Median progression-free survival and survival times were, respectively, 10 and 19 months. Of 12 patients in clinical CR evaluated at second-look laparotomy, four had a pathological CR (33%), and three had microscopic residual disease (MD). The overall rate of pathological CR was 16%. Sch A was associated with less neutropenia (P = .10), thrombocytopenia (P less than .01), anemia (P less than .01), and renal toxicity (P less than .05) than sch B. Of four patients withdrawn for toxicity, three were on sch B (one death). Mean dose intensities (DIs) of THP and cisplatin, respectively, decreased by 30% and 47% over the five initial courses. Such decrease was significantly more pronounced for sch B than for sch A in previously untreated patients (P from 2-way analysis of variance [ANOVA] less than .01). THP-cisplatin is active against advanced ovarian cancer, and its toxicities can be significantly decreased by dosing THP in the early morning and cisplatin in the late afternoon as compared with THP in the evening and cisplatin the next morning.

Antineoplastic Combined Chemotherapy Protocols

Day-night differences in effects of cosmetic treatments on facial skin. Effects on facial skin appearance.

Two groups of 24 healthy caucasian women, similar with regard to age classes (from 19 to 55) as well as fair and dark complexion of skin and hair, volunteered to use during a 14-day span a conventional facial cream (active placebo: AP) and thereafter, during a 21-day span Noctosome (Noctos). The latter is a new generation of liposome made with non-ionic lipids leading to microspheres which include glycopeptides in the aqueous compartment of the vesicle, alpha-tocopherol ester in the membrane-like structure and sphingo-ceramides at the surface of the microspheres. The aim of the study was to test the beneficial effects of Noctos (vsAP) with respectively morning (7-9-hr) and evening (21-23-hr) applications as facial ointments. Observed differences were validated using several statistical tests: ANOVA, cosinor, etc. Subjects were socially synchronized with a diurnal activity from 7 hr to 23 hr and a nocturnal rest. Each day, at fixed clock hours (7, 10, 20 and 23 hr), each subject used visual analogue scales to self-rate a set of variables characterizing facial aspects. Brilliance of complexion and texture of skin exhibited a circadian rhythm (peak time at 10 hr), both with AP and Noctos. The latter produces a beneficial effect with regard to reference values (AP). The evening application of Noctos is more efficient than the morning one. However, the magnitude of this beneficial effect is related both to age (greater for the age class 25-35 years than for younger and older subjects) and to skin complexion (greater for fair than dark complexioned subjects). Major beneficial effects of Noctos in the evening hours are related neither to fatigue nor to mood of the women since the respective circadian rhythms of these variables appear to vary independently from those of facial skin characteristics.

Adult

[Legal time shifting and biologic rhythms: summer hour in question?].

In France daylight saving time is set on last sunday of march (legal time becomes GMT + 2 h instead of GMT + 1h) and set off last sunday of september. Fifteen years ago when it was established this change of time was generally welcomed by the public. Since then strong rejection reflexes have appeared and an association against the summer daylight saving time has been founded. The arguments sustained by the oponents to this system are based on economical, agricultural and/or health considerations. A growing number of individuals claim they cannot withstand the change of legal time and suffer from various troubles mainly fatigue and sleep disturbances. An alteration of biologic rhythms has been put forward by some to explain these troubles. We will here discuss the problems related to the change of legal time and especially those in the field of health. For the latter we will show that troubles when they are present can not ascribed to a desynchronization.

Biological Clocks

Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice.

The toxicities and tissue uptake of cisplatin (CDDP) and carboplatin (CBDCA) vary largely according to the time of injection of a single dose. Repeated dosages may alter the mechanisms involved with such circadian-dependent toxicity. Weekly i.v. injections of CDDP (5 mg/kg) or CBDCA (50 mg/kg) were given over 2 months to 288 male B6D2F1 mice standardized by an alternation of 12 hr of light and 12 hr of darkness at any one of three circadian dosing times (0, 8 or 16 hr after light onset--HALO). Survival; body weight; complete blood cell counts; histologic lesions in kidney, liver, spleen, bone marrow and intestinal tract; platinum concentration in kidney, spleen and colon were determined every 2 weeks throughout treatment. Thrombocytopenia was 10-fold larger following CBDCA as compared with CDDP. Severe bone marrow necrosis was cumulative following CDDP, but reversible following CBDCA. Leukopenia and bone marrow lesions were, respectively, half as severe following the dosing of either drug at 16 HALO compared with 0 or 8 HALO. Cortical tubular necrosis was observed in CDDP-treated mice. It was cumulative and half as extensive after drug dosing at 16 HALO, as compared with 0 or 8 HALO (P less than or equal to .05). Total Pt accumulation in all three tissues was 3- to 4-fold higher following repeated dosages of CDDP as compared with CBDCA. Tissue Pt uptake was halved after CDDP or CBDCA dosing at 16 HALO as compared with 8 HALO (P less than or equal to .01). Dosing either Pt complex at the appropriate time is even more critical if administrations are to be repeated. Mechanisms appear to involve the circadian rhythm-dependent ability of target tissues to take up the drug.

Animals

Circadian rhythm in toxicities and tissue uptake of 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) in mice.

Mechanisms involved in the circadian rhythm in murine tolerance for the new platinum analogue, 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) (1-OHP) were sought in 404 male C57BL/6 x DBA/2 F1 mice standardized by 12 h light-12 h dark. A potentially lethal dose of 1-OHP (17 mg/kg i.v.) resulted in 76% long-term survival at 15 h after light onset (HALO) (activity span) as compared to 24% after treatment at 7 HALO (rest span) (chi 2 21.3; P less than 0.001). A total of 204 mice received the same dose of 1-OHP at one of three circadian stages (0, 8, or 16 HALO). No renal toxicity was encountered. Bone marrow and jejunal villi constituted the chief targets of 1-OHP toxicity at this dosage and schedule. Hematological tolerance as gauged by leukocyte counts was optimal when the drug was given at 16 HALO (P from analysis of variance, less than 0.001). Jejunal lesions were less severe after 1-OHP dosing at 16 HALO as compared to 8 HALO (P less than 0.001). Total platinum concentrations were determined in 18 tissues 24 h after 1-OHP dosing. The highest levels of platinum were found in the spleen on day 1 as well as on day 5 following 1-OHP treatment. Despite the fact that the highest platinum concentrations in tissues usually corresponded to drug dosing at 8 HALO, no correlation was documented between such variables and tissue toxicity. Tissue pharmacokinetics of 1-OHP contribute only in part if at all to the circadian rhythm in hematological and jejunal toxicity of this drug.

Animals

Circadian and seasonal variations of electrolytes in aging humans.

The circadian and seasonal variations of a set of routinely determined variables (chloride, sodium, potassium, calcium, inorganic phosphorus, magnesium, creatinine, urea and urate) were documented in young men (mean age +/- SD: 24.0 +/- 3.9 yr) and in healthy elderly men (75.3 +/- 6.6) and women (78.2 +/- 9.1). The same urinary variables, except magnesium, were studied in young men. The circadian variability of serum variables was between 2 and 11% except for serum inorganic phosphorus (12-22% according to the group). By contrast, urinary chloride, sodium and potassium revealed large peak-trough differences (55-75%) and the variability of urinary creatinine, urate and urea was also not negligible (20-30%). ANOVA validated seasonal variations for most of the plasma variables and for urinary calcium, phosphorus and uric acid. No age or sex difference in either 24 h means or amplitudes could be observed. These data are of interest for the concept of reference values, for the diagnosis of certain bone and renal disease as well as for chronooptimization in treatment of potential electrolytes deficiency states.

Aged

[Axillary temperature rhythms: the predominance of ultradian periodicity in major affective disorders].

Axillary temperature was recorded at least twice during a 48 hrs. span at 6 min. intervals in 10 hospitalized subjects with major affective disorders (DSM III 296. xx). During the clinical occurrence of acute symptoms 7 out of 10 subjects exhibited a prominent ultradian periodicity (period tau less than 20 hrs.) in their temperature time series. Whatever the used therapeutic mean (electroconvulsive therapy and/or chemotherapy) the improvement was associated with a circadian rhythmicity (20 hrs. less than or equal to tau less than or equal to 28 hrs.). A prominent temperature ultradian rhythm (which occurs only in the new born) could be the index of an internal desynchronization associated with major affective disorders.

Activity Cycles

Alteration of period and amplitude of circadian rhythms in shift workers. With special reference to temperature, right and left hand grip strength.

48 male shift workers in various industries volunteered to document circadian rhythms in sleeping and working, oral temperature, grip strength of both hands, peak expiratory flow and heart rate. All physiological variables were self-measured 4 to 5 times a day for 2 to 4 weeks. Individual time series were analyzed according to several statistical methods (power spectrum, cosinor, chi squares, ANOVA, correlation, etc.) in order to estimate rhythm parameters such as circadian period (tau) and amplitude (A), and to evaluate subgroup differences with regard to tolerance to shift work, age, duration of shift work, speed of rotation and type of industry. The present study confirms for oral temperature and extends to other variables (grip strength of both hands, heart rate) that intolerance to shift work is frequently associated with both internal desynchronization and small circadian amplitude. The internal desynchronization among several circadian rhythms supports the hypothesis that these latter are driven by several oscillators. Many differences were observed between circadian rhythms in right and left hand grip strength: circadian tau in oral temperature was correlated with that in the grip strength of the dominant hand but not with that of the other hand; changes in tau s of the non-dominant hand were age-related but did not correlate with temperature tau; only the circadian A of the non-dominant hand was associated with a desynchronization. Thus, circadian rhythms in oral temperature and dominant hand grip strength may be driven by the same oscillator while that of the non-dominant hand may be governed by a different one. Internal desynchronization between both hand grip rhythms as well as desynchronization of performance rhythms reported by others provide indirect evidence that circadian oscillator(s) may be located in the human cerebral cortex.

Adult

Circadian time dependence of murine tolerance for carboplatin.

A large amplitude circadian rhythm in murine tolerance for the anticancer agent, carboplatin (cyclobutane dicarboxylatoplatinum II, CBDCA) was demonstrated. Two studies were performed in a total of 266 male B6D2F1 mice standardized by LD 12:12. In the first experiment CBDCA (80 mg/kg/day) was administered intravenously (iv) daily for three consecutive days at all six circadian stages (3, 7, 11, 15, 19, or 23 hr after light onset, HALO). CBDCA dosing at 15 HALO resulted in 58% long-term survivors as compared to 0% after treatment at 3 or 23 HALO (chi 2 = 28; p less than 0.001). In the second experiment, CBDCA (72 or 80 mg/kg/day X 3 days, iv) was administered at any of three circadian stages (0, 8, or 16 HALO). Mice were killed, blood was collected, and seven tissues were obtained 5 and 10 days after the first dose, in order to determine serum urea and creatinine concentrations, leukocyte and red blood cell counts, and to evaluate histologic lesions. No renal toxicity was encountered. Bone marrow and colon mucosa were the major target tissues of CBDCA in these dosages and schedules. CBDCA dosing at 16 HALO was least toxic to the bone marrow as assessed by peripheral leukocyte count and histologic score (p from ANOVA less than 0.05). Histologically assessed lesions of the colon mucosa were less severe after CBDCA dosing at 16 HALO as compared to those at 8 HALO, and significantly so for the lowest dosage tested (p approximately 0.05). Uptake of CBDCA 24 hr after the third dose ranged from 23 micrograms/g of dry tissue in the colon to 7 micrograms/g in the duodenum. Mean tissue concentrations increased between Day 4 and Day 10 for the liver and spleen, and remained similar for the kidney. No consistent circadian dependence was found with regard to Day 4 mean Pt uptake in different tissues, whereas the lowest Day 10 Pt concentrations corresponded to CBDCA dosing at 16 HALO for all tissues investigated. Toxicity did not appear to be directly related to the total platinum concentration in these tissues.

Animals

Circadian and circannual rhythms of allergic rhinitis: an epidemiologic study involving chronobiologic methods.

Seven hundred sixty-five patients, living in France and suffering from allergic rhinitis (eg, with positive skin tests to various antigens), agreed to self-rate (visual analog scales), four times daily, symptoms such as sneezing, stuffy or blocked nose, runny nose, itchy nose, itchy eyes, wheeze, or cough. Despite acute symptoms, patients did not take medications of any kind by any route during 36 hours. Several statistical methods (eg, Student's t test, analysis of variance, cosinor, chi-square, etc.) were used to validate both circadian and circannual rhythms of these symptoms in the group as a whole, as well as in subgroups related to age, sex, etc. Large-amplitude circadian rhythms with early morning peak times (eg, approximately 6 AM) were validated for sneezing, stuffy nose, and runny nose (with p less than 0.0001) but not for wheeze or cough. Such time-dependent changes were related neither to age (from 10 to 80 years) nor to sex. However, small differences were observed in subgroups sorted with regard to duration of disease (old versus new cases), smoking habits, and geographic location (north versus south France). Reanalysis of data taking into account interindividual differences revealed that the respective peak times of the three major symptoms occurred in the early morning in about 60% to 70% of the patients. Annual changes were validated as well with the annual peak time being January to April. The proposed interpretation of both circadian and circannual rhythms suggests taking into account endogenous component rhythms (eg, involving metabolic, immunologic, and endocrine systems), since they contribute to time-dependent changes in the human susceptibility to antigens. In addition, the elevated severity of symptoms in the morning experienced by 60% to 70% of patients should serve as a guide to individually optimize dosing time(s) of medications, such as antihistamines.

Age Factors

Annual variation in semen characteristics and plasma hormone levels in men undergoing vasectomy.

Prevasectomy levels of plasma luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2), and 20 alpha-dihydroprogesterone (20 alpha-DHP), as well as semen analyses including semen volume, sperm count, and sperm motility from 260 healthy men were evaluated for annual changes. A statistically significant (P less than or equal to 0.015) high-amplitude seasonal variation with the peak in April to May was detected in semen volume, sperm count, and sperm motility. A statistically significant (P less than or equal to 0.04) annual change of moderate T to large FSH amplitude was detected in each of the five plasma endocrine variables as well. Plasma LH, T, and E2 peaked in autumn, while FSH and 20 alpha-DHP peaked in summer. Analysis of postvasectomy LH, FSH, E2, 20 alpha-DHP, and T blood levels for the 3 years following vasectomy revealed loss of seasonal rhythmicity as a group phenomenon in LH, E2, and T. The amplitude of the seasonal variation in FSH was decreased and that in 20 alpha-DHP was unchanged compared with before-vasectomy baselines. For those annual rhythms which persisted following vasectomy, the peak time was unchanged. Compared with the prevasectomy group annual mean, that for each of the endocrine values was unchanged, except for that of LH and T, which was slightly, yet statistically significantly, elevated. The existence of prominent annual variation implicates their consideration in the design of research protocols involving investigation of reproductive phenomena in human beings.

20-alpha-Dihydroprogesterone