The internal variability of the mesothelium during regeneration following trauma applied at various times of the day

A quantitative investigation of the mitotic activity (MA) dynamics, size of the cells, amount of their mutual contacts (as an index of the epithelial layer regulation) and amount of nucleoli in the nuclei of mesothelium after a trauma, performed at 9 a.m. and at 9 p.m. has been carried out. The investigation lasted for 96 h. According to statistically significant differences two zones are revealed: a nearer and a remote one. Changeability of mesothelium increases in both zones, but it is greater manifested in the nearer zone. MA dynamics in both zones demonstrates a quick growing and a similarly quick drop, except the remote zone after the morning operation, where MA decreases slower. Amount of the cells, whose nuclei contain more nucleoli than in the norm, increases before the development of the MA waves. MA increase is accompanied with decreasing size of the cells. Normalization of MA and size of the cells occur approximately simultaneously. This process is more manifested after the morning operation, and after the evening one, normalization of these signs, during the time of observation, is reached only in the remote zone. Disorganization of mesothelium, as a tissue system, precedes the MA increase. A significant difference of this sign from the control takes place only in the nearer zone after the morning operation. As a whole, the changeability of mesothelium is more manifested after the morning operation.     

Dependence of the circadian changes in stressor response of the rat hypophyseal-adrenocortical system on the stress intensity

Circadian responses of the hypophyseal-adrenal axis to stress were greater is the PM as compared with AM after small stress intensity, but it were similar after high stress intensity. Was shown to depend on the intensity of the stress factor. The circadian variations of the adrenal glands response to the ACTH seem to play a major role in determining the character of the hypophyseal-adrenal axis response to stress.     

THE HAMSTER CLOCK PHASE-RESPONSE CURVE FROM SUMMERLIKE LIGHT:DARK CYCLES AND ITS ROLE IN DAILY AND SEASONAL TIMEKEEPING

We address the subject of entrainment of the hamster clock by the day:night cycle in summer when the sun sets after 6 PM and rises before 6 AM (nights<12 h). Summer day:night cycles were simulated by 6 light:dark (LD) cycles with D<12 h (summerlike, SLD) ranging from SLD 12.5h:11.5h (D, 6:15 PM–5:45 AM) to 18h:6h (D, 9 PM–3 AM). These are the near limiting SLDs for constant PM timing (entrainment) of behavioral estrus and wheel running in hamsters. The onset of estrus was observed every 4 d in the same hamsters as a phase marker of their 24h clock. On the day before an experimental estrus, preceded and followed by control onsets, a dark period was imposed to cover a putative 6 PM–6 AM light-sensitive period (LSP). This was scanned with a light pulse (and periodic 5sec bell alarms) lasting 5–240 min. Shifts in onset of estrus on the next day were plotted vs. the end of the light pulse for PM times (“dusk”) and its onset for AM times (“dawn”). The resulting phase shifts from the six SLDs were similar, permitting their combination into a single phase-response curve (PRC) of 1605 shifts. This SLD composite PRC rose at 10:15 PM, peaked at 2 AM (81min advanced shift), fell linearly to 5:55 AM, and then abruptly to normal at 6 AM (no shift). Peak shift was unaffected by light pulse duration or intensity, or hamster age. The SLD composite PRC lacked the 6 PM–9 PM curve of delayed shifts present in reported PRCs from LD 12h:12h and DD. However, a two-pulse experiment showed that all light from 6 PM to L-off was needed to block (balance) the advancing action of a 5min morning light pulse, thereby maintaining entrainment. A working hypothesis to explain daily entrainment and seasonal fertility in the golden hamster is illustrated. A nomenclature for labeling the phases of the hamster clock (circadian time) is proposed.     

Effect of the time of the day when the lesion was produced on the course of mesothelial proliferation

The course of mitotic activity in the rabbit mesothelium of parietal peritoneum was studied depending upon the daytime when the lesion was produced. In the first series of experiments (I) the operation was performed from 8 to 10 a. m., and in the second series (II) - from 8 to 10 P. M. After the operation the animals were sacrifieced: one animal every 3 h during 5 days. Mitotic activity was investigated along 13 mm from the edge of the wound in flat film preparations. The data obtained were statistically treated applying approximation of the process course by the method of weighed sliding averages. The first mesothelial mitoses appeared: in the first series (I) of experiments - in 24 h, in the second series (II) of experiments - 21 h. Further, proliferation of the mesothelium appeared in different parts of the tissue with various intencity and was of wavy character. Regardless of the time when the lesion was produced, mitotic activity was the greatest in the first zone, 4.8 mm wide its maximum 33 h after the operation. The character of the regenerative process in the mesothelium depends on the circadian phase of the organism at the time of the operation, that influences the time when mitotic activity begins, its quantitative indices, the area of the tissue involving into the reaction, expressiveness of the rhythmicity of the process. During 5 days, in the II series of experiments three waves were noted, and in the I series - five waves were noted and their periods were near the diurnal.     

The hamster clock phase-response curve from summerlike light:dark cycles and its role in daily and seasonal timekeeping

We address the subject of entrainment of the hamster clock by the day:night cycle in summer when the sun sets after 6 PM and rises before 6 AM (nights < 12 h). Summer day:night cycles were simulated by 6 light:dark (LD) cycles with D < 12 h (summerlike, SLD) ranging from SLD 12.5 h:11.5 h (D, 6:15 PM-5:45 AM) to 18 h:6 h (D, 9 PM-3 AM). These are the near limiting SLDs for constant PM timing (entrainment) of behavioral estrus and wheel running in hamsters. The onset of estrus was observed every 4 d in the same hamsters as a phase marker of their 24 h clock. On the day before an experimental estrus, preceded and followed by control onsets, a dark period was imposed to cover a putative 6 PM-6 AM light-sensitive period (LSP). This was scanned with a light pulse (and periodic 5 sec bell alarms) lasting 5-240 min. Shifts in onset of estrus on the next day were plotted vs. the end of the light pulse for PM times ("dusk") and its onset for AM times ("dawn"). The resulting phase shifts from the six SLDs were similar, permitting their combination into a single phase-response curve (PRC) of 1605 shifts. This SLD composite PRC rose at 10:15 PM, peaked at 2 AM (81 min advanced shift), fell linearly to 5:55 AM, and then abruptly to normal at 6 AM (no shift). Peak shift was unaffected by light pulse duration or intensity, or hamster age. The SLD composite PRC lacked the 6 PM-9 PM curve of delayed shifts present in reported PRCs from LD 12 h:12 h and DD. However, a two-pulse experiment showed that all light from 6 PM to L-off was needed to block (balance) the advancing action of a 5 min morning light pulse, thereby maintaining entrainment. A working hypothesis to explain daily entrainment and seasonal fertility in the golden hamster is illustrated. A nomenclature for labeling the phases of the hamster clock (circadian time) is proposed.     

Circadian uterine activity in the pregnant rhesus macaque: do prostaglandins play a role?

Eight rhesus macaques between 127 and 132 days of gestation had catheters implanted into maternal femoral vessels and the amniotic fluid cavity and were placed in a vest-and-tether system for chronic catheter maintenance. Uterine activity was continuously recorded, and paired maternal arterial blood and amniotic fluid samples were collected at 0900 h (AM) and 2100 h (PM) until delivery and analyzed for prostaglandin metabolites (PGFM and PGEM-II). A circadian pattern in uterine contractility was observed, with peak activity occurring between 1900 and 0100 h (p less than 0.001). No significant AM-PM differences were observed in maternal plasma PGFM (240 +/- 24 AM vs. 273 +/- 35 PM) or PGEM-II (537 +/- 41 AM vs. 484 +/- 34 PM) or amniotic fluid PGFM (360 +/- 72 AM vs. 287 +/- 70 PM) or PGEM-II (1626 +/- 383 AM vs. 1771 +/- 431 PM). All values represent mean +/- SEM, pg/ml. Additional samples were collected at 3-h intervals for 24 h at selected times during the study. This more intensive sampling protocol also failed to reveal any significant time trends in maternal plasma or amniotic fluid prostaglandins. Despite the lack of AM-PM differences, amniotic fluid PGFM and PGEM-II increased significantly as delivery approached (p less than 0.01). It appears that circadian uterine activity is not related to changes in maternal plasma or amniotic fluid prostaglandins. Although prostaglandins are responsible for the progression of labor, other factors may be involved in the generation of uterine activity rhythms prior to the initiation of labor.     

Effect of cholesterol feeding on circadian rhythm of hepatic and intestinal cholesterol biosynthesis in hamsters.

Forty-eight adult hamsters were divided equally into two groups fed a control diet and a 2% cholesterol diet, respectively, under a rigid lighting (6 PM-6 AM) and feeding (6 PM-8 AM) schedule for three weeks. The cholesterol synthetic activity of the liver, stomach, small intestine, cecum, colon and kidney was measured by in vivo conversion of acetate-1-14C to cholesterol in four animals each time at 4 hour intervals. A remarkable circadian rhythm with the peak at midnight and the nadir at noon was found in the liver of the control hamsters, but was completely abolished in the cholesterol-fed animals since the activity was nearly totally suppressed at all times. The small intestine exhibited a similar rhythm with the peak at midnight but maintained a high baseline activity from 8 AM to 6 PM. Cholesterol feeding did not alter the baseline activity but reduced 17% of the peak activity. Other organs failed to show such a circadian rhythm.     

Circadian clock regulates metabolism and toxicity of Fuzi(lateral root of Aconitum carmichaeli Debx) in mice

BackgroundTherapeutic applications of Fuzi (lateral root of Aconitum carmichaeli Debx) are seriously concerned with its toxic effects. Strategies and approaches to reducing toxicity are of great interest.PurposeWe aimed to characterize the diurnal rhythm of Fuzi toxicity, and to determine the role of metabolism and pharmacokinetics in generating toxicity rhythmicity.MethodsToxicity was determined based on assessment of heart injury and animal survival after dosing mice with Fuzi decoction at different circadian time points. Circadian clock control of pharmacokinetics and toxicity was investigated using Bmal1-deficient (Bmal1^−/−) mice.ResultsFuzi exhibited a diurnal rhythmicity in cardiotoxicity (reflected by plasma CK-MB and LDH levels). The highest level of toxicity was observed at ZT10 (5 PM), while the lowest level of toxicity occurred at ZT22 (5 AM). Also, a higher mortality rate was observed at ZT10 and lower mortality rates at other times of the day. ZT10 dosing of Fuzi generated higher systemic exposures of three toxic alkaloid ingredients aconitine (AC), hypaconitine (HA) and mesaconitine (MA) compared to ZT22. This was accompanied by reduced the formation of the metabolites (N-deethyl-AC, didemethyl-HA and 2‑hydroxyl‑MA) at ZT10. Bmal1 ablation resulted in an increased level of Fuzi toxicity at ZT22, while having no influences when drug was dosed at ZT10. As a consequence, circadian time-dependent toxicity of Fuzi was lost in Bmal1-deficient mice. In addition, Bmal1 ablation increased the plasma concentrations of AC, HA and MA in mice after oral gavage of Fuzi, and reduced formation of their metabolites (N-deethyl-AC, didemethyl-HA and 2‑hydroxyl‑MA). Moreover, Fuzi metabolism in wild-type liver microsomes was more extensive at ZT22 than at ZT10. Bmal1 ablation abrogated circadian time-dependency of hepatic Fuzi metabolism.ConclusionsFuzi chronotoxicity in mice was attributed to time-varying hepatic metabolism and systemic exposure regulated by circadian clock. The findings may have implications in reducing Fuzi toxicity with a chronotherapeutic approach.     

Circadian rhythms of finches under steadily changing light intensity: Are self-sustaining circadian rhythms self-excitatory?

Summary Finches (Chloris chloris, Fringilla montifringilla) showed clear freerunning circadian rhythms when exposed to constant dim light. Increasing the light intensity by doubling it each day made them become arrhythmic at a certain threshold intensity of illumination, showing continuous locomotor activity. When the light intensity was decreased steadily at the reversed rate, the finches became rhythmic again. 7 out of 8 finches had a clear start in their rhythms, from one day to the next, at light intensities about 4 times higher than the point where they had become arrhythmic. The last finch started its freerunning circadian rhythm gradually, a few days after the light intensity had reached a constant dim illumination (0.2 lux).The results of all birds are taken as proof of the self-excitatory capacity of the circadian system. This means, it characterizes the dynamics of the system that the clock mechanism is continuously in operation, and not only after a passive reaction to external stimuli exceeds any threshold. Simultaneously, the results of all but one bird allow the evaluation of the contribution of proportional and differential effects of light in the control of circadian rhythmicity. A relative change in light intensity by 100% in the course of one day is nearly equivalent to a change of 100% in the absolute intensity of illumination.     

Myosin light-chain expression during avian muscle development

Monoclonal antibodies to adult chicken myosin light chains were generated and used to quantitate the types of myosin light-chain (MLC) isoforms expressed during development of the pectoralis major (PM), anterior latissimus dorsi (ALD), and medial adductor (MA) muscles of the chicken. These are muscles which, in the adult, are composed predominantly of fast, slow, and a mixture of fiber types, respectively. Three distinct phases of MLC expression characterized the development of the PM and MA muscles. The first identifiable pase occurred during the period of 5-7 d of incubation in ovo. Extracts of muscles from the pectoral region (which included the presumptive PM muscle) contained only fast MLC isoforms. This period of exclusive fast light-chain synthesis was followed by a phase (8- 12 d of incubation in ovo) in which coexpression of both fast and slow MLC isoforms was apparent in both PM and MA muscles. During the period, the composition of both fast and slow MLC isoforms in the PM and MA muscles was identical. Beginning at day 12 in ovo, the ALD was also subjected to immunochemical analyses. The proportion of fast and slow MLCs in this muscle at day 12 was similar to that present in the other muscles studied. The third development phase of MLC expression began at approximately 12 d of incubation in ovo and encompassed the transition in MLC composition to the isoform patterns incubation in ovo and encompassed the transition in MLC composition to the isoform patterns typical of adult muscle. During this period, the relative proportion of slow MLC rose in both the MA and ALD and fell in the PM. By day 16, the third fast light chain, LC(3f), was apparent in extracts of both the PM and MA. These results show that there is a developmental progression in the expression of MLC in the two avian muscles studied from day 5 in ovo; first, only fast MLCs are accumulated, then both fast and slow MLC isoforms are expressed. Only during the latter third of development in ovo is the final MLC isoform pattern characteristic of a particular muscle type expressed.     

Influence of circadian time structure on acute hormonal responses to a single bout of heavy-resistance exercise in weight-trained men

Both testosterone (T) and cortisol (C) exhibit circadian rhythmicity being highest in the morning and lowest in the evening. T is a potent stimulator of protein synthesis and may possess anti-catabolic properties within skeletal muscle, and C affects protein turnover, thereby altering the balance between hormone-mediated anabolic and catabolic activity. Physiological reactions of these hormones and training adaptations may influence the post-exercise recovery phase by modulating anabolic and catabolic processes, therefore affecting metabolic equilibrium, and may lead to intensification of catabolic processes. We investigated the effect of the circadian system on the T and C response of weight-trained men to heavy resistance exercise. Thirteen young (21.8 +/- 2.2 yr) weight-trained men (12 months training experience) performed an eight-station heavy-resistance exercise protocol on two separate occasions (AM: 06:00 h and PM: 18:00 h), completing 3 sets of 8-10 repetitions at 75% of each subject's one-repetition maximum (1-RM). Blood samples were obtained prior to, during, and following the exercise bout, and serum total T and C concentrations were determined by competitive immunoassay technique. Performing the single bout of heavy-resistance exercise in the PM as compared to the AM positively altered the C and T/C ratio hormonal response. Pre-exercise C concentrations were significantly lower (p < 0.05) in the PM session, which resulted in a lower peak value, and the accompanying increased T/C ratio suggested a reduced catabolic environment. These data demonstrate that the exercise-induced hormonal profile can be influenced by the circadian time structure toward a profile more favorable for anabolism, therefore optimizing skeletal muscle hypertrophic adaptations associated with resistance exercise.     

Quantitative changes in steroidogenic organelles in the corpus luteum of the pregnant rat in relation to progestin secretion on day 16 and in the morning and afternoon of day 22

The present study was carried out to determine whether the major steroidogenic organelles of luteal cells quantitatively reflect variations in ovarian steroid secretion rates during pregnancy in the rat. Assessments were made on day 16 and in the morning (AM) and afternoon (PM) of day 22 (term is day 23). Ovarian steroidogenesis differs both quantitatively and qualitatively between these stages of pregnancy, so together they provide an ideal physiological model to study structural-functional relationships in the ovary. Corpora lutea of five rats were examined at each stage after progesterone and 20 alpha-hydroxypregn-4-en-3-one (20 alpha-OHP) secretion rates had been determined by a venous outflow technique. Total progestin secretion (progesterone plus 20 alpha-OHP) fell from 32.5 +/- 5.2 to 9.8 +/- 1.2 micrograms/hr per ovary (mean +/- SEM) between day 16 and day 22 AM but then increased to 22.6 +/- 1.4 micrograms/hr per ovary by day 22 PM. The total volume of luteal cell cytoplasm was slightly greater at day 22 AM and PM than at day 16. Similarly, the volumes of smooth endoplasmic reticulum (SER), lipid droplets, and membrane-bound granules all increased, but the volume of mitochondria decreased slightly. In contrast, the surface areas of SER and the inner and outer mitochondrial membranes did not change between day 16 and day 22 AM but then increased substantially by day 22 PM. Therefore, steroid secretion rates per unit area of steroidogenic membrane showed no consistent pattern over the stages examined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reactive growth of the mesothelium of the parietal leaf of the peritoneum]

In the process of reparative regeneration of the mesothelium caused by suturing of a portion of the jugular vein into the peritoneum defect the inflammatory mesothelial growings are formed. They have different configuration, consist only of the mesotheliumor the connective tissue covered with the mesothelium and are observed from the 4th day till 3 months after operation, being always faced to the abdominal cavity. The capacity of mesothelial cells to high mitotic activity and wedging out from the layer underlies the formation of posttraumatic structures of the mesothelium.     

Influence of Circadian Time Structure on Acute Hormonal Responses to a Single Bout of Heavy-Resistance Exercise in Weight-Trained Men

Both testosterone (T) and cortisol (C) exhibit circadian rhythmicity being highest in the morning and lowest in the evening. T is a potent stimulator of protein synthesis and may possess anti-catabolic properties within skeletal muscle, and C affects protein turnover, thereby altering the balance between hormone-mediated anabolic and catabolic activity. Physiological reactions of these hormones and training adaptations may influence the post-exercise recovery phase by modulating anabolic and catabolic processes, therefore affecting metabolic equilibrium, and may lead to intensification of catabolic processes. We investigated the effect of the circadian system on the T and C response of weight-trained men to heavy resistance exercise. Thirteen young (21.8±2.2 yr) weight-trained men (12 months training experience) performed an eight-station heavy-resistance exercise protocol on two separate occasions (AM: 06:00 h and PM: 18:00 h), completing 3 sets of 8–10 repetitions at 75% of each subject's one-repetition maximum (1-RM). Blood samples were obtained prior to, during, and following the exercise bout, and serum total T and C concentrations were determined by competitive immunoassay technique. Performing the single bout of heavy-resistance exercise in the PM as compared to the AM positively altered the C and T/C ratio hormonal response. Pre-exercise C concentrations were significantly lower (p < 0.05) in the PM session, which resulted in a lower peak value, and the accompanying increased T/C ratio suggested a reduced catabolic environment. These data demonstrate that the exercise-induced hormonal profile can be influenced by the circadian time structure toward a profile more favorable for anabolism, therefore optimizing skeletal muscle hypertrophic adaptations associated with resistance exercise.     

Activity of cytosolic 5'-nucleotidase in regenerating rat liver after partial hepatectomy

The specific activity of the cytosolic 5'-nucleotidase in regenerating liver increased to 175% of the control level of sham-operated animals during the 2nd and 3rd day and remained elevated most of the experimental period. The total cytosolic 5'-nucleotidase activity of the regenerating liver reached the level of control rats between 2 and 3 days after the operation. The variation pattern of the enzyme, which was distinctly different from variations of other known phosphohydrolases, was strikingly similar to that of the salvage enzyme hypoxanthine/guanine phosphoribosyltransferase.     

The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors

Background

Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (∼9AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise.

Methodology/Principal Findings

We studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6–17% peak-trough amplitudes; p≤0.01). These circadian peaks occurred at a circadian phase corresponding to 8–9AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3–8PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors.

Conclusions/Significance

These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans—independent of the sleep/wake cycle, other behavioral influences and the environment. The ∼9AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies.     

Effects of circadian restricted feeding on parameters of metabolic syndrome among healthy subjects

ABSTRACT

Experimental studies indicate that energy homeostasis to the circadian clock at the behavioral, physiological, and molecular levels, emphasize that timing of food intake may play a significant role in the development of obesity and central obesity. Therefore, resetting the circadian clock by circadian energy restriction via food intake in the morning or evening, may be used as a new approach for prevention of obesity, metabolic syndrome and related diseases. After ethical clearance and written, informed consent, free living subjects were included if they volunteered to take most of the total daily meals (approximately 2000 Kcal./day) in the evening (4 weeks) or morning (4 weeks). Of 22 adults, half were randomly selected by computer generated numbers to eat in the morning and the other half in the evening, after 8.00 PM. The eating pattern was changed after 4 weeks of intervention and a 4-week washout period, those who ate in the morning were advised to eat in the evening and vice versa. Validated questionnaires were used to assess food intakes, physical activity, and intake of alcohol and tobacco. Physical examination included measurement of body weight, height, and blood pressure (BP) by sphygmomanometer. Data were regularly recorded blindly, in all subjects at start of study and during follow-up. Blood samples were collected after an overnight fast for analysis of blood glucose and Hb1c. Feeding in the evening was associated with significant increase in body weight by 0.80 kg (P < .001), body mass index (BMI) by 0.30 kg/m² (P < .001) and waist circumference by 1.13 cm (P < .05). Feeding the same amount of energy in the morning was not associated with any significant change in weight, BMI or waist circumference (P > .500). Lesser increases in all three variables were associated with AM versus PM feeding (P < .05). Systolic BP slightly increased on PM and decreased on AM feeding, with a difference between the two responses of 1.55 mmHg (P < .05). Fasting blood glucose was lower on AM than on PM feeding (74.86 vs. 77.95 mg/dl, paired t = 4.220, P < .001). Hb1C increased on PM feeding by 0.28 (from 4.45 to 4.73; t = 9.176, P < .001), but decreased on AM feeding by 0.077 (from 4.53 to 4.45; t = ?6.859, P < .001). The difference in Hb1C response between AM and PM feeding is also statistically significant (t = ?11.599, P < .001). Eating in the evening can predispose to obesity, central obesity and increases in fasting blood glucose and Hb1c that are indicators of the metabolic syndrome. By contrast, eating in the morning can decrease Hb1c and systolic BP, indicating that it may be protective against the metabolic syndrome.     

Heat Shock Effects on the Circadian Rhythm of Protein Synthesis and Phosphorylation of Ribosomal Proteins in Gonyaulax polyedra

Circadian changes in protein synthesis and phosphorylation of ribosomal and cytoplasmic proteins in the marine dinoflagellate Gonyaulax polyedra were analyzed by radioactive labeling and polyacrylamide gel electrophoresis. Maximal rates of protein synthesis were found during the subjective night and minimal rates during the subjective day. Protein synthesis was inhibited by heat shock to a different extent at different circadian phases—maximally during the subjective night. Heat shock proteins (HSPs) having molecular weights of approximately 105, 89, 83, 66, 35, and 18 kDa were induced by these treatments. Induction of HSP89 and HSP35 showed circadian differences with maximal synthesis rates at CT 15, whereas most HSPs maintained a constant constitutive and induced synthesis. Recovery of normal protein synthesis after heat shock occurred faster during the subjective night than during the subjective day. Ribosomal proteins with molecular weights of 16 and 18 kDa were highly phosphorylated by [³⁵S] thio gamma adenosine triphosphate during day phase in a light-dark cycle or at CT 6 in constant dim light and labeled only to a minor degree during night phase or at CT 18. A ribosome-associated protein (35 kDa) was labeled during the day and not during the night, but after heat shock during both day and night. In the 200,000 g cytosolic fraction, a 35-kDa protein was found to be more intensely labeled at night than during the day phase after heat shock. The results of this study show a correlation between circadian changes in the overall protein synthesis and ribosomal protein phosphorylation. The rhythm of protein synthesis and phosphorylation of a ribosome-associated protein are drastically altered by heat shock and dependent on the circadian phase.     

Morning versus evening dosing of desloratadine in seasonal allergic rhinitis: a randomized controlled study [ISRCTN23032971].

BACKGROUND: A circadian rhythm of symptoms has been reported in allergic rhinitis and some studies have shown the dosing time of antihistamines to be of importance for optimizing symptom relief in this disease. The objective of this study was to examine the efficacy of morning vs. evening dosing of the antihistamine desloratadine at different time points during the day. METHODS: Patients >/= 18 years, with seasonal allergic rhinitis received desloratadine 5 mg orally once daily in the morning (AM-group) or evening (PM-group) for two weeks. Rhinorrhea, nasal congestion, sneezing and eye symptoms were scored morning and evening. Wilcoxon rank sum and 2-way ANOVA test were used. RESULTS: Six-hundred and sixty-three patients were randomized; 336 in the AM-group; 327 in the PM-group. No statistically significant differences were seen between the AM and PM group at any time points. In the sub-groups with higher morning or evening total symptom score no difference in treatment efficacy was seen whether the dose was taken 12 or 24 hours before the higher score time. There was a circadian variation in baseline total symptom score; highest during daytime and lowest at night. The circadian variation in symptoms was reduced during treatment. This reduction was highest for daytime symptoms. CONCLUSIONS: A circadian rhythm was seen for most symptoms being more pronounced during daytime. This was less apparent after treatment with desloratadine. No statistically significant difference in efficacy was seen whether desloratadine was given in the morning or in the evening. This gives the patients more flexibility in choosing dosing time.