Circadian rhythms and photoperiodic time measurement in mammals

Many mammalian species display seasonal breeding patterns correlated with annual cycles of change in the physiology and morphology of the reproductive system. Such annual reproductive cycles are often photoperiodically controlled (i.e, the annual change in day length determines when reproductive activity begins and when it ends within the annual cycle). Photoperiodic control of seasonally appropriate changes in reproductive activity is dependent on an endogenous time measuring process. Among mammals the physiological basis of photoperiodic time measurement has been studied most extensively in the golden hamster. Studies with this species indicate that photoperiodic time measurement is executed by the circadian system. The time measuring process depends on a circadian oscillation of responsiveness to light with properties similar to those of the hypothetical rhythm originally proposed by Bünning to explain photoperiodic phenomena in plants. The available evidence strongly suggests the participation of the pineal gland and the suprachiasmatic nucleus (SCN) in the photoperiodic regulation of mammalian reproductive cycles. However, little is known regarding concrete physiological mechanisms, and the extent to which the SCN and the pineal gland may participate in the time measuring process per se remains to be determined.     

Photic entrainment of the mammalian rhythm in melatonin production

This review summarizes studies on the photic entrainment of the circadian rhythm in the rat pineal melatonin production, namely of the rhythm in N-acetyltransferase (NAT) activity, and compares the NAT rhythm resetting with preliminary results on the resetting of an intrinsic rhythmicity in the suprachiasmatic nucleus (SCN) of the hypothalamus, namely with the entrainment of the rhythm in the light-induced c-fos gene expression. Phase delaying of the NAT rhythm after various light stimuli proceeds within 1 day with almost no transients, whereas during phase advancing of the rhythm only the morning NAT decline is phase advanced within 1 day and the evening rise phase shifts through transients. A light stimulus encompassing the middle of the night may phase delay the evening NAT rise, phase advance the morning decline, compress the rhythm waveform, and eventually lower its amplitude. Similarly, a long photoperiod compresses the NAT rhythm waveform. The magnitude of phase shifts of the NAT rhythm, as well as their direction, depends on a previous photoperiod. Phase shifts of the evening rise in c-fos gene photoinduction in the SCN and of the morning decline are similar to those of the pineal NAT rhythm after all light stimuli studied so far. The data indicate that the resetting of the rhythm in melatonin production in the rat pineal gland reflects changes in the SCN functional state and suggest that the underlying SCN pacemaking system is complex.     

Circadian secretion patterns of melatonin after major surgery

Despite our advances in the diagnosis and treatment of asthma, the incidence of mortality is increasing in developed countries. As patients and health care providers seek new options for the treatment and prevention of asthma, various complementary and alternative medical therapies are being used. With funding from the Office of Alternative Medicine, National Institutes of Health, our goal was to identify the type and prevalence of complementary and alternative treatments for asthma in use in the United States in order to establish a research agenda for the study of the most promising therapies. A survey was developed by an expert panel. After undergoing a preliminary round of testing and improvement, the survey was then sent along with a postage-paid return envelope as inserts in the May 1996 issue of Alternative Therapies in Health and Medicine, a peer-reviewed periodical of complementary and alternative medical research and scholarly activity; 10,000 surveys were distributed. We asked that only those who treated asthma respond. The surveys were designed to identify characteristics of the respondent, their particular practice type, use of complementary and alternative medicine, or conventional medicine in general, patient characteristics and numbers, and their use of 20 specific potential therapies to treat asthma. A total of 564 surveys were returned. The 5.64% response rate was low but was reflective of the demographics of the readership of this journal of complementary and alternative medicine. The survey population was 46% male and 43% female; 11% did not specify gender. They ranged in age from under 31 years old to over 70. The largest group (37%) of respondents held degrees as medical doctors, 27% held doctorates in complementary and alternative medicine related disciplines, 11% had registered nursing degrees, 4% were acupuncturists and 18% did not specify their training. Practice characteristics between MD and non-MD asthma care providers did not differ. The majority had general practices (75%) seeing all ages of patients. MDs were less likely to employ complementary and alternative medicine techniques for asthma compared to non-MDs. Both groups identified dietary and nutritional approaches as their most prevalent and useful asthma treatment option. Use of botanicals, meditation and homeopathy were frequently cited; statistically significant differences appeared in the rankings of treatment usefulness and prevalence between MD and non-MDs. Non-MD asthma care providers were more likely to ask patients about their use of complementary and alternative treatments for asthma than MDs (92% vs. 70%), while both groups showed statistically significant increases in their levels of patient inquiries compared to 2 years previously (up 9% and 8% for MDs and non-MDs respectively). The predominance of diet and nutrition supplementation used by MDs and non-MDs suggests that further attention and research efforts should be directed toward this area of complementary and alternative practice. Other complementary and alternative medicine practices such as botanicals, meditation and homeopathy appear to warrant research efforts. Differences between MDs and non-MDs in their use of such therapies may reflect different philosophies as well as training.     

Exogenous melatonin fails to counteract the light-induced phase delay of human melatonin rhythm

HIV-1, subtype F was isolated from a seronegative child aged 2.5 yr. ELISA tests (Behring HIV-1 + 2, Abbott HIV-1 + 2, Wellcozyme HIV-1 Recombinant, Clonatec HIV-1 + 2, Genelavia Mixt), and also rapid tests (Abbott Pack, Serodia) were all negative, although some of them presented borderline reactivities. Western Blot (Cambridge Biotech) revealed an undetermined profile (traces of anti-gp160 plus anti-p24). A new WB test (Sanofi Dg. Pasteur) performed at a higher serum concentration (1/25) revealed a complete antibody profile, despite the very low intensity of bands. A new serum sample prelevated 6 month later was completely negative on all tests used. Both samples, were negatives in WB for HIV2 and HTLVs. A heparinised blood sample was used for the co-cultivation of PBMC and was proven to be positive in the 14th day of culture. The isolated DNA from end-culture cells was subjected to PCR amplifications for Heteroduplex Mobility Assay direct subtyping (primers ES7 and ES8) and for the investigation of genotypic sensitivity to AZT (primers A/NE1). Lymphocyte populations phenotyping revealed leukocytosis (> 15,000/mL) with a predominance of the CD8+ subset CD4/CD8 ratio was < 1. Plasmatic HIV-1 load (measured by bDNA--Chiron) did not reached detectable levels of HIV-1 RNA. p24 Ag assay (EIA-Coulter) revealed a detectable p24 antigenemia only in the first serum sample and only after acid dissociation. So, this patient may present an integrated HIV-1 infection until now "silent".     

Circadian changes in levels of free amino acids in rat retina, and regulation of them by melatonin

Alpha-tocopherol (vitamin E) is an important fat-soluble antioxidant in biological systems and, as a result of scavenging reactive oxygen, it is converted to alpha-tocopherylquinone. Alpha-tocopherol binds to alpha-tocopherol transfer protein (alphaTTP) in the liver cytosol, whereas alpha-tocopherylquinone does not. We found that alpha-tocopherylquinone binds to a liver protein with a molecular mass of about 40 kDa that is distinct from alphaTTP. This alpha-tocopherylquinone binding protein was purified further by multiple-step column chromatography. Sodium dodecylsulfate-polyacrylamide gel electrophoresis of the final preparation yielded a single band with an apparent molecular mass of 25 kDa, which microsequencing revealed was identical to glutathione-S-transferase (GST). The GST activity was inhibited in the presence of alpha-tocopherylquinone, as it is by other non-substrate ligands for GST, confirming that GST and alpha-tocopherylquinone interact directly. Alpha-tocopherylquinone binds to GST and may be transported to the site of metabolism or excreted in the bile as other non-substrate ligands for GST.     

The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement

The present investigation used a placebo-controlled, double-blind, crossover design to assess the sleep-promoting effect of three melatonin replacement delivery strategies in a group of patients with age-related sleep-maintenance insomnia. Subjects alternated between treatment and "washout" conditions in 2-week trials. The specific treatment strategies for a high physiological dose (0.5 mg) of melatonin were: (1) EARLY: An immediate-release dose taken 30 minutes before bedtime; (2) CONTINUOUS: A controlled-release dose taken 30 minutes before bedtime; (3) LATE: An immediate-release dose taken 4 hours after bedtime. The EARLY and LATE treatments yielded significant and unambiguous reductions in core body temperature. All three melatonin treatments shortened latencies to persistent sleep, demonstrating that high physiological doses of melatonin can promote sleep in this population. Despite this effect on sleep latency, however, melatonin was not effective in sustaining sleep. No treatment improved total sleep time, sleep efficiency, or wake after sleep onset. Likewise, melatonin did not improve subjective self-reports of nighttime sleep and daytime alertness. Correlational analyses comparing sleep in the placebo condition with melatonin production revealed that melatonin levels were not correlated with sleep. Furthermore, low melatonin producers were not preferentially responsive to melatonin replacement. Total sleep time and sleep efficiency were correlated with the timing of the endogenous melatonin rhythm, and particularly with the phase-relationship between habitual bedtime and the phase of the circadian timing system.     

Circadian melatonin and young-to-old pineal grafting postpone aging and maintain juvenile conditions of reproductive functions in mice and rats

Chronic, night administration of melatonin to aging mice and transplantation of a young pineal gland into the thymic rudiment of older mice and rats have been studied with the aim of evaluating their effects on aging of gonadal, sexual, and reproductive functions. Both melatonin administration and young-to-old pineal grafting positively affect size and function of testes and maintenance of juvenile hippocampal and testicular LHRH-receptors and beta-adrenergic receptors in the tests of old rats and mice. These results demonstrate that a pineal-directed circadian function and cyclicity is fundamental for the regulation of sexual, reproductive physiology, and that proper intervention with melatonin may potentially postpone aging of both neural and gonadal sexual function.     

Exploring postinfarction reentrant ventricular tachycardia with entrainment mapping

Ventricular tachycardia late after myocardial infarction is usually due to reentry in the infarct region. These reentry circuits can be large, complex and difficult to define, impeding study in the electrophysiology laboratory and making catheter ablation difficult. Pacing through the electrodes of the mapping catheter provides a new approach to mapping. When pacing stimuli capture the effects on the tachycardia depend on the location of the pacing site relative to the reentry circuit. The effects observed allow identification of various portions of the reentry circuit, without the need for locating the entire circuit. Isthmuses where relatively small lesions produced by radiofrequency catheter ablation can interrupt reentry can often be identified. A classification that divides reentry circuits into one or more functional components helps to conceptualize the reentry circuit and predicts the likelihood that heating with radiofrequency current will terminate tachycardia. These methods are helping to define human reentry circuits.     

Adapting to phase shifts, II. Effects of melatonin and conflicting light treatment

The effects of melatonin (MT) and placebo (P) on adaptation to a rapid 9-h advance phase shift, in the presence and absence of inappropriate bright light (BL) exposure were examined. Volunteers were initially subjected to a gradual 9-h delay phase shift over 5 days (D1-D5) using a combination of bright light and darkness/sleep. Readaptation to a subsequent rapid 9-h advance phase shift was studied using: 1) MT, 5 mg, 2300 h, D6-D8, 2) BL, 2,000 lx, 0800-1200 h, D7-D8, 3) MT+BL and 4) P, 2300 h, D6-D8. MT treatment was timed to phase advance and BL to phase delay. BL delayed the 6-sulphatoxymelatonin rhythm in five out of seven subjects. Two subjects delayed and five phase advanced with both MT and MT+BL. MT consistently improved subjective sleep, alertness, and performance even in the presence of inappropriate BL and before phase readaptation had occurred. BL improved alertness and performance transiently. The beneficial effects of MT are not wholly mediated through an effect on the biological clock.     

Generation and entrainment of circadian rhythms

1. The present brief review examines some of the new developments in the area of circadian rhythm research. 2. The discovery of the mouse clock and m-per genes and their similarity to other clock genes like per and tim has provided new insight into the control of rhythms in vertebrates. In mice, these genes are expressed in the site of the biological clock, the suprachiasmatic nucleus (SCN), and so will now become a focus of research into the generation of rhythmicity. 3. Because SCN cells expressing endogenous rhythms have a periodicity different from 24 h, there must be mechanisms in place to reset the rhythms on a daily basis. This is achieved in mammals by retinal light perception and neural transmission through several discrete pathways to the SCN. 4. The nature of the neurotransmitters involved in this transfer of environmental information to the timing system is controversial and may even very between similar species but, in the rat, there is compelling evidence that a serotonergic pathway is pre-eminent in mediating the effects of light. How the re-setting is achieved at the cellular level is not known.     

Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms

This study demonstrates the involvement of the MT2 (Mel1b) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt1 and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 microg/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 microg/mouse; 0.98+/-0.08 h (n=15) maximal advance at 9 microg/mouse]. Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 microg/mouse, s.c.) nor luzindole (300 microg/mouse, s.c.), which shows 25-fold higher affinity for the MT2 than the mt1 subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 microg melatonin. This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circadian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders.     

Focused and shifting attention in children with heavy prenatal alcohol exposure.

Attention deficits are a hallmark of the teratogenic effects of alcohol. However, characterization of these deficits remains inconclusive. Children with heavy prenatal alcohol exposure and nonexposed controls were evaluated using a paradigm consisting of three conditions: visual focus, auditory focus, and auditory-visual shift of attention. For the focus conditions, participants responded manually to visual or auditory targets. For the shift condition, participants alternated responses between visual targets and auditory targets. For the visual focus condition, alcohol-exposed children had lower accuracy and slower reaction time for all intertarget intervals (ITIs), while on the auditory focus condition, alcohol-exposed children were less accurate but displayed slower reaction time only on the longest ITI. Finally, for the shift condition, the alcohol-exposed group was accurate but had slowed reaction times. These results indicate that children with heavy prenatal alcohol exposure have pervasive deficits in visual focused attention and deficits in maintaining auditory attention over time. However, no deficits were noted in the ability to disengage and reengage attention when required to shift attention between visual and auditory stimuli, although reaction times to shift were slower. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Photic entrainment of circadian rhythms in rodents

Photic entrainment of circadian rhythms occurs as a consequence of daily, light-induced adjustments in the phase and period of the suprachiasmatic nuclei (SCN) circadian clock. Photic information is acquired by a unique population of retinal photoreceptors, processed by a distinct subset of retinal ganglion cells, and conveyed to the SCN through the retinohypothalamic tract (RHT). RHT neurotransmission is mediated by the release of the excitatory amino acid glutamate and appears to require the activation of both NMDA- and non-NMDA-type glutamate receptors, the expression of immediate early genes (IEGs), and the synthesis and release of nitric oxide. In addition, serotonin appears to regulate the response of the SCN circadian clock to light through postsynaptic 5-HT1A or 5-ht7 receptors, as well as presynaptic 5-HT1B heteroreceptors on RHT terminals.     

Conceptual shifting in chronic alcoholics.

Examined the inferior performance of chronic alcoholics on abstracting tasks. After, administering the Wisconsin Card Sorting Test to 24 alcoholics, it was found that alcoholics took more trials to reach criterion and made more errors than either a group of 24 hospital controls or 24 students. Error pattern analysis indicates that these differences could not be attributed to perseveration. The deficit appeared to be in sustaining a pattern of search and persistence in problem solution. Duration of drinking history was related to impairment of task persistence. Results are consistent with the hypothesis of subcortical organic involvement with a concomitant deficit in conceptual shifting tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aminopeptidases in the mammals

The BAX system for screening Salmonella is one of the first commercial PCR-based systems for the detection of food-borne pathogens. It is able to give a confirmed result within 28 h. There was 98.6% and 95.8% agreement between the BAX system and conventional cultural analysis for the detection of Salmonella in artificially inoculated and uninoculated food samples, respectively. In both cases, the BAX system generated more positive detections than cultural analysis. The speed of assay, case of use and high specificity and sensitivity of the BAX system for the detection of food-borne Salmonella make it an attractive method for routine food microbiology laboratories.     

Circadian occurrence of variceal bleeding in patients with liver cirrhosis

Several clinical events have a rhythmicity over the 24 h period. We assessed the presence of periodic rhythm in the occurrence of haematemesis in patients with liver cirrhosis under different daylight regimens, namely during standard time and during daylight savings. Over a 48 month period there were 212 consecutive admissions of 118 cirrhotics with variceal bleeding. Complete data were available for 181 episodes of bleeding: 121 (66.9%) started with haematemesis and 60 (33.1%) started with melaena. One hundred and two (56%) episodes occurred during daylight savings and 79 (44%) occurred during standard time. The cosinor test showed a 24 h biphasic peak for the occurrence of haematemesis (09.45 and 21.45 h). Moreover, a biphasic diurnal asymmetric frequency was also found by multiple component rhythmometry. The time peaks of onset of variceal haemorrhage did not change significantly during standard time and daylight savings. Patients with more than one haematemesis episode significantly bled over the same time interval. The present study confirms that over the 24 h period variceal bleeding in cirrhotic patients occurs with a predictable rhythmicity that does not seem to be under the control of the light-dark cycle. The finding of a chronorisk for variceal haemorrhage addresses specific questions for pathophysiological studies as well as for new treatment strategies.     

Breast cancer--incidence, mortality and stage shifting in Norway

The age-standardized incidence rate of breast cancer has increased by 50% over the period 1965-94. There has been a much lesser increase in the corresponding age-standardized mortality rate because of better treatment and stage shifting. Stage shifting means that the proportion of individuals with a given clinical stage changes over time. The proportion of individuals diagnosed as clinical stage 1 was seen to increase from about 50% to 60% in the time period mentioned above. The proportion classified as stage 2 at the time of diagnosis is constant at 30%. The relative numbers of individuals diagnosed as stage 3 or 4 were reduced from 10% to 3% and from 10% to 5%, respectively. After correction for confounding effect of age and the clinical stage, the age-standardized 3-year relative survival rate increased from 90% to 95% and from 67% to 85% for stages 1 and 2, respectively. The impact of advancing breast cancer diagnosis independent of the screening programme, is discussed. Finally, the evaluation of screening programmes using shift migration models and simulations is discussed.