Relationship between REM sleep and testosterone secretion in older men.
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Adult↗
Biomedical subjects
K Spiegel
Publications and source records attributed to K Spiegel.
[Impact of sleep debt on physiological rhythms].
Sleep loss due to voluntary bedtime curtailment has become a hallmark of modern society. Even though sleep deprivation in rodents has been shown to result in death, it was until a few years ago thought that sleep loss results in increased sleepiness and decreased cognitive performance but has little or no adverse effects on human health. We measured sleep and 24-hour hormonal profiles in 11 healthy young males after 6 days of sleep restriction (4-hour bedtime) and after 6 days of sleep recovery (12-hour bedtime). At the end of sleep restriction, we observed reduced amounts of slow wave sleep (SWS) and rapid eye movement (REM) sleep and an alteration in the temporal distribution of these sleep stages, i.e. an increased pressure for REM sleep at the beginning of the sleep period and a decrease in the amount of slow wave activity (SWA) during the first sleep cycle. These later abnormalities are usually observed in depression. In addition, numerous alterations in the 24-hour hormonal profiles were observed in the state of sleep debt. The amount of melatonin secreted was reduced because of a delay in the onset of the nocturnal secretion and a reduction in the value of the acrophase. If the overall 24-hour cortisol profile was preserved, sleep restriction was associated with increased cortisol levels in late afternoon and evening hours and the duration of the quiescent period was reduced. The 24-hour mean TSH levels were reduced and the nocturnal TSH elevation was markedly dampened, most likely as a result of elevated levels of thyroid hormones. The acrophase of the 24-hour leptin profile occurred earlier, the amplitude of the rhythm and the overall mean levels were reduced. The nocturnal elevation of prolactin levels was abrupt but of short duration and the 24-hour mean levels were decreased. A pulse of growth hormone occurred prior to sleep onset, therefore affecting SWA distribution at the beginning of the sleep period. Since these alterations are qualitatively and quantitatively similar to those observed during aging and sometimes during depression, a state of sleep debt, as is experienced by a substantial fragment of the population in modern societies, is likely to increase the severity of depression and widespread age-related chronic conditions such as obesity, diabetes and hypertension.
Adult↗
Analysis of fatty acid ethyl esters in hair as possible markers of chronically elevated alcohol consumption by headspace solid-phase microextraction (HS-SPME) and gas chromatography-mass spectrometry (GC-MS).
Fatty acid ethyl esters (FAEE) are products of the nonoxidative ethanol metabolism, which are known to be detectable in blood only about 24h after the last alcohol intake. After deposition in hair they should be suitable long-term markers of chronically elevated alcohol consumption. Therefore, a method for the analysis of ethyl myristate, ethyl palmitate, ethyl oleate and ethyl stearate from hair was developed based on the extraction of the hair sample by a dimethylsulphoxide (DMSO)/n-hexane mixture, separation and evaporation of the n-hexane phase and application of headspace solid-phase microextraction (HS-SPME) in combination with gas chromatography-mass spectrometry (GC-MS) to the extract. For use as internal standards, the corresponding D(5)-ethyl esters were prepared. The HS-SPME/GC-MS measurements were automatically performed using a multi-purpose sampler. The detection limits of the FAEE were between 0.01 and 0.04ng/mg and the reproducibility was between 3.5 and 16%. By application of the method to hair samples of 21 fatalities with known heavy alcohol abuse 0.045-2.4ng/mg ethyl myristate, 0.35-13.5ng/mg ethyl palmitate, 0.25-7.7ng/mg ethyl oleate and 0.05-3.85ng/mg ethyl stearate were measured. For social drinkers (30-60g ethanol per week), the concentrations were about one order of magnitude smaller. For 10 teetotalers negative results or traces of ethyl palmitate were found. It was shown by supplementary investigations in single cases that FAEE are also present in sebum, that there is no strong difference in their concentrations between pubic, chest and scalp hair, and that they are detectable in hair segments after a 2 months period of abstinence. From the results follows that the measurement of FAEE concentrations in hair is a useful way for a retrospective detection of alcohol abuse.
Adolescent↗
The role of complement in Alzheimer's disease pathology.
Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review will examine the origins of complement in the brain and the role of beta-amyloid peptide (Abeta) in complement activation in Alzheimer's disease, an event that might serve as a nidus of chronic inflammation. Pharmacology therapies that may serve to inhibit Abeta-mediated complement activation will also be discussed.
Alzheimer Disease↗
Are there possibilities for the detection of chronically elevated alcohol consumption by hair analysis? A report about the state of investigation.
The analysis of suitable ethanol markers in hair would be an advantageous tool for chronic alcohol abuse control because of the wide diagnostic window allowed by this specimen and the possibility of segmental investigation. Between the markers practically used or thoroughly investigated in blood or urine, ethylglucuronide, fatty acid ethylesters, phosphatidylethanol, acetaldehyde adducts to protein and 5-hydroxytryptophol can be regarded as possible candidates also in hair, but preliminary data were found in the literature only for ethylglucuronide and acetaldehyde modified proteins. By using headspace gas chromatography and headspace solid phase microextraction in combination with gas chromatography-mass spectrometry (SPME-GC/MS), in alkaline hydrolysates of hair it was possible to determine between 17 and 135 ng/mg of ethanol beside acetone and several other volatile compounds with slightly higher ethanol values for alcoholics than for social drinkers and teetotalers. A part of this is ethanol only absorbed in the hair matrix from the surrounding environment and consequently is not applicable as a diagnostic criterion. By extraction with aqueous buffer, methanol or a methanol/chloroform mixture and subsequent alkaline hydrolysis it was found that another part is generated from ethylesters, which are preferentially deposited in the lipid fraction of hair. In a specific search for ethylesters of 17 carboxylic acids by GC/MS-SIM in most cases ethyl 4-hydroxybenzoate (0.1 to 5.9 ng/mg, a preservative in hair cosmetics) and in four cases traces of indolylacetic acid ethylester were found. Furthermore, diethyl phthalate (a softening agent, present also in many cosmetic products) was identified in the hair of alcoholics as well as of children. As potential markers of alcohol intake, ethyl palmitate, ethyl stearate and ethyl oleate were detected in hair samples of alcoholics by headspace SPME-GC/MS of the chloroform/methanol extracts.
Acetaldehyde↗
Pathophysiology of human circadian rhythms.
The 24 h profiles of hormonal secretions represent a good model for the study of the human circadian system. Diurnal hormonal variations generally reflect the modulation of ultradian or pulsatile release at 1-2 h intervals by signals occurring at nearly 24 h periods and result from the interaction of an internal timekeeping system--or circadian clock--with the sleep-wake homeostasis and various environmental factors, including the light-dark cycle, periodic changes in activity levels and the meal schedule. This temporal organization is altered in many pathophysiological conditions, including ageing, sleep loss, night or shift work, jet lag, affective disorders and endocrine diseases. Both photic and non-photic stimuli may affect the regulation of the circadian pacemaker and, therefore, the diurnal pattern of hormonal secretions. Appropriately timed stimuli may induce either a phase-advance or a phase-delay of the circadian clock, according to the timing of administration. Phase-shifting effects have been shown in humans for light and for dark pulses, physical exercise, melatonin and melatonin agonists, and benzodiazepine hypnotics. These results open new perspectives for the treatment of a variety of disorders involving dysregulation of the circadian rhythmicity.
Animals↗
CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology.
The five muscarinic receptor subtypes (M1-M5) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M1 subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, O-(3-aryl-2-propynyl) oximes. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0-3.2 and 0.1-0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100-178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic A beta and increased secretion of soluble APP. Thus, CI-1017, besides treating AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.
Animals↗
On the similarity of properties in solution or in the crystalline state: a molecular dynamics study of hen lysozyme.
As protein crystals generally possess a high water content, it is assumed that the behaviour of a protein in solution and in crystal environment is very similar. This assumption can be investigated by molecular dynamics (MD) simulation of proteins in the different environments. Two 2ns simulations of hen egg white lysozyme (HEWL) in crystal and solution environment are compared to one another and to experimental data derived from both X-ray and NMR experiments, such as crystallographic B-factors, NOE atom-atom distance bounds, 3J(H N alpha)-coupling constants, and 1H-15N bond vector order parameters. Both MD simulations give very similar results. The crystal simulation reproduces X-ray and NMR data slightly better than the solution simulation.
Animals↗
The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease.
Effective therapeutic intervention in Alzheimer disease (AD) will be most effective if it is directed at early events in the pathogenic sequence. The cholinergic deficit may be such an early event. In the present study, the brains of 26 subjects who had no history of cognitive loss and who were in early histopathologic stages of AD (average Braak stage less than II) were examined at autopsy to determine whether a cortical cholinergic decrement was associated with Abeta concentration or deposition. In the superior frontal and inferior temporal gyri, the choline acetyltransferase (ChAT) activity of plaque-containing cases was significantly decreased (p < 0.05, unpaired, two-tailed t-tests), measuring 70.9% and 79.5%, respectively, relative to plaque-free cases. In the inferior temporal gyrus, Spearman's rank correlation analysis showed that ChAT activity had a significant inverse correlation with Abeta concentration (p = 0.075; r = -0.3552). The results indicate that the cholinergic deficit is established at an early histopathologic stage of AD, before the onset of clinical symptoms.
Aged↗
Traumatic brain injury elevates the Alzheimer's amyloid peptide A beta 42 in human CSF. A possible role for nerve cell injury.
The increased risk for Alzheimer's Disease (AD) associated with traumatic brain injury (TBI) suggests that environmental insults may influence the development of this age-related dementia. Recently, we have shown that the levels of the beta-amyloid peptide (A beta 1-42) increase in the cerebrospinal fluid (CSF) of patients after severe brain injury and remain elevated for some time after the initial event. The relationships of elevated A beta with markers of blood-brain barrier (BBB) disruption, inflammation, and nerve cell or axonal injury were evaluated in CSF samples taken daily from TBI patients. This analysis reveals that the rise in A beta 1-42 is best correlated with possible markers of neuronal or axonal injury, the cytoskeletal protein tau, neuron-specific enolase (NSE), and apolipoprotein E (ApoE). Similar or better correlations were observed between A beta 1-40 and the three aforementioned markers. These results imply that the degree of brain injury may play a decisive role in determining the levels of A beta 1-42 and A beta 1-40 in the CSF of TBI patients. Inflammation and alterations in BBB may play lesser, but nonetheless significant, roles in determining the A beta level in CSF after brain injury.
Acute-Phase Proteins↗
Adaptation of the 24-h growth hormone profile to a state of sleep debt.
In normal men, the majority of GH secretion occurs in a single large postsleep onset pulse that is suppressed during total sleep deprivation. We examined the impact of semichronic partial sleep loss, a highly prevalent condition, on the 24-h growth hormone profile. Eleven young men were studied after six nights of restricted bedtimes (0100-0500) and after 7 nights of extended bedtimes (2100-0900). Slow-wave sleep (SWS) was estimated as the duration of stages III and IV. Slow-wave activity (SWA) was calculated as electroencephalogram power density in the 0.5- to 3-Hz frequency range. During the state of sleep debt, the GH secretory pattern was biphasic, with both a presleep onset "circadian" pulse and a postsleep onset pulse. Postsleep onset GH secretion was negatively related to presleep onset secretion and tended to be positively correlated with the amount of concomitant SWA. When sleep was restricted, both SWS and SWA were increased during early sleep. Unexpectedly, the increase in SWA affected the second, rather than the first, SWA cycle, suggesting that presleep onset GH secretion may have limited SWA in the first cycle, possibly via an inhibition of central GH-releasing hormone activity. Thus neither the GH profile nor the distribution of SWA conformed with predictions from acute sleep deprivation studies, indicating that adaptation mechanisms are operative during chronic partial sleep loss.
Adaptation, Physiological↗
Doxepin toxicity in a child following topical administration.
OBJECTIVE: To describe a case of a child with altered mental status following the topical administration of doxepin. CASE SUMMARY: A five-year-old Hispanic girl was brought to the emergency department because she was difficult to arouse at school. She had recently developed a generalized eczematous rash for which she was prescribed doxepin hydrochloride 5% cream. An entire tube (30 g) of doxepin cream was applied in the 24 hours prior to presentation. The patient was responsive only to noxious stimuli, with no focal neurologic abnormalities. She was decontaminated and observed in a pediatric intensive care unit. By 18 hours after presentation, she had fully recovered and was discharged. CONCLUSIONS: Topical doxepin, available as a 5% cream, is indicated for the treatment of pruritus secondary to eczematous dermatoses in adults. Diminished skin integrity and the application of a massive quantity of doxepin 5% cream to a large body surface area contributed to the toxicity in this child. Since the safety and efficacy of doxepin cream has not been established in children younger than 12 years, it should be used with caution in this population.
Administration, Topical↗
Impact of sleep debt on metabolic and endocrine function.
BACKGROUND: Chronic sleep debt is becoming increasingly common and affects millions of people in more-developed countries. Sleep debt is currently believed to have no adverse effect on health. We investigated the effect of sleep debt on metabolic and endocrine functions. METHODS: We assessed carbohydrate metabolism, thyrotropic function, activity of the hypothalamo-pituitary-adrenal axis, and sympathovagal balance in 11 young men after time in bed had been restricted to 4 h per night for 6 nights. We compared the sleep-debt condition with measurements taken at the end of a sleep-recovery period when participants were allowed 12 h in bed per night for 6 nights. FINDINGS: Glucose tolerance was lower in the sleep-debt condition than in the fully rested condition (p<0.02), as were thyrotropin concentrations (p<0.01). Evening cortisol concentrations were raised (p=0.0001) and activity of the sympathetic nervous system was increased in the sleep-debt condition (p<0.02). INTERPRETATION: Sleep debt has a harmful impact on carbohydrate metabolism and endocrine function. The effects are similar to those seen in normal ageing and, therefore, sleep debt may increase the severity of age-related chronic disorders.
Adult↗
Sleep as a mediator of the relationship between socioeconomic status and health: a hypothesis.
This article discusses the hypothesis that the adverse impact of low socioeconomic status (SES) on health may be partly mediated by decrements in sleep duration and quality. Low SES is frequently associated with a diminished opportunity to obtain sufficient sleep or with environmental conditions that compromise sleep quality. In a recent study, we examined carbohydrate metabolism, endocrine function, and sympatho-vagal balance in young, healthy adults studied after restricting sleep to four hours per night for six nights as compared to a fully rested condition obtained by extending the bed-time period to 12 hours per night for six nights. The state of sleep debt was associated with decreased glucose tolerance, elevated evening cortisol levels, and increased sympathetic activity. The alterations in glucose tolerance and hypothalamo-pituitary-adrenal function were qualitatively and quantitatively similar to those observed in normal aging. These results indicate that sleep loss can increase the "allostatic load" and facilitate the development of chronic conditions, such as obesity, diabetes, and hypertension, which have an increased prevalence in low SES groups.
Adult↗
Lactoferrin increases the output of neutrophil precursors and attenuates the spontaneous production of TNF-alpha and IL-6 by peripheral blood cells.
The aim of this report was to investigate the effects of bovine lactoferrin (BLF) taken orally (per os) by healthy individuals, on selected immune parameters. Three groups of volunteers (7 persons per group) were taken daily for 7 days, one capsule containing 2, 10 or 50 mg of BLF. A control group has taken placebo only. Venous blood was taken for tests a few hours before the first dose of BLF, one day and 14 days after the last dose of the preparation. For the evaluation of BLF action on the immune response system we have chosen 3 parameters: content of neutrophil precursors in the peripheral blood (in percentage), spontaneous production of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) by unstimulated blood cell cultures. We found that oral treatment of volunteers with BLF caused a transient (one day after last dose) increase of immature forms of neutrophils in the circulating blood. That increase was more than 2-fold in the case of 10 mg dose. However, statistically significant increases in the percentage of neutrophil precursors were also registered at doses of 2 and 50 mg of BLF. No change in the immature cell content was observed in the placebo group. The treatment with BLF also resulted in a profound decrease of the spontaneous production of IL-6 and TNF-alpha by cultures of peripheral blood cells. This decrease was significant (10 mg/dose) one day following the last dose of BLF and persisted for additional 14 days. These results confirmed our earlier data on the effects of per os treatment with a nutritional preparation containing BLF. Furthermore, we were able to closer establish the optimal dose of BLF affecting selected immune indices.
Adjuvants, Immunologic↗
Traumatic brain injury increases beta-amyloid peptide 1-42 in cerebrospinal fluid.
The beta-amyloid peptides, A beta1-42 and A beta1-40, were quantified in ventricular CSF taken daily for up to 3 weeks from six individuals with severe traumatic brain injury (TBI). There was considerable interindividual variability in the levels of A beta peptides, but in general A beta1-42 levels equalled or exceeded those of A beta1-40. Averaging the daily totals of our trauma cohort revealed that the levels of A beta1-42 and A beta1-40 rose after injury, peaking in the first week and then declining toward control levels over the next 2 weeks. A beta1-42 levels were on average two to three times higher in the trauma cohort than in CSF from nontrauma samples. Compared with nontrauma samples, the A beta1-40/A beta1-42 ratio decreased about fivefold in the trauma patients, further indicative of increased A beta1-42 levels. The ratio remained low at all time points studied. No change was measured in the levels of beta-amyloid precursor protein during the same interval. These results suggest that A beta1-42 becomes elevated in the CSF after severe brain trauma.
Adult↗
Genetic and environmental influences on prolactin secretion during wake and during sleep.
To delineate the contributions of genetic and environmental factors in the regulation of human prolactin (PRL) secretion, the 24-h profile of plasma PRL was obtained at 15-min intervals in 10 pairs of monozygotic and 10 pairs of dizygotic twins. Sleep was monitored polygraphically. PRL secretory rates were derived from plasma concentrations by deconvolution. Diurnal (24-h) variations were quantified by a regression curve to define nadir, acrophase, and amplitude. Pulses of PRL secretion were identified using a computerized algorithm. A procedure specifically developed for twin studies was used to partition the variance into genetic and environmental contributions. Significant genetic effects were identified for daytime PRL concentrations, rhythm amplitude, and overall wave-shape of the daily PRL profile. In contrast, environmental effects were dominant for mean concentrations during sleep, total secretory output during sleep, overall 24-h concentrations, and total 24-h secretion. However, when interindividual variations in sleep fragmentation were taken into account, the estimates of genetic variance for PRL concentrations and secretion during sleep approached statistical significance. Significant genetic influences were identified for slow-wave sleep (SWS). Because SWS is associated with increased nocturnal PRL secretion, it is possible that genetic effects on PRL secretion during sleep reflect genetic influences on SWS. In conclusion, genetic factors determine partially both the basal daytime concentrations of PRL and the temporal organization of PRL secretion over the 24-h cycle in normal young men.
Adult↗
Hair concentrations and self-reported abuse history of 20 amphetamine and ecstasy users.
Hair samples of 20 volunteers of the techno-music scene, who more or less regularly consumed ecstasy tablets and speed and anonymously reported their abuse history, were analyzed in one to seven 3 cm segments for amphetamine (A), methamphetamine (MA), methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA), methylenedioxyethamphetamine (MDE) and N-methyl-1-(1,3-benzodioxol-5-yl)-2-butylamine (MBDB) by digestion in 1 M NaOH, subsequent extraction with C18 Bond Elut columns, derivatization with pentafluoropropionyl anhydride and GC/MS-SIM measurements using deuterated standards of A, MA, MDA and MDMA. The concentrations were in the regions 0.1 to 4.8 ng/mg for A (17 samples), 0.05 to 0.89 ng/mg for MDA (16 samples), 0.1 to 8.3 ng/mg for MDMA (16 samples), 0.12 to 15 ng/mg for MDE (13 samples) and 0.21 to 1.3 ng/mg for MBDB (2 samples). MA was not detected. For comparison the frequency and the concentration of these drugs in 124 different ecstasy tablets were determined by HPLC. The drug concentration in the hair segments were compared with the volunteers' reports. Despite the enormous interindividual differences qualitatively an increase of the total concentration of MDA, MDMA and MDE in the proximate 3 cm segments with increasing ecstasy abuse frequency during the last three month before sampling is recognized. In the individual comparison with the chronological consumer reports in most cases a longer interruption or a change of the abuse intensity is not clearly seen at the segment concentrations. As a reason the incorporation of the drugs from sweat into elder hair regions and the slow removal by washing are discussed.
Adolescent↗