Daily salivary cortisol patterns in midlife women with hot flashes.

OBJECTIVE: Diurnal salivary cortisol patterns in healthy adults are well established but have not been studied in midlife women with hot flashes. We hypothesized that frequent hot flashes are associated with aberrant cortisol patterns similar to sleep-deficient individuals. DESIGN: Cross-sectional. PARTICIPANTS: A total of 306 women, ages 40-62, randomized to a behavioural intervention for hot flashes. MEASUREMENTS: Baseline comparisons of cortisol geometric means (nmol/l) from four daily time points averaged over two consecutive days plus other calculated cortisol measures were made between groups defined by baseline: (i) mean daily hot flash frequency tertile (≤5·5, N = 103; >5·5-8·8, N = 103; >8·8, N = 100) and (ii) selected characteristics. Repeated-measures linear regression models of log-transformed cortisol evaluated group differences, adjusting for covariates. RESULTS: Women were 67% White and 24% African American, with 7·6 (SD 3·9) hot flashes per day. Salivary cortisol geometric means (nmol/l) among all women were as follows: 75·0 (SD 44·8) total, 8·6 (SD 5·6) wake, 10·0 (SD 7·5) wake +30 min, 3·7 (SD 3·3) early afternoon and 1·6 (SD 1·8) bedtime. Wake + 30-minute values showed an 18% median rise from wake values (interquartile range -24 to 96%), and means varied by hot flash frequency tertile, from lowest to highest: 11·4(SD 7·3), 10·3 (SD 6·5) and 8·6 (SD 7·8), respectively, P = 0·003. Beside the early afternoon value (P = 0·02), cortisol values did not vary by hot flash frequency. CONCLUSION: Taken together, these findings suggest that high frequency of moderate-to-severe hot flashes may be associated with subtle abnormalities in cortisol concentrations - a pattern consistent with chronic sleep disturbance.

Multimodality sensor system for long-term sleep quality monitoring.

Sleep monitoring is an important issue and has drawn considerable attention in medicine and healthcare. Given that traditional approaches, such as polysomnography, are usually costly, and often require subjects to stay overnight at clinics, there has been a need for a low-cost system suitable for long-term sleep monitoring. In this paper, we propose a system using low-cost multimodality sensors such as video, passive infrared, and heart-rate sensors for sleep monitoring. We apply machine learning methods to automatically infer a person's sleep state, especially differentiating sleep and wake states. This is useful information for inferring sleep latency, efficiency, and duration that are important for long-term monitoring of sleep quality in healthy individuals and in those with a sleep-related disorder diagnosis. Our experiments show that the proposed approach offers reasonable performance compared to an existing standard approach (i.e., actigraphy), and that multimodality data fusion can improve the robustness and accuracy of sleep state detection.

Decreased nocturnal levels of prolactin and growth hormone in women with fibromyalgia.

Fibromyalgia (FM) is a complex syndrome, primarily of women, characterized by chronic pain, fatigue, and sleep disturbance. Altered function of the somatotropic axis has been documented in patients with FM, but little is known about nocturnal levels of PRL. As part of a laboratory study of sleep patterns in FM, we measured the serum concentrations of GH and PRL hourly from 2000--0700 h in a sample of 25 women with FM (mean, 46.9 +/- 7.6 yr) and in 21 control women (mean, 42.6 +/- 8.1 yr). The mean (+/-SEM ) serum concentrations (micrograms per L) of GH and of PRL during the early sleep period were higher in control women than in patients with FM [GH, 1.6 +/- 0.4 vs. 0.6 +/- 0.2 (P < 0.05); PRL, 23.2 +/- 2.2 vs. 16.9 +/- 2.0 (P < 0.025)]. The mean serum concentrations of GH and PRL increased more after sleep onset in control women than in patients with FM [GH, 1.3 +/- 0.4 vs. 0.3 +/- 0.2 (P < 0.05); PRL, 16.2 +/- 2.4 vs. 9.7 +/- 1.5 (P < 0.025)]. Sleep efficiency and amounts of sleep or wake stages on the blood draw night were not different between groups. There was a modest inverse relationship between sleep latency and PRL and a direct relationship between sleep efficiency and PRL in FM. There was an inverse relationship between age and GH most evident in control women. Insulin-like growth factor I levels were not different between the groups. These data demonstrate altered functioning of both the somatotropic and lactotropic axes during sleep in FM and support the hypothesis that dysregulated neuroendocrine systems during sleep may play a role in the pathophysiology of FM.

Self-reported nap behavior and polysomnography at home in midlife women with and without insomnia.

STUDY OBJECTIVES: To describe self-reported nap behavior and relationships among nap history, nap behavior during the study, indicators of subjective and objective insomnia, and self-reported daytime sleepiness from data previously obtained in a week-long field study of sleep in midlife women with and without insomnia. DESIGN: Descriptive/comparative secondary analysis. SETTING: Individual homes of the participants. PARTICIPANTS: Midlife women (mean age 46+/-4 years) with self-reported insomnia (n=101) and women with adequate sleep (n=30). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Sleep patterns were assessed by polysomnography (PSG), daily diaries, and a sleep history form. Although all women were requested not to nap, 47% of the women reported nap behavior during the study. Strong relationships were observed between a history of daytime naps and nap behavior (chi2 = 25.63, p < or = .001), and a history of feeling sleepy or struggling to stay awake during the daytime (i.e., sleepiness) and nap behavior (chi2 = 18.05, p < or = .001) during the study. There was also a modest significant (p < or = .05) correlation (r = .25) between tiredness and nap duration during the study. There were no statistical differences in sleep variables between the napping and non-napping groups. In the napping group, there were no differences between women with sleep efficiency < 85% (objective insomnia) and those with sleep efficiency > 85%. CONCLUSIONS: Habitual nap behavior may be indicative of daytime sleepiness in women with insomnia, but it is not necessarily related to subjective or objective measures of insomnia. Women who routinely nap may be unable to refrain from napping during the daytime in long-term research studies.

Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women.

OBJECTIVE: To determine whether disrupted slow wave sleep (SWS) would evoke musculoskeletal pain, fatigue, and an alpha electroencephalograph (EEG) sleep pattern. We selectively deprived 12 healthy, middle aged, sedentary women without muscle discomfort of SWS for 3 consecutive nights. Effects were assessed for the following measures: polysomnographic sleep, musculoskeletal tender point pain threshold, skinfold tenderness, reactive hyperemia (inflammatory flare response), somatic symptoms, and mood state. METHODS: Sleep was recorded and scored using standard methods. On selective SWS deprivation (SWSD) nights, when delta waves (indicative of SWS) were detected on EEG, a computer generated tone (maximum 85 decibels) was delivered until delta waves disappeared. Musculoskeletal tender points were measured by dolorimetry; skinfold tenderness was assessed by skin roll procedure; and reactive hyperemia was assessed with a cotton swab test. Subjects completed questionnaires on bodily feelings, symptoms, and mood. RESULTS: On each SWSD night, SWS was decreased significantly with minimal alterations in total sleep time, sleep efficiency, and other sleep stages. Subjects showed a 24% decrease in musculoskeletal pain threshold after the third SWSD night. They also reported increased discomfort, tiredness, fatigue, and reduced vigor. The flare response (area of vasodilatation) in skin was greater than baseline after the first, and again, after the third SWSD night. However, the automated program for SWSD did not evoke an alpha EEG sleep pattern. CONCLUSION: Disrupting SWS, without reducing total sleep or sleep efficiency, for several consecutive nights is associated with decreased pain threshold, increased discomfort, fatigue, and the inflammatory flare response in skin. These results suggest that disrupted sleep is probably an important factor in the pathophysiology of symptoms in fibromyalgia.

Sleep deprivation alters body temperature dynamics to mild cooling and heating not sweating threshold in women.

Sleep deprivation alters thermoregulatory responses. We used control of skin temperature to produce mild thermal challenge, both cool (32 degrees C) and warm (38 degrees C), and recorded esophageal and rectal temperatures, sweat rate and forearm blood flow in six healthy young women at rest. We discovered that after one night of sleep deprivation (1) both mean esophageal and rectal temperatures were reduced, (2) the mean threshold for sweating was not altered, and (3) there was no direct indication that skin blood flow was set at different levels with skin temperature neutral or cool. Peripheral vasodilation was attenuated when skin temperature was held at 38 degrees C. Following this period of mild hyperthermia, esophageal and rectal temperatures decreased much more rapidly in sleep-deprived subjects when skin temperature was cooled and held constant at 32 degrees C. We conclude that sleep-deprived women lose heat rapidly in response to a mild cooling stimulus. Sleep-deprived humans may be more vulnerable to heat loss with reduced ability to warm even at temperatures thought to be associated with thermal comfort.

Sleep, psychological distress, and stress arousal in women with fibromyalgia.

The purpose of this investigation was to compare self-reported sleep quality and psychological distress, as well as somnographic sleep and physiological stress arousal, in women recruited from the community with self-reported medically diagnosed fibromyalgia (FM) to women without somatic symptoms. Eleven midlife women with FM, when compared to 11 asymptomatic women, reported poorer sleep quality and higher SCL-90 psychological distress scores. Women with FM also had more early night transitional sleep (stage 1) (p < 0.01), more sleep stage changes (p < 0.03) and a higher sleep fragmentation index (p < 0.03), but did not differ in alpha-EEG-NREM activity (a marker believed to accompany FM). No physiological stress arousal differences were evident. Less stable sleep in the early night supports a postulate that nighttime hormone (e.g., growth hormone) disturbance is an etiologic factor but, contrary to several literature assertions, alpha-EEG-NREM activity sleep does not appear to be a specific marker of FM. Further study of mechanisms is needed to guide treatment options.

Effects of 72 hours sleep deprivation on wound healing in the rat.

The purpose of this study was to examine effects of sleep deprivation on cellular and biochemical markers of wound healing. Expanded polytetrafluoroethylene tubing inserted in subcutaneous tissue created miniature wounds in the dorsal skin of 12 rats. Seven days later, 6 rats were deprived of sleep by the platform method for 72 hr; control rats remained on usual sleep/wake routines. Numbers of macrophages, granulocytes, fibroblasts, and extent of connective tissue present and total amounts of protein, DNA, and hydroxyproline in the implants were not different between sleep-deprived and control rats. There is no evidence from this study that sleep deprivation impairs cellular and biochemical indicators of tissue repair.

The active state of the thin filament is destabilized by an internal deletion in tropomyosin.

The function of three of tropomyosin's sequential quasiequivalent regions was studied by deletion from skeletal muscle alpha-tropomyosin of internal residues 49-167. This deletion mutant tropomyosin spans four instead of the normal seven actins, and most of the tropomyosin region believed to interact with troponin is retained and uninterrupted in the mutant. The mutant tropomyosin was compared with a full-length control molecule that was modified to functionally resemble muscle tropomyosin (Monteiro, P. B., Lataro, R. C., Ferro, J. A., and Reinach, F. C. (1994) J. Biol. Chem. 269, 10461-10466). The tropomyosin deletion suppressed the actin-myosin subfragment 1 MgATPase rate and the in vitro sliding of thin filaments over a heavy meromyosin-coated surface. This inhibition was not reversed by troponin plus Ca2+. Comparable tropomyosin affinities for actin, regardless of the deletion, suggest that the deleted region has little interaction with actin in the absence of other proteins. Similarly, the deletion did not weaken binding of the troponin-tropomyosin complex to actin. Furthermore, Ca2+ had a 2-fold effect on troponin-tropomyosin's affinity for actin, regardless of the deletion. Notably, the deletion greatly weakened tropomyosin binding to myosin subfragment 1-decorated actin, with the full-length tropomyosin having a 100-fold greater affinity. The inhibitory properties resulting from the deletion are attributed to defective stabilization of the myosin-induced active state of the thin filament.

Sleep deprivation in the rat: XVIII. Regional brain levels of monoamines and their metabolites.

Several theories have linked sleep with change in monoamine activity. However, the use of sleep deprivation to show that changes in sleep generate changes in monoamines (directly or through feedback) has produced inconsistent results. To explore whether longer sleep deprivation, better documented sleep loss, more complete controls or regional brain analyses would produce clear sleep loss-induced change, eight rats were subjected to total sleep deprivation (TSD) by the disk-over-water method for 11-20 days and were guillotined along with yoked control (TSC) and home-cage control (HCC) rats. Brains were removed and dissected to obtain the caudate, frontal cortex, hippocampus, hypothalamus, midbrain and hindbrain (pons-medulla). Tissue sections were analyzed for concentrations of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and either norepinephrine or, in the caudate section, the DA metabolite homovanillic acid. The ratios DOPAC/DA and 5HIAA/5HT, which under some conditions are indicators of turnover, were also calculated. Because sleep deprivation time varied across sets of TSD, TSC and HCC rats and not all eight sets were analyzed simultaneously, a repeated-measures ANOVA was performed within sets with HCC, TSC and TSD considered as successive levels of sleep deprivation treatment. In no case did TSD rats have significantly higher or lower values of amines, metabolites or ratios than both HCC and TSC rats. The most common outlying values were for TSC rats. Thus, these results failed to demonstrate sleep loss-induced regional changes in levels of major brain monoamines or their metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep deprivation in the rat: XVII. Effect of aspirin on elevated body temperature.

Previous studies of total sleep deprivation (TSD) in the rat have shown an elevation of waking body temperature (Tb) early in the deprivation period. TSD rats defend this rise behaviorally by selecting warm ambient temperatures and autonomically by increasing heat production, thus indicating an elevation of thermoregulatory setpoint. Prostaglandins (PGs) can elevate setpoint and Tb. To investigate whether the TSD-induced rise in setpoint and Tb was mediated by PGs, aspirin, which blocks the synthesis of PGs, was administered 100 mg/kg s.q. to 11 TSD and 13 control (TSC) rats in baseline and deprivation. During baseline, aspirin produced a nonsignificant (0.16 degrees C) rise across all rats in waking Tb. For the sampled time period, waking Tb during deprivation day 3 was significantly elevated in TSD rats (0.64 degrees C, p < 0.01) but not in TSC rats (0.27 degrees C). Aspirin was administered on deprivation day 4. It produced a fall in waking Tb in TSD rats from its deprivation-induced elevation. The difference between the response to aspirin during baseline and during deprivation was significant (-0.25 degrees C, p < 0.05) for TSD rats but not TSC rats (-0.17 degrees C). Time awake after aspirin increased significantly (16.2%, p < 0.05) during baseline and declined nonsignificantly (1.1%) during deprivation. These data imply that at least part of the rise in Tb that is characteristic of TSD is mediated by PGs. To the extent that PGD2 promotes lower Tb and sleep in rats but PGE2 has opposite effects, the results are consistent with a shift from PGD2 predominance in baseline toward PGE2 predominance during TSD.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of Egr-1 in the brain of sleep deprived rats.

In previous research, rats subjected to prolonged sleep deprivation have shown disturbances of thermoregulation, hormonal and metabolic changes in apparent response to the thermoregulatory problems, lesions on the tail and paws, and eventual death. To search for alterations of functional activity in brain, the expression of the immediate early gene Egr-1 was examined by immunocytochemistry and Northern blotting in rats subjected to total sleep deprivation (TSD) for 10 days. Controls included yoked stimulus-control (TSC) rats, surgically implanted but otherwise undisturbed control rats, and unoperated control rats. Photographs of immunoreacted coronal sections from four sets of rats were ranked blindly for 25 brain regions. TSD rats showed tendencies for regionally specific increases in Egr-1-like immunoreactivity in dorsal raphe, lateral habenula, superior colliculus, and ventral periaqueductal grey. However, most regions showed no differences in Egr-1-like immunoreactivity between TSD and control rats. Neither was there a difference in whole brain Egr-1 mRNA by Northern blot in two additional sets of rats. Thus, this study, like previous studies of brain histology, amines, adrenoceptors, and glucose utilization, does not provide positive support for the hypothesis that sleep protects the central nervous system against massive global damage, fatigue, or dysfunction.

Sleep deprivation in the rat: XV. Ambient temperature choice in paradoxical sleep-deprived rats.

Previous studies of total sleep deprivation (TSD) and paradoxical sleep deprivation (PSD) in the rat by the disk-over-water method have indicated that both produce changes in thermoregulation. In both kinds of deprivation, there was a progressive, large increase in heat production as indicated by measures of energy expenditure (EE). In TSD there was an initial increase in waking body temperature (Tb) followed by a later decrease; in PSD there was only a progressive decrease. The increases in heat production far in excess of heat storage indicated increased heat loss in both groups. Because the increase in Tb in TSD rats was supported by ambient temperature choices (Tch) in a thermal gradient that became progressively higher during deprivation, an increase in waking temperature setpoint (TSET) was indicated. Because the rats resorted to behavioral warming in spite of greatly increased thermogenesis, they must have had some failure to retain body heat. Prior to the present study, changes in TSET, had not been evaluated in PSD rats. Because they had not shown increases in Tb, PSD rats might not have an elevated TSET, which would indicate a functional difference between PS and nonrapid eye movement (NREM) sleep. Also, an evaluation of behavioral thermoregulation in PSD rats would clarify whether their Tb decline resulted from excessive heat loss or from a lowered TSET. To evaluate changes in heat flow and TSET, EE, Tb and Tch were measured in five PSD rats and their yoked control (PSC) rats. PSD rats showed progressive increases in EE and decreases in Tb as in the earlier PSD study; Tch rose progressively. PSC rats showed minimal changes in all three parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein.

Activating mutations in the gene for the alpha-chain of Gs, the stimulatory regulator of adenylyl cyclase, have been identified in human GH-secreting pituitary tumors. Using the polymerase chain reaction and allele-specific oligonucleotide hybridization, we screened 25 GH-secreting tumors for the presence of the activating mutations. We also reviewed the clinical charts of the patients from whom the tumors were removed. Of 25 tumors, 10 (40%) contained activating mutations. Patients in the mutation-positive group came to surgery with smaller tumors and had lower GH levels. The activating mutations identify a subgroup of GH-secreting pituitary tumors that probably arise from a shared oncogenic mechanism.

Two G protein oncogenes in human endocrine tumors.

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the alpha polypeptide chain (alpha s) of Gs into a putative oncogene, termed gsp. These mutations, which activate alpha s by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein alpha chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein alpha chain genes. The first gene so far tested, which encodes the alpha chain of Gi2, showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant alpha i2 gene is a putative oncogene, referred to as gip2. In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein alpha chain genes.

Mutational analysis of the structure and function of GTP-binding proteins.

Structural, biochemical and molecular genetic studies of EF-Tu, p21ras and alpha s have begun to reveal the inner workings of the molecular machine used by these and other GTP-binding proteins. Further understanding of this molecular machine will ultimately come from crystal structures of the G protein alpha chains as well as from crystal structures of the GTP-bound forms of p21ras and EF-Tu. Mutational analysis will continue to add meaning to the static pictures provided by these crystal structures. Aside from their intrinsic biological interest, other reasons motivate our exploration of the GTP-dependent molecular machine used by GTP-binding proteins. Mutations or bacterial toxins cause disease by inhibiting the GTPase function of p21ras and alpha s. Other G protein alpha chains carry signals that regulate important cell functions, including proliferation. Malfunctions of these other G proteins are highly likely to cause disease. Applying our knowledge of p21ras and alpha s to these additional proteins may turn out to have significant practical consequences.

GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours.

A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein alpha chain, alpha(s). The resulting activation of adenylyl cyclase bypasses the cells' normal requirement for trophic hormone. Amino acids substituted in the putative gsp oncogene identify a domain of G protein alpha-chains required for intrinsic ability to hydrolyse GTP. This domain may serve as a built-in counter-part of the separate GTPase-activating proteins required for GTP hydrolysis by small GTP-binding proteins such as p21ras.