[Falling asleep at the wheel: chronicle of a predicatable accident].
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Accidents, Traffic↗
Biomedical subjects
P Lavie
Publications and source records attributed to P Lavie.
Actigraphic sleep monitoring in posttraumatic stress disorder (PTSD) patients.
Posttraumatic stress disorder (PTSD) patients frequently complain that they suffer from sleep disturbances. To date, the polysomnographic studies that have attempted to study PTSD patients' subjective complaints of sleep difficulties have produced conflicting results. The objective of the present study was to compare PTSD patients' subjective complaints of poor sleep and objective actigraphic recordings of their sleep over a period of several consecutive nights. The results indicate that PTSD patients do not suffer from poorer sleep than a control group, based on actigraphic measures, and that their subjective sleep evaluation is inconsistent with objective sleep measures. These patients fail to correctly estimate their sleep.
Adult↗
Pulsatile patterns of melatonin secretion in patients with gonadotropin-releasing hormone deficiency: effects of testosterone treatment.
Recently, we have demonstrated that male patients with gonadotropin-releasing hormone (GnRH) deficiency had increased nocturnal melatonin secretion that decreased to normal levels during testosterone treatment. The purpose of the current study was to examine if the abnormally increased melatonin levels in these patients were associated with pulsatile secretory patterns, and, if these were modified during testosterone administration. Characteristics of nocturnal melatonin and luteinizing hormone (LH) secretion were compared in six normal young males, six males with idiopathic hypogonadotropic hypogonadism (IGD), and in six males with constitutional delayed puberty (DP). Patients were examined in the untreated state and following the administration of 250 mg testosterone enanthate/month for 4 months. Serum samples for melatonin and LH levels were obtained every 15 min from 19.00 hr to 07.00 hr in a controlled light-dark environment. Pulse detection and pulse characteristics were determined by the program ULTRA. In comparison with normal controls, untreated IGD patients showed significantly higher pulse frequency, lower relative increments and shorter half-life times for melatonin. Similar findings were observed in DP patients, although statistically of borderline significance. Treatment with testosterone normalized melatonin pulse characteristics in both IGD and DP patients. The secretory pattern of LH release in these patients was characterized by significantly higher relative and absolute increments and shorter half-life time without any significant change in the number of LH pulses. Taken together, these data suggest that melatonin is secreted in a pulsatile pattern in normal adult males and in male patients with GnRH deficiency. The abnormally increased nocturnal melatonin secretion observed in these patients may indicate that the pineal pulse generator is expressing an altered activity pattern within its normal capabilities. Testosterone administration normalized melatonin secretory patterns in IGD and DP patients. The lack of relationship between the pulsatile LH and melatonin secretory patterns suggest an independent signal for the nocturnal pulsatile melatonin and LH secretions.
Adolescent↗
Impaired respiratory response to resistive loading during sleep in healthy offspring of patients with obstructive sleep apnea.
To evaluate the possibility that healthy offspring of patients with obstructive sleep apnea syndrome (OSAS) may have covert signs of sleep disordered breathing, we compared the respiratory response to inspiratory resistive loads (IRL) in 10 adult offspring of fathers previously diagnosed with OSAS with that of 14 offspring of healthy parents. None of the offspring in either group had any sign of OSAS, and groups were age, weight, and body mass index matched. Both ventilatory response to progressively increasing levels of IRL and the IRL required to produce severe hypopnea (tidal volume [V(T)] < 20% of unloaded magnitude) were determined, during NREM sleep. Offspring of patients with OSAS (OSAS offspring) responded to all levels of IRL with greater decreases in V(T). Their V(T) decreased in the second breath on IRL of 23 cm H2O/l/s by 39 +/- 10%, as compared with a decrease of 19 +/- 4% (mean +/- SD) in the control group (p < 0.05). Severe hypopnea occurred in the OSAS offspring in response to smaller IRL compared to controls (79 +/- 20 and 153 +/- 14 cm H2O/l/s, respectively, p < 0.005). Total upper airway occlusion in response to IRL occurred in three of the OSAS offspring, but in none of the controls. We conclude that apparently healthy offspring of patients with OSAS may inherit subtle defects that reduce their ability to compensate for increased loads and maintain upper airway patency during sleep. We speculate that offspring of OSAS patients with decreased tolerance to IRL may be prone to developing OSAS later on in life.
Adolescent↗
The effects of evening bright light on next-day sleep propensity.
The present study investigated the effects of evening bright light (BL) compared to dim light (DL) on next-day sleep propensity as well as the acrophase of oral temperature and mood scores. A total of 12 male subjects (mean age 23.5 +/- 2.6 years) were exposed to 2 h of evening DL or BL 30 min after sunset for 5 consecutive days. The experimental period started after the 5th day of exposure. After light exposure, subjects remained awake in the sleep laboratory until 07:00 h, when they began the 7/13 ultrashort sleep-wake paradigm, which continued for 24 h until 07:00 h the next day. Oral temperature was measured hourly. The results showed that evening exposure to BL, in comparison to DL, significantly delayed the next-day sleep gate as well as the acrophase of the oral temperature curve and the acrophase of negative mood. The effects of BL on the next-day distribution of sleep stages showed an increase of Stage 2 and less REM (rapid eye movement) during the morning. The results indicate that sleep propensity is regulated by a circadian pacemaker that is responsive to evening BL exposure.
Adult↗
Immunohistochemical localization of gonadotropin and gonadal steroid receptors in human pineal glands.
Recently, we demonstrated that melatonin secretion was increased in male patients with GnRH deficiency and decreased to normal levels during testosterone treatment. These data suggested that gonadal steroids modulate melatonin secretion, probably by activating specific receptors in the pineal gland. We used immunohistochemistry to localize gonadotropin (LH and FSH) and gonadal steroid (androgens and estrogens) receptors in human pineal glands. Tissues were obtained at autopsy from 25 males, aged 19-87 yr, and five prepubertal children, aged 0.2-10 yr. Positive staining for all four types of receptors (LH, FSH, androgen, and estrogen) in the pineal parenchymal cells, pinealocytes, was evident in all 30 glands examined. Double staining revealed that nuclear receptors (androgen or estrogen) co-existed with cytoplasmatic receptors (LH or FSH) in the same cells. The results demonstrate the presence of gonadotropin and gonadal steroid receptors in human pinealocytes from infancy to old age.
Adult↗
Bioavailability, antinociceptive and antiinflammatory properties of BP 2-94, a histamine H3 receptor agonist prodrug.
(R)alpha-Methylhistamine [(R)alpha-MeHA], a potent and selective histamine H3 receptor agonist in vitro and in vivo in rodents, was found to display comparatively low plasma level in healthy human volunteers, attributable to an extensive methylation of the drug's imidazole ring by histamine-N-methyltransferase. To limit this inactivation process, BP 2-94, ie., (R)-(-)-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino]phenylmethyl] phenol, was selected as a prodrug. A sensitive radioimmunoassay was developed to study the generation of (R)alpha-MeHA slowly released from BP 2-94 in vitro and in vivo by chemical hydrolysis. In mice after oral administration of BP 2-94 high levels of both prodrug and (R)alpha-MeHA were detected in plasma and various tissues except in the brain. In humans receiving 0.1 mmol BP 2-94 orally, plasma levels of (R)alpha-MeHA-like immunoreactivity decayed with a t(1/2) more than 24 hr, the area under the curve being two orders of magnitude higher than after oral administration of (R)alpha-MeHA. BP 2-94 displayed antiinflammatory and antinociceptive properties in rodents, related to the H3 receptor stimulation. It dose-dependently inhibited capsaicin-induced plasma protein extravasation in many rat tissues with ED50s of 0.6 to 14 micromol/kg p.o., and maximal reductions by 35 to 87%. BP 2-94 also reduced zymosan-induced paw swelling in mice with an ED50 of 1 micromol/kg p.o. and showed marked activity in the phenylbenzoquinone-induced writhing (ED50 = 0.03 micromol/kg, p.o.) or formalin tests in mice, but not in the hot plate jump test. From its pharmacokinetics and pharmacological profile BP 2-94 appears to be a promising novel therapeutic agent in disorders such as asthma, migraine or a variety of inflammatory diseases and pain associated with these disorders.
Adult↗
Hypnotic and hypothermic effects of melatonin on daytime sleep in humans: lack of antagonism by flumazenil.
In this double-blind, placebo-controlled study we investigated whether 10 mg flumazenil, a pure benzodiazepine antagonist, can block the hypnotic and hypothermic effects of 3 mg melatonin. The design comprised four 7-h (1200-1900 h) testing periods, preceded by a 'no-treatment' adaptation period of the "7/13' sleep-wake paradigm. Six young healthy adult males were paid to participate. During each experimental period, tablets were administered at 1145 h (flumazenil or placebo) and at 1200 h (melatonin or placebo) in a randomized, double-blind, partially repeated Latin square design. Polysomnographic recordings and core body temperature recordings revealed that melatonin, either in combination with placebo or with flumazenil, significantly increased the amounts of sleep, and decreased core body temperature in comparison with placebo alone or the combination of flumazenil plus placebo. These results do not support the hypothesis that melatonin exerts its hypothermic and hypnotic effects via the central benzodiazepine receptors.
Adult↗
[Insomnia in infancy and childhood--causes, significance, assessment and approach to treatment].
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Child↗
Abnormal melatonin secretion in male patients with hypogonadism.
Recently we have demonstrated that melatonin secretion is increased in untreated male patients with GnRH deficiency. Testosterone administration to these patients decreased melatonin secretion to normal levels. These data, however, did not exclude a gonadotropic effect on melatonin secretion. To further elucidate whether gonadal steroids and/or gonadotropins modulate melatonin secretion in humans we compared untreated young males with hypogonadotropic hypogonadism (IGD, n = 6), and hypergonadotropic hypogonadism caused by KlinEfelter's syndrome (KS, n = 11) to normal pubertal male controls (n = 7). KS patients were subdivided into two groups: KS-1, with low testosterone; and KS-2, with normal testosterone levels. Serum samples for melatonin concentrations were obtained every 15 min from 7 PM to 7 AM in a controlled light-dark environment with simultaneous sleep recordings. All KS patients had elevated gonadotropin levels and decreased melatonin levels. Mean (+/- SD) dark-time nocturnal melatonin levels in KS-1 were 92 +/- 21 pmol/L and were 146 +/- 46 pmol/L in KS-2 compared with 178 +/- 64 pmol/L in controls. Integrated nocturnal melatonin secretion values (AUC) were 64 +/- 14 pmol/min x L x 10(3) in KS-1 and 96 +/- 29 pmol/min x L x 10(3) in KS-2 compared with 116 +/- 42 pmol/min x L x 10(3) in controls. All IGD patients had low gonadotropin and testosterone levels. Their dark-time melatonin levels (286 +/- 26 pmol/L) and the AUC values (184 +/- 15 pmol/min/L x 10(3)) were increased. These data indicate that melatonin secretion is increased in male patients with GnRH deficiency and decreased in low testosterone hypergonadotropic hypogonadal patients. Taken together, our results suggest that both gonadotropins and gonadal steroids modulate melatonin secretion in humans.
Adolescent↗
Decreased nocturnal melatonin secretion in patients with Klinefelter's syndrome.
OBJECTIVE: We have recently demonstrated that GnRH deficient male patients have increased nocturnal melatonin secretion which decreases to normal levels during testosterone treatment. The results suggested that sex steroids, rather than LH, modulate pineal melatonin in an inverse fashion. The purpose of this study was to characterize circulating melatonin levels in untreated males with hypergonadotrophic hypogonadism due to Klinefelter's syndrome (KS). DESIGNS: Prospective, controlled. SUBJECTS: Eleven patients with Klinefelter's syndrome and seven controls. Patients were subdivided into two groups: (1) with low testosterone, and (2) with normal testosterone levels. MEASUREMENTS: Serum samples for melatonin concentrations were obtained every 15 minutes from 1900 to 0700 h in a controlled light-dark environment. RESULTS: All patients had elevated FSH, LH and oestradiol (E2) levels. Mean (+/-SD) dark time nocturnal melatonin levels were significantly lower in low testosterone KS (92 +/- 19 pmol/l) compared with 146 +/- 42 pmol/l in normal testosterone KS and 179 +/- 59 pmol/l in controls (P < 0.02). A similar pattern was observed for the mean (+/-SD) peak melatonin levels (165 +/- 41, 236 +/- 59 and 293 +/- 89 pmol/l) in low testosterone KS, normal testosterone KS and controls, respectively (P < 0.01). Integrated nocturnal melatonin secretion values (AUC) were also lower in low testosterone KS (64 +/- 13) compared with 96 +/- 26 in normal testosterone KS and 116 +/- 39 pmol/min 1 x 10(3) in controls (P < 0.02). The time of melatonin peak and the time of the nocturnal melatonin rise as well as the light-time mean (+/-SD) serum melatonin levels were similar in all three groups. No correlations were found between melatonin and LH, FSH, or E2 levels. CONCLUSIONS: Melatonin secretion is decreased in male patients with low testosterone hypergonadotrophic hypogonadism whereas in normal testosterone Klinefelter's syndrome patients, melatonin secretory profiles are normal. The results suggest that the suppression of melatonin secretion in these patients is mediated by GnRH (either directly or indirectly) and/or oestradiol.
Adolescent↗
Nocturnal melatonin and luteinizing hormone rhythms in women with hyperprolactinemic amenorrhea.
To examine the role of melatonin in pathological hyperprolactinemia we compared untreated young females (N = 5) with hyperprolactinemic amenorrhea owing to pituitary microadenoma to healthy female controls (N = 6). Serum samples for melatonin, prolactin, and luteinizing hormone (LH) concentrations were obtained every 15 min from 1900 hr to 0700 hr in a controlled light-dark environment with simultaneous sleep recordings. The mean (+/- SD) light-time period, dark-time period, and the integrated nocturnal melatonin secretion values (area under the curve, or AUC) in patients (51 +/- 11 pmol/L, 157 +/- 33 pmol/L, and 102 +/- 19 pmol/min.L x 10(3), respectively) were similar to the values obtained in controls (79 +/- 39, 165 +/- 44, 111 +/- 31, respectively). The onset of the nocturnal melatonin rise, peak level, and peak time were similar in the two groups. A significant nocturnal prolactin rise was observed in patients (112 +/- 9 vs. 65 +/- 11 micrograms/L, P < 0.006) and controls (19 +/- 2 vs. 10 +/- 3 micrograms/L, P < 0.006). The time of prolactin peak was similar in patients and controls (0424 +/- 3:36 vs. 0350 +/- 2:21) and paralleled that of melatonin (0354 +/- 1:46 vs. 0337 +/- 1:30). The mean +/- SD light-time period, dark-time period, and the AUC values of LH were similar in patients and controls. The number of LH pulses in patients (7.2 +/- 1.9 per 12 hr) were not different from those in controls (7.7 +/- 2.1). The LH pulse interval was 100 +/- 22 min in patients compared with 94 +/- 23 min in controls. The mean (+/- SD) nocturnal estradiol (E2) levels were significantly lower in patients (84 +/- 15 pmol/L) than in controls (224 +/- 77) (P < 0.005). Analysis of LH and melatonin secretory profiles revealed significant pulses for both hormones. No significant relationship was observed between the LH and melatonin pulses. However, a negative correlation between LH pulse amplitude and the number of melatonin pulses (P < 0.04) and a positive correlation between LH amplitude and duration of melatonin pulses (P < 0.04) were observed. Taken together, these data suggest that the suppression of normal ovarian cycles in women with hyperprolactinemic amenorrhea owing to pituitary microadenoma may be mediated by blocking of gonadotropin action by prolactin at the ovarian level; yet it remains possible that chronically elevated prolactin might prevent the LH surge and thus lead to amenorrhea. Pulsatile melatonin secretion is unaltered in these patients, and frequent occurrence of amenorrhea in this population is not mediated by melatonin.
Adenoma↗
Nocturnal secretory patterns of melatonin, luteinizing hormone, prolactin and cortisol in male patients with gonadotropin-releasing hormone deficiency.
To clarify whether disorders of gonadotropin releasing hormone (GnRH) deficiency are associated with altered melatonin and pituitary hormones secretory patterns, we studied male patients with hypogonadotropic hypogonadism (IGD; n = 6), delayed puberty (DP; n = 7) and age-matched pubertal controls (n = 7). Serum samples for the determination of melatonin, luteinizing hormone (LH), prolactin and cortisol levels were obtained at 15 min intervals from 1900 to 0700 in a controlled light-dark environment, complete bed-rest and fasting with simultaneous sleep recordings. Mean (+/- SD) dark-time melatonin levels were significantly higher in IGD (286 +/- 26 pmol/L) and DP (205 +/- 44 pmol/L) compared with 178 +/- 64 pmol/L in controls (P < 0.003). So were the mean (+/- SD) peak melatonin levels (453 +/- 63, 346 +/- 106 and 292 +/- 96 pmol/L) in IGD, DP and controls, respectively (P < 0.03). Integrated nocturnal melatonin (AUC) values were also higher in IGD and DP (184 +/- 15 and 134 +/- 28 pmol/min/L x 10(3)) compared with 116 +/- 42 pmol/min/L x 10(3) in controls (P < 0.003). The time of onset of the nocturnal melatonin rise was observed earlier in IGD and DP patients as compared to controls. No correlations were found between melatonin and LH levels, between melatonin and prolactin levels, or between melatonin and cortisol levels. These data indicate that melatonin secretion is enhanced in male patients with GnRH deficiency. The lack of correlation between melatonin and LH suggest that circulating gonadal steroids, rather than LH, modulate melatonin secretion in a reverse fashion.
Adolescent↗
Early morning melatonin levels in hypogonadal men.
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Circadian Rhythm↗
Testosterone treatment alters melatonin concentrations in male patients with gonadotropin-releasing hormone deficiency.
Recently, we demonstrated that melatonin secretion is increased in untreated male patients with GnRH deficiency. As testosterone (T) can be aromatized to estradiol (E2), and both T and E2 increase during T enanthate treatment, we were interested in determining whether T treatment (when T and E2 levels were well matched with pubertal control values) has an effect on melatonin levels in these patients. We measured nocturnal serum melatonin levels during the administration of 250 mg testosterone enantale/month for 4 months in 12 male patients with idiopathic hypogonadotropic hypogonadism (IGD; n = 6) and delayed puberty (DP; n = 6). Serum samples for melatonin and LH determinations were obtained every 15 min from 1900-0700 h in a controlled light-dark environment. The results of melatonin profiles were compared with the pretreatment values in each group and with values obtained in six normal pubertal male controls. After 4 months of testosterone treatment, all patients attained normal serum testosterone (19.5 +/- 3.7 in IGD vs. 20.8 +/- 4.1 nmol/L in DP) and E2 levels (83 +/- 12 in IGD vs. 84 +/- 9 pmol/L in DP). Serum LH levels were suppressed in all patients during T treatment (0.12 +/- 0.1 in IGD vs. 0.12 +/- 0.2 IU/L in DP). Before T treatment, patient melatonin levels were greater than those in age-matched pubertal controls. Melatonin levels were equal in patients and controls when T and E2 levels were well matched. Mean (+/- SD) dark-time melatonin levels decreased from 286 +/- 23 to 157 +/- 36 pmol/L in IGD and from 217 +/- 32 to 133 +/- 47 pmol/L in DP (vs. 183 +/- 64 pmol/L in controls). The integrated melatonin values decreased to normal (from 184 +/- 16 to 102 +/- 21 in IGD and from 142 +/- 19 to 90 +/- 26 pmol/min.L x 10(3) in DP vs. 119 +/- 61 pmol/min.L x 10(3) in controls). The intraindividual variations in melatonin levels ranged from 7.2-14.5%. These data indicate that male patients with GnRH deficiency have increased nocturnal melatonin secretion. T treatment decreased melatonin secretion to normal levels. The results suggest that in GnRH-deficient male patients, sex steroids, rather than LH, modulate pineal melatonin in a reverse fashion.
Adolescent↗
Melatonin replacement corrects sleep disturbances in a child with pineal tumor.
A child with a germ cell tumor involving the pineal region had marked suppression of melatonin secretion associated with severe insomnia. Exogenous melatonin (3 mg in the evening) for 2 weeks restored sleep continuity, as demonstrated by objective monitoring of rest-activity cycles. This case report provides direct evidence of the essential role of melatonin in normal sleep.
Adolescent↗
A crossover study comparing the efficacy of continuous positive airway pressure with anterior mandibular positioning devices on patients with obstructive sleep apnea.
OBJECTIVE: This study compared the efficacy of a removable anterior mandibular positioning (AMP) device to continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) using a fully balanced crossover design. DESIGN: Twenty-three male subjects with confirmed OSA were recruited from the Technion Sleep Laboratory in Haifa, Israel, from February 18, 1991 to December 17, 1992. Twenty-one of the 23 subjects enrolled completed all aspects of the study. RESULTS: The mean apnea-hypopnea index (AHI) before treatment was 33.86 +/- 14.30. The mean AHI decreased with CPAP to 59.50%, but decreased only 38.91% with the AMP device. The lowest mean recorded oxygen saturation level for the 21 subjects was 84.30 before treatment, 91.10 after CPAP treatment, and 90.20 after AMP treatment. Sleep data revealed a significant decrease in stage 1 and 2 (p=0.0088) and an increase in rapid eye movement percent (p=0.0066) for both treatments when compared with baseline. Three- to 10-month posttreatment phone interviews showed that 1 subject was not using either device, 1 subject was using CPAP, and 2 subjects were using the AMP device intermittently due to occasional temporomandibular joint pain symptoms. The remaining 17 subjects were all using the AMP device nightly. The symptoms of excessive daytime sleepiness also decreased significantly by both AMP and CPAP. CONCLUSIONS: The AMP device achieved substantial success in most cases, but was less effective than CPAP, especially for the more severe cases. In general, the AMP device was strongly preferred over the CPAP by the subjects of this study.
Adult↗
Surgical treatment of sleep apnea syndrome.
Several surgical procedures have been developed for the treatment of sleep apnea syndrome. These include nasal, uvulopalatopharyngeal, and head and neck surgery, weight reduction surgery, and tracheostomy. Despite over 15 years of experience with some of these operations, there is still a lack of consensus regarding the indications, success rate, complications, and long-term prognosis associated with these procedures. The current status of these surgical procedures is reviewed.
Adult↗