Features of patients and fracture risk in hypoparathyroidism; a single center study.

PURPOSE: Patients with hypoparathyroidism (hypoPT) have low bone turnover and high bone mineral density (BMD). However, data on fracture risk are conflicting. The objectives of this study were: 1. To describe clinical/biochemical characteristics of hypoPT patients followed at a single medical center. 2. To identify postsurgical hypoPT patients and investigate their fracture rate compared with gender/age-matched post-surgical normocalcemic patients. METHODS: Retrospective analysis of patient's medical records treated at the tertiary medical center in 2010-2021 identified by computerized medical database search. RESULTS: The cohort included 133 patients (91% women, mean age 64 ± 13 years) of whom 105 (79%) had post-thyroidectomy hypoparathyroidism and the remainder had an autoimmune/idiopathic/other etiology. Mean follow-up time was 21 ± 12 and 27 ± 12 years, respectively. The control group included 142 post-thyroidectomy patients without hypoparathyroidism. Patients in the postsurgical hypoparathyroidism group were older and had higher calcium and PTH levels at diagnosis than the non-surgical hypoPT patients. Comparing the postsurgical hypoPT and postsurgical normocalcemic control patients revealed a significantly higher BMD in the hypoPT group. Yet, fracture rates were 31% in the postsurgical hypoparathyroidism group and 21% in the control group (P = 0.1) over a similar median follow-up period (17 and 18.4 years, respectively). In both groups the most common fracture site was the spine (50% and 70%, respectively; p = 0.33), mainly nonclinical morphometric fractures. Higher phosphorus blood level was associated with increased fracture risk. CONCLUSIONS: The relatively high BMD in patients with postsurgical hypoparathyroidism is not associated with lower fracture risk. Silent morphometric fractures are quite common in this group of patients.

Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?

Hypocalcemia was reported at low rates (0.05-1.7%) in denosumab-treated postmenopausal women with osteoporosis. This real-life study shows a 7.4% rate of denosumab-induced hypocalcemia in community-dwelling osteoporotic men and women. Pretreatment serum calcium and creatinine levels are major predictors for this complication. Serum-calcium monitoring may help to identify and prevent severe hypocalcemia. PURPOSE: RCTs have reported a 0.05-1.7% rate of hypocalcemia in denosumab-treated postmenopausal women with osteoporosis, but long-term real-life data are lacking. We assessed the rate of hypocalcemia in osteoporotic community-dwelling patients treated with denosumab. METHODS: A retrospective analysis was conducted based on medical records (2010-2018) from a large HMO. An albumin-adjusted serum calcium concentration lower than 8.5 mg/dL was defined as hypocalcemia. RESULTS: We included 2005 patients (93% women, mean age 76 ± 9 years). Hypocalcemia developed during treatment in 149 patients (7.4%; 1% less than 8 mg/dL): in 66 after 0.5-1 years; 48 after 1-2 years; 35 after > 2 years. On comparison of the hypocalcemic and normocalcemic patients, the strongest predictors of hypocalcemia were pretreatment levels of albumin-adjusted serum calcium (9.1 ± 0.4 vs. 9.4 ± 0.5 mg/dL, respectively; p < 0.05) and creatinine (0.9 ± 0.5 vs. 0.8 ± 0.3 mg/dL, respectively; p < 0.05). The hypocalcemia rate increased in parallel to a decrease in eGFR (p = 0.032 for the difference between eGFR ranges). Baseline calcium level ≤ 9.31 mg/dL predicted hypocalcemia with a sensitivity of 77% and specificity of 56%. A model of (- 2)*calcium + creatinine predicted hypocalcemia (3.7% when lower and 17.1% when higher than - 17.4). Gender, age, 25-hydroxyvitamin-D, parathyroid hormone, alkaline phosphatase, and whether denosumab was given as first or advanced line of osteoporotic therapy had no predictive value. CONCLUSION: Real-life rates of denosumab-induced hypocalcemia are higher than previously reported. Hypocalcemia might develop after each dose of denosumab in ongoing treatment. Adequate calcium and vitamin D supplementation are needed. Serum calcium monitoring is advised in high-risk patients for early detection of severe hypocalcemia.

Gender differences in homocysteine concentrations, a population-based cross-sectional study.

BACKGROUND AND AIMS: High concentrations of homocysteine are considered a risk factor for atherosclerosis and coronary artery disease. The aim of this study was to assess whether or not there are gender differences in the plasma concentrations of homocysteine. METHODS AND RESULTS: Data were collected from medical records of individuals examined at a screening center in Israel between the years 2000-2014. Cross sectional analysis was carried out on 9237 men and 4353 women. Mean (SD) age of the study sample was 48.4 (9.7) and 47.7 (9.7) years for men and women respectively. Average homocysteine concentrations were 12.6 (5.9) and 9.6 (3.2) µmol/L in men and women respectively (p < 0.001). Prevalence of homocysteine concentrations above 15 µmol/L was found to be significantly higher in men than in women; 15.5% vs 3.9% respectively (p < 0.001). Low concentrations of vitamin (B12 < 200 pmol/L) and low concentrations of folate (<12 nmol/L) were found to be significantly higher in men than in women 20.4% vs. 16.0% and 18.5% vs. 10.8% respectively. Compared to women, men had a significantly higher odds ratio (95% CI) of having homocysteine concentrations above 15 µmol/L: non adjusted model, 4.47 (3.80-5.26); adjusted model for age, smoking status, body mass index, diabetes mellitus, kidney function and low serum concentrations of vitamin B12 and folate, 3.44 (2.89-4.09). CONCLUSION: Plasma homocysteine concentrations are higher in men than in women. This may be a contributing factor to gender differences for developing atherosclerosis and coronary artery disease.

High blood glucose variability is associated with bacteremia and mortality in patients hospitalized with acute infection.

BACKGROUND: Limited data are available regarding the association between glucose levels variability (GV) and outcomes of patients hospitalized with acute infectious diseases. AIM: To determine the association between GV and bacteremia, length of stay (LOS) and mortality. METHODS: A retrospective study of patients hospitalized in departments of medicine with respiratory tract, urinary tract and skin and soft tissue infections during 2011-17. GV was assessed by the coefficient of variation (CV) of glucose levels during hospitalization and was divided into tertiles (CV ≤ 16%, 17-29%, >29%). LOS, bacteremia rates and all-cause mortality (30 days, 90 days and after 5 years) were evaluated for the patients with and without DM according the three GV categories. RESULTS: The study consisted of 1485 patients, 838 (56%) were diabetic. There was no significant association between GV and LOS. Bacteremia rates were higher in the upper GV tertile compared with the lower one (6% vs. 2%, P = 0.007). Mid and upper tertiles compared with the lower one were significantly associated with increased 30-day mortality (13% vs. 5%, P = 0.005; and 40% vs. 5%, P = 0.002, respectively). A decreased 5 years survival was observed for both diabetic and non-diabetic patients in the mid and upper GV tertiles [adjusted HRs 0.8 (95% CI, 0.6-1.04) and 0.6 (95% CI, 0.5-0.9) in diabetic patients and 0.7 (95% CI, 0.5-0.9) and 0.5 (95% CI, 0.3-0.7) in the non-diabetic ones]. CONCLUSION: In diabetic and non-diabetic patients, hospitalized in non-ICU setting with acute infectious diseases, increased GV is associated with increased risk of bacteremia, short and long-term mortality.

Fine-needle aspiration cytology for parotid lesions, can we avoid surgery?

OBJECTIVE: Salivary gland neoplasms are rare tumours, with most arising in the parotid gland. Fine-needle aspiration cytology (FNAC) is a common method for preoperative evaluation of parotid masses, although its usefulness is controversial. This study was designed to evaluate the accuracy of FNAC in a large cohort of patients, with emphasis on diagnosis of benign tumours and especially Warthin tumour which can be managed conservatively. STUDY DESIGN: Retrospective case series with chart review. SETTING: Tertiary medical centre. SUBJECTS AND METHODS: From 1991 to 2014, all patients 18 or older with both preoperative FNAC and postoperative pathology report were included. Patients with a history of head and neck malignancy or chronic sialoadenitis and patients who had undergone prior oncological treatment were excluded. RESULTS: 470 patients were available for analysis. Overall accuracy was 82.6%. Positive predictive value (PPV) varied between 88.6% and 94.3% for pleomorphic adenoma and 77.1%-100% for Warthin tumour, with values varying depending on different characteristics of patients (eg age, smoking status). For pathologically proven malignant tumours, the FNAC diagnosis was benign or non-diagnostic in 26% of the cases. CONCLUSION: Fine-needle aspiration cytology has limited utility in confirming a benign diagnosis of a parotid mass for most patients, although for some subpopulations, the PPV may be high enough to defer surgery.

Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations.

Oncotype-DX assay has never been validated for BRCA mutation carriers. This study compares the recurrence score (RS) distribution in BRCA-positive breast cancer patients with that of a general population (GP) of patients and reports their outcomes. Eligible patients were BRCA carriers who performed the Oncotype-DX assay. Two sets of databases were cross-linked: BRCA carriers at Rabin Medical Center and Sheba Medical Center with Oncotype-DX tests performed through Clalit Health Services HMO, from 2003 to 2015. Fifty-eight BRCA patients were included (20 BRCA1, 38 BRCA2). The GP included 1020 patients. Compared to the GP, BRCA1 patients were younger, had higher rate of grade three tumors, and higher Ki67. BRCA2 patients had lower PR index, higher rate of grade three tumors, and higher Ki67. Among the GP, 52.9, 37.9, and 9.1 % had low, intermediate, and high risk RS, respectively. Corresponding rates were 15, 35, and 50 % in BRCA1 patients, and 18.4, 52.6, and 29 % in BRCA2 patients. Subgroup analysis revealed a similar RS distribution pattern regardless of the nodal status. Median follow-up was 45 months. Four BRCA patients (7 %) developed disease recurrence. RS of these patients were in the intermediate and low range. All recurrences occurred in chemo-naïve patients who had not undergone bilateral oophorectomy. This study revealed significantly different RS distributions between BRCA patients and the GP. RS values shifted toward high and intermediate risk categories. This pattern held regardless of the nodal status and was more pronounced in the BRCA1 group.

Prevalence of asthma in a large group of Israeli adolescents: influence of country of birth and age at migration.

BACKGROUND: The occurrence of asthma has geographic variations and is lower in developing compared with industrialized countries. Both environmental and genetic factors may influence its prevalence. We aimed to evaluate the importance and effect of immigration (country of birth and age at immigration to Israel) on the prevalence of asthma in a large group of Israeli adolescents. METHODS: Computerized medical records of 17-year-old adolescents, who underwent routine examination before military recruitment, were studied. The sample comprised both native-born Israelis (NBI) and immigrants from Ethiopia, the Former Soviet Union (FSU), and Western countries (WC). Asthma was defined as clinical symptoms and signs compatible with the disease accompanied by abnormal spirometry or documented chronic use of inhaled steroids. RESULTS: Our cohort consisted of 1 466 654 adolescents, including 1 317 556 (89.8%) NBI and 149 098 (10.2%) immigrants. The prevalence of asthma at age 17 was higher in NBI compared with Ethiopian immigrants [4.7% (61 921) vs 2.6% (418), respectively, P < 0.0005], lower compared with immigrants from WC [5.6% (2177), P < 0.0005], and similar to immigrants from the FSU. Further analysis of the association between age at immigration and the risk for developing asthma showed that the younger immigrants from the FSU and Ethiopia arrived to Israel, the higher their prevalence of asthma at the age of 17 was. CONCLUSIONS: Both environmental and genetic factors seem to influence the prevalence of asthma in 17-year-old adolescents. However, the higher risk for developing asthma associated with young age of immigration points toward an environmental predominance.

Screening for erectile dysfunction as part of periodic examination programs--concept and implementation.

Erectile dysfunction (ED) can be an early and first sign of an underlying systemic disease. A screening program is offered by the Israeli Defense Force for career servicemen at the staff periodic examination center (SPEC), the aim of which was early detection of morbidity. We introduced the Sexual Human Inventory for Males (SHIM) questionnaire, in order to detect examinees with ED, and offer them suitable treatment options. The purpose of this study is to introduce the concept of an ED questionnaire as part of a screening program, and to describe the first months of its implementation. A computerized questionnaire is used to collect the medical history. The SHIM questionnaire was incorporated into the medical questionnaire. Relevant data including compliance to reply, SHIM scores, age and accompanying diseases of patients were collected from the computerized database of SPEC. A total of 2182 patients reported to SPEC from 1/5/01 to 1/11/01, 1980 of whom were males. Of the males, 881 (44.5%) chose to fill the SHIM questionnaire (mean age 34.5 +/- 6.7 y), and 244 of them (27.7%) had a score of 21 or less (20.7% had 17-21, 5.7% 11-16, 1.4% 0-10). The prevalence of ED and its severity increases with age. An inverted linear correlation was found between age and SHIM score (r = -0.22, P<0.0001). Prevalence of hypertension and diabetes mellitus is higher in patients with SHIM score < or =16 compared to those with a score > or =22. Only 15% of men with ED refer themselves for medical help. The concept of adding an ED questionnaire to a screening program may encourage more men to seek treatment, not only for their ED, but also for the underlying disease. The platform of a periodic examination offers maximum privacy to the examinees, resulting in better cooperation.

The SleepStrip: an apnoea screener for the early detection of sleep apnoea syndrome.

Sleep apnoea svndrome (SAS) is a largely undiagnosed and prevalent disorder. It is associated with cardiovascular morbidity as well as excessive daytime sleepiness and poor quality of life. In the present study the SleepStrip, a novel screening device is introduced, which is low cost and easy to use and is aimed for widespread use. The results of three independent validation studies, which compared the SleepStrip score (Sscore) against "gold standard" polysomnographically-determined apnoea/ hypopnoea index (AHI), are reported both separately and combined. Four hundred and two patients suspected of SAS underwent full polysomnography recordings concomitantly with the use of the SleepStrip. For all samples combined, the correlation between AHI and Sscore was r=0.73, sensitivity and specificity values ranged from 80-86% and 57-86% respectively, and the area under the curve derived from receiver-operating characteristic curves ranged from 0.81-0.92 at varying AHI thresholds. Though not intended as a substitute for polysomnography, the SleepStrip may provide initial screening information, which may be useful in both clinical and experimental settings.

Sleep Disorders in the Elderly.

Sleep disturbances in the elderly may not be a result of the aging process per se, but rather are likely caused by many factors that are amenable to treatment. These factors include medical and psychiatric problems, medications, and circadian rhythm changes, all of which can cause difficulties during sleep at night, and can lead to complaints of insomnia. Other factors that cause disturbances include a high prevalence of specific sleep disorders such as sleep disordered breathing (SDB), periodic limb movements during sleep (PLMS) and rapid eye movement (REM) sleep behavior disorder (RBD). Although these disorders are more prevalent in the older than younger population, they are not exclusive to this age group, and treatment options that are applicable to young adults are also applicable to older adults. On the other hand, dementia and Parkinson's disease are two neurologic disorders that are almost exclusive to the elderly and most often involve sleep disturbances. Because there are many causes of sleep complaints, when considering treatment options one must identify the underlying problem. If caused by illness, effective treatment of a specific medical or psychiatric problem should help alleviate the sleep problem as well. Changes in the timing of drug administration may improve sleep. For the treatment of chronic insomnia, behavior techniques should always be used in combination with pharmacologic therapy, and sedative-hypnotic medications should be considered when appropriate. The treatment of choice for obstructive sleep apnea is continuous positive airway pressure (CPAP). For PLMS, dopaminergic agents are most effective. For RBD, clonazepam effectively controls the aversive sleep behaviors. Sleep disturbances secondary to dementia and Parkinson's disease are usually problematic for the patient as well as the caregiver, whether in the home or in the nursing home. Proper management of these disturbances is beneficial in terms of delaying institutionalization and reducing nursing care costs, as well as improving the quality of life for both patient and caregiver.

Changes in cognitive function associated with sleep disordered breathing in older people.

OBJECTIVES: Sleep disordered breathing (SDB) is very common in older people and is known to be associated with complaints of impaired daily functioning, including excessive daytime sleepiness and cognitive impairments. As part of a larger study on SDB and aging, it became possible to examine the relationship between SDB and cognition in older men and women. DESIGN: A population-based longitudinal study. SETTING: In-home interviews and home sleep recordings in the greater San Diego area. PARTICIPANTS: Community-dwelling people age 65 and older with high risk for SDB were originally studied from 1981 through 1985 and then followed every 2 years. Data from the 46 subjects who completed Visit 3 and Visit 4 are presented. MEASUREMENTS: Subjects were interviewed in the home about their sleep and medical condition before each visit. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Daytime sleepiness was based on self-report. Objective sleep was recorded in the home and scored for sleep, apneas and hypopneas, and oximetry variables. RESULTS: Increases in respiratory disturbance index (RDI) (P= .036) and increases in daytime sleepiness (P= .002) were associated with decreases in cognitive performance (i.e., increases in cognitive impairment). Increases in RDI were also associated with increases in daytime sleepiness (P= .012). Change in MMSE scores was therefore regressed onto changes in RDI, daytime sleepiness, age, and education, resulting in decreases in MMSE scores being associated with increases in daytime sleepiness (P= .019) but not with changes in RDI (P= .515). There was no significant relationship between changes in oxygen saturation levels and changes in MMSE. CONCLUSIONS: The results of this study suggest that declining cognitive function is associated primarily with increases in daytime sleepiness. Although cognitive decline was also associated with increases in RDI, this association did not hold in the more inclusive model which also included variable of SDB, oximetry, sleep and subjective report. One theoretical model could suggest that any relationship between SDB and cognitive function may be mediated by the effect of SDB on daytime sleepiness. These results suggest that older patients suffering from mild to moderate SDB may benefit from the treatment of SDB, even if they are not markedly hypoxemic.

Assessment and treatment of sleep disturbances in older adults.

Sleep disturbances are common in older adults. These disturbances are often secondary to medical illness and/or medication use or are due to specific problems such as sleep disordered breathing, periodic limb movements in sleep and circadian rhythm disturbances. The prevalence of sleep disordered breathing and periodic limb movement in sleep increases with age. The circadian rhythm tends to advance with age, causing older people to awaken early in the morning. Insomnia is often caused by pain associated with medical illness. Insomnia can also be caused by stimulating medications. In institutionalized elderly, sleep becomes even more disturbed and fragmented than in community-dwelling older adults. Accurate assessment and diagnosis is crucial since effective treatment strategies are available for these sleep disturbances. The effect, prevalence and treatment of each of these conditions is reviewed.

Circadian rhythms of agitation in institutionalized patients with Alzheimer's disease.

Agitation is a common problem in institutionalized patients with Alzheimer's disease (AD). "Sundowning," or agitation that occurs primarily in the evening, is estimated to occur in 10-25% of nursing home patients. The current study examined circadian patterns of agitation in 85 patients with AD living in nursing homes in the San Diego, California, area. Agitation was assessed using behavioral ratings collected every 15 minutes over 3 days, and activity and light exposure data were collected continuously using Actillume recorders. A five-parameter extension of the traditional cosine function was used to describe the circadian rhythms. The mean acrophase for agitation was 14:38, although there was considerable variability in the agitation rhythms displayed by the patients. Agitation rhythms were more robust than activity rhythms. Surprisingly, only 2 patients (2.4%) were "sundowners." In general, patients were exposed to very low levels of illumination, with higher illumination during the night being associated with less robust agitation rhythms with higher rhythm minima (i.e., some agitation present throughout the day and night). Seasonality was examined; however, there were no consistent seasonal patterns found. This is the largest study to date to examine agitation rhythms using behavioral observations over multiple 24 h periods. The results suggest that, although sundowning is uncommon, agitation appears to have a strong circadian component in most patients that is related to light exposure, sleep, and medication use. Further research into the understanding of agitation rhythms is needed to examine the potential effects of interventions targeting sleep and circadian rhythms.

Illumination levels in nursing home patients: effects on sleep and activity rhythms.

Studies examining levels of illumination in adult populations have demonstrated that the level and amount of light exposure are lower in the elderly compared with younger adults, particularly in institutionalized patients with dementia. Although insufficient light exposure has been implied as a cause of sleep fragmentation, evidence for such a relationship is scant. Sixty-six institutionalized elderly had their activity and light exposure monitored for a 3-day period. Mean and median light levels, minutes spent over 1000 and over 2000 lux, percent sleep and wake, and number of naps were computed for daytime intervals, defined as 07.00-18.59. Percentages of sleep and wake, number of awakenings and mean duration of wake periods were computed for night-time intervals, defined as 22.00-05.59. Mesor, amplitude and acrophase of activity and of light were determined by cosinor analysis. A mixed linear model was used to assess the effects of daytime Actillume measures on subsequent night-time measures, and vice versa. Spearman correlations were computed, and multiple regression analyses were carried out with light variables and dementia level as predictors and sleep-wake and activity measures as dependent variables. The median light level was 54 lux and a median of only 10.5 min were spent over 1000 lux. Higher light levels predicted fewer night-time awakenings, and severe dementia predicted more daytime sleep and lower mean activity. Increased bright light exposure predicted later activity acrophase. There was an association between the acrophases of light and of activity, with maximum illumination preceding peak activity. These results suggest that daytime light exposure has an impact on both night-time sleep consolidation and timing of peak activity level.

Sleep in the elderly.

Older adults frequently experience difficulties with sleep that can be caused by specific sleep disorders (such as sleep-disordered breathing or periodic limb movements in sleep) and circadian rhythm disturbances. These all can be effectively treated. Medical illnesses and medications also can have a negative affect on sleep and effective management of these can significantly improve sleep in older adults. Sleep in institutionalized older adults is even more disturbed than sleep of community-dwelling older people and special considerations can be made to improve the quality of sleep in institutional settings.

Insomnia in primary care patients.

STUDY OBJECTIVES: To determine the prevalence and characteristics of insomnia in primary care patients, to examine patients' help-seeking behavior, and to compare the frequency of insomnia in primary care patients to the general population. METHODS: 286 patients from primary care clinics in San Diego, California (n = 96), and in Haleiwa and Honolulu, Hawaii (n = 190) participated. Sleep study questionnaires were distributed by front desk receptionists to all patients over 18 years of age upon arrival at the clinic for an appointment with the physician. Completed questionnaires were collected at the clinic or returned by mail. Comparisons were made by using nonparametric statistics. A logistic regression analysis using backward elimination was done to develop a model showing predictors of who would consult with the physician about a sleep problem. RESULTS: The prevalence of insomnia in primary care patients was 69%, with 50% reporting occasional insomnia and 19% reporting chronic insomnia. As expected, patients with chronic insomnia had the most severe sleep complaints as well as the poorest daytime functioning, and exhibited the most help-seeking behaviors. The four predictors of discussing insomnia with a physician were how patients felt physically, number of years of insomnia, age, and income. CONCLUSIONS: The primary care population has a higher prevalence of insomnia than the general population, probably because of concomitant psychiatric and medical illnesses. Although many of the characteristics of the sleep complaints are easily detected, most patients with insomnia are not treated effectively.

Melatonin administered in the afternoon decreases next-day luteinizing hormone levels in men: lack of antagonism by flumazenil.

The role of melatonin in the regulation of human reproduction remains unclear. In the present study, we examined the influence of exogenous melatonin on pulsatile luteinizing hormone (LH), diurnal rhythm of testosterone, and endogenous melatonin profile in six healthy young adult males. To test the hypothesis that the effect of melatonin on LH or testosterone secretory patterns may be mediated through the benzodiazepine-(BNZ) gamma-amino-butyric acid (GABA) receptor complex, a benzodiazepine receptor antagonist (Flumazenil) was administered. The study design comprised four 10-h (4:00 PM-2:00 AM) testing periods. During each experimental period, subjects were given an oral dose of placebo, or 3 mg melatonin or 10 mg flumazenil, at 5:00 PM, in a randomized, double-blind, partially repeated Latin square design in the following combinations: placebo-placebo, placebo-melatonin, flumazenil-placebo, and flumazenil-melatonin. The following day, serum samples were obtained every 20 min between 4:00 PM and 2:00 AM in a controlled light-dark environment for the determination of LH and melatonin levels. Serum testosterone concentrations were determined every 20 min between 7:00 and 8:00 AM and 7:00 and 8:00 PM. A significant decrease in mean serum LH levels (p < 0.02) was observed in the melatonin-treated groups as compared with placebo-flumazenil groups. There was no change in LH pulse frequency, testosterone levels, or in melatonin onset time and amplitude. No additional effect of flumazenil on LH or testosterone levels was observed. These data indicate that an evening melatonin administration decreases the next-day LH secretion in normal adult males without altering testosterone levels or the endogenous nocturnal melatonin secretory pattern. This effect of melatonin is not mediated through the benzodiazepine-GABA receptor complex.

Hourly profiles of sleep and wakefulness in severely versus mild-moderately demented nursing home patients.

The purpose of the current study was to examine differences in hour-by-hour sleep/wakefulness profiles between severely and mild-moderately demented patients, and to assess how many elderly patients remain almost fully asleep or nearly fully awake in each hour of a 24-hour period. Sleep/wakefulness patterns of 67 demented nursing home residents (mean age = 85.7 years) were recorded using Actillume recorders. One 24-hour period was used, and numbers of minutes spent asleep or awake were computed for every hour. There were 46 severely demented patients, and 21 mild-moderately demented patients. The amount of sleep and wakefulness recorded for each hour was compared between the two groups. In addition, the frequencies of patients who remained asleep for more than 90% of each hour, and of those who sustained wakefulness for more than 90% of each hour were computed for every hour, and comparisons were again made between the two groups. Multivariate analysis of variance showed a significant effect of dementia group on the percent of sleep/wakefulness over 24 hours (p = 0.028). Subsequent t-tests performed separately for each hour revealed significant differences between the two dementia groups in 13 out of the 24 hours. Significant differences in the frequencies of patients asleep > 90% or awake > 90% of each hour were centered around the early night and early morning hours. Patients with mild-moderate dementia showed a disproportionate amount of wakefulness during the night, whereas, in addition, patients with severe dementia showed a disproportionate amount of sleepiness during the day. With the progression of dementia, both the capacity to maintain sleep and the capacity to maintain wakefulness are impaired, and result in complete fragmentation of sleep/wakefulness during the night and day.

Melatonin--the key to the gate of sleep.

This article reviews the evidence that melatonin, a hormone produced by the pineal gland during the dark hours, plays a major role in the regulation of the sleep-wake cycle. In recent years, our laboratory has been involved in a large-scale project aimed at investigating the role of endogenous melatonin in sleep-wake regulation and the effects of nonpharmacological levels of melatonin on sleep. Based on our finding on the precise coupling between the endogenous nocturnal increase in melatonin secretion and the opening of the nocturnal sleep gate, we propose that the role of melatonin in the induction of sleep does not involve the active induction of sleep, but is rather mediated by an inhibition of a wakefulness-producing mechanism in the central nervous system. Our studies also suggest that exogenously administered melatonin may be beneficial in certain types of insomnia that are related to disturbances in the normal secretion of the hormone.

Nocturnal melatonin onset is phase locked to the primary sleep gate.

In this study, we used the "ultrashort sleep-wake paradigm" (7/13), which measures sleep propensity three times an hour for 29 h, from 0700 to 1200 the next day, on 6 healthy male subjects concomitantly with melatonin plasma level. Melatonin was measured once an hour during the morning and early afternoon of the first day and three times an hour from 1600 to 1000 the following morning. Rectal temperature was measured continuously for four subjects. Subjects underwent the 7/13 paradigm three times, and in all three sessions consistent phase relationships were found between the nocturnal onset of melatonin secretion and opening of the nocturnal sleep gate; also, there was an inverse relationship between melatonin and core body temperature and an almost perfect out-of-phase relationship between sleep propensity and temperature, with the temperature peak falling precisely in the middle of the "forbidden zone" for sleep, i.e., the early evening nadir in sleepiness. On the basis of these phase relationships and previous findings from our laboratory on the effects of exogenous melatonin on the sleep propensity function, we conclude that melatonin participates in sleep-wake regulation in humans.