Proof of pharmacology of Org 48775-0, a p38 MAP kinase inhibitor, in healthy volunteers.

Aim: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of the highly selective oral p38alpha/beta mitogen-activated protein (MAP) kinase inhibitor Org 48,775-0 in a first-in-human study.

Methods: In the single ascending dosing (SAD) study, an oral dose of Org 48,775-0 (0.3-600 mg) was evaluated in healthy males.

Detection of colorectal polyps in humans using an intravenously administered fluorescent peptide targeted against c-Met.

Colon cancer prevention currently relies on colonoscopy using white light to detect and remove polyps, but small and flat polyps are difficult to detect and frequently missed when using this technique. Fluorescence colonoscopy combined with a fluorescent probe specific for a polyp biomarker may improve polyp detection. Here we describe GE-137, a water-soluble probe consisting of a 26-amino acid cyclic peptide that binds the human tyrosine kinase c-Met conjugated to a fluorescent cyanine dye.

Evaluation of the EndoPAT as a Tool to Assess Endothelial Function.

Endothelial dysfunction is a potential target for (pharmaceutical) intervention of several systemic pathological conditions. We investigated the feasibility of the EndoPAT to evaluate acute changes in endothelial function with repeated noninvasive measurements and assessed its discriminating power in different populations. Endothelial function was stable over a longer period of time in renally impaired patients (coefficient of variation 13%).

Excessive daytime sleepiness in a general population sample: the role of sleep apnea, age, obesity, diabetes, and depression.

Context: Excessive daytime sleepiness (EDS) is commonly considered a cardinal sign of sleep apnea; however, the mechanism underlying the association is unclear.

Objective: The purpose of this study was to assess the association between the complaint of EDS and sleep apnea, considering a wide range of possible risk factors in a population sample.

Design And Setting: We examined this question in the Penn State cohort (a random sample of 16,583 men and women from central Pennsylvania, ranging in age from 20 to 100 yr).

Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines.

Total sleep restriction in humans is associated with increased daytime sleepiness, decreased performance, and hormonal/metabolic disturbances. The effects of mild chronic sleep restriction that mimic real life are not known. To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory.

Neuroendocrine aspects of chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800000 Americans of all ages, races, socioeconomic groups and genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the neuroendocrine system. A symposium was organized in March 2001 to explore the possibility of an association between neuroendocrine dysfunction and CFS, with special emphasis on the interactions between neuroendocrine dysfunction and other abnormalities noted in the immune and autonomic nervous systems of individuals with CFS.

Impaired nighttime sleep in healthy old versus young adults is associated with elevated plasma interleukin-6 and cortisol levels: physiologic and therapeutic implications.

IL-6 and TNF alpha secretion is increased by sleep loss or restriction. IL-6 secretion progressively increases with age, yet its association with decreased quality and quantity of sleep in old adults is unknown. This study examined the alteration of 24-h secretory pattern of IL-6, TNF alpha, and cortisol in 15 young and 13 old normal sleepers who were recorded in the sleep laboratory for four consecutive nights.

Insomnia in central Pennsylvania.

Objective: Establish the association between insomnia and various physical and mental health symptoms as well as objective measures of sleep disturbance while controlling for age, gender and BMI in a large random sample of the general public.

Methods: A subsample (N=1741) was selected for a single-night sleep laboratory evaluation from a larger random sample (N=16,583) of the general public (20-100 years old).

Results: The prevalence of insomnia was 7.

Chronic insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to daytime.

Chronic insomnia, by far the most commonly encountered sleep disorder in medical practice, is characterized by difficulty falling or staying asleep at night and increased fatigue during the day. Interleukin-6 (IL-6) and tumor necrosis factor (TNF) are fatigue-inducing cytokines, and the daytime secretion of IL-6 is negatively influenced by the quantity and quality of the previous night's sleep. We hypothesize that the poor quality of insomniacs' sleep is associated with a hypersecretion of these 2 cytokines during the daytime, which, in turn, correlates with the fatigue experienced by these patients.

Chronic insomnia is associated with nyctohemeral activation of the hypothalamic-pituitary-adrenal axis: clinical implications.

Although insomnia is, by far, the most commonly encountered sleep disorder in medical practice, our knowledge in regard to its neurobiology and medical significance is limited. Activation of the hypothalamic-pituitary-adrenal axis leads to arousal and sleeplessness in animals and humans; however, there is a paucity of data regarding the activity of the hypothalamic-pituitary-adrenal axis in insomniacs. We hypothesized that chronic insomnia is associated with increased plasma levels of ACTH and cortisol.

Middle-aged men show higher sensitivity of sleep to the arousing effects of corticotropin-releasing hormone than young men: clinical implications.

The prevalence of insomnia associated with emotional stress increases markedly in middle-age. Both the top and end hormones of the hypothalamic-pituitary-adrenal axis, i.e.

Prevalence of sleep-disordered breathing in women: effects of gender.

The prevalence of sleep-disordered breathing has not been well studied in women, especially in terms of the effects of age, body mass index (BMI), and menopause. We evaluated this question using a two-phase random sample from the general population. In Phase I, 12,219 women and 4,364 men ranging in age from 20 to 100 yr were interviewed; and in Phase II, 1,000 women and 741 men of the Phase I subjects were selected for one night of sleep laboratory evaluation.

Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, characterized by chronic hyperandrogenism, oligoanovulation, and insulin resistance. Obstructive sleep apnea (OSA) and excessive daytime sleepiness (EDS) are strongly associated with insulin resistance and hypercytokinemia, independently of obesity. We hypothesized that women with PCOS are at risk for OSA and EDS.

Association of hypertension and sleep-disordered breathing.

Background: To our knowledge, the association between sleep-disordered breathing (SDB) and hypertension has not been evaluated in subjects from the general population with a wide age range while adjusting for the possible confounding factors of age, body mass index, sex, menopause and use of hormone replacement therapy, race, alcohol use, and smoking.

Methods: In the first phase of this study, we interviewed 4364 men and 12,219 women, aged 20 to 100 years. In the second phase of this study, 741 men and 1000 women, previously interviewed, were selected based on the presence of risk factors for SDB (snoring, daytime sleepiness, obesity, hypertension, and, for women, menopause).

Differences in nocturnal and daytime sleep between primary and psychiatric hypersomnia: diagnostic and treatment implications.

Objective: The differential diagnosis of primary (idiopathic) vs. psychiatric hypersomnia is challenging because of the lack of specific clinical or laboratory criteria differentiating these two disorders and the frequent comorbidity of mental disorders in patients with primary hypersomnia. The aim of this study was to assess whether polysomnography aids in the differential diagnosis of these two disorders.

Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.

Sleep apnea and associated daytime sleepiness and fatigue are common manifestations of mainly obese middle-aged men. The onset of sleep apnea peaks in middle age, and its morbid and mortal sequelae include complications from accidents and cardiovascular events. The pathophysiology of sleep apnea remains obscure.

Sleep deprivation effects on the activity of the hypothalamic-pituitary-adrenal and growth axes: potential clinical implications.

Objectives: Although several studies have shown that sleep deprivation is associated with increased slow wave sleep during the recovery night, the effects of sleep deprivation on cortisol and growth hormone (GH) secretion the next day and recovery night have not been assessed systematically. We hypothesized that increased slow wave sleep postsleep deprivation is associated with decreased cortisol levels and that the enhanced GH secretion is driven by the decreased activity of the HPA axis.

Design And Subjects: After four consecutive nights in the Sleep Laboratory, 10 healthy young men were totally deprived of sleep during the fifth night, and then allowed to sleep again on nights six and seven.

Circadian interleukin-6 secretion and quantity and depth of sleep.

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion.

Sleep and its disorders.

Sleep disorders are very prevalent in the general population and are associated with significant medical, psychological, and social disturbances. Insomnia is the most common. When chronic, it usually reflects psychological/behavioral disturbances.

Chronic insomnia and activity of the stress system: a preliminary study.

The aim of this study was to assess whether there is an association between chronic insomnia and the activity of the stress system. Fifteen young adult insomniacs (<40 years) were studied. After an adaptation night, each subject was recorded in the sleep laboratory for three consecutive nights.

A comparison of efficacy of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in the therapeutic setting of chemotherapy-induced myelosuppression.

A randomized, double-blind, multicenter study in 181 afebrile cancer patients with ANC levels < 500/microL receiving myelosuppressive chemotherapy was undertaken to compare sargramostim (yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor, RhuGM-CSF) and filgrastim (bacteria-derived recombinant human granulocyte colony-stimulating factor, RhuG-CSF) in the treatment of chemotherapy-induced myelosuppression. Patients received daily subcutaneous (SC) injections of either agent until ANC levels reached at least 1500/microL. There was no statistical difference between treatment groups in the mean number of days to reach an ANC of 500/microL, but the mean number of days to reach ANC levels of 1000/microL and 1500/microL was approximately one day less in patients receiving filgrastim.

Obesity without sleep apnea is associated with daytime sleepiness.

Background: Daytime sleepiness and fatigue is a frequent complaint of obese patients even among those who do not demonstrate sleep apnea.

Objective: To assess in the sleep laboratory whether obese patients without sleep apnea are sleepier during the day compared with healthy controls with normal weight.

Methods: Our sample consisted of 73 obese patients without sleep apnea, upper airway resistance syndrome, or hypoventilation syndrome who were consecutively referred for treatment of their obesity and 45 controls matched for age.