Continuous Positive Airway Pressure-Mandibular Advancement Device Combination Therapy for Moderate-to-Severe Obstructive Sleep Apnea: A Preliminary Study.

OBJECTIVES: The purpose of this pilot study was to determine whether compliance to auto-adjusting positive airway pressure (APAP) improves with the addition of a mandibular advancement device (MAD). Secondary outcome measures included were APAP pressure, subjective daytime sleepiness, apnea-hypopnea index (AHI), and mask leaks. SETTING AND SAMPLE POPULATION: Participants included were diagnosed with moderate-to-severe obstructive sleep apnea (OSA) and became noncompliant to prescribed APAP. Thirteen participants with a mean age of 61.6 years were recruited for this study. MATERIALS AND METHODS: All participants were given a MAD to use with their APAP. Parameters measured included APAP pressure, AHI, mask leak reported via ResMed AirViewTM software, and self-reported daytime sleepiness (Epworth Sleepiness Scale [ESS]). A paired two-sample for mean t-test was performed to determine significance. RESULTS: The mean difference of pre- and postintervention APAP compliance was 23.1%, which was statistically significant (p = 0.015). The mean APAP air pressures were unchanged. The difference between pre- and postintervention mean ESS scores was 1.4 and was statistically significant (p = 0.027). The mean difference between pre- and postintervention AHI values and mask leak showed no significant difference. CONCLUSION: This study showed that combination of APAP-MAD therapy, for patients with moderate-to-severe OSA who were noncompliant to APAP use, significantly increased compliance with APAP therapy, and significantly decreased the daytime sleepiness of participants.

Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

INTRODUCTION: The purpose of this systematic review is to provide supporting evidence for a clinical practice guideline on the use of behavioral and psychological treatments for chronic insomnia disorder in adult populations. METHODS: The American Academy of Sleep Medicine commissioned a task force of 9 experts in sleep medicine and sleep psychology. A systematic review was conducted to identify randomized controlled trials that addressed behavioral and psychological interventions for the treatment of chronic insomnia disorder in adults. Statistical analyses were performed to determine if the treatments produced clinically significant improvements in a range of critical and important outcomes. Finally, the Grading of Recommendations Assessment, Development, and Evaluation process was used to evaluate the evidence for making specific treatment recommendations. RESULTS: The literature search identified 1,244 studies; 124 studies met the inclusion criteria, and 89 studies provided data suitable for statistical analyses. Evidence for the following interventions is presented in this review: cognitive-behavioral therapy for insomnia, brief therapies for insomnia, stimulus control, sleep restriction therapy, relaxation training, sleep hygiene, biofeedback, paradoxical intention, intensive sleep retraining, and mindfulness. This review provides a detailed summary of the evidence along with the quality of evidence, the balance of benefits vs harms, patient values and preferences, and resource use considerations.

Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline.

INTRODUCTION: This guideline establishes clinical practice recommendations for the use of behavioral and psychological treatments for chronic insomnia disorder in adults. METHODS: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine and sleep psychology to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The task force evaluated a summary of the relevant literature and the quality of evidence, the balance of clinically relevant benefits and harms, patient values and preferences, and resource use considerations that underpin the recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS: The following recommendations are intended as a guide for clinicians in choosing a specific behavioral and psychological therapy for the treatment of chronic insomnia disorder in adult patients. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation is one that requires that the clinician use clinical knowledge and experience, and to strongly consider the patient's values and preferences to determine the best course of action. 1. We recommend that clinicians use multicomponent cognitive behavioral therapy for insomnia for the treatment of chronic insomnia disorder in adults. (STRONG). 2. We suggest that clinicians use multicomponent brief therapies for insomnia for the treatment of chronic insomnia disorder in adults. (CONDITIONAL). 3. We suggest that clinicians use stimulus control as a single-component therapy for the treatment of chronic insomnia disorder in adults. (CONDITIONAL). 4. We suggest that clinicians use sleep restriction therapy as a single-component therapy for the treatment of chronic insomnia disorder in adults. (CONDITIONAL). 5. We suggest that clinicians use relaxation therapy as a single-component therapy for the treatment of chronic insomnia disorder in adults. (CONDITIONAL). 6. We suggest that clinicians not use sleep hygiene as a single-component therapy for the treatment of chronic insomnia disorder in adults. (CONDITIONAL).

Investigation of 4-piperidinols as novel H3 antagonists.

Compounds containing a substituted 4-piperidinol core have been found to be potent antagonists of the human H(3) receptor. The compounds exhibited up to a 60-fold preference for inhibiting the human H(3) receptor over the mouse and showed a low binding affinity for the hERG channel.

3-Indolyl sultams as selective CRTh2 antagonists.

CRTh2 (DP(2)) is a prostaglandin D(2) receptor implicated in the recruitment of eosinophils and basophils within the asthmatic lung. Here we report the discovery of a novel series of 3-indolyl sultam antagonists with low nM affinity for CRTh2. These compounds proved to be selective over the other primary prostaglandin D(2) receptor (DP1) as well as the thromboxane A(2) receptor (TP).

Sleep medicine content of major medical textbooks continues to be underrepresented.

OBJECTIVE: Sleep-related material in medical textbooks may be the only method by which physicians educate themselves about sleep. In the last decade significant progress in sleep research has been made, but how textbooks in relevant fields reflect it has not been examined. Our purpose was to review and compare (2005 with 1998) sleep content in representative medical textbooks. METHODS: Sleep content of the latest edition of textbooks in four specialties was evaluated. Present sleep content in seven textbooks was compared with that found in 1998. Numbers of pages devoted to sleep were counted and reported for the subjects covered and for the specialty of the textbook. RESULTS: Thirty-one textbooks were examined for current content and seven textbooks for content comparison. Sleep coverage in medical textbooks uniformly received less than 2% of the text volume. Focus of topics covered varied with specialty. Compared with 1998, the proportion of pages devoted to sleep remained the same or decreased. Coverage of new topics remained minimal. CONCLUSIONS: Major medical textbooks present small amounts of sleep content and few provide a comprehensive overview of sleep medicine. In comparison to textbook editions from the 1990s, current editions still devote little attention to sleep, and the diversity of topics has not improved.

Sleep and older patients.

Sleep disturbances are common among older adults. The elderly population reports more symptoms associated with poor sleep initiation and maintenance and increased daytime napping. Sleep problems may be caused by various factors, including medication use, medical and psychiatric illnesses, and primary sleep disorders. The consequences of poor sleep quality may include cognitive impairment, daytime sleepiness, and reduced quality of life. The evaluation and management of these disorders is discussed in this review.

Impact of Obstructive Sleep Apnea on Neurocognitive Function and Impact of Continuous Positive Air Pressure.

There is evidence that obstructive sleep apnea (OSA) can negatively impact attention, memory, learning, executive function, and overall intellectual function in adults and children. Imaging techniques, including MRI, MR diffusion tensor imaging, MR spectroscopy, and fMRI, have provided additional insight into the anatomic and functional underpinnings of OSA-related cognitive impairment. Both animal and human studies have looked to elucidate the separate effects of oxygen desaturation and sleep fragmentation on independent aspects of cognition. Data from animal models point to neuro-inflammation and oxidative stress as driving factors of cognitive impairment.

High-throughput target discovery using cell-based genetics.

High-throughput target discovery requires robust disease models and the ability to rapidly survey the genome for function. In the post-genomics era, there has been a strong emphasis placed upon "gene-to-function" approaches that take advantage of the large amount of gene sequence information now available. Here, we advocate a return to "function-to-gene" approaches as a first step in target discovery (and validation), followed by hypothesis-driven research to validate new targets identified by their activity in cell-based disease models.

Discovery of S-phase arresting agents derived from noscapine.

Analogues of the natural product noscapine were synthesized, and their potential as antitumor agents were examined. The discovery of a novel regio- and stereoselective O-demethylation led to the synthesis of several O-alkylated analogues that induced an unexpected S-phase arrest of mammalian cells. Compound 4a was the most potent analogue inhibiting cell proliferation at an EC(50) of 1.9 microM.

Identification of novel and improved antimitotic agents derived from noscapine.

Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.

GPRC6A null mice exhibit osteopenia, feminization and metabolic syndrome.

BACKGROUND: GPRC6A is a widely expressed orphan G-protein coupled receptor that senses extracellular amino acids, osteocalcin and divalent cations in vitro. The physiological functions of GPRC6A are unknown. METHODS/PRINCIPAL FINDINGS: In this study, we created and characterized the phenotype of GPRC6A(-/-) mice. We observed complex metabolic abnormalities in GPRC6A(-/-) mice involving multiple organ systems that express GPRC6A, including bone, kidney, testes, and liver. GPRC6A(-/-) mice exhibited hepatic steatosis, hyperglycemia, glucose intolerance, and insulin resistance. In addition, we observed high expression of GPRC6A in Leydig cells in the testis. Ablation of GPRC6A resulted in feminization of male GPRC6A(-/-) mice in association with decreased lean body mass, increased fat mass, increased circulating levels of estradiol, and reduced levels of testosterone. GPRC6A was also highly expressed in kidney proximal and distal tubules, and GPRC6A(-/-) mice exhibited increments in urine Ca/Cr and PO(4)/Cr ratios as well as low molecular weight proteinuria. Finally, GPRC6A(-/-) mice exhibited a decrease in bone mineral density (BMD) in association with impaired mineralization of bone. CONCLUSIONS/SIGNIFICANCE: GPRC6A(-/-) mice have a metabolic syndrome characterized by defective osteoblast-mediated bone mineralization, abnormal renal handling of calcium and phosphorus, fatty liver, glucose intolerance and disordered steroidogenesis. These findings suggest the overall function of GPRC6A may be to coordinate the anabolic responses of multiple tissues through the sensing of extracellular amino acids, osteocalcin and divalent cations.

Sleep problems in primary care: a North Carolina Family Practice Research Network (NC-FP-RN) study.

BACKGROUND: The prevalence and nature of sleep disorders in primary care has not been widely studied. As part of a survey conducted in 5 family practice offices in North Carolina, we screened adult patients for sleep syndromes and sought to ascertain which demographic status and health status were associated with these disorders. METHODS: We approached 2963 consecutive adults who presented for office visits to the 5 study practices. The 4-page study questionnaire, which was available in English and Spanish, included items on insomnia, excessive daytime sleepiness, obstructive sleep apnea syndrome, and restless legs syndrome. Analyses evaluated the relationship between sleep syndromes and demographic factors, health status, and disability. RESULTS: We enrolled 1935 patients (65.3% response rate). More than half reported excessive daytime sleepiness, one third had insomnia, more than 25% had symptoms of restless legs syndrome, and 13% to 33% reported obstructive sleep apnea syndrome symptoms. Participants who rated their health as poor reported significantly higher rates of all sleep disturbance items. Patients with hypertension, pain syndromes, and depression had a significantly increased risk for all sleep complaints. Patients who reported limited activity had a significant risk of restless legs syndrome. CONCLUSION: Sleep complaints are highly prevalent in primary care populations. Patients with the highest risk for sleep disturbance are those with pain, mental illness, limited activity, and overall "poor physical and mental health." Because sleep disorders are associated with a significant health impact, positive responses to questions regarding sleep symptoms should prompt further diagnostic inquiry.

Treatment of sleep disorders in elderly patients.

Sleep disorders are common among the elderly and are associated with diminished quality of life, increased risk for development of psychiatric disorders, inappropriate use of sleep aids, and decreased daytime functioning. The most common and important sleep disorders in the elderly include insomnia, obstructive sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, and the advanced sleep phase syndrome. In this article, we summarize the current treatment strategies for each of these sleep-related disorders. Before contemplating specific treatments, the authors recommend that more conservative and nonpharmacologic therapies be attempted first because the elderly are more likely to have medication side effects or complications related to surgery. Many sleep problems can be treated by simple sleep hygiene modifications that can be implemented and adopted easily. For others, therapies that specifically consider older adults may be required. For each of the sleep disorders we provide an updated discussion of therapies beginning with diet and lifestyle, pharmacologic treatment, interventional procedures, surgery, assistive devices, physical and speech therapy, exercise, and emerging therapies with specific considerations for older adults.

Identification of a novel extracellular cation-sensing G-protein-coupled receptor.

The C family G-protein-coupled receptors contain members that sense amino acid and extracellular cations, of which calcium-sensing receptor (CASR) is the prototypic extracellular calcium-sensing receptor. Some cells, such as osteoblasts in bone, retain responsiveness to extracellular calcium in CASR-deficient mice, consistent with the existence of another calcium-sensing receptor. We examined the calcium-sensing properties of GPRC6A, a newly identified member of this family. Alignment of GPRC6A with CASR revealed conservation of both calcium and calcimimetic binding sites. In addition, calcium, magnesium, strontium, aluminum, gadolinium, and the calcimimetic NPS 568 resulted in a dose-dependent stimulation of GPRC6A overexpressed in human embryonic kidney cells 293 cells. Also, osteocalcin, a calcium-binding protein highly expressed in bone, dose-dependently stimulated GPRC6A activity in the presence of calcium but inhibited the calcium-dependent activation of CASR. Coexpression of beta-arrestins 1 and 2, regulators of G-protein signaling RGS2 or RGS4, the RhoA inhibitor C3 toxin, the dominant negative Galpha(q)-(305-359) minigene, and pretreatment with pertussis toxin inhibited activation of GPRC6A by extracellular cations. Reverse transcription-PCR analyses showed that mouse GPRC6A is widely expressed in mouse tissues, including bone, calvaria, and the osteoblastic cell line MC3T3-E1. These data suggest that in addition to sensing amino acids, GPRC6A is a cation-, calcimimetic-, and osteocalcin-sensing receptor and a candidate for mediating extracellular calcium-sensing responses in osteoblasts and possibly other tissues.

Isosteric ramatroban analogs: selective and potent CRTH-2 antagonists.

The chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH-2), also found on eosinophils and basophils, is a prostaglandin D2 receptor involved in the recruitment of these cell types during an inflammatory response. In this report, we describe the synthesis and optimization of a ramatroban isostere that is a selective and potent antagonist of CRTH-2 which may be useful in the treatment of certain diseases.