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The ability to distinguish endometrial serous carcinoma (SC) from high-grade endometrioid adenocarcinoma is of great importance given their differences in prognosis and management. In practice, this distinction typically relies upon the use of a focused immunohistochemical panel including p53, p16, and mismatch repair proteins. The expression of p16 is characteristically strong and diffuse in SCs, and weak and/or patchy in many high-grade endometrioid adenocarcinomas. Here, we report a subset of SCs that are entirely negative for p16 immunostaining, a pattern we refer to as "p16 null." This pattern was identified in 2 of 63 cases of SC diagnosed at our institution-1 with histologically classic features and 1 with ambiguous high-grade histologic features. These tumors otherwise showed a SC signature by immunohistochemical and demonstrated an SC pattern of genetic mutations. No mutation in the gene for p16, cyclin-dependent kinase inhibitor 2A (CDKN2A), was identified in either case. However, molecular correlates for the absent p16 expression were present, including homozygous deletion of CDKN2A in one case and hemizygous deletion of CDKN2A with promotor hypermethylation of the remaining allele in the other case. To our knowledge, this constitutes the first report conclusively demonstrating the existence of a small subset of SCs that are completely negative by p16 immunohistochemistry, and the molecular lesions responsible for this pattern. In the context of an otherwise clinically and histologically classic example of SC, we endorse this "null" p16 staining pattern as an alternative aberrant staining pattern that should not deter one from committing to this diagnosis.

BACKGROUND: Polycystic kidney disease (PKD) accounts for approximately 15% of kidney transplants, but long-term outcomes in patients with PKD who have received a kidney transplant are not well understood. METHODS: In primary recipients of kidney transplants at our center (1994–2014), we compared outcomes of underlying PKD (N=619) with other native diseases (non-PKD, N=4312). Potential factors influencing outcomes in PKD were evaluated using Cox proportional-hazards regression and a rigorous multivariable model. RESULTS: Patients with PKD were older and were less likely to be sensitized or to experience delayed graft function (DGF). Over a median follow-up of 5.6 years, 1256 of all recipients experienced death-censored graft failure (DCGF; 115 patients with PKD) and 1617 died (154 patients with PKD). After adjustment for demographic, dialysis, comorbid disease, surgical, and immunologic variables, patients with PKD had a lower risk of DCGF (adjusted hazard ratio [aHR], 0.73; 95% CI, 0.57 to 0.93; P=0.01) and death (aHR, 0.62; 95% CI, 0.51 to 0.75; P

This article outlines the fundamental brain mechanisms that control sleep-wake patterns and reviews how pathologic changes in these control mechanisms contribute to common sleep disorders.Discrete but interconnected clusters of cells located within the brainstem and hypothalamus comprise the circuits that generate wakefulness, non-rapid eye movement (non-REM) sleep, and REM sleep. These clusters of cells use specific neurotransmitters, or collections of neurotransmitters, to inhibit or excite their respective sleep- and wake-promoting target sites. These excitatory and inhibitory connections modulate not only the presence of wakefulness or sleep, but also the levels of arousal within those states, including the depth of sleep, degree of vigilance, and motor activity. Dysfunction or degeneration of wake- and sleep-promoting circuits is associated with narcolepsy, REM sleep behavior disorder, and age-related sleep disturbances.Research has made significant headway in identifying the brain circuits that control wakefulness, non-REM, and REM sleep and has led to a deeper understanding of common sleep disorders and disturbances.

BACKGROUND: Chromosome instability (CIN) generates genetic and karyotypic diversity and is common in hematological malignancies. Low to moderate levels of CIN are well tolerated and can promote cancer proliferation; however, high levels of CIN are lethal. Thus, CIN may serve both as a prognostic factor to predict clinical outcome and as a predictive biomarker. METHODS: A retrospective study was performed to evaluate CIN in acute myeloid leukemia (AML). Chromosome mis-segregation frequency was correlated with clinical outcome in bone marrow core biopsy specimens from 17 AML cases. Additionally, we induced chromosome segregation errors in AML cell lines with AZ3146, an inhibitor of the Mps1 mitotic checkpoint kinase to quantify the phenotypic effects of high CIN. RESULTS: We observed a broad distribution of chromosome mis-segregation frequency in AML bone marrow core specimens. High CIN correlated with complex karyotype AML, as expected, although there was no clear survival effect. In addition to CIN, experimentally inducing chromosome segregation errors by Mps1 inhibition in AML cell lines causes DNA damage, micronuclei formation and upregulation of interferon stimulated genes (ISGs). CONCLUSIONS: High levels of CIN appear to be immunostimulatory, suggesting an opportunity to combine mitotic checkpoint inhibitors with immunotherapy in treatment of AML.

The detection of acquired copy-number abnormalities (CNAs) and copy-neutral loss of heterozygosity (CN-LOH) in neoplastic disorders by chromosomal microarray analysis (CMA) has significantly increased over the past few years with respect to both the number of laboratories utilizing this technology and the broader number of tumor types being assayed. This highlights the importance of standardizing the interpretation and reporting of acquired variants among laboratories. To address this need, a clinical laboratory-focused workgroup was established to draft recommendations for the interpretation and reporting of acquired CNAs and CN-LOH in neoplastic disorders. This project is a collaboration between the American College of Medical Genetics and Genomics (ACMG) and the Cancer Genomics Consortium (CGC). The recommendations put forth by the workgroup are based on literature review, empirical data, and expert consensus of the workgroup members. A four-tier evidence-based categorization system for acquired CNAs and CN-LOH was developed, which is based on the level of available evidence regarding their diagnostic, prognostic, and therapeutic relevance: tier 1, variants with strong clinical significance; tier 2, variants with some clinical significance; tier 3, clonal variants with no documented neoplastic disease association; and tier 4, benign or likely benign variants. These recommendations also provide a list of standardized definitions of terms used in the reporting of CMA findings, as well as a framework for the clinical reporting of acquired CNAs and CN-LOH, and recommendations for how to deal with suspected clinically significant germline variants.

Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+(TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histaminein vitroinhibited the acid-sensitive K+current, indicating a functionally coupled signaling mechanism. We then studied the role of TASK channels in modulating electrocortical activityin vivousing freely behaving wild-type (n= 12) and ChAT-Cre:TASKf/fmice (n= 12), the latter lacking TASK-1/3 channels on cholinergic neurons. TASK channel deletion on cholinergic neurons significantly altered endogenous electroencephalogram oscillations in multiple frequency bands. We then identified the effect of TASK channel deletion during microperfusion of histamine into the basal forebrain. In non-rapid eye movement sleep, TASK channel deletion on cholinergic neurons significantly attenuated the histamine-induced increase in 30–50 Hz activity, consistent with TASK channels contributing to histamine action on basal forebrain cholinergic neurons. In contrast, during active wakefulness, histamine significantly increased 30–50 Hz activity in ChAT-Cre:TASKf/fmice but not wild-type mice, showing that the histamine response depended upon the prevailing cortical arousal state. In summary, we identify TASK channel modulation in response to histamine receptor activationin vitro, as well as a role of TASK channels on cholinergic neurons in modulating endogenous oscillations in the electroencephalogram and the electrocortical response to histamine at the basal forebrainin vivo.SIGNIFICANCE STATEMENTAttentive states and cognitive function are associated with the generation of γ EEG activity. Basal forebrain cholinergic neurons are important modulators of cortical arousal and γ activity, and in this study we investigated the mechanism by which these neurons are activated by the wake-active neurotransmitter histamine. We found that histamine inhibited a class of K+leak channels called TASK channels and that deletion of TASK channels selectively on cholinergic neurons modulated baseline EEG activity as well as histamine-induced changes in γ activity. By identifying a discrete brain circuit where TASK channels can influence γ activity, these results represent new knowledge that enhances our understanding of how subcortical arousal systems may contribute to the generation of attentive states.

BackgroundThe risk of death is elevated in patients taking opioids for chronic non-cancer pain. Respiratory depression is the main cause of death due to opioids and sleep apnoea is an important associated risk factor.MethodsIn chronic pain clinics, we assessed the STOP-Bang questionnaire (a screening tool for sleep apnoea; Snoring, Tiredness, Observed apnoea, high blood Pressure, Body mass index, age, neck circumference and male gender), Epworth Sleepiness Scale, thyromental distance, Mallampati classification, daytime oxyhaemoglobin saturation (SpO2) and calculated daily morphine milligram equivalent (MME) approximations for each participant, and performed an inlaboratory polysomnogram. The primary objective was to determine the predictive factors for sleep apnoea in patients on chronic opioid therapy using multivariable logistic regression models.ResultsOf 332 consented participants, 204 underwent polysomnography, and 120 (58.8%) had sleep apnoea (AHI ≥5) (72% obstructive, 20% central and 8% indeterminate sleep apnoea), with a high prevalence of moderate (23.3%) and severe (30.8%) sleep apnoea. The STOP-Bang questionnaire and SpO2 are predictive factors for sleep apnoea (AHI ≥15) in patients on opioids for chronic pain. For each one-unit increase in the STOP-Bang score, the odds of moderate-to-severe sleep apnoea (AHI ≥15) increased by 70%, and for each 1% SpO2 decrease the odds increased by 33%. For each 10 mg MME increase, the odds of Central Apnoea Index ≥5 increased by 3%, and for each 1% SpO2 decrease the odds increased by 45%.ConclusionIn patients on opioids for chronic pain, the STOP-Bang questionnaire and daytime SpO2 are predictive factors for sleep apnoea, and MME and daytime SpO2 are predictive factors for Central Apnoea Index ≥5.Trial registration numberNCT02513836

A combination of oligonucleotide and single-nucleotide polymorphism probes on the same array platform can detect copy-number abnormalities and copy-neutral aberrations such as uniparental disomy and long stretches of homozygosity. The single-nucleotide polymorphism probe density in commercially available platforms varies widely, which may affect the detection of copy-neutral abnormalities. We evaluated the ability of array platforms with low (Oxford Gene Technology CytoSure ISCA uniparental disomy), mid-range (Agilent custom array), and high (Affymetrix CytoScan HD) single-nucleotide polymorphism probe density to detect copy-number variation, mosaicism, uniparental isodisomy, and absence of heterozygosity in 50 clinical samples. All platforms reliably detected copy-number variation, mosaicism, and uniparental isodisomy; however, absence-of-heterozygosity detection varied significantly. The low-density array called absence-of-heterozygosity regions not confirmed by the other platforms and also overestimated the length of true absence-of-heterozygosity regions. Furthermore, the low- and mid-density platforms failed to detect some small absence-of-heterozygosity regions that were identified by the high-density platform. Variation in single-nucleotide polymorphism density can lead to major discrepancies in the detection of and confidence in copy-neutral abnormalities. Although suitable for uniparental disomy detection, copy-number plus single-nucleotide polymorphism arrays with 30,000 or fewer unique single-nucleotide polymorphism probes miscall absence-of-heterozygosity regions due to identity by descent. Genet Med 15 9, 706–712.

Background Opioid analgesia is an essential component of perioperative care, but effective analgesia can be limited by excessive sedation and respiratory depression. The cortical signatures associated with sedation by opioids and the relationship between changes in cortical activity and respiratory function are not well understood. The objectives of this study were to identify the electroencephalogram signatures of sedation and respiratory changes induced by morphine in a pediatric population after elective surgery. Methods After otologic surgery, patients (14.8 ± 2.8 yr, n = 10) stayed overnight for pain relief with morphine (3 to 10 mg), hydration, and clinical observation. Electroencephalogram activity and polysomnography were performed before and after morphine, and electroencephalogram spectral properties and cardiorespiratory activities were analyzed. Results Compared to wakefulness and non–rapid eye movement sleep, morphine reduced high-frequency β1 (13.5 to 20 Hz) and β2 (20 to 30Hz) electroencephalogram powers (n = 10) and decreased coherence between frontal and occipital β2 electroencephalogram activities (n = 9), therefore indicating that morphine induced a deep sedative state. Morphine also reduced respiratory rate by 8.3% (n = 10). Interestingly, there was a significant correlation between the reduction in β1 electroencephalogram activity and the depression in respiratory rate induced by morphine (R = 0.715, n = 10). With significant reduction in β1 power, respiratory rate was decreased by more than 25%, suggesting that reduction in cortical arousal is associated with the severity of respiratory rate depression. Conclusions Analgesic doses of morphine are associated with reduction in respiratory rate when accompanied by reduction in β1 electroencephalogram power, indicating a powerful effect of cortical arousal state per se in respiratory rate depression by morphine.

The various neural mechanisms affecting the control of the upper airway muscles are discussed in this review, with particular emphasis on structure-function relationships and integrative physiological motor-control processes. Particular foci of attention include the respiratory function of the upper airway muscles, and the various reflex mechanisms underlying their control, specifically the reflex responses to changes in airway pressure, reflexes from pulmonary receptors, chemoreceptor and baroreceptor reflexes, and postural effects on upper airway motor control. This article also addresses the determinants of upper airway collapsibility and the influence of neural drive to the upper airway muscles, and the influence of common drugs such as ethanol, sedative hypnotics, and opioids on upper airway motor control. In addition to an examination of these basic physiological mechanisms, consideration is given throughout this review as to how these mechanisms relate to integrative function in the intact normal upper airway in wakefulness and sleep, and how they may be involved in the pathogenesis of clinical problems such obstructive sleep apnea hypopnea. © 2012 American Physiological Society. Compr Physiol 2:479-535, 2012.

The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.

Respiratory muscles with dual respiratory and non-respiratory functions (e.g. the pharyngeal and intercostal muscles) show greater suppression of activity in sleep than the diaphragm, a muscle almost entirely devoted to respiratory function. This sleep-related suppression of activity is most apparent in the tonic component of motor activity, which has functional implications of a more collapsible upper airspace in the case of pharyngeal muscles, and decreased functional residual capacity in the case of intercostal muscles. A major source of tonic drive to respiratory motoneurons originates from neurons intimately involved in states of brain arousal, i.e. neurons not classically involved in generating respiratory rhythm and patternper se. The tonic drive to hypoglossal motoneurons, a respiratory motor pool with both respiratory and non-respiratory functions, is mediated principally by noradrenergic and glutamatergic inputs, these constituting the essential components of thewakefulness stimulus. These tonic excitatory drives are opposed by tonic inhibitory glycinergic and γ-amino butyric acid (GABA) inputs that constrain the level of respiratory-related motor activity, with the balance determining net motor tone. In sleep, the excitatory inputs are withdrawn and GABA release into the brainstem is increased, thus decreasing respiratory motor tone and predisposing susceptible individuals to hypoventilation and obstructive sleep apnoea.

Background Research indicates that the length of time needed to describe dietary diversity is approximately 2 weeks. This is the first study conducted to develop a dietary variety measurement tool that is sensitive to the effect of time on dietary variety without the burden of gathering data for 2 weeks. Objective To determine whether 3 days of 24-hour dietary recall logs collected during a 15-day period would predict food variety as well as 15 consecutive days. The study also determined which set of 3 days (consecutive vs interval days) within a 15-day period would better predict 15-day food variety. Design Prospective survey of the dietary practices of children. Subjects/setting Seventy-two children aged 9 to 12 years attending fourth and fifth grades in a public elementary school in a Midwestern town in the fall of 2005. Main outcome measures Predicted 15-day cumulative dietary variety score from 3 consecutive days and 3 interval days of dietary data. Statistical analysis performed Two prediction models were obtained from multiple linear regression analyses in which natural log-transformed (log e ) 15-day variety scores were regressed on log e 3-day variety scores (consecutive and interval days). The ability of each model to predict the 15-day cumulative variety score was assessed by comparisons of mean bias, mean-squared error, coefficient of determination ( R 2 ), and Pearson product-moment correlation coefficients. Results Three days of dietary data accurately estimated dietary variety over time for this sample of 9- to 12-year-old children using the predictive equation generated in this study. Three interval days predicted 15-day food variety more precisely than 3 consecutive days. Conclusions The predictive equation is accurate in estimating food variety over time for this population and, if validated in independent samples, could be applied to similar populations.

Hypoglossal motoneurons are influenced by a variety of neuromodulators, some of which change dynamically across sleep–wake states to alter motoneuron excitability and responses to pharmacological manipulations. Determining the mechanisms underlying the modulation of hypoglossal motoneurons during sleep is relevant to understanding the increased upper airway resistance, airflow limitation and hypoventilation in normal sleeping individuals, as well as the airway obstruction underlying the pathogenesis of obstructive sleep apnea. This review summarizes current concepts underlying the neurobiology of sleep and arousal states, and so identifies the rationale for focus on particular neuromodulators and their effects on hypoglossal motoneurons. Emphasis is placed on the control of hypoglossal motoneurons by components of the aminergic arousal system, i.e., serotonergic, noradrenergic and histaminergic inputs. The role of inhibitory mechanisms at the hypoglossal motor nucleus, including glycine and γ-amino butyric acid, and the mixed excitatory and inhibitory influences of acetylcholine are also reviewed. New concepts on the control of hypoglossal motoneurons by sedative hypnotics are also discussed.

The pharyngeal muscles are essential for effective lung ventilation because they help maintain an open upper airspace for the unhindered passage of air into the lungs. Sleep, especially rapid-eye-movement sleep, however, causes fundamental modifications of pharyngeal muscle tone and reflex responses that in normal individuals lead to airway narrowing and hypoventilation. In individuals with already anatomically narrow upper airways, these effects of sleep predispose them to inspiratory flow limitation (hypopneas), airway closure, and obstructive sleep apnea. Obstructive sleep apnea is a common disorder affecting at least 2% to 4% of North American adults and is associated with serious clinical, social, and economic consequences. This review addresses the physiology and pathophysiology of obstructive sleep apnea, hypopneas, and snoring, that is, the full spectrum of the most common sleep-related breathing events involving the upper airway. Specifically, the anatomical features of the upper airway that are important to its mechanical properties and degree of collapsibility are reviewed. The sites of airway narrowing and closure and the implications for common treatments strategies are also discussed. This article also focuses on the neuromuscular control mechanisms operating in wakefulness and sleep that influence pharyngeal muscle tone and upper airway collapsibility. The effects of sleep on the reflex mechanisms that normally operate to protect the upper airspace from suction collapse during breathing are also addressed. Throughout this review, these mechanisms are discussed with an emphasis on understanding the physiology and pathophysiology of sleep-disordered breathing and obstructive sleep apnea.

with cognitive deficits and behavioral abnormalities, but this does not occur in all children and is not fully accounted for by OSA severity. Gozal and colleagues (3) hypothesized that C-reactive protein levels may identify children with OSA who have high susceptibility for cognitive abnormalities. In a community-based study of snoring and nonsnoring school-aged children (5–7 yr, n 5 278 subjects), C-reactive protein levels were measured in the morning after full polysomnography, and a battery of neurocognitive tests were also performed. C-reactive protein levels were nearly double in the children with OSA compared with control subjects (0.36 6 0.11 vs. 0.19 6 0.07 mg/dl). Importantly, these levels were further elevated in the children with OSA who also exhibited neurocognitive deficits compared with the children with OSA who had normal cognitive assessments, again with the difference being approximately twofold (0.48 6 0.12 vs. 0.21 6 0.08 mg/dl). Although cause and effect were not proven in this study, the results highlight that the level of systemic inflammation in pediatric sleepdisordered breathing, as indicated by C-reactive protein, is associated with adverse neurobehavioral outcomes. The effects of OSA on behavioral outcomes may relate to recent findings that exposure to long-term intermittent hypoxia in a mouse model of OSA causes irreversible impairments in the neuronal systems regulating wakefulness, especially selective loss of catecholaminergic arousal neurons via NADPH oxidase–mediated neuronal injury (4).

Purpose of review Our understanding of rapid eye movement (REM) sleep and how it is generated remains a topic of debate. Understanding REM sleep mechanisms is important because several sleep disorders result from disturbances in the neural circuits that control REM sleep and its characteristics. This review highlights recent work concerning how the central nervous system regulates REM sleep, and how the make up and breakdown of these REM sleep-generating circuits contribute to narcolepsy, REM sleep behaviour disorder and sleep apnea. Recent findings A complex interaction between brainstem REM sleep core circuits and forebrain and hypothalamic structures is necessary to generate REM sleep. Cholinergic activation and GABAergic inhibition trigger the activation of subcoeruleus neurons, which form the core of the REM sleep circuit. Summary Untimely activation of REM sleep circuits leads to cataplexy - involuntary muscle weakness or paralysis - a major symptom of narcolepsy. Degeneration of the REM circuit is associated with excessive muscle activation in REM sleep behaviour disorder. Inappropriate arousal from sleep during obstructive sleep apnea repeatedly disturbs the activity of sleep circuits, particularly the REM sleep circuit.

Drugs acting on μ-opioid receptors (MOR) are widely used as analgesics but present serious side-effects such as addiction and respiratory depression. The latter is critical considering its potential lethality and the current absence of treatments to prevent it. The development of therapies to reduce respiratory depression is limited because the critical neural sites and mechanisms of action of opioids in causing respiratory depression are unclear. Here we discuss evidence highlighting the importance of the preBotzinger complex (preBotC), a critical site in the medulla for respiratory rhythm generation, in mediating respiratory rate depression by MOR drugs. This is of significance given that the isolated preBotC in vitro is widely utilized to develop and test new therapies to prevent respiratory depression (Manzke et al. 2003; Ren et al. 2006).

A fetal electrocardiogram (FECG) from the abdominal surface will be from 20 microVpp to unmeasurable. The intrauterine catheter signal will be from 50 microVpp to unmeasureable and will be corrupted with a significant direct current component of 10 to 200 microV. For electrophysiological information to be obtained from the abdominal and intrauterine catheter signals, the signals must be in a 0.05 to 100.0 Hz bandwidth. Because typical adult electrocardiogram systems have a noise specification of 5 to 10 microVpp from instrumentation, these systems are unacceptable for obtaining a FECG via the intrauterine catheter or noninvasively. Therefore, custom instrumentation has been developed with a noise specification of approximately 1.5 microVpp in a 0.05 to 100.0 Hz bandwidth. Design details of the custom instrumentation will be presented along with a laptop computer based data acquisition and signal processing system using LabVIEW. In addition, clinical data from the intrauterine catheter and noninvasive abdominal wall are presented to determine the feasibility of obtaining a FECG via the custom instrumentation. Clinical data obtained and documented indicates that after maternal electrocardiogram cancellation, a FECG with a good signal-to-noise ratio can be obtained in a diagnostic bandwidth of 0.05 to 100.0 Hz. Because the diagnostic bandwidth is preserved, electrophysiological information can be determined along with heart rate.

The root cause of the most common and serious of the sleep disorders is impairment of breathing, and a number of factors predispose a particular individual to hypoventilation during sleep. In turn, obstructive hypopneas and apneas are the most common of the sleep-related respiratory problems and are caused by dysfunction of the upper airway as a conduit for airflow. The overarching principle that underpins the full spectrum of clinical sleep-related breathing disorders is that the sleeping brain modifies respiratory muscle activity and control mechanisms and diminishes the ability to respond to respiratory distress. Depression of upper airway muscle activity and reflex responses, and suppression of arousal (i.e., waking-up") responses to respiratory disturbance, can also occur with commonly used sedating agents (e.g., hypnotics and anesthetics). Growing evidence indicates that the sometimes critical problems of sleep and sedation-induced depression of breathing and arousal responses may be working through common brain pathways acting on common cellular mechanisms. To identify these state-dependent pathways and reflex mechanisms, as they affect the upper airway, is the focus of this paper. Major emphasis is on the synthesis of established and recent findings. In particular, we specifically focus on 1) the recently defined mechanism of genioglossus muscle inhibition in rapid-eye-movement sleep; 2) convergence of diverse neurotransmitters and signaling pathways onto one root mechanism that may explain pharyngeal motor suppression in sleep and drug-induced brain sedation; 3) the lateral reticular formation as a key hub of respiratory and reflex drives to the upper airway. Copyright © 2014 the American Physiological Society.

Rapid eye movement (REM) sleep is accompanied by periods of upper airway motor suppression that cause hypoventilation and obstructive apneas in susceptible individuals. A common idea has been that upper airway motor suppression in REM sleep is caused by the neurotransmitters glycine and γ-amino butyric acid (GABA) acting at pharyngeal motor pools to inhibit motoneuron activity. Data refute this as a workable explanation because blockade of this putative glycine/GABAergic mechanism releases pharyngeal motor activity in all states, and least of all in REM sleep. Here we summarize a novel motor-inhibitory mechanism that suppresses hypoglossal motor activity largely in REM sleep, this being a muscarinic receptor mechanism linked to G-protein-coupled inwardly rectifying potassium (GIRK) channels. We then outline how this discovery informs efforts to pursue therapeutic targets to reactivate hypoglossal motor activity throughout sleep via potassium channel modulation. One such target is the inwardly rectifying potassium channel Kir2.4 whose expression in the brain is almost exclusive to cranial motor nuclei.

Obstructive sleep apnea is a common breathing problem that results in recurrent episodes of nighttime hypoxemia, hypercapnia, bradytachycardia, and hypertension, as well as sleep disturbance and daytime hypersomnolence. The obstruction is located in the oropharynx and is caused by hypotonia of the pharyngeal dilator muscles. In this paper, the various mechanisms affecting motor output to the upper airway muscles are reviewed. In particular, the respiratory function of the pharyngeal dilator muscles, the various reflex mechanisms underlying their control, and the effects of sleep on these mechanisms are discussed. The literature relevant to the central neuronal circuits and neurotransmitters that may be involved in the state-dependent activity of the pharyngeal dilator muscles is also reviewed. In addition to an examination of these basic mechanisms, consideration is given throughout this review as to how these mechanisms may relate to the normal control of pharyngeal patency awake and asleep and how they may be involved in the pathogenesis of obstructive sleep apnea.

The expression of the myogenic determination gene MyoD1 plays a primary role in the commitment of primitive mesenchymal cells to a striated muscle lineage and is down-regulated during later stages of differentiation. To determine the potential role of this gene in myopathic conditions, we examined its expression by means of immunohistochemical analysis, using a series of muscle biopsies from 14 patients with a variety of primary myopathies and neurogenic disorders. Utilizing the avidin-biotin-complex technique, cryostat sections were stained with monoclonal antibody 5.8 A, which we have previously described as having a high level of specificity for tumors with rhabdomyoblastic differentiation. Of special interest was the observation in 4 of 8 cases of neurogenic atrophy of varying levels of cytoplasmic positivity of muscle fibers, appearing to correlate with their degree of atrophy, in addition to weak nuclear staining. Muscle biopsies from 2 patients with Duchenne's muscular dystrophy and 2 patients with autoimmune inflammatory myopathies demonstrated various levels of nuclear positivity in scattered foci that appeared to correlate with areas of regeneration. A biopsy from a single case of neurogenic atrophy secondary to infantile spinal muscular atrophy (Werdnig-Hoffmann's disease) demonstrated diffuse but relatively weak staining of myofiber nuclei, in contrast to sections of normal striated muscle and muscle biopsies from patients with unexplained myoglobinuria, which exhibited only minimal amounts of staining. These data are compatible with observations that MyoD1 expression is related to electrical activity and muscle regeneration.

The neural networks controlling vital functions such as breathing are embedded in the brain, the neural and chemical environment of which changes with state, i.e., wakefulness, non-rapid eye movement (non-REM) sleep and REM sleep, and with commonly administered drugs such as anaesthetics, sedatives and ethanol. One particular output from the state-dependent chemical brain is the focus of attention in this paper; the motor output to the muscles of the tongue, specifically the actions of state-dependent modulators acting at the hypoglossal motor pool. Determining the mechanisms underlying the modulation of the hypoglossal motor output during sleep is relevant to understanding the spectrum of increased upper airway resistance, airflow limitation, hypoventilation and airway obstructions that occur during natural and drug-influenced sleep in humans. Understanding the mechanisms underlying upper airway dysfunction in sleep-disordered breathing is also important given the large and growing prevalence of obstructive sleep apnea syndrome which constitutes a major public health problem with serious clinical, social and economic consequences.

Although skin cancers on the eyelids, lips, genitalia, and the nail unit are infrequent, some skin cancers can have higher recurrence rates in these anatomic locations. Intrinsic to Mohs micrographic surgery (MMS) is maximal tissue preservation and high cure rates, making it a worthwhile procedure for these sensitive anatomic areas to ameliorate any functional or aesthetic compromise. The Mohs surgeon can provide a great service to patients by being aware of the anatomy, specialized instruments, unique histology, and potential complications when performing MMS on these areas.

1. Ventilation has been studied during hypocapnia produced by passive mechanical ventilation in ten normal human subjects. 2. During wakefulness, disconnection of the ventilator led to inconsistent apnoea of only brief duration. During sleep, at a similar degree of hypocapnia, disconnection of the ventilator led more consistently to apnoea which was also of much longer duration; the deeper the sleep stage, the longer the apnoea. 3. The resumption of breathing during sleep could precede or follow arousal or be unaccompanied by arousal; in the absence of prior arousal, the evidence suggests that a starting end-tidal CO2 pressure (PET, CO2) less than 41 mmHg could result in an apnoea during sleep stages I and II. 4. Subjects did not report any common sensation which led them to breathe following an apnoea whilst awake. 5. Prior hyperoxia in one subject prolonged the apnoea duration in both slow-wave sleep and rapid eye movement sleep. 6. The results are interpreted as showing that even during light sleep, the maintenance of the respiratory rhythm is critically dependent on the arterial CO2 and O2 tensions. During wakefulness, other behavioural drives, which may not reach consciousness, supervene.

The ability to detect small changes in tidal volume (VT) during either volitional or passive breathing was compared in seven normal subjects. Passive breathing was achieved with positive pressure applied at the mouth by a ventilator. Although baseline breathing pattern was similar for each subject during the two types of breathing, the ability of the subjects to detect changes in VT was at least as good, and in general better, during passive as compared to volitional breathing. This suggests that the generation of a motor cortical command to inspire and the resultant respiratory muscle contraction are not essential to the perception of a change in lung volume. An increase in information from receptors in the mouth, pharynx and extrathoracic airways sensitive to positive pressure may be responsible for the increased ability of most subjects to detect changes in VT during passive breathing.

In animals, tonic vagal activity from lung receptors provides a means by which changes in end-expiratory lung volume can influence respiratory timing. We wished to examine whether increasing the end-expiratory lung volume within the tidal volume range had a similar effect in man. In order to minimize behavioral influences on breathing, the study was performed in subjects during deep non-rapid eye movement sleep. Five laryngectomized subjects were chosen for the study since their permanent tracheal stomata allow simple, airtight connection to respiratory apparatus and avoided problems with glottic closure. During EEG-documented sleep, end-expiratory volume was increased by up to 350 ml with the addition of expiratory threshold loads of 1 to 10 cm H2O. End-expiratory volume increased linearly with expiratory pressure. Inspiratory and expiratory times (TI and TE) were not affected by increases in end-expiratory volume. Tidal volume (VT) was decreased such that end-inspiratory volume remained unchanged. The decrease in VT may result from a reduction in inspiratory muscle efficiency at a higher lung volume. The results of the study provide no evidence that tonic vagal afferent information from the lungs is important in controlling respiratory rhythm within the tidal volume range in man when behavioral control of breathing is minimized.

the characteristic pattern of breathing for an individual when awake at rest may be due to forebrain influences upon breathing. To examine this hypothesis we have studied the breathing pattern in 18 healthy subjects during relaxed wakefulness (W) and during Stage 4 sleep (S4), when forebrain influences upon breathing are absent or minimal. Inspiratory and expiratory times, respiratory frequency, tidal volume, and ventilation were quantified noninvasively by respiratory inductance plethysmography. The stability of respiratory variables between W and S4 sleep was tested within individuals. The results show that (i) individuals breathe differently from each other when awake and when in S4 sleep; the range between individuals during sleep being as large as it is when awake; (ii) differences in breathing pattern between two S4 periods within an individual are relatively small; (iii) the characteristic breathing pattern of an individual when awake tends to be maintained in S4 sleep. This persistence of a respiratory ‘personality’ into S4 sleep probably indicates that there are individual differences in respiratory rhythm generation in the absence of any forebrain influences upon breathing.

Pharyngeal muscle tone decreases in sleep and this predisposes some individuals to obstructive sleep apnea. This review summarizes the control of the genioglossus muscle by sleep-state dependent neuromodulators at the hypoglossal motor nucleus, the source of motor output to the genioglossus muscle of the tongue. Knowledge of such mechanisms is relevant to identifying and developing new strategies to augment pharyngeal muscle activity in sleep, potentially as treatments for obstructive sleep apnea.

Since Koebner's first observance of the isomorphic response of psoriasis in a tattoo in 1872, a paucity of written reports has appeared in the literature describing this phenomenon, although it appears to be common knowledge among dermatologists. We report a strep-induced guttate psoriasis isomorphic response in a Winnie the Pooh tattoo in a 19-year-old.

Sleep, especially rapid-eye-movement sleep, causes fundamental modifications of respiratory muscle activity and control mechanisms, modifications that can predispose individuals to sleep-related breathing disorders. One of the most common of these disorders is obstructive sleep apnea (OSA) that affects approximately 4% of adults. OSA is caused by repeated episodes of pharyngeal airway obstruction that can occur hundreds of times per night, leading to recurrent asphyxia, arousals from sleep, daytime sleepiness, and adverse cardiovascular and cerebrovascular consequences. OSA is caused by the effects of sleep on pharyngeal muscle tone in individuals with already narrow upper airways. Moreover, since OSA occurs only in sleep, this disorder by definition is a state-dependent process ultimately caused by the influence of sleep neural mechanisms on the activity of pharyngeal motoneurons. This review synthesizes recent findings relating to control of pharyngeal muscle activity across sleep-wake states, with special emphasis on the influence of neuromodulators acting at the hypoglossal motor nucleus that inervates the genioglossus muscle of the tongue. The results of such basic physiological studies may be relevant to identifying and developing new pharmacological strategies to augment pharyngeal muscle activity in sleep, especially rapid-eye-movement sleep, as potential treatments for OSA.

Normal spontaneous arousals from sleep are associated with transient increases in blood pressure, heart rate, and ventilation caused by large transient changes in autonomic output. These autonomic changes are out of proportion to obvious physiological need and are in excess of those observed in later periods of quiet wakefulness. This paper discusses some of the mechanisms underlying the cardio-respiratory consequences of arousal from sleep, and discusses why the normal onset of wakefulness may be associated with such large changes in autonomic output.

Obstructive sleep apnoea is a common and serious breathing problem that is caused by effects of sleep on pharyngeal muscle tone in individuals with narrow upper airways. There has been increasing focus on delineating the brain mechanisms that modulate pharyngeal muscle activity in the awake and asleep states in order to understand the pathogenesis of obstructive apnoeas and to develop novel neurochemical treatments. Although initial clinical studies have met with only limited success, it is proposed that more rational and realistic approaches may be devised for neurochemical modulation of pharyngeal muscle tone as the relevant neurotransmitters and receptors that are involved in sleep-dependent modulation are identified following basic experiments.

Suppression of respiratory muscle activity in sleep, particularly evident in the pharyngeal muscles, is pivotal to the pathogenesis of common sleep-related breathing disorders such as obstructive sleep apnea. Obstructive apneas are caused by sleep-related decrements in pharyngeal muscle activity that leads to snoring and airway obstruction in individuals with underlying structural narrowing of the upper airway. Since obstructive apneas occur exclusively during sleep, this disorder by definition is state-dependent and ultimately caused by the influences of brainstem sleep mechanisms on pharyngeal motoneurons in individuals with compromised upper airway anatomy. This paper reviews the central neuronal mechanisms by which sleep reduces the output to the pharyngeal muscles and the neurotransmitters implicated in this alteration. The experimental approaches used to address this problem are also mentioned and their relative advantages and disadvantages discussed. In particular, the information derived from reduced animal preparations is reviewed and the need for studies in natural sleep is emphasised. Identifying the central neuronal mechanisms and neurotransmitters involved in sleep-related suppression of pharyngeal muscle activity not only has important basic relevance to understanding state-dependent respiratory control, it also has immediate clinical relevance to understanding common sleep-related breathing disorders at the central neuronal level. Determining these basic mechanisms also has immediate clinical relevance to understanding the pathogenesis of airway occlusions, and guiding neuro-pharmacological approaches aimed at preventing the sleep-related decrements in pharyngeal muscle tone that are ultimately the root cause of obstructive sleep apnea.

This paper summarizes evidence for reflex genioglossus muscle activation by stimuli of negative airway pressure in normal, awake human subjects. Stimuli of negative airway pressure (range -5 to -35 cm H2O) caused activation of the genioglossus muscle. The larger values of negative pressure gave larger responses. Response latencies (median = 34 milliseconds) were much faster than the time for voluntary muscle activation (median = 184 milliseconds), suggesting that the responses were reflex in origin. The reflex nature of the responses was confirmed by studies with local anesthetics. The trigeminal, superior laryngeal and the glossopharyngeal nerves all mediated a component of the responses observed from the upper airway.

To determine whether the Hering-Breuer inflation reflex could be demonstrated in the presence and absence of behavioral influences on breathing, lung inflation was performed via the tracheal stoma in eleven laryngectomized subjects: seen seated at rest with their eyes closed and six recumbent during their deepest non-rapid eye movement sleep. Laryngectomized subjects were chosen for study since their permanent tracheal stoma and absence of a glottis abolisehd the sensation of inflation in the upper airways, avoided problems with glottic closure and allowed simple, airtight connection to respiratory apparatus. At rest, awake, inflation volumes of 500–3050 ml caused no reproducible apnea. During EEG-documented sleep, the inflation reflex was tested on 75 occasions using inflation volumes of 540–2100 ml. On the 66 occasions not associated with subject arousal inflation exceeding approximately 1 L produced apnea terminated by inspiration; greater volumes gave longer apneas. At the end of the study the subjects were woken and retested; no reproducible apnea was found. We conclude that the Hering-Breuer inflation reflex can be demonstrated above the resting tidal volume range in adult man in the absence of the behavioral control breathing.

The arterial supply of the thumb was studied in 50 cadaver hands. In 80% the princeps pollicis artery was the first palmar metacarpal artery, a major branch of the deep radial arch. In 50% of the specimens the princeps pollicis artery also supplied the proper radial digital artery to the index finger. Variations of the thumb arterial patterns were present in 25%. In 75% there was a single end-arterial blood supply to the thumb. The anatomic findings are correlated with problems of radial artery injections, thrombosis, and surgical injury to illustrate the clinical importance of the princeps pollicis artery.

Within a combined cross-sectional and longitudinal design, several analyses showed that studentrated teaching effectiveness in university professors declined with age. For 106 full-time psychology teachers, aged 26 to 55, who were studied for time periods ranging from 2 to 15 years, an overall negative correlation of r = — .33 (p < .05) was found between age and general teaching effectiveness. A similar decrement with age occurred for items measuring specific teaching behaviors. Age accounted for 8% of the variance in general teaching effectiveness. The relation between age and faculty performance has received considerable attention for more than 50 years. Currently, it may be particularly salient given the increasing average age of university faculty. The two indicators of faculty performance typically studied are teaching effectiveness and research productivity. In the case of research productivity, several investigators have found a curvilinear age function, with productivity beginning at a relatively low rate in the late 20s, peaking around 40, and declining thereafter (Cole, 1979; Dennis, 1956; Homer, Rushton, & Vernon, 1986; Lehman, 1953). With respect to teaching effectiveness, investigators have provided less definitive results. Recent reviewers have concluded that either no relation or a negative relation exists between age and quality of teaching (Blackburn & Lawrence, 1986;Feldman, 1983).

A decapeptide isolated from highly purified preparations of human prealbumin was able to restore azathioprine (Az) sensitivity, a property of a sub-class of T-lymphocytes, to the spleen rosette-forming cells (RFC) of adult thymectomized (ATx) mice in vitro. The peptide was sequenced by the Edman method and shown to correspond to the ten amino-terminal residues of prealbumin, Gly-Pro-Thr-Gly-Thr-Gly-Glu-Ser-Lys-Cys. Synthesis of this peptide by solid phase methodology confirmed its activity both in vitro and in vivo. Synthesis of a number of structural analogues indicated that the amino-terminal deca, undeca and dodecapeptides of prealbumin as well as some of their derivatives were also able to restore Az sensitivity to RFC in vitro and in vivo. The Cys10 residue and the Glu7 residues both contributed significantly to potency in vitro. Removal of up to three amino acids from the N-terminus of the decapeptide led to a progressive loss of activity. The data indicates that the ability of human prealbumin to restore the Az sensitivity to the RFC of adult Tx mice is intrinsic to the protein and resides in the amino-terminal domain of the molecule.

We have assessed the contribution of intrathoracic pulmonary nerves to the control of breathing in humans. During relaxed wakefulness and during sleep the level, pattern and variability of breathing have been quantified in 8 healthy patients 1 month to 2 years after combined heart--lung transplantation. These data have been compared with similar data from both of 2 matched control groups; either healthy normal controls, or healthy patients after heart transplantation alone. We found no significant differences in the mean levels of respiratory variables between the 3 groups either during relaxed wakefulness or sleep. There were no significant differences between groups (other than would be expected by chance alone) either in the variability of breathing, or in the shapes of the frequency distributions of respiratory variables during these states. There were no respiratory disorders associated with sleep nor any disturbances in blood gases in any group. We conclude that in man breathing is remarkably normal, during relaxed wakefulness and during sleep, after chronic pulmonary denervation. When the ventilatory demands are minimal the human ventilation system functions normally in the absence of a control loop involving pulmonary proprioceptors and the medullary respiratory centres.

Using a cross-sequential design involving four birth cohorts and five measurement periods, a curvilinear relation between aging and research productivity was found for more than 1,000 academic psychologists. Productivity typically began at a low rate in the 20s, increased to a peak around age 40, then decreased in the later years. Substantial individual differences were also observed. Those who began as high publishers remained more productive than the low or medium groups at each age level examined, and even at ages 55-64 they were more productive than the medium or low publishers were at their highest rate. Altogether, across cohorts and publishing levels, age accounted for 6.5% of the variance in publication rate from ages 25-34 to 55-64.