The John Rankin Laboratory of Pulmonary Medicine, Departments of Population Health Sciences and of Orthopedics and Rehabilitation, School of Medicine and Public Health, University of Wisconsin, ...Madison, Wisconsin; Center for Sleep and Respiratory Neurobiology and Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia; and Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1 ) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2 ) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the "metabolic syndrome" remains unsettled. 3 ) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect hypoxic-induced "neural injury." We discuss future research into understanding the pathophysiology of sleep apnea as a basis for uncovering newer forms of treatment of both the ventilatory disorder and its multiple sequelae.
This tutorial review highlights the use of catalytic asymmetric 2-naphthol couplings in total synthesis. The types of chirality, chiral biaryl natural products, prior approaches to chiral biaryl ...natural products, and other catalytic asymmetric biaryl couplings are outlined. The three main categories of chiral catalysts for 2-naphthol coupling (Cu, V, Fe) are described with discussion of their limitations and advantages. Applications of the copper catalyzed couplings in biomimetic syntheses are discussed including nigerone, hypocrellin, calphostin D, phleichrome, and cercosporin.
We address adaptive vs. maladaptive responses to hypoxemia in healthy humans and hypoxic-tolerant species during wakefulness, sleep, and exercise. Types of hypoxemia discussed include short-term and ...life-long residence at high altitudes, the intermittent hypoxemia attending sleep apnea, or training regimens prescribed for endurance athletes. We propose that hypoxia presents an insult to O2 transport, which is poorly tolerated in most humans because of the physiological cost.
Key points
The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is ...often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end‐organ responses.
Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady‐state eucapnic hypoxia were measured in a cohort of 82 middle‐aged individuals.
Ventilatory and MSNA responsiveness to hyperoxia and hypoxia were not significantly correlated within individuals.
It was concluded that ventilatory responses to hypoxia and hyperoxia do not predict MSNA responses and it is recommended that tests using the specific outcome of interest, i.e. MSNA or ventilation, are required.
Transient hyperoxia is recommended as a sensitive and reliable means of quantifying tonic chemoreceptor‐driven levels of sympathetic nervous system activity and respiratory drive.
Hypersensitivity of the carotid chemoreceptor leading to sympathetic nervous system activation and ventilatory instability has been implicated in the pathogenesis and consequences of several common clinical conditions. A variety of treatment approaches aimed at lessening chemoreceptor‐driven sympathetic overactivity are now under investigation; thus, the ability to quantify this outcome variable with specificity and precision is crucial. Accordingly, we measured ventilatory and neurocirculatory responses to chemoreflex inhibition elicited by transient hyperoxia and chemoreflex excitation produced by exposure to graded, steady‐state eucapnic hypoxia in middle‐aged men and women (n = 82) with continuous positive airway pressure‐treated obstructive sleep apnoea. Progressive, eucapnic hypoxia produced robust and highly variable increases in ventilation (+83 ± 59%) and muscle sympathetic nerve activity (MSNA) burst frequency (+55 ± 31%), whereas transient hyperoxia caused marked reductions in these variables (−35 ± 14% and −42 ± 16%, respectively). Coefficients of variation for ventilatory and MSNA burst frequency responses, indicating test–retest reproducibility, were respectively 9% and 24% for hyperoxia and 35% and 28% for hypoxia. Based on statistical measures of rank correlation or even comparisons across quartiles of corresponding ventilatory and MSNA responses, we found that the magnitudes of ventilatory inhibition with hyperoxia or excitation with eucapnic hypoxia were not correlated with corresponding MSNA responses within individuals. We conclude that, in conscious, behaving humans, ventilatory sensitivities to progressive, steady‐state, eucapnic hypoxia and transient hyperoxia do not predict MSNA responsiveness. Our findings also support the use of transient hyperoxia as a reliable, sensitive, measure of the carotid chemoreceptor contribution to tonic sympathetic nervous system activity and respiratory drive.
Key points
The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end‐organ responses.
Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady‐state eucapnic hypoxia were measured in a cohort of 82 middle‐aged individuals.
Ventilatory and MSNA responsiveness to hyperoxia and hypoxia were not significantly correlated within individuals.
It was concluded that ventilatory responses to hypoxia and hyperoxia do not predict MSNA responses and it is recommended that tests using the specific outcome of interest, i.e. MSNA or ventilation, are required.
Transient hyperoxia is recommended as a sensitive and reliable means of quantifying tonic chemoreceptor‐driven levels of sympathetic nervous system activity and respiratory drive.
This quasi-experimental study evaluated the effectiveness of a multi-modal experiential stress management course for college students. Experiential approaches included yoga, mindfulness hiking, and ...equine-assisted stress management activities. Univariate analysis of covariance revealed significantly lower perceived stress for the experimental group at the conclusion of the stress management course. Repeated measures univariate analysis of variance revealed that the stress management course significantly reduced present moment stress over time and that equine-assisted activities were as effective as yoga and mindfulness hiking in reducing student stress.
“On Story is film school in a box, a lifetime’s worth of filmmaking knowledge squeezed into half-hour packages."—Kenneth Turan, film critic for the Los Angeles Times Austin Film Festival (AFF) is the ...first organization to focus on writers’ creative contributions to film and television. Its annual Film Festival and Conference offers screenings, panels, workshops, and roundtable discussions that help new writers and filmmakers connect with mentors and gain advice and insight from masters, as well as reinvigorate veterans with new ideas. To extend the Festival’s reach, AFF produces On Story, a television series currently airing on PBS-affiliated stations and streaming online that presents high-caliber artists talking candidly and provocatively about the art and craft of screenwriting and filmmaking, often using examples from their own work. On Story—The Golden Ages of Television explores the transformation of television’s narrative content over the past several decades through interviews with some of TV’s best creators and writers, including Garry Shandling (The Larry Sanders Show), Carl Reiner (The Dick Van Dyke Show), Issa Rae (Insecure), Vince Gilligan (Breaking Bad), Greg Daniels (The Office), Paula Pell (Saturday Night Live), Noah Hawley (Fargo), Liz Meriwether (New Girl), David Chase (The Sopranos), Alan Yang (Master of None), Marta Kauffman (Friends), Jenji Kohan (Orange Is the New Black), and many more. Their insights, behind-the-scenes looks at the creative process, production tales, responses to audiences’ reactions, and observations on how both TV narratives and the industry have changed make this book ideal for TV lovers, pop culture fans, students taking screenwriting courses, and filmmakers and writers seeking information and inspiration.
A dynamic approach: The key step in the total synthesis of hypocrellin A involves a potentially biomimetic 1,8‐diketone aldol reaction, which constructs the seven‐membered ring. The helical ...configuration is established first from an axially chiral biaryl unit and is then used in a dynamic stereochemical transfer process to form the remaining stereocenters in the intramolecular aldol reaction (see scheme).
The perylenequinones are a class of natural products characterized by a pentacyclic conjugated chromophore giving rise to photoactivity. Potentially useful light‐activated biological activity, ...targeting protein kinase C (PKC), has been identified for several of the natural products. Recently discovered new members of this compound class, as well as several related phenanthro‐perylenequinones, are reviewed. Natural product modifications that improve biological profiles are outlined, as well as avenues for the total synthesis of analogs not available from the natural product series. An overview of structure/function relationships is provided.
Perylenequinones are a class of natural products characterized by a pentacyclic conjugated chromophore giving rise to photoactivity. Their structural complexity and light‐induced biological activity have resulted in extensive study of these compounds. This review focuses on recent isolates in this class, total synthesis work, semisynthetic analogs, and biological activity studies.
A palladium-catalyzed aromatic decarboxylation reaction has been developed. With electron-rich aromatic acids, the reaction proceeds efficiently under fairly mild conditions in good yields. The ...method was useful with complex functionalized substrates containing hindered carboxylic acids.
We evaluated several methods for characterizing hypoxic chemosensitivity in the conscious rat. Adult Sprague-Dawley rats (n = 30) were exposed to normobaric hypoxia inspired oxygen fraction (Fio2) ...0.15, 0.12, and 0.09. We measured ventilation (V̇e; barometric plethysmography), arterial oxygen saturation (SpO2; pulse oximeter), and oxygen consumption and carbon dioxide production (V̇o2 and V̇co2; analysis of expired air). Linear regression analysis was used to define stimulus-response relationships. Testing was performed on 2 days to assess day-to-day reproducibility. Exposure to graded, steady-state hypoxia caused progressive reductions in SpO2 that were, for any given Fio2, quite variable (SpO2 range, 20-30%) among individuals. Hypoxia produced progressive increases in V̇e caused by increases in both tidal volume (VT) and breathing frequency. Hypoxia also increased the VT:inspiratory time (Ti) ratio, an indicator of central respiratory "drive." Hypoxia caused consistent, progressive declines in V̇o2, V̇co2, and core temperature (>20% at the lowest SpO2). We propose that optimal quantification of carotid chemoreceptor hypoxic sensitivity in the unanesthetized rodent should employ SpO2 a surrogate for arterial Po2 (PaO2 ) as the stimulus variable and the ventilatory equivalent for V̇co2 (V̇e/V̇co2) and/or mean inspiratory flow rate (VT/Ti) normalized for V̇co2 as the response variables. Both metrics take into account not only the important influence of a falling metabolic rate, but also SpO2, which represents the hypoxic stimulus at the carotid body. Because of the somewhat curvilinear nature of these responses, exposure to multiple levels of graded hypoxia provides the most complete characterization of hypoxic chemosensitivity.
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