Showing papers by "James P. Butler published in 2017"

Universal geometric constraints during epithelial jamming

Abstract: As an injury heals, an embryo develops, or a carcinoma spreads, epithelial cells systematically change their shape. In each of these processes cell shape is studied extensively, whereas variation of shape from cell-to-cell is dismissed most often as biological noise. But where do cell shape and variation of cell shape come from? Here we report that cell shape and shape variation are mutually constrained through a relationship that is purely geometrical. That relationship is shown to govern maturation of the pseudostratified bronchial epithelial layer cultured from both non-asthmatic and asthmatic donors as well as formation of the ventral furrow in the epithelial monolayer of the Drosophila embryo in vivo. Across these and other vastly different epithelial systems, cell shape variation collapses to a family of distributions that is common to all and potentially universal. That distribution, in turn, is accounted for quantitatively by a mechanistic theory of cell-cell interaction showing that cell shape becomes progressively less elongated and less variable as the layer becomes progressively more jammed. These findings thus uncover a connection between jamming and geometry that is generic -spanning jammed living and inert systems alike- and demonstrate that proximity of the cell layer to the jammed state is the principal determinant of the most primitive features of epithelial cell shape and shape variation.

Estimation of Pharyngeal Collapsibility During Sleep by Peak Inspiratory Airflow

Abstract: Objectives Pharyngeal critical closing pressure (Pcrit) or collapsibility is a major determinant of obstructive sleep apnea (OSA) and may be used to predict the success/failure of non-continuous positive airway pressure (CPAP) therapies. Since its assessment involves overnight manipulation of CPAP, we sought to validate the peak inspiratory flow during natural sleep (without CPAP) as a simple surrogate measurement of collapsibility. Methods Fourteen patients with OSA attended overnight polysomnography with pneumotachograph airflow. The middle third of the night (non-rapid eye movement sleep [NREM]) was dedicated to assessing Pcrit in passive and active states via abrupt and gradual CPAP pressure drops, respectively. Pcrit is the extrapolated CPAP pressure at which flow is zero. Peak and mid-inspiratory flow off CPAP was obtained from all breaths during sleep (excluding arousal) and compared with Pcrit. Results Active Pcrit, measured during NREM sleep, was strongly correlated with both peak and mid-inspiratory flow during NREM sleep (r = -0.71, p < .005 and r = -0.64, p < .05, respectively), indicating that active pharyngeal collapsibility can be reliably estimated from simple airflow measurements during polysomnography. However, there was no significant relationship between passive Pcrit, measured during NREM sleep, and peak or mid-inspiratory flow obtained from NREM sleep. Flow measurements during REM sleep were not significantly associated with active or passive Pcrit. Conclusions Our study demonstrates the feasibility of estimating active Pcrit using flow measurements in patients with OSA. This method may enable clinicians to estimate pharyngeal collapsibility without sophisticated equipment and potentially aid in the selection of patients for non- positive airway pressure therapies.

Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure.

Abstract: Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance “strength”) rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain—consequent to increased chemosensitivity and delay—the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = −0.68) oscillations (P < 0.001 for all, both groups combined). Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population.

Modeling the adenosine system as a modulator of cognitive performance and sleep patterns during sleep restriction and recovery.

Abstract: Sleep loss causes profound cognitive impairments and increases the concentrations of adenosine and adenosine A1 receptors in specific regions of the brain. Time courses for performance impairment and recovery differ between acute and chronic sleep loss, but the physiological basis for these time courses is unknown. Adenosine has been implicated in pathways that generate sleepiness and cognitive impairments, but existing mathematical models of sleep and cognitive performance do not explicitly include adenosine. Here, we developed a novel receptor-ligand model of the adenosine system to test the hypothesis that changes in both adenosine and A1 receptor concentrations can capture changes in cognitive performance during acute sleep deprivation (one prolonged wake episode), chronic sleep restriction (multiple nights with insufficient sleep), and subsequent recovery. Parameter values were estimated using biochemical data and reaction time performance on the psychomotor vigilance test (PVT). The model closely fit group-average PVT data during acute sleep deprivation, chronic sleep restriction, and recovery. We tested the model's ability to reproduce timing and duration of sleep in a separate experiment where individuals were permitted to sleep for up to 14 hours per day for 28 days. The model accurately reproduced these data, and also correctly predicted the possible emergence of a split sleep pattern (two distinct sleep episodes) under these experimental conditions. Our findings provide a physiologically plausible explanation for observed changes in cognitive performance and sleep during sleep loss and recovery, as well as a new approach for predicting sleep and cognitive performance under planned schedules.

Stable Breathing in Patients With Obstructive Sleep Apnea Is Associated With Increased Effort but Not Lowered Metabolic Rate.

Abstract: Study objectives In principle, if metabolic rate were to fall during sleep in a patient with obstructive sleep apnea (OSA), ventilatory requirements could be met without increased respiratory effort thereby favoring stable breathing. Indeed, most patients achieve periods of stable flow-limited breathing without respiratory events for periods during the night for reasons that are unclear. Thus, we tested the hypothesis that in patients with OSA, periods of stable breathing occur when metabolic rate (VO2) declines. Methods Twelve OSA patients (apnea-hypopnea index >15 events/h) completed overnight polysomnography including measurements of VO2 (using ventilation and intranasal PO2) and respiratory effort (esophageal pressure). Results Contrary to our hypothesis, VO2 did not differ between stable and unstable breathing periods in non-REM stage 2 (208 ± 20 vs. 213 ± 18 mL/min), despite elevated respiratory effort during stable breathing (26 ± 2 versus 23 ± 2 cmH2O, p = .03). However, VO2 was lowered during deeper sleep (244 to 179 mL/min from non-REM stages 1 to 3, p = .04) in conjunction with more stable breathing. Further analysis revealed that airflow obstruction curtailed metabolism in both stable and unstable periods, since CPAP increased VO2 by 14% in both cases (p = .02, .03, respectively). Patients whose VO2 fell most during sleep avoided an increase in PCO2 and respiratory effort. Conclusions OSA patients typically convert from unstable to stable breathing without lowering metabolic rate. During sleep, OSA patients labor with increased respiratory effort but fail to satisfy metabolic demand even in the absence of overt respiratory events.

Corrigendum: Airway and Parenchymal Strains during Bronchoconstriction in the Precision Cut Lung Slice

Abstract: [This corrects the article on p. 309 in vol. 7, PMID: 27559314.].

Backgrounds and/or Triggers of Hospitalized Dementia with Behavioral Psychological Symptoms

Abstract: Backgrounds and/or triggers of dementia are vague except brain diseases such as cerebral stroke, brain injury, alcoholism, and schizophrenia. However, the backgrounds and/or triggers of patients who suffer from severe behavioral psychological symptoms of dementia (BPSD) and may require hospitalizations in institutions that specialize in the treatment of severe BPSD have not been specifically studied. In this work, we retrospectively investigated, through family interviews, the backgrounds and/or triggers of patients with BPSD hospitalized in Sendai Tomizawa Hospital, one of the psychiatric dementia hospitals.