Hypercapnia and sleep O2 desaturation in chronic obstructive pulmonary disease

There is a wide clinical spectrum in chronic obstructive pulmonary disease (COPD). The extremes of this spectrum, the "pink puffer" (PP) and "blue bloater" (BB) stereotypes differ in their degree of sleep hypoxemia and pulmonary hypertension. Most patients cannot be characterized as either PP or BB. The data amassed in the recent nocturnal oxygen therapy trial provide an opportunity to see to what extent differences in sleep oxygenation and hemodynamics in a large hypoxemic COPD population are related to awake hypoxemia and hypercapnia. From a large hypoxemic COPD population sleep SaO2 was examined in those with (PaCO2 greater than 44 mm Hg) and without (PaCO2 less than or equal to 44 mm Hg) hypercapnia. Hypercapnic patients (mean PaCO2 49.8 mm Hg) had the same PaO2 and degree of airflow obstruction as normocapnic patients (PaCO2 37.4 mm Hg) but had far greater sleep hypoxemia (measured by mean sleep SaO2, low sleep SaO2, and awake-low sleep SaO2, p less than 0.05). In addition, arterial blood gases of the large sleep O2 desaturaters were compared with those of the small desaturaters; PaO2 was similar in both groups, whereas PaCO2 was different (p less than 0.01). Two common subsets of hypoxemic patients were also compared; one was hypercapnic and overweight, the other normocapnic and hyperinflated. We found that patients in the hypercapnic group had far worse sleep hypoxemia, although they had better lung function. We conclude that hypercapnia is a marker for sleep O2 desaturation in hypoxemic COPD.     

Obestatin alters sleep in rats

Obestatin is a recently identified peptide derived from the ghrelin gene. Ghrelin stimulates food intake whereas obestatin has an opposite effect in rats. Previous experiments in our laboratory revealed that ghrelin also induces wakefulness in rats. The aim of the present experiments was to study the effect of obestatin on sleep. Rats received intraperitoneal (n = 7; 16 or 64 microg/kg) or intracerebroventricular (i.c.v.; n = 11) injection of pyrogen-free isotonic NaCl or obestatin (1, 4 and 16 microg in a volume of 4 microl) at dark onset. Sleep-wake activity was recorded for 23 h. I.c.v. administration of 16 microg obestatin induced a significant increase (approximately 58%) in the time spent in non-rapid-eye-movement sleep (NREMS) in the first hour after the injection. This resulted from an increase in the number of NREMS episodes and shortened sleep latency. Electroencephalographic (EEG) slow-wave activity (0.5-4 Hz) was reduced by obestatin treatment. The initial increase in NREMS time was followed by a decrease in both NREMS and REMS in the second hour after the injection. Peripheral injection of obestatin did not induce significant changes in sleep in any post-injection hours. Results suggest that the sleep-promoting effect of centrally administered obestatin may be part of the behavioral manifestation of satiety elicited by the peptide. Current results confirm the finding that two regulatory peptides derived from the same gene have opposite actions in the same species.     

Aging induced endoplasmic reticulum stress alters sleep and sleep homeostasis

Alterations in the quality, quantity, and architecture of baseline and recovery sleep have been shown to occur during aging. Sleep deprivation induces endoplasmic reticular (ER) stress and upregulates a protective signaling pathway termed the unfolded protein response. The effectiveness of the adaptive unfolded protein response is diminished by age. Previously, we showed that endogenous chaperone levels altered recovery sleep in Drosophila melanogaster. We now report that acute administration of the chemical chaperone sodium 4-phenylbutyrate (PBA) reduces ER stress and ameliorates age-associated sleep changes in Drosophila. PBA consolidates both baseline and recovery sleep in aging flies. The behavioral modifications of PBA are linked to its suppression of ER stress. PBA decreased splicing of X-box binding protein 1 and upregulation of phosphorylated elongation initiation factor 2 α, in flies that were subjected to sleep deprivation. We also demonstrate that directly activating ER stress in young flies fragments baseline sleep and alters recovery sleep. Alleviating prolonged or sustained ER stress during aging contributes to sleep consolidation and improves recovery sleep or sleep debt discharge.     

Reproductive hormone replacement alters sleep in mice

Several studies have reported that reproductive hormones can alter baseline sleep–wake states, however, no studies in mice have examined whether reproductive hormone replacement in adult females and males influences sleep. In this study, we determined whether androgen replacement in males and estrogen replacement in females alter sleep–wake amount and sleep rebound after extended wakefulness. The gonads from adult male and female C57BL/6J mice were removed and animals were implanted with continuous release hormone or placebo pellets. Male mice received testosterone and females received 17β-estradiol. Recording electrodes were implanted to monitor sleep–wake states under baseline conditions and in response to 6 h of sleep deprivation. During baseline recording estradiol-treated females exhibited a reduction in NREM sleep amount that was predominant during the dark phase. Testosterone-treated males conversely, exhibited an increase in NREM sleep amount. After sleep deprivation, hormone-treated males and females exhibited similar amounts of recovery sleep however males exhibited slightly more sleep than placebo-treated controls. The results of these experiments demonstrate that the androgens and estrogens are primarily responsible for sex differences in baseline sleep–wake amount but do not have substantial effects on homeostatic sleep rebound after extended wakefulness.     

Fever alters characteristics of sleep in rats

This study examined the effects of a fungal infection on body temperature (Tb) and sleep states. Tb and sleep were recorded in male rats for 24 hr after a saline injection and 48 hr after a subcutaneous injection of live brewer's yeast, at ambient temperatures (Ta's) of 20 degrees and 30 degrees C. Peak fevers of 1.6-3.1 degrees C occurred within 6-10 hr at both Ta's. The rats remained febrile for the next 12-24 hr. For the first 24 hr postyeast, amounts of SWS increased by 19 +/- 3% at 20 degrees C and 12 +/- 2% at 30 degrees C. Specifically, SWS was significantly increased from hr 5-8 (lights-on) and 13-24 (lights-off) at 20 degrees, and from hr 5-8 and 17-24 at 30 degrees C. Ta did not affect the changes in Tb or the changes in SWS after either saline or yeast. Duration of REMS varied with Ta after saline. After yeast, REMS increased by 21 +/- 12% at 20 degrees and decreased by 28 +/- 6% at 30 degrees C, with the net result that REMS at the two Ta's was equal during the fever. Furthermore, while the rats were febrile the normal diurnal variation in REMS was eliminated. Sleep and Tb returned to control values during the second fever day. These results suggest that an activated immune system both increases SWS and overrides the diurnal and thermoregulatory modulations of REMS.     

Imposed breathing pattern alters respiratory work during exercise

Previous studies have shown the existence of an ideal respiratory rate (f _R) for a given ventilation at which the respiratory work rate (J·s^–1) is minimum. The purpose of the present study was to measure the effect off _R, tidal volume and breathing pattern on the respiratory work per breath and respiratory work rate during exercise on a cycle ergometer. Three work rates on the cycle ergometer were used and at each work rate the ventilation was kept constant. Two different breathing patterns were applied at each ventilation. Nine male trained cyclists [mean (SD) maximum oxygen consumption, 57 (5.47) ml·kg^–1·min^–1] participated in this study. The results indicated that there was a significant difference in the respiratory work per breath, with different breathing patterns at a given ventilation and for all levels of ventilation. There was no significant difference in the respiratory work rate with different breathing patterns at a given ventilation and for all levels of ventilation. In addition, the respiratory work per breath and respiratory work rate were increased with increasing ventilation. Thus, the data indicated that the manipulation of tidal volume, respiratory rate and breathing pattern had no significant effect on the energy cost of breathing for a given ventilation. The absence of this significant effect on respiratory work rate was observed across a range of ventilation from 24 to 72 l·min^–1. These findings suggest that the breathing pattern is predominantly an expression of the function of the higher respiratory brain center instead of energy economy, at least within this range of ventilation.     

Intravenous instrumentation alters the autonomic state in humans

Intravascular instrumentation may induce syncope or presyncope. It is not known whether asymptomatic subjects also have autonomic reactions, albeit concealed. We addressed this issue by studying 44 healthy young male subjects of various levels of fitness, ranging from inactivity to athletic [mean maximal oxygen uptake was 49.1 (SD 10.7) ml·kg^–1·min^–1, range 28.7–71.9 ml·kg^–1·min^–1]. The autonomic response to venous cannulation was quantified by measuring heart rate before cannulation (HR1), after cannulation (HR₂), and after complete pharmacological autonomic blockade (HR₀ = the intrinsic heart rate). The sympathovagal balance before and after cannulation was computed as HR₁/HR₀ and HR₂/HR₀, respectively. The group means of heart rate and sympathovagal balance decreased significantly (paired Student's t-test P <0.01) from 62.5 to 59.9 beats·min^–, and from 0.71 to 0.68, respectively. The maximal decrease in heart rate was 8.8 beats·min^–1, and in the sympathovagal balance was 0.11. Our study demonstrated that the asymptomatic subjects responded to intravenous instrumentation with a concealed autonomic reaction. Thus, from our findings it would seem that intravenous instrumentation interferes with measurements relating to autonomic nervous system activity.     

Food restriction alters the diurnal distribution of sleep in rats

The purpose of the present study was to determine the effects of restricting food and water intake to the light period on sleep and brain temperature (Tbr). Sprague-Dawley male rats were anesthetized and provided with electrodes and thermistors for electroencephalographic (EEG) and Tbr recordings. Baseline recordings were performed after a 3-week recovery period. After baseline recordings, access to food and water was restricted (FWR) to the light period for 29 days. During FWR, the diurnal distribution of rapid-eye-movement sleep (REMS) and Tbr were reversed, while the distribution of non-REMS (NREMS) between the dark and light periods was attenuated. Daily food and water intake, body weight, and the diurnal distribution of EEG slow-wave activity within NREMS remained unchanged. In a separate study, sham-operated and pinealectomized rats were studied in a similar manner. The sleep responses of pinealectomized and sham-operated rats to FWR were similar. Further, FWR did not affect melatonin levels in the sham-operated rats, thereby suggesting that the pineal gland does not mediate the effects of FWR on sleep.     

Fractal dimension of the sleep state waveform in obstructive sleep apnea

Question of the study

Sleep represents a complex interplay of biological processes. This study examines whether the dynamics of the sleep state changes exhibit fractal properties and the implications of such changes in obstructive sleep apnea.

Patients and methods

Overnight polysomnography data on 25 volunteers from a publicly available data set were analyzed to assess whether the sleep states over time demonstrated a fractal nature. Fractal dimension of the raw sleep state waveform as well as a zero-order-hold transformed counterpart were estimated using three methods: Katz, Sevcik, and Lee. Statistical analyses were conducted using correlation, multivariate linear and logistic regression, autocorrelation, power spectrum analysis, and receiver-operating characteristic curve.

Results

Both untransformed and transformed sleep state waveforms exhibited self-similarity. FD of the transformed waveform was significantly associated with a higher apnea–hypopnea index irrespective of the measure of FD. A high proportion of the transition from state 0–2 was significantly associated with a higher fractal dimension and a higher risk of moderate/severe apnea.

Conclusion

In this study, it was demonstrated that the fractal nature of the sleep state waveform is affected in obstructive sleep apnea.     

Evidence for genetic influences on sleep disturbance and sleep pattern in twins

The etiologic role of genotype and environment in sleep pattern (daytime napping, habitual bedtime, and sleep duration) and subjective sleep quality and sleep disturbance was examined using a general population sample of 3,810 adult Australian twin pairs, aged 17-88 years. Genetic differences accounted for at least 33% of the variance in sleep quality and sleep disturbance and 40% of the variance in sleep pattern. There was no evidence for a decline in the importance of genetic predisposition with age. Short-term environmental fluctuations accounted for as much as 30% of the variance, and more stable nonfamilial environmental effects accounted for the remainder. No effect of shared family environment on sleep characteristics was found.     

Hypnotic suggestion alters the state of the motor cortex

Hypnosis often leads people to obey a suggestion of movement and to lose perceived voluntariness. This inexplicable phenomenon suggests that the state of the motor system may be altered by hypnosis; however, objective evidence for this is still lacking. Thus, we used transcranial magnetic stimulation of the primary motor cortex (M1) to investigate how hypnosis, and a concurrent suggestion that increased motivation for a force exertion task, influenced the state of the motor system. As a result, corticospinal excitability was enhanced, producing increased force exertion, only when the task-motivating suggestion was provided during hypnotic induction, showing that the hypnotic suggestion actually altered the state of M1 and the resultant behavior.     

Pneumocystis infection alters the activation state of pulmonary macrophages

Recent studies show a substantial incidence of Pneumocystis jirovecii colonization and infection in patients with chronic inflammatory lung conditions. However, little is known about the impact of Pneumocystis upon the regulation of pulmonary immunity. We demonstrate here that Pneumocystis polarizes macrophages towards an alternatively activated macrophage-like phenotype. Genetically engineered mice that lack the ability to signal through IL-4 and IL-13 were used to show that Pneumocystis alternative macrophage activation is dependent upon signaling through these cytokines. To determine whether Pneumocystis-induced macrophage polarization would impact subsequent immune responses, we infected mice with Pneumocystis and then challenged them with Pseudomonas aeruginosa 14 days later. In co-infected animals, a higher proportion of macrophages in the alveolar and interstitial spaces expressed both classical and alternatively activated markers and produced the regulatory cytokines TGFβ and IL-10, as well as higher arginase levels than in mice infected with P. aeruginosa alone. Our results suggest that Pneumocystis reprograms the overall macrophage repertoire in the lung to that of a more alternatively-activated setpoint, thereby altering subsequent immune responses. These data may help to explain the association between Pneumocystis infection and decline in pulmonary function.     

Night sleep in patients with vegetative state

Polysomnographic recording of night sleep was carried out in 15 patients with the diagnosis vegetative state (syn. unresponsive wakefulness syndrome). Sleep scoring was performed by three raters, and confirmed by means of a spectral power analysis of the electroencephalogram, electrooculogram and electromyogram. All patients but one exhibited at least some signs of sleep. In particular, sleep stage N1 was found in 13 patients, N2 in 14 patients, N3 in nine patients, and rapid eye movement sleep in 10 patients. Three patients exhibited all phenomena characteristic for normal sleep, including spindles and rapid eye movements. However, in all but one patient, sleep patterns were severely disturbed as compared with normative data. All patients had frequent and long periods of wakefulness during the night. In some apparent rapid eye movement sleep episodes, no eye movements were recorded. Sleep spindles were detected in five patients only, and their density was very low. We conclude that the majority of vegetative state patients retain some important circadian changes. Further studies are necessary to disentangle multiple factors potentially affecting sleep pattern of vegetative state patients.     

Ventilation and sleep state in the new-born

1. Ventilation, oesophageal pressure and sleep state were measured in fourteen babies between 25 hr and 7 days of age.2. Trunk plethysmograph records showed that respiratory rate and minute volume were significantly higher in REM sleep than non-REM sleep. Tidal volume was not significantly altered.3. Tidal volume, respiratory rate and minute volume were all more variable in each baby in REM sleep, both on breath to breath analysis and over successive 20 sec periods.4. Major oesophageal peristaltic activity was observed in REM sleep only.5. In response to a sharp rise in P(O2) the tidal volume and minute volume fell significantly by the same proportion in both sleep states. Respiratory rate did not change significantly.     

Redox state alters anti‐cancer effects of wedelolactone

Wedelolactone is one of the active plant polyphenolic compounds. Anti‐tumor effects of this drug have been demonstrated recently. We have described that wedelolactone acts as catalytic inhibitor of DNA topoisomerase IIα. The aim of this study was to further characterize the mechanism of its anti‐tumor effects. We showed that wedelolactone inhibits binding of DNA topoisomerase IIα to plasmid DNA and antagonizes formation of etoposide‐induced DNA cleavage complex. The inhibition of topoisomerase IIα by wedelolactone is reversible by excess of the enzyme but not DNA. The in vitro inhibitory effect of wedelolactone on the topoisomerase IIα activity is redox‐dependent as it diminished in the presence of reducing agents. Cytotoxicity of wedelolactone was partially inhibited by N‐acetylcysteine and glutathione ethyl ester in breast cancer MDA‐MB‐231 and MDA‐MB‐468 cells while the inhibitory effect of catalase was observed only in the former cell line. Finally, we found that wedelolactone can be oxidized in the presence of copper ions resulting in DNA strand break and abasic site formation in vitro. However, wedelolactone induced neither DNA damage in MDA‐MB‐231 cells nor mutations in bacterial cells detectable by Ames test suggesting that wedelolactone may not be an effective inducer of DNA damage. We conclude that the topoisomerase IIα inhibitory‐ and DNA damaging activities of wedelolactone in vitro depend on its redox state. Pro‐oxidant activity could, however, explain only part of wedelolactone‐induced cytotoxicity. Therefore, the major cellular target(s) of wedelolactone and the exact mechanism of wedelolactone‐induced cytotoxicity still remain to be identified. Environ. Mol. Mutagen. 2012. © 2012 Wiley Periodicals, Inc.     

Hypercapnia selectively attenuates the somato-sympathetic reflex

The effects of hyperoxic hypercapnia (5, 10 or 15% CO2 in O2) on splanchnic sympathetic nerve activity (sSNA) and sympathetic reflexes such as the somato-sympathetic reflex or baroreflex were studied in urethane anaesthetised, paralysed, artificially ventilated and vagotomized Sprague-Dawley rats. Hypercapnia caused a small increase in mean arterial blood pressure (MAP) in the 10% CO2 group and a fall in heart rate (HR) in all three groups. sSNA increased in all three groups. Phrenic frequency and amplitude increased during hypercapnia, with frequency adapting back towards baseline during the CO2 exposure. The somato-sympathetic reflex was attenuated in the 5% CO2 group and abolished in the 10 and 15% CO2 groups, whereas there was little effect on the sSNA baroreflex. Hypercapnia significantly affects phrenic nerve activity (PNA), sSNA and selectively inhibits the somato-sympathetic reflex with little effect on the sSNA baroreflex.     

Emphysema alters the deposition pattern of inhaled particles in hamsters.

How does pulmonary emphysema affect aerosol deposition? Groups of awake hamsters with emphysema (intratracheal elastase, 0.2 mg/100 g body wt) and age-matched controls (intratracheal saline) were exposed for 30 minutes to an insoluble radioactive aerosol (0.45 mu aerodynamic diameter) at 30, 60, or 90 days after instillation. Immediately after exposure, the animals were sacrificed. The lungs were excised, dried at total lung capacity, and sliced into 1-mm thick sections. Each slice was cut into pieces, which were counted for radioactivity and weighed. Then a measure of the uniformity of deposition, the evenness index (EI), was calculated. With perfect uniformity, all EIs would be one. We found fewer particles in the emphysematous, as compared with the control, lungs at 60 or 90 days after elastase instillation. The deposited particles were distributed less uniformly throughout the emphysematous lungs than in the control lungs. In controls, the standard deviation (SD) of the EI distribution (mean 1.0) averaged 0.33 for the three times studied. In elastase animals, the SD increased to 0.48 at 30 days, and at 60 days and 90 days the distributions were no longer normally distributed. This increased heterogeneity of deposition was also manifested as a loss of the normal apex-base gradient observed in control animals, an increase in the amount of nonventilated parenchyma, enhanced airway deposition, and an altered lobar deposition pattern. Morphometric analysis showed an increase in the mean linear intercept (MLI) of emphysematous lungs as compared with control lungs. However, the author found no correlation between MLI, a measure of emphysema, and EI, a measure of deposition, quantified in the same lung pieces. It is concluded that the emphysematous lesions produced by elastase markedly alter the deposition of an inhaled submicrometric aerosol. Factors that may contribute to these changes include airway obstruction and differences in breathing pattern in emphysematous as compared with control animals.     

Preliminary evidence that misalignment between sleep and circadian timing alters risk-taking preferences

Decision-making has been shown to suffer when circadian preference is misaligned with time of assessment; however, little is known about how misalignment between sleep timing and the central circadian clock impacts decision-making. This study captured naturally occurring variation in circadian alignment (i.e., alignment of sleep–wake timing with the central circadian clock) to examine if greater misalignment predicts worse decision-making. Over the course of 2 weeks, 32 late adolescent drinkers (aged 18–22 years; 61% female; 69% White) continuously wore actigraphs and completed two overnight in-laboratory visits (Thursday and Sunday) in which both dim-light melatonin onset (DLMO) and behavioural decision-making (risk taking, framing, and strategic reasoning tasks) were assessed. Sleep–wake timing was assessed by actigraphic midsleep from the 2 nights prior to each in-laboratory visit. Alignment was operationalised as the phase angle (interval) between average DLMO and average midsleep. Multilevel modelling was used to predict performance on decision-making tasks from circadian alignment during each in-laboratory visit; non-linear associations were also examined. Shorter DLMO-midsleep phase angle predicted greater risk-taking under conditions of potential loss (B = −0.11, p = 0.06), but less risk-taking under conditions of potential reward (B = 0.14, p = 0.03) in a curvilinear fashion. Misalignment did not predict outcomes in the framing and strategic reasoning tasks. Findings suggest that shorter alignment in timing of sleep with the central circadian clock (e.g., phase-delayed misalignment) may impact risky decision-making, further extending accumulating evidence that sleep/circadian factors are tied to risk-taking. Future studies will need to replicate findings and experimentally probe whether manipulating alignment influences decision-making.