Spinal adenosine A2(A) receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia.

Phrenic long term facilitation (pLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia. pLTF requires spinal serotonin receptor activation, new BDNF synthesis and TrkB receptor activation. Spinal adenosine 2A (A(2A)) receptor activation also elicits phrenic motor facilitation, but by a distinct mechanism involving new TrkB synthesis. Because extracellular adenosine increases during hypoxia, we hypothesized that A(2A) receptor activation contributes to acute intermittent hypoxia (AIH)-induced pLTF. A selective A(2A) receptor antagonist (MSX-3, 8 microg kg(-1), 12 microl) was administered intrathecally (C4) to anaesthetized, vagotomized and ventilated male Sprague-Dawley rats before AIH (three 5 min episodes, 11% O(2)). Contrary to our hypothesis, pLTF was greater in MSX-3 versus vehicle (aCSF) treated rats (97 +/- 6% vs. 49 +/- 4% at 60 min post-AIH, respectively; P < 0.05). MSX-3 and aCSF treated rats did not exhibit facilitation without AIH (time controls; 7 +/- 5% and 9 +/- 9%, respectively; P > 0.05). A second A(2A) receptor antagonist (ZM2412385, 7 microg kg(11), 7 microl) enhanced pLTF (85 +/- 11%, P < 0.05), but an adenosine A(1) receptor antagonist (DPCPX, 3 microg kg(-1), 10 microl) had no effect (51% +/- 8%, P > 0.05), indicating specific A(2A) receptor effects. Intrathecal methysergide (306 microg kg(-1), 15 microl) blocked AIH-induced pLTF in both MSX-3 and aCSF treated rats, confirming that enhanced pLTF is serotonin dependent. Intravenous MSX-3 (140 microg kg(-1), 1 ml) enhanced both phrenic (104 +/- 7% vs. 57 +/- 5%, P < 0.05) and hypoglossal LTF (46 +/- 13% vs. 28 +/- 10%; P < 0.05). In conclusion, A(2A) receptors constrain the expression of serotonin-dependent phrenic and hypoglossal LTF following AIH. A(2A) receptor antagonists (such as caffeine) may exert beneficial therapeutic effects by enhancing the capacity for AIH-induced respiratory plasticity.

Selected Contribution: Regulation of sleep-wake states in response to intermittent hypoxic stimuli applied only in sleep.

Recurrent sleep-related hypoxia occurs in common disorders such as obstructive sleep apnea (OSA). The marked changes in sleep after treatment suggest that stimuli associated with OSA (e.g., intermittent hypoxia) may significantly modulate sleep regulation. However, no studies have investigated the independent effects of intermittent sleep-related hypoxia on sleep regulation and recovery sleep after removal of intermittent hypoxia. Ten rats were implanted with telemetry units to record the electroencephalogram (EEG), neck electromyogram, and body temperature. After >7 days recovery, a computer algorithm detected sleep-wake states and triggered hypoxic stimuli (10% O2) or room air stimuli only during sleep for a 3-h period. Sleep-wake states were also recorded for a 3-h recovery period after the stimuli. Each rat received an average of 69.0 +/- 6.9 hypoxic stimuli during sleep. The non-rapid eye movement (non-REM) and rapid-eye-movement (REM) sleep episodes averaged 50.1 +/- 3.2 and 58.9 +/- 6.6 s, respectively, with the hypoxic stimuli, with 32.3 +/- 3.2 and 58.6 +/- 4.8 s of these periods being spent in hypoxia. Compared with results for room air controls, hypoxic stimuli led to increased wakefulness (P < 0.005), nonsignificant changes in non-REM sleep, and reduced REM sleep (P < 0.001). With hypoxic stimuli, wakefulness episodes were longer and more frequent, non-REM periods were shorter and more frequent, and REM episodes were shorter and less frequent (P < 0.015). Hypoxic stimuli also increased faster frequencies in the EEG (P < 0.005). These effects of hypoxic stimuli were reversed on return to room air. There was a rebound increase in REM sleep, increased slower non-REM EEG frequencies, and decreased wakefulness (P < 0.001). The results show that sleep-specific hypoxia leads to significant modulation of sleep-wake regulation both during and after application of the intermittent hypoxic stimuli. This study is the first to determine the independent effects of sleep-related hypoxia on sleep regulation that approximates OSA before and after treatment.

Repeated hypoxic exposures change respiratory chemoreflex control in humans.

1. A group of seven volunteers (5 male, 2 female) were exposed to 20 min isocapnic (eucapnic) hypoxia once daily for 14 consecutive days. Their chemoreflexes were measured before and after each exposure. The same volunteers repeated the exposures with air substituted for the hypoxic gas mixture in a pseudorandom crossover design. 2. On day 1 an initial ventilatory response to hypoxia and subsequent decline was discernible in two volunteers, but the mean response for all volunteers at this stage was not significant. However, the response gradually increased, and by day 14 was discernible in six volunteers making the mean response for all volunteers significant. No change was observed over the 14 days of air exposure. 3. Only the chemoreflex threshold measured in iso-oxic (hypoxic) modified rebreathing tests changed significantly, and only for the series of exposures to hypoxia. 4. Over 14 days, the mean +/- S.E.M. threshold for all volunteers fell proportionately, from 42 +/- 1.1 mmHg on day 1 to 39 +/- 1.0 mmHg on day 14. By contrast, the mean +/- S.E.M. threshold, for all volunteers and all days, rose from 40 +/- 0.4 mmHg before to 42 +/- 0.5 mmHg after the hypoxic exposures. 5. We conclude that the enhancement of the initial ventilatory response to hypoxia induced by repeated hypoxic exposure is produced by a decrease in chemoreflex threshold. However, the decline in the ventilatory response during a single exposure is produced by an increase in the chemoreflex threshold. Since threshold changes were only found for hypoxic (iso-oxic) modified rebreathing tests, we conclude that only the peripheral chemoreflex changed.

A model of the chemoreflex control of breathing in humans: model parameters measurement.

We reviewed the ventilatory responses obtained from rebreathing experiments on a population of 22 subjects. Our aim was to derive parameter estimates for an 'average subject' so as to model the respiratory chemoreflex control system. The rebreathing technique used was modified to include a prior hyperventilation, so that rebreathing started at a hypocapnic P(CO2) and ended at a hypercapnic P(CO2). In addition, oxygen was added to the rebreathing bag in a controlled manner to maintain iso-oxia during rebreathing, which allowed determination of the response at several iso-oxic P(O2) levels. The breath-by-breath responses were analysed in terms of tidal volume, breathing frequency and ventilation. As P(CO2) rose, ventilation was first steady at a basal value, then increased as P(CO2) exceeded a breakpoint. We interpreted this first breakpoint as the threshold of the combined central and peripheral chemoreflex responses. Above, ventilation increased linearly with P(CO2), with tidal volume usually contributing more than frequency to the increase. When breathing was driven strongly, such as in hypoxia, a second breakpoint P(CO2) was often observed. Beyond the second breakpoint, ventilation continued to increase linearly with P(CO2) at a different slope, with frequency usually contributing more than tidal volume to the increase. We defined the parameters of the variation of tidal volume, frequency and ventilation with P(O2) and P(CO2) for an average subject based on a three-segment linear fit of the individual responses. These were incorporated into a model of the respiratory chemoreflex control system based on the general scheme of the 'Oxford' model. However, instead of considering ventilatory responses alone, the model also incorporates tidal volume and frequency responses.

The contribution of chemoreflex drives to resting breathing in man.

The contribution of automatic drives to breathing at rest, relative to behavioural drives such as "wakefulness", has been a subject of debate. We measured the combined central and peripheral chemoreflex contribution to resting ventilation using a modified rebreathing method that included a prior hyperventilation and addition of oxygen to maintain isoxia at a P(ET,O2) (end-tidal partial pressure of oxygen) of 100 mmHg. During rebreathing, ventilation was unrelated to P(ET,CO2) (end-tidal partial pressure of carbon dioxide) in the hypocapnic range, but after a threshold P(ET,CO2) was exceeded, ventilation increased linearly with P(ET,CO2). We considered the sub-threshold ventilation to be an estimate of the behavioural drives to breathe (mean +/- S.E.M. = 3.1 +/- 0.5 l min(-1)), and compared it to ventilation at rest (mean +/- S.E.M. = 9.1 +/- 0.7 l min(-1)). The difference was significant (Student's paired t test, P < 0.001). We also considered the threshold P(CO2) observed during rebreathing to be an estimate of the chemoreflex threshold at rest (mean +/- S.E.M. = 42.0 +/- 0.5 mmHg). However, P(ET,CO2) during rebreathing estimates mixed venous or tissue P(CO2), whereas the resting P(ET,CO2) during resting breathing estimates P(a,CO2) (arterial partial pressure of carbon dioxide). The chemoreflex threshold measured during rebreathing was therefore reduced by the difference in P(ET,CO2) at rest and at the start of rebreathing (the plateau estimates the mixed venous P(CO2) at rest) in order to make comparisons. The corrected chemoreflex thresholds (mean +/- S.E.M. = 26.0 +/- 0.9 mmHg) were significantly less (paired Student's t test, P < 0.001) than the resting P(ET,CO2) values (mean +/- S.E.M. = 34.3 +/- 0.5 mmHg). We conclude that both the behavioural and chemoreflex drives contribute to resting ventilation. Experimental Physiology (2001) 86.1, 109-116.

[Cleft lip and palate treatment in the plastic surgery department in the university hospital center in Lille]. / Prise en charge des fentes labio-maxillo-palatines au sein du service de chirurgie plastique du centre hospitalier universitaire de Lille.

The aim of cleft care is to favor a normal socialization of patients with fewer therapeutic coercion. It supposes a full multidisciplinary team including psychologist, speech therapeutic, dental orthopedist, oto-rhino-laryngologist and surgeons. All of them have to be well trained which supposes a sufficient amount of cases: anglo-saxon studies have proven that a mean of at least 20 new cases per year of primary cleft were necessary. With purposes to enhance the effectiveness of treatment: prospective studies and measurements of results must be evaluated with the help of objective criteria. These are the goals of our team in lille. Our surgical principles are those of functional procedures, which privilege the muscle function's repair.