Restoration of Sleep Architecture after Maxillomandibular Advancement: Success Beyond the Apnea-Hypopnea Index.

While effects of maxillomandibular advancement (MMA) on respiratory parameters for patients with obstructive sleep apnea (OSA) are well described, effects on sleep architecture before and after MMA are not. A retrospective cohort analysis on sleep architecture was examined in 10 OSA patients who underwent MMA surgery between July 2013 and November 2014, and had prespecified complete polysomnography (PSG) datasets. Sleep stages were examined relative to a Western European population-based control group. All of the respiratory parameters improved significantly post MMA. Rapid eye movement (REM) latency decreased from 178.0±142.8 to 96.6±64.5min (P=0.035). %NREM (non-rapid eye movement)1 (P=0.045) and %WASO (wakefulness after sleep onset) (P=0.006) decreased, while %REM increased (P=0.002) after MMA. WASO decreased from 64.2±57min to 22.4±15.4min (P=0.017). Preoperatively, OSA subjects showed significantly lower sleep efficiency (P=0.016), sleep onset latency (P=0.015), and % REM (P<0.001) than the normative population dataset, while post MMA there was a significant decrease in %NREM1 sleep (P<0.001) and in %WASO (P<0.001). MMA results in a marked decrease in WASO and increase in REM, and to a lesser extent NREM sleep. Patients after MMA show values similar to population controls except for a lower WASO.

Right ventricle dimensions and function in response to acute hypoxia in healthy human subjects.

AIM: Acute hypoxia produces acute vasoconstriction in the pulmonary circulation with consequences on right ventricular (RV) structure and function. Previous investigations in healthy humans have been restricted to measurements after altitude acclimatization or were interrupted by normoxia. We hypothesized that immediate changes in RV dimensions in healthy subjects in response to normobaric hypoxia differ without the aforementioned constraints. METHODS: Transthoracic echocardiography was performed in 35 young, healthy subjects exposed to 11% oxygen, as well as six controls under sham hypoxia (20.6% oxygen, single blind) first at normoxia and after 30, 60, 100, 150 min of hypoxia or normoxia respectively. A subgroup of 15 subjects continued with 3-min cycling exercise in hypoxia with subsequent evaluation followed by an assessment 1 min at rest while breathing 4 L min-1 oxygen. RESULTS: During hypoxia, there was a significant linear increase of all RV dimensions (RVD1 + 29 mm, RVD2 + 42 mm, RVD3 + 41 mm, RVOT + 13 mm, RVEDA + 18 mm, P < 0.01) in the exposure group vs. the control group. In response to hypoxia, right ventricular systolic pressure (RVSP) showed a modest increase in hypoxia at rest (+7.3 mmHg, P < 0.01) and increased further with physical effort (+11.8 mmHg, P < 0.01). After 1 min of oxygen at rest, it fell by 50% of the maximum increase. CONCLUSION: Acute changes in RV morphology occur quickly after exposure to normobaric hypoxia. The changes were out of proportion to a relatively low-estimated increase in pulmonary pressure, indicating direct effects on RV structure. The results in healthy subjects are basis for future clinically oriented interventional studies in normobaric hypoxia.

HLA-DQ association and allele competition in Chinese narcolepsy.

In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQß*06:02 narcolepsy heterodimer to reduce susceptibility.

Two weeks of buspirone protects against posthypoxic ventilatory pauses in the C57BL/6J mouse strain.

The purpose was to determine if 2 weeks of buspirone suppressed post-hypoxic breathing instability and pauses in the C57BL/6J (B6) mouse. Study groups were vehicle (saline, n=8), low-dose (1.5 mg/kg, n=8), and high-dose buspirone (5.0 mg/kg, n=8). Frequency, measured by plethysmography, was the major metric, and a pause defined by breathing cessation >2.5 times the average frequency. Mice were tested after 16 days of ip injections of vehicle or drug. On day 17, 4 mice in each group were tested after buspirone and the 5-HT(1A) receptor antagonist, 4-iodo-N-{2-[4-(methoxyphenyl)-1-piperazinyl] ethyl}-N-2-pyridinyl-benzamide (p-MPPI, 5 mg/kg). A post-hypoxic pause was present in 6/8 animals given vehicle and 1/16 animals given buspirone at either dose, but always present (8/8) with p-MPPI, regardless of buspirone dose. Post-hypoxic frequency decline was blunted by buspirone (-10% vehicle vs. -5% at both doses) and restored by p-MPPI; ventilatory stability as described by the coefficient of variation which was reduced by buspirone (p<0.04) was increased by p-MPPI (0.01). In conclusion, buspirone administration after 2 weeks acts through the 5-HT(1A) receptor to reduce post-hypoxic ventilatory instability in the B6 strain.

Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status.

We hypothesised that hypocretin (orexin) plays a role in the determination of ventilatory chemosensitivity. 130 patients with narcolepsy-cataplexy (mean ± SD age 20 ± 10 yrs, 69% male) and 117 controls (22 ± 6.9 yrs, 62% male) were recruited and tested for human leukocyte antigen (HLA)-DQB1*0602 status, hyperoxia hypercapnic (change in minute ventilation (δV'(E))/carbon dioxide tension (δP(CO(2))) L·min(-1)·mmHg(-1)) and hypoxic (δV'(E) /change in arterial oxygen saturation measured by probe oximetry (δS(p,O(2))) L·min(-1) per %S(p,O(2))) responsiveness, and by spirometry. Hypocretin deficiency was determined either by measures of cerebrospinal fluid hypocretin-1 (37 patients) or by positive HLA-DQB1*0602 status. All patients and 49% of controls underwent polysomnography and multiple sleep latency testing. Despite similar spirometric values, patients had a higher apnoea/hypopnoea index (AHI) (2.8 ± 5.4 versus 0.8 ± 1.6 h(-1); p = 0.03) and lower minimal oxygen saturation during sleep (87% ± 7 versus 91 ± 4%; p = 0.0002), independent of age, sex and body mass index. Patients had depressed hypoxic responsiveness (0.13 ± 0.09 versus 0.19 ± 0.13 L·min(-1) per %S(p,O(2)); p<0.0001), independent of AHI, but hypercapnic responsiveness did not differ. Examined by HLA status, positive (26 out of 117) controls had lower hypoxic but similar hypercapnic responsiveness than those marker-negative (0.13 ± 0.08 versus 0.20 ± 0.14 L·min(-1) per %S(p,O(2)); p<0.0001). Thus, a lower hypoxic responsiveness in the narcolepsy-cataplexy group is a result of DQB1*0602 status rather than the clinical features of disease.

The effect of clomipramine on wake/sleep and orexinergic expression in rats.

We have previously found that neonatal treatment with clomipramine (CLI) induced a decrease in brain orexins during the juvenile period and that these changes were reversed at adulthood. This study investigated the effect of CLI on the orexinergic component and sleep/wake states. Two groups of adult male rats were conducted for 48-h polysomnographic recording. One group of rats was treated with CLI (20 mg/kg every 12 h), and a second group was treated with equivolume of saline (SAL) simultaneously after the first 24 h of polysomnographic recording. Rats were killed 2 h after the third dose of treatment. Brain tissues were collected for radioimmunoassay quantification of orexins and real-time PCR analysis of prepro-orexin and orexin receptor mRNA. The CLI group had significantly shorter rapid eye movement (REM) sleep and longer REM latency compared with both the baseline day and the SAL group and had significantly less active wake and more quiet wake. Compared with the control rats, the CLI rats had significantly higher mRNA expression of prepro-orexin in the hypothalamus and the frontal cortex, but not in the hippocampus. The CLI rats also had significantly less orexin B in the hypothalamus than the control rats. These results suggest that suppression of active wake and orexin B by CLI may be a factor responsible for CLI-induced depression and that the increase of prepro-orexin mRNA may be a sign of increased brain orexins found in this model.

Changes in brain orexin levels in a rat model of depression induced by neonatal administration of clomipramine.

Depression is associated with a deficiency of serotonergic neurons that have been found to suppress orexinergic neurons, which in turn activate these neurons in a feedback loop. This evidence suggests that orexins may be involved in the pathology of depression. Long Evans rats were treated with clomipramine (CLI) and saline (SAL) from postnatal days 8 through 21. One set of rats from both groups was sacrificed at 35 days of age for quantification of orexins in multiple brain regions. At 3-4 months of age a second set of rats was tested for immobility in a forced swim procedure, a common test for depressive signs in rats, and a third set was sacrificed for the quantification of orexins. Compared with the control rats, adult rats with neonatal CLI treatment had (1) increased forced swim immobility and (2) increased orexins A and B in the hypothalamus. However, both orexins A and B levels were decreased in multiple brain regions in the juvenile CLI rats compared with same-age controls. We concluded that although orexin levels were decreased in juvenile CLI rats, adult CLI rats with features of depression had significantly higher levels of hypothalamic orexins compared with adult controls. These results imply that orexins are likely to be involved in the pathological regulation of depression.

The effects of an intervention to teach medical students about obstructive sleep apnea.

BACKGROUND AND PURPOSE: To assess the effects of teaching clinically relevant core concepts about obstructive sleep apnea (OSA) to third-year core clerkship students in internal medicine. PATIENTS AND METHODS: The curriculum included a lecture and case-based discussions about OSA at one clerkship site consisting of six groups of core clerkship students in the graduating Classes of 2000 and 2001 at Case Western Reserve University School of Medicine. Students who received exposure to a lecture followed by case-based discussions (n=130) were compared to students at clerkship sites who did not (n=129). Outcomes were measured using a station on the required end-of-rotation Objective Structured Clinical Examination (OSCE), consisting of 13 items and 36 points. RESULTS: When compared to groups of students who did not have a scheduled lecture and case-based discussions, those who did scored significantly higher (P

Ventilatory behavior after hypoxia in C57BL/6J and A/J mice.

Given the environmental forcing by extremes in hypoxia-reoxygenation, there might be no genetic effect on posthypoxic short-term potentiation of ventilation. Minute ventilation (VE), respiratory frequency (f), tidal volume (VT), and the airway resistance during chemical loading were assessed in unanesthetized unrestrained C57BL/6J (B6) and A/J mice using whole body plethysmography. Static pressure-volume curves were also performed. In 12 males for each strain, after 5 min of 8% O2 exposure, B6 mice had a prominent decrease in VE on reoxygenation with either air (-11%) or 100% O2 (-20%), due to the decline of f. In contrast, A/J animals had no ventilatory undershoot or f decline. After 5 min of 3% CO2-10% O2 exposure, B6 exhibited significant decrease in VE (-28.4 vs. -38.7%, air vs. 100% O2) and f (-13.8 vs. -22.3%, air vs. 100% O2) during reoxygenation with both air and 100% O2; however, A/J mice showed significant increase in VE (+116%) and f (+62.2%) during air reoxygenation and significant increase in VE (+68.2%) during 100% O2 reoxygenation. There were no strain differences in dynamic airway resistance during gas challenges or in steady-state total respiratory compliance measured postmortem. Strain differences in ventilatory responses to reoxygenation indicate that genetic mechanisms strongly influence posthypoxic ventilatory behavior.

REM sleep and catecholamine excretion: a study in elite athletes.

We investigated the potential influence of catecholamines on sleep architecture in endurance-trained athletes. The hypothesis was that endogenous levels of aminergic neurotransmitters influence sleep architecture. Thirteen well-trained male street cyclists (all members of the German national amateur team, mean age 23.9 years, mean body mass index 21.9 kg/m2) completed the protocol. Each subject was studied during training after a race competition (C) and later in a recovery/rest period (R) with no training and no competition. Polysomnography (PSG) was performed for one night (C) and for a second night some weeks later (R). Urinary levels of catecholamines collected during the preceding day and over the night of PSG were used as an index of excretion rate of circulating adrenergic agonists. Nighttime and daytime excretion of epinephrine and norepinephrine was significantly elevated after exercise (C vs R; P<0.01). Rapid-eye-movement sleep (REM) onset latency was significantly increased (P=0.03) and REM was significantly decreased in the first half of the night in the training compared to the resting condition (C vs R, P=0.05). REM latency was correlated with increased epinephrine excretion on the day of exercise (C, r=0.63, P=0.02). The temporal appearance of REM during the night appears to be affected in part by the intense exercise associated with race competition, and urinary catecholamines are markers that are correlated with this alteration in REM appearance.

Treatment effects on carbon dioxide retention in patients with obstructive sleep apnea-hypopnea syndrome.

OBJECTIVES: This study was designed to examine respiratory control in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS), with or without CO(2) retention. METHODS: We recruited 10 body mass index-matched, apnea-hypopnea index-matched, age-matched, and lung function-matched OSAHS patients, according to their awake PaCO(2). Five patients were hypercapnic (PaCO(2), > or = 45 mm Hg), and five patients were eucapnic. Hypoxic responses (the ratio of the change in minute ventilation [DeltaV(E)] to the change in arterial oxygen saturation [DeltaSaO(2)] and the ratio of the change in mouth occlusion pressure over the first 100 ms of inspiration against an occluded airway [DeltaP(0.1)] to DeltaSaO(2)) and hypercapnic responses (DeltaV(E)/DeltaPCO(2) ratio and DeltaP(0.1)/DeltaPCO(2) ratio) were tested during wakefulness before treatment in all 10 patients, and before and during treatment (at 2, 4, and 6 weeks) with pressure support in the hypercapnic group. RESULTS: Hypercapnic patients had lower mean (+/- SD) DeltaV(E)/DeltaSaO(2) ratio than eucapnic patients (-0.17 +/- 0.04 vs -0.34 +/- 0.04 L /min/%SaO(2), respectively), lower mean DeltaP(0.1)/DeltaSaO(2) ratio (-0.04 +/- 0.02 vs -0.14 +/- 0.03 cm H(2)O/%SaO(2), respectively), and lower DeltaP(0.1)/DeltaPCO(2) ratio (0.23 +/- 0.1 vs 0.49 +/- 0.1 cm H(2)O/mm Hg, respectively) [p < 0.05]. After receiving noninvasive ventilation treatment, the hypercapnic and hypoxic responses of the hypercapnic patients increased. At 4 to 6 weeks, values for both responses had increased to within the normal range and PaCO(2) had fallen to < 45 mm Hg, while weight was unchanged. CONCLUSIONS: Depressed chemoresponsiveness plays a role that is independent of obesity in the development of CO(2) retention in some OSAHS patients, and it may be a response to sleep-disordered breathing.

Childhood narcolepsy in North China.

STUDY OBJECTIVES: The purpose is to report the results of an effort to diagnose children with narcolepsy in a pediatric referral clinic. DESIGN: Between September 1998 and December 1999, a program was implemented to emphasize recognition of childhood narcolepsy. Patients underwent brain computed tomography (CT) scan and magnetic resonance imaging (MRI) testing. All children received a MSLT test following a routine night's sleep, and serological HLA typing for HLA DR2. Three who reported occasional snoring also underwent nocturnal PSG prior to the MSLT. SETTING: N/A. PATIENTS OR PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: 29 (21 male, 8 female) children were identified with sleepiness and cataplexy. There was no evidence for brain functional or structural disease or for drug use. Sleep paralysis was elicited in 41%; hypnagogic hallucinations, in 59%. Psychosocial problems including emotional irritability and social isolation were present in 93% of the patients. Mean sleep latency on MSLT was 2.0+/-1.3 minutes; sleep-onset rapid eye movement (SOREM) occurred during 2/5 naps in 28 of 29 patients and 3/5 in 26/29 patients. The average number and latency of SOREM episodes were 4.2+/-0.9 episodes and 4.0+/-1.7 minutes, respectively. In those with snoring, a nocturnal PSG did not disclose sleep apneas/hypopneas. All patients but one were HLA DR2 positive. The estimated clinic incidence was 0.04%. CONCLUSIONS: A program for recognition in a referral neurology clinic combined with an availability of the MSLT and HLA testing resulted in the new identification in North China of a number of children with narcolepsy syndromes.

Ventilatory behavior and metabolism in two strains of obese rats.

This study examined differences in metabolism and ventilatory responsiveness in the Zucker (Z) and Koletsky (K) rat which each carry a different recessive mutation of the leptin receptor gene. The Null hypothesis was that the obese (homozygous) rats from the strains would not differ among the variables assessed. Male and female rats of obese and lean phenotypes were studied, with 5-6 animals in each group. Animals of the same age were assessed for ventilation and metabolism by whole-body plethysmography and the open circuit method. During quiet wakefulness, each animal was exposed to 5 min presentations of: room air; 10% O(2)/bal N(2); 100% O(2); room air, and 7% O(2)/93% O(2). Differences in metabolism, independent of phenotype included: KZ females and Z>K for males; CO(2) production in obese KK often for every challenge (P<0.001). A higher f and VE in Z compared with K rats was present in both genders, and persisted with each challenge. In conclusion, obese rats from these two strains do not breathe the same, even when age, weight, body mass index, and diet are alike. We conclude that that factors other than fat accumulation contribute to the expression of respiratory control and ventilation in obesity in the rat.

Incorporating inheritance into models for understanding ventilatory behavior.

Ventilation and its components (frequency and tidal volume) appear to be determined to a significant extent by inheritance. Gene manipulation, gene identification, and functional genomics now offer powerful tools to identify the strength and mode of inheritance for ventilatory behavior under steady-state and non-steady-state conditions, in health and in disease. Conscious integration of genetic principles into existing explanatory models may increase the likelihood of detecting traits that correlate with protein systems responsible for the structures and the functional components of respiration.

Medical student competence in eliciting a history for "chronic fatigue".

PURPOSE: We report an observational study of medical students' abilities in taking a complex history for which sleep disorders is one of several possible conditions. METHODS: Students are observed taking a focused history from a simulated patient whose chief complaint is "I am tired. I cannot get anything done." Nine groups of students (n = 360) completing the internal medicine core-clerkship were evaluated by one of three examiners. Students received full, partial, or no credit for each item on a uniform behavioral checklist, which included prompts for common medical and psychiatric disorders associated with chronic fatigue. RESULTS: Observed means were lowest for items pertaining to sleep behaviors and head trauma. Fewer than half of the students inquired about whether or not the person had difficulty falling asleep at night, family history of sleep apnea, and frequency and length of naps. In contrast, the majority of students inquired about heart disease, metabolic disorders, the use of illicit drugs, alcohol consumption, and the taking of medications. Examiners accounted for a significant source of variance in scores; yet the station discriminated among top and bottom students as measured by the Objective Structured Clinical Examination (OSCE) overall. No statistically significant differences were observed on the basis of clerkship site, primary care versus traditional-track students, time of year, or gender. CONCLUSION: A majority of students do not adequately cover issues relevant to sleep in contrast to other associated disorders when taking a focused history for chronic fatigue.

Vasculogenic impotence and cavernosal oxygen tension.

AIMS OF THIS STUDY: To determine the associations, if any, of cavernosal oxygen tension with vasculogenic impotence. MATERIALS AND METHODS: We evaluated penile cavernosal blood gas levels in men with suspected vasculogenic impotence during penile duplex ultrasonography and/or dynamic infusion cavernosometry and cavernosography (DICC). Patients with suspected impotence were evaluated from 1992-1996. Patient ages ranged from 24-75 y (mean 48 y). Eighteen men had arteriogenic impotence diagnosed by abnormal penile duplex ultrasound after injection of a vasoactive agent, and 23 men had venous leakage diagnosed by DICC. RESULTS: Eighteen men with arteriogenic impotence had the following mean blood gas values: pH = 7.38+/-0.01, PCO2 = 45.50+/-0.94, PO2 = 65.17+/-2.16. Twenty-three men with venogenic (venous leak) impotence had the following mean cavernosal blood gas values: pH = 7.41+/-0.01, PCO2 = 42.26+/-0.83, PO2 = 74.17+/-2.51. The differences in PO2 were significant (P<0.05). A subgroup of men with severe venous leakage had PO2 values that were similar to the low arterial PO2 values. CONCLUSION: The low PO2 in patients with arteriogenic impotence, and the subset of men with severe venous leak impotence, support a global concept of low cavernosal PO2 as a mechanism for both arteriogenic and venogenic impotence.