Patent Foramen Ovale Closure in Obstructive Sleep Apnea Improves Blood Pressure and Cardiovascular Function.

UNLABELLED: Obstructive sleep apnea (OSA) is a frequent syndrome characterized by intermittent hypoxemia and increased prevalence of arterial hypertension and cardiovascular morbidity. In OSA, the presence of patent foramen ovale (PFO) is associated with increased number of apneas and more severe oxygen desaturation. We hypothesized that PFO closure improves sleep-disordered breathing and, in turn, has favorable effects on vascular function and arterial blood pressure. In 40 consecutive patients with newly diagnosed OSA, we searched for PFO. After initial cardiovascular assessment, the 14 patients with PFO underwent initial device closure and the 26 without PFO served as control group. Conventional treatment for OSA was postponed for 3 months in both groups, and polysomnographic and cardiovascular examinations were repeated at the end of the follow-up period. PFO closure significantly improved the apnea-hypopnea index (ΔAHI -7.9±10.4 versus +4.7±13.1 events/h, P=0.0009, PFO closure versus control), the oxygen desaturation index (ΔODI -7.6±16.6 versus +7.6±17.0 events/h, P=0.01), and the number of patients with severe OSA decreased significantly after PFO closure (79% versus 21%, P=0.007). The following cardiovascular parameters improved significantly in the PFO closure group, although remained unchanged in controls: brachial artery flow-mediated vasodilation, carotid artery stiffness, nocturnal systolic and diastolic blood pressure (-7 mm Hg, P=0.009 and -3 mm Hg, P=0.04, respectively), blood pressure dipping, and left ventricular diastolic function. In conclusion, PFO closure in OSA patients improves sleep-disordered breathing and nocturnal oxygenation. This translates into an improvement of endothelial function and vascular stiffening, a decrease of nighttime blood pressure, restoration of the dipping pattern, and improvement of left ventricular diastolic function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01780207.

Sleepiness and performance is disproportionate in patients with non-organic hypersomnia in comparison to patients with narcolepsy and mild to moderate obstructive sleep apnoea.

BACKGROUND/AIMS: Clinical differentiation between organic hypersomnia and non-organic hypersomnia (NOH) is challenging. We aimed to determine the diagnostic value of sleepiness and performance tests in patients with excessive daytime sleepiness (EDS) of organic and non-organic origin. METHODS: We conducted a retrospective comparison of the multiple sleep latency test (MSLT), pupillography, and the Steer Clear performance test in three patient groups complaining of EDS: 19 patients with NOH, 23 patients with narcolepsy (NAR), and 46 patients with mild to moderate obstructive sleep apnoea syndrome (OSAS). RESULTS: As required by the inclusion criteria, all patients had Epworth Sleepiness Scale (ESS) scores >10. The mean sleep latency in the MSLT indicated mild objective sleepiness in NOH (8.1 ± 4.0 min) and OSAS (7.2 ± 4.1 min), but more severe sleepiness in NAR (2.5 ± 2.0 min). The difference between NAR and the other two groups was significant; the difference between NOH and OSAS was not. In the Steer Clear performance test, NOH patients performed worst (error rate = 10.4%) followed by NAR (8.0%) and OSAS patients (5.9%; p = 0.008). The difference between OSAS and the other two groups was significant, but not between NOH and NAR. The pupillary unrest index was found to be highest in NAR (11.5) followed by NOH (9.2) and OSAS (7.4; n.s.). CONCLUSION: A high error rate in the Steer Clear performance test along with mild sleepiness in an objective sleepiness test (MSLT) in a patient with subjective sleepiness (ESS) is suggestive of NOH. This disproportionately high error rate in NOH may be caused by factors unrelated to sleep pressure, such as anergia, reduced attention and motivation affecting performance, but not conventional sleepiness measurements.

Adaptive servo-ventilation as treatment of persistent central sleep apnea in post-acute ischemic stroke patients.

BACKGROUND: Adaptive servo-ventilation (ASV) is a well-established treatment of central sleep apnea (CSA) related to congestive heart failure (CHF). Few studies have evaluated the effectiveness and adherence in patients with CSA of other etiologies, and even less is known about treatment of CSA in patients of post ischemic stroke. METHODS: A single-centre retrospective analysis of ASV treatment for CSA in post-acute ischemic stroke patients without concomitant CHF was performed. Demographics, clinical data, sleep studies, ventilator settings, and adherence data were evaluated. RESULTS: Out of 154 patients on ASV, 15 patients had CSA related to ischemic stroke and were started on ASV a median of 11 months after the acute cerebrovascular event. Thirteen out of the 15 patients were initially treated with continuous positive airway pressure (11/15) and bilevel positive airway pressure (2/15) therapy with unsatisfactory control of CSA. ASV significantly improved AHI (46.7 ± 24.3 vs 8.5 ± 12/h, P = 0.001) and reduced ESS (8.7 ± 5.7 vs 5.6 ± 2.5, P = 0.08) with a mean nightly use of ASV of 5.4 ± 2.4 h at 3 months after the initiation of treatment. Results were maintained at 6 months. CONCLUSION: ASV was well tolerated and clinically effective in this group of patients with persistent CSA after ischemic stroke.

Sleep-disordered breathing in acute ischemic stroke and transient ischemic attack: effects on short- and long-term outcome and efficacy of treatment with continuous positive airways pressure--rationale and design of the SAS CARE study.

OBJECTIVES: Sleep-disordered breathing represents a risk factor for cardiovascular morbidity and mortality and negatively affects short-term and long-term outcome after an ischemic stroke or transient ischemic attack. The effect of continuous positive airways pressure in patients with sleep-disordered breathing and acute cerebrovascular event is poorly known. The SAS CARE 1 study assesses the effects of sleep-disordered breathing on clinical evolution, vascular functions, and markers within the first three-months after an acute cerebrovascular event. The SAS CARE 2 assesses the effect of continuous positive airways pressure on clinical evolution, cardiovascular events, and mortality as well as vascular functions and markers at 12 and 24 months after acute cerebrovascular event. METHODS: SAS CARE 1 is an open, observational multicenter study in patients with acute cerebrovascular event acutely admitted in a stroke unit: a sample of 200 acute cerebrovascular event patients will be included. Vascular functions and markers (blood pressure, heart rate variability, endothelial function by peripheral arterial tonometry and specific humoral factors) will be assessed in the acute phase and at three-months follow-up. SAS CARE 2 will include a sample of patients with acute cerebrovascular event in the previous 60-90 days. After baseline assessments, the patients will be classified according to their apnea hypopnea index in four arms: non-sleep-disordered breathing patients (apnea hypopnea index <10), patients with central sleep-disordered breathing, sleepy patients with obstructive apnea hypopnea index ≥20, which will receive continuous positive airways pressure treatment, nonsleepy patients with obstructive sleep-disordered breathing (apnea hypopnea index ≥20), which will be randomized to receive continuous positive airways pressure treatment or not. CONCLUSIONS: The SAS CARE study will improve our understanding of the clinical sleep-disordered breathing in patients with acute cerebrovascular event and the feasibility/efficacy of continuous positive airways pressure treatment in selected patients with acute cerebrovascular event and sleep-disordered breathing.

Identification of problems in functioning of people with sleep disorders in a clinical setting using the International Classification of Functioning Disability and Health (ICF) Checklist.

We conducted an explorative, cross-sectional, multi-centre study in order to identify the most common problems of people with any kind of (primary) sleep disorder in a clinical setting using the International Classification of Functioning, Disability and Health (ICF) as a frame of reference. Data were collected from patients using a structured face-to-face interview of 45-60 min duration. A case record form for health professionals containing the extended ICF Checklist, sociodemographic variables and disease-specific variables was used. The study centres collected data of 99 individuals with sleep disorders. The identified categories include 48 (32%) for body functions, 13 (9%) body structures, 55 (37%) activities and participation and 32 (22%) for environmental factors. 'Sleep functions' (100%) and 'energy and drive functions', respectively, (85%) were the most severely impaired second-level categories of body functions followed by 'attention functions' (78%) and 'temperament and personality functions' (77%). With regard to the component activities and participation, patients felt most restricted in the categories of 'watching' (e.g. TV) (82%), 'recreation and leisure' (75%) and 'carrying out daily routine' (74%). Within the component environmental factors the categories 'support of immediate family', 'health services, systems and policies' and 'products or substances for personal consumption [medication]' were the most important facilitators; 'time-related changes', 'light' and 'climate' were the most important barriers. The study identified a large variety of functional problems reflecting the complexity of sleep disorders. The ICF has the potential to provide a comprehensive framework for the description of functional health in individuals with sleep disorders in a clinical setting.

Sleepiness is not always perceived before falling asleep in healthy, sleep-deprived subjects.

OBJECTIVE: To test whether subjects spontaneously signal sleepiness before falling asleep under monotonous conditions. METHODS: Twenty-eight healthy students were deprived of sleep for one night and then underwent a "maintenance-of-wakefulness test" (MWT) consisting of four 40-min trials. They were told to give a signal as soon as they felt sleepy and to try to stay awake as long as possible. In a first series of tests, the subjects were given no reward (nr); in a second series, monetary rewards (wr) were given both for an accurate perception of sleepiness and for staying awake longer. RESULTS: Seventeen of the 28 subjects (60.7%) did not signal sleepiness before a sleep fragment occurred in at least one of the four MWT trials. Women were more reliably aware of sleepiness than men in the nr trials (p=.02), while the men's performance improved in the wr trials (p<.02), becoming equivalent to the women's performance. CONCLUSIONS: Our results cast doubt on the general assumption that one cannot fall asleep without feeling sleepy first. If similar results can be obtained in monotonous driving or working situations, this will imply that accidents caused by sleepiness or by falling asleep cannot necessarily be attributed to an individual's negligence.

Taurolidine in the prevention and therapy of lung metastases.

OBJECTIVE: During surgery for colon carcinoma, tumour cells may spread into the blood and may lead to the development of distant metastases. The most frequent sites of metastases are the liver and lungs. A new therapeutic approach is required to prevent tumour implantation of freely circulating tumour cells during and after surgery and to treat established metastases. The aim of this prospective study was to observe the influence of long-term intravenous taurolidine on the development of lung metastases after intravenous injection of colon adenocarcinoma cells. METHODS: Tumour cells (DHD/K12/TRb colon adenocarcinoma cell line, 1 x 10(6) cells) were injected into the right vena jugularis interna of BDIX rats. The animals (n=13) were randomised into three groups: group 1: tumour cell implantation without taurolidine application (control group); group 2: tumour cell implantation and simultaneous start of the taurolidine injection through osmotic pump, removal of the osmotic pump on day 7; group 3: tumour cell implantation on day 0 and start of the taurolidine injection through osmotic pump on day 14. RESULTS: In the taurolidine groups, the number and size of lung metastases were significantly lower compared to the control group (p=0.018; p=0.018 and p=0.036; p=0.018). Although the results of the intravenous long-term therapy with taurolidine in group 2 did not reach statistical significance in comparison with the results of group 3, a positive trend was revealed: The mean number of metastases in group 2 was 18.2 versus 28.2 in group 3. CONCLUSIONS: The application of taurolidine tends to prevent the development of lung metastases. Furthermore, taurolidine seems to reduce established lung metastases in this in vivo model. Taurolidine may offer additional therapeutic options in patients with colon adenocarcinoma.

Respiratory polygraphy in sleep apnoea diagnosis. Report of the Swiss respiratory polygraphy registry and systematic review of the literature.

BACKGROUND: Sleep related breathing disorders (SBD) are common and associated with morbidity and mortality. Since polysomnography, the conventional diagnostic gold standard is costly and not generally available, ambulatory respiratory polygraphic sleep studies (RP) are used. To evaluate whether RP reimbursement by health insurance companies was justified, the Swiss Federal Office of Public Health (FOPH) requested registration of RP during 36 months and a literature review on RP. The results are reported here. METHODS: RP reimbursed from July 2002 to December 2005 by Swiss health insurance companies were analysed. A review of the literature from 2003 comparing RP with PSG was updated. The outcome of interest was the apnoea/hypopnoea index. RESULTS: Datasets on 11,485 RP were evaluated, 8179 were performed to evaluate suspected obstructive sleep apnoea syndrome (OSAS). In patients with snoring, witnessed apnoea and hypersomnia (n = 4180), 80.2% of RP confirmed OSAS, 3.5% of RP were inconclusive prompting polysomnography. Six studies published between 2003 and 2005 were pooled with a former review of 12 studies. With a mean pre-test probability of 64% for OSAS, the post-test probability after a negative result ranged from 8% (negative likelihood ratio of 0.05) to 23% (negative likelihood ratio of 0.20). The post-test probability after a positive result was within a range of 98% (positive likelihood ratio of 23.8) to 90% (positive likelihood ratio of 5.7). CONCLUSIONS: In selected patients with clinically suspected OSAS RP allows accurate and simple diagnosis of OSAS. According to the practice in Switzerland as reflected by the registry additional PSG are rarely required, suggesting relevant cost savings by RP. Granting reimbursement for RP as introduced in the meantime by the FOPH seems justified.

Central periodic breathing during sleep in acute ischemic stroke.

BACKGROUND AND PURPOSE: It has been suggested that central periodic breathing during sleep (CPBS) may develop in unilateral supratentorial stroke without cardiopulmonary disease and disturbed consciousness. Not many data existed about such patients. METHODS: Of 31 patients with first-ever stroke, we report 3 patients with CPBS in the absence of cardiopulmonary and vigilance disturbances. Patient assessments included polysomnography, MRI and echocardiography. Nocturnal breathing was reassessed after 1 to 3 months. RESULTS: The patients had ischemic strokes in the left cingulate cortex, left insula and right paramedian thalamus. They were fully conscious when submitted to sleep recordings and lacked overt cardiovascular dysfunctions (ejection fractions=67%, 48%, 65%). CPBS was present during 18% to 24% of sleep. In all patients, breathing improved during stroke recovery. CONCLUSIONS: CPBS may be present in strokes involving autonomic (insula) and volitional (cingulate cortex, thalamus) respiratory networks. As such, CPBS partly resolves within weeks.

Effects of sleep fragmentation on the arousability to resistive loading in NREM and REM sleep in normal men.

STUDY OBJECTIVE: In healthy subjects, arousability to inspiratory resistive loading is greater during rapid eye movement (REM) sleep compared with non-REM (NREM) sleep but is poorest in REM sleep in patients with sleep apnea. We therefore examined the hypothesis that sleep fragmentation impairs arousability, especially from REM sleep. DESIGN: Two blocks of 3 polysomnographies (separated by at least 1 week) were performed randomly. An inspiratory-loaded night followed either 2 undisturbed control nights (LN(C)) or 2 acoustically fragmented nights (LN(F)) SETTING: Sleep laboratory. PARTICIPANTS: Sixteen healthy men aged 20 to 29 years. INTERVENTIONS: In both loaded nights, an inspiratory resistive load was added via a valved facemask every 2 minutes during sleep and turned off either when arousal occurred or after 2 minutes. MEASUREMENTS AND RESULTS: During LN(F), arousability remained significantly greater in REM sleep (71% aroused within 2 minutes) compared with stage 2 (29%) or stage 3/4 (16%) sleep. After sleep fragmentation, arousability was decreased in stage 2 sleep (LN(F): 29%; LN(C): 38%; p < .05) and low in early REM sleep, increasing across the night (p < .01). In stage 3/4 sleep, neither an attenuation nor a change across the night was seen after sleep fragmentation. CONCLUSIONS: Mild sleep fragmentation is already sufficient to attenuate arousability in stage 2 sleep and to decrease arousability in early, compared with late, REM sleep. This means that sleep fragmentation affects the arousal response to increasing resistance and that the effects are different in stage 2 and REM sleep. The biologic reason for this increase in the arousal response in REM sleep across the night is not clear.

Epilepsy and obstructive sleep apnea.

A few publications documented the coexistence of epilepsy and obstructive sleep apnea (OSA). The extent, nature, and clinical relevance of this association remain poorly understood. We retrospectively reviewed the database of our sleep center to identify patients with both sleep apnea and epilepsy. Characteristics of epilepsy, sleep history, presence of excessive daytime sleepiness [Epworth Sleepiness Scale (ESS)] and polysomnographic data were assessed. The effect of continuous positive airway pressure (CPAP) on seizure reduction was prospectively analyzed after a median interval of 26 months (range: 2-116 months) from the diagnosis of OSA. OSA was found in 29 epilepsy patients (25 men and 4 women) with a median age of 56 years (range: 37-79). The median apnea hypopnea index was 33 (range: 10-85), the oxygen desaturation index was 12 (range 0-92), and 52% of the patients had an ESS score >10. In 27 patients, epilepsy appeared 1 month to 44 years prior to the diagnosis of OSA. In 21 patients, the appearance of OSA symptoms coincided with a clear increase in seizure frequency or the first appearance of a status epilepticus. Treatment with CPAP was continued with good compliance in 12 patients and led to a significant reduction of both ESS scores and seizure frequency in 4 patients. Our data suggest the importance of considering diagnosis and treatment of OSA in epilepsy patients with poor seizure control and/or reappearance of seizures after a seizure-free interval.

Sleep-disordered breathing and acute ischemic stroke: diagnosis, risk factors, treatment, evolution, and long-term clinical outcome.

BACKGROUND AND PURPOSE: Sleep-disordered breathing (SDB) is frequent in stroke patients. Risk factors, treatment response, short-term and long-term outcome of SDB in stroke patients are poorly known. METHODS: We prospectively studied 152 patients (mean age 56+/-13 years) with acute ischemic stroke. Cardiovascular risk factors, Epworth sleepiness score (ESS), stroke severity/etiology, and time of stroke onset were assessed. The apnea-hypopnea index (AHI) was determined 3+/-2 days after stroke onset and 6 months later (subacute phase). Continuous positive airway pressure (CPAP) treatment was started acutely in patients with SDB (AHI > or =15 or AHI > or =10+ESS >10). CPAP compliance, incidence of vascular events, and stroke outcome were assessed 60+/-16 months later (chronic phase). RESULTS: Initial AHI was 18+/-16 (> or =10 in 58%, > or =30 in 17% of patients) and decreased in the subacute phase (P<0.001). Age, diabetes, and nighttime stroke onset were independent predictors of AHI (r2=0.34). In patients with AHI > or =30, age, male gender, body mass index, diabetes, hypertension, coronary heart disease, ESS, and macroangiopathic etiology of stroke were significantly higher/more common than in patients with AHI <10. Long-term incidence of vascular events and stroke outcome were similar in both groups. CPAP was started in 51% and continued chronically in 15% of SDB pts. Long-term stroke mortality was associated with initial AHI, age, hypertension, diabetes, and coronary heart disease. CONCLUSIONS: SDB is common particularly in elderly stroke male patients with diabetes, nighttime stroke onset, and macroangiopathy as cause of stroke; it improves after the acute phase, is associated with an increased poststroke mortality, and can be treated with CPAP in a small percentage of patients.

Synergistic effect of low dose cyclosporine A and human interleukin 10 overexpression on acute rejection in rat lung allotransplantation.

OBJECTIVE: Electroporation mediated transfer of plasmid DNA into peripheral muscle results in high transfection efficiency. The aim of this study was to investigate the effect of gene transfer of human IL-10 (hIL-10) into the tibialis anterior muscle (MTA) in combination with low dose Cyclosporine A (CsA) on acute rejection of lung allografts in the rat. METHODS: Lung allotransplantation was performed from male BN donor to male Fisher F344 rats. Gene transfer was achieved by intramuscular injection into the MTA of the recipient followed by electroporation (4 x 20 ms impulses at 200 V/cm) 24 h prior to the transplantation. Group A (n=5) received CsA (2.5 mg/kg bw ip) for 5 days post-transplant and group B (n=5) 2.5 microg of PCIK hIL-10 (plasmid expression vector containing human CMV immediate early gene promoter and enhancer) and a low dose CsA (2.5 mg/kg bw i.p.). Graft function was assessed by blood gas at day 5 after exclusion of the native lung. Animals were sacrificed and blood was drawn to measure serum hIL-10 levels (ELISA) and tissue was sampled for histological grading of rejection. RESULTS: Local expression of hIL-10 was confirmed at the mRNA level by in situ hybridization. All group A control animals showed severe signs of rejection. At day 5 all grafts in group B showed good gas exchange mean PaO2 233+/-123 mmHg, vs 44+/-8 mmHg in group A. Histological examination revealed moderate to severe rejection in all animals in group A (IIIB, ISHLT) in contrast to low moderate rejection in group B (II-IIIA). hIL-10 serum levels on day 5 were 14+/-7 pg/ml in group B vs. 0 in group A. CONCLUSIONS: Electroporation mediated hIL-10 overexpression in a peripheral muscle of the recipient in combination with low dose CsA reduces acute rejection in this model of rat lung allotransplantation.

Restless legs syndrome: clinical experience with long-term treatment.

BACKGROUND AND PURPOSE: There are limited data on long-term treatment efficacy, and almost none on predictors of treatment response in patients with restless legs syndrome (RLS). To assess: (1) long-term efficacy of RLS treatment in a clinical setting, (2) predictors of a good treatment response, and (3) the value of the RLS-severity score according to the criteria of the International Restless Legs Syndrome Study Group (IRLSSG). PATIENTS AND METHODS: Over three years 70 patients (36 men, 34 women; mean age: 59 years; range: 29-79) with RLS were prospectively assessed. Diagnosis of RLS was made according to international criteria Severity of RLS symptoms was were assessed at the outset by the IRLSSG rating scale. Treatment was chosen individually according to clinical judgement. After a mean follow-up time of 16 months (range: 1-106 months) evolution of symptoms was assessed by both overall clinical impression and IRLSSG rating scale. Clinical characteristics and treatment effect were compared between patients never treated for RLS before this study ('naïve'=N-pts) and those with previous treatment ('treated'=T-pts). Predictors of treatment response were sought for comparing patients with good treatment response (good, better or much better on follow-up) and those with bad (B-pts) treatment response. RESULTS: There were 40 N-pts and 30 T-pts. The mean IRLSSG score (hereinafter, IRLSSG) at baseline was 26 (range 12-38). No significant differences were found between N-and T-pts in age, gender, etiology and duration of RLS, positive family history, presenting sleep complaint, IRLSSG, or percentage of patients with periodic limb movements in sleep (PLMS) on polysomnography (PSG). At final follow-up 30 (76%) of 40 N-pts and 23 (77%) of 30 T-pts had a good (G-pts) treatment response. The mean IRLSSG at follow-up was 19 (range:1-36). There was a significant correlation between improvement of overall clinical impression (better or much better on final follow-up) and reduction of IRLSSG (P<0.0001). PLMS were more common in B- than G-pts (100 vs 58% of patients, P=0.02). In all other variables considered the two groups were similar. CONCLUSION: (1) A good long-term treatment response can be obtained and maintained in a clinical setting in about 80% of RLS patients. (2) Patients with RLS and without PLMS may have a better long-term treatment response, and (3) the IRLSSG is a useful tool for assessment of evolution of RLS symptoms over time in individual patients.

Grading airway stenosis down to the segmental level using virtual bronchoscopy.

OBJECTIVE: To assess the sensitivity of noninvasive virtual bronchoscopy based on multirow detector CT scanning in detecting and grading central and segmental airway stenosis using flexible bronchoscopic findings as the reference standard. MATERIALS AND METHODS: In a blinded controlled trial, multirow detector CT virtual bronchoscopy and flexible bronchoscopy were used to search for and grade airway stenosis in 20 patients. CT scan data were obtained with a multirow detector CT scanner using 4 x 1 mm collimation. Flexible bronchoscopy findings were graded by a pulmonologist and served as the reference standard for 176 central airway regions (ie, trachea, main bronchi, and lobar bronchi) and 302 segmental airway regions. The extent of airway narrowing was categorized as grade 0 (no narrowing), grade 1 (< 50%), or grade 2 (> or =50%). RESULTS: Flexible bronchoscopy revealed 30 stenoses in the central airways and 10 in the segmental airways. Virtual bronchoscopy detected 32 stenoses in the central airways (sensitivity, 90.0%; specificity, 96.6%; accuracy, 95.5%) and 22 in the segmental airways (sensitivity, 90.0%; specificity, 95.6%; accuracy, 95.5%). The number of false-positive findings was higher in the segmental airways (13 false-positive findings) than in the central airways (5 false-positive findings), which caused a lower positive predictive value for the segmental airways (40.9%) than for the central airways (84.4%). Flexible and virtual bronchoscopic gradings correlated better for central airway stenosis (r = 0.87) than for segmental airway stenosis (r = 0.61). CONCLUSION: Although a high sensitivity was found for the detection of both central and segmental airway stenosis, the number of false-positive findings was higher for segmental airways. However, noninvasive multirow detector CT virtual bronchoscopy enables high-resolution endoluminal imaging of the airways down to the segmental bronchi.

The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A).

OBJECTIVES: Biological markers of narcolepsy with cataplexy (classical narcolepsy) include sleep-onset REM periods (SOREM) on multiple sleep latency tests (MSLT), HLA-DQB1*0602 positivity, low levels of cerebrospinal fluid (CSF) hypocretin-1 (orexin A), increased body mass index (BMI), and high levels of CSF leptin. The clinical borderland of narcolepsy and the diagnostic value of different markers of narcolepsy remain controversial and were assessed in a consecutive series of 27 patients with hypersomnia of (mainly) neurological origin. METHODS: Diagnoses included classical narcolepsy (n=3), symptomatic narcolepsy (n=1), narcolepsy without cataplexy (n=4), idiopathic hypersomnia (n=5), hypersomnia associated with psychiatric disorders (n=5), and hypersomnia secondary to neurological disorders or of undetermined origin (n=9). Clinical assessment included BMI, Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), and history of REM-symptoms (sleep paralysis, hallucinations). HLA-typing, electrophysiological studies (conventional polysomnography, MSLT, 1-week actigraphy), and measurements of CSF levels of hypocretin and leptin were also performed. RESULTS: Hypocretin-1 was undetectable in three patients with classic narcolepsy and detectable in the remaining 24 patients. Other narcoleptic markers also frequently found in patients without narcolepsy included ESS>14 (78% of 27 patients), UNS>14 (75%), REM symptoms (30%), sleep latencies on MSLT<5 min (41%), >/=2 SOREM (30%), DQB1*0602 positivity (52%), BMI>25 (52%), and increased CSF leptin (48%). Hypersomnia was documented by an increased time 'asleep' in 41% of patients. Overlapping clinical and electrophysiological findings were seen mostly in patients with narcolepsy without cataplexy, idiopathic hypersomnia, and psychiatric hypersomnia. CONCLUSIONS: (1) Hypocretin dysfunction is not the 'final common pathway' in the pathophysiology of most hypersomnolent syndromes that fall on the borderline for a diagnosis of narcolepsy. (2) The observed overlap among these hypersomnolent syndromes implies that current diagnostic categories are not entirely unambiguous. (3) A common hypothalamic, hypocretin-independent dysfunction may be present in some of these syndromes.

Strong additive effect of 1,25-dihydroxycholecalciferol and cyclosporine A but not tacrolimus in rat lung allotransplantation.

OBJECTIVES: 1,25-Dihydroxycholecalciferol (calcitriol, vitamin D3) has immunosuppressive properties. This study evaluates the effect of calcitriol in combination with either cyclosporine A or tacrolimus on acute lung allograft rejection in a rat model of unilateral left lung allotransplantation. METHODS: Unilateral left lung transplantation was performed in male rats (Brown-Norway to Fischer F344, 200-250 g body weight). For immunosuppression, the following subtherapeutic doses were used: calcitriol 0.5 microg/kg/day, cyclosporine A 2.5 mg/kg/day i.p., and tacrolimus 40 microg/kg i.m. Five groups (n = 5) were analyzed: cyclosporine A; cyclosporine A and calcitriol; calcitriol; tacrolimus and calcitriol; and tacrolimus. The injections were performed for 5 days starting from the day of transplantation. Recipients were sacrificed on day 5 post-transplant. The contralateral right main bronchus and pulmonary artery were occluded for 5 min and blood was drawn for blood gas analysis. The grafts were excised, fixed in formaline and embedded in paraffin. Histological evaluation was done in blinded fashion (ISHLT 1999/rank scale). The mean and standard error of the mean (PaO2) or the median and range (rejection grading) are given. ANOVA followed by planned comparison for the PaO2 and Kruskal-Wallis ANOVA for rejection grading were applied, p < 0.05 considered significant. RESULTS: Arterial PaO2 on day 5 was very low in animals treated with subtherapeutic dosages of either cyclosporine A (48 +/- 10 mmHg), calcitriol (51 +/- 3) or tacrolimus (86 +/- 22). Combined treatment with cyclosporine A and calcitriol revealed a significant improvement (248 +/- 78; p < 0.05 vs. other groups), whereas the combination of tacrolimus with calcitriol did not reveal any benefit (65 +/- 9). Rejection grading with these subtherapeutic doses did not show any significant difference between groups. CONCLUSIONS: Our data indicate that cyclosporine A, but not tacrolimus, has a strong additive effect with calcitriol on acute rat lung allograft rejection.

Progressive genomic alterations in intraductal papillary mucinous tumours of the pancreas and morphologically similar lesions of the pancreatic ducts.

Intraductal papillary mucinous tumours (IPMTs) of the pancreas are rare neoplasms characterized by a prominent intraductal component, and by malignant potential. Little data exists concerning numerical chromosome aberrations in IPMTs. The biological significance of mucinous epithelial changes (mucinous hyperplasia) in small branching ducts adjacent to IPMTs also remains unclear. From a series of 12 IPMTs, we investigated by interphase cytogenetics 22 foci with mucinous hyperplasia, 27 foci with borderline lesions, and 11 samples with either intraductal (CIS) or invasive carcinoma. Chromosome 6 loss was detected in areas with mucinous hyperplasia (36.3%), borderline lesions (96.3%), and CIS/invasive carcinoma (100%). Similar losses, indicating clonal progression, were found for chromosome 17 (18.2%, 81.5%, and 100%), and for chromosome 18 (0%, 18.5%, and 100%). Quantitative analysis showed a significant intraductal expansion of cell clones harbouring these numerical aberrations within the spectrum of IPMTs. Mucinous epithelial changes in 11 resection samples with chronic pancreatitis showed monosomy 6 (36%) and monosomy 17 (27%). Conversely, areas with low-grade pancreatic intraepithelial neoplasia (PanIN-1), obtained from eight surgical specimens with ductal adenocarcinoma, showed monosomies for chromosome 6, 17, and 18 (100%, 87%, and 50%, respectively). We conclude that monosomies, as defined by FISH analysis, are frequent in both IPMTs and mucinous hyperplasia of pancreatic ducts adjacent to IPMTs. Monosomy 6 may represent an early event in the stepwise accumulation of genomic mutations necessary for the neoplastic transformation of pancreatic duct epithelia, whereas loss of chromosome 18 may be implicated in the progression of borderline to malignant IPMT. The detection of complex chromosomal aberrations in mucinous epithelial changes, and the quantitative expansion of monosomic cell clones in pancreatic ducts, provide evidence for a continuum between hyperplastic and dysplastic epithelial changes.

In vivo platelet activation is increased during sleep in patients with obstructive sleep apnea syndrome.

BACKGROUND: Patients with obstructive sleep apnea syndrome (OSAS) have an increased risk of cardiovascular events including myocardial infarction and stroke. OBJECTIVE: To determine whether in vivo platelet activation and the generation of procoagulant platelet-derived microparticles (PMP) are increased during sleep in patients with OSAS. METHODS: In vivo platelet activation and PMP formation was determined using flow cytometry in 12 patients with untreated OSAS during and after sleep (4 and 7 a.m.). To study the effect of treatment with continuous positive airway pressure (CPAP), the measurements were repeated at the same time points after initiation of CPAP therapy. Healthy volunteers served as controls (n = 6). RESULTS: Patients with OSAS had an increased percentage of platelets positive for the activation-dependent epitopes CD63 and CD62P during sleep (4 a.m.) compared to controls (4.8 +/- 0.8 vs. 1.9 +/- 0.4% for CD63, p < 0.01, and 2.0 +/- 0.5 vs. 1.1 +/- 0.3% for CD62P, p < 0.05). In OSAS patients, the amount of CD63- and CD62P-positive platelets was significantly elevated at 4 compared to 7 a.m. (4.8 +/- 0.8 vs. 2.6 +/- 0.4% for CD63 and 2.0 +/- 0.5 vs. 1.1 +/- 0.2% for CD62P, p < 0.05), but not in the control group. The levels of PMP were similar in patients with OSAS and controls at 4 and 7 a.m. After 1 night of CPAP therapy, there was a trend to reduced levels of CD63- and CD62P-positive platelets at 4 a.m. CONCLUSIONS: Patients with OSAS have increased in vivo platelet activation during sleep, which may contribute to the increased incidence of cardiovascular events in patients with OSAS.