Efficacy and safety of virtual bronchoscopic navigation with fused fluoroscopy and vessel mapping for access of pulmonary lesions.

BACKGROUND AND OBJECTIVE: Virtual bronchoscopic navigation (VBN) with fused fluoroscopy and vessel mapping provides a point of entry (POE) for puncturing airway wall to biopsy lesions. The study was designed to evaluate the safety and efficacy of this technology to diagnose peripheral pulmonary lesions. METHODS: It was a prospective, single-arm, multicentre study. Patients underwent lesions biopsy with the Archimedes® VBN System via a POE using one of the two techniques: (1) bronchoscopic transparenchymal nodule access (BTPNA) and (2) guided transbronchial needle aspiration (TBNA). Biopsy yield, sampling yield and diagnostic yield were mainly determined in lesions biopsy attempted. RESULTS: One hundred and thirty patients underwent anaesthesia and constituted the intention-to-treat population. One hundred and four patients with 114 lesions had biopsy attempted. Mean lesion size was 2.4 ± 1.13 cm. Sufficient tissue samples were obtained from 86 lesions with a biopsy yield of 75.4%. Nevertheless, sufficient samples for diagnosis based on histology ± cytology were obtained from 107 lesions with a sampling yield of 93.9%. Follow-up was conducted for more than 1 year, with a diagnostic yield of 75.4% and 72.8%, respectively, on high and low estimate with consideration of three lesions without follow-up. Two (1.9%) pneumothoraxes and one (1.0%) mild bleeding occurred. CONCLUSION: BTPNA and guided TBNA contribute to safe and effective sampling of peripheral pulmonary lesions. A relatively high biopsy yield was obtained independent of the presence or absence of a bronchus sign (BS), and high sampling yield and diagnostic yield were obtained independent of location, lesion size and presence or absence of a BS.

Proteinuria is associated with sleep apnea in chronic kidney disease.

BACKGROUND: The prevalence and severity of sleep apnea (SA) in the chronic kidney disease (CKD) population is not well characterized. Recent studies have yielded highly variable prevalence rates due to cohort heterogeneity and interstudy inconsistencies in defining SA. This study sought to determine the association of SA with CKD by recruiting a uniform cohort to undertake overnight polysomnography (PSG). METHODS: A total of 141 male Chinese CKD patients, ages 40-60 years, underwent overnight PSG to delineate the prevalence and severity of SA and nocturnal hypoxemia (NH). Body mass index (BMI), neck girth, estimated glomerular filtration rate, urinary protein excretion and Epworth sleepiness scale (ESS) score were collected at baseline to determine associative factors. RESULTS: The prevalence rates of SA and NH were 35.5 and 10.6%, respectively, in this study population [mean (±SD) age 51.44 ± 6.05 years; BMI 26.05 ± 4.22 kg/m(2)]. The adjusted odds ratios (ORs) for SA by BMI and proteinuria were 1.18 [95% confidence interval (CI) 1.02, 1.37; P ≤ 0.05] and 1.57 (95% CI 1.12, 2.46; P ≤ 0.05), respectively. The adjusted ORs for the median cohort oxygen desaturation index (ODI) by BMI and proteinuria were 1.23 (95% CI 1.05, 1.45; P ≤ 0.05) and 1.75 (95% CI 1.12, 2.76; P ≤ 0.05). However, no significant correlation between the prevalence and severity of SA and NH with progressive renal deterioration was observed. Furthermore, no significant mean difference in the apnea-hypopnea index and ODI was observed for an ESS above and below 10. CONCLUSIONS: SA is prevalent in CKD patients and strongly correlated with BMI and proteinuria, but not with renal function. The ESS is an investigative tool that lacks discriminatory power in patients with renal insufficiency. Therefore clinical vigilance for SA is paramount when attending to CKD patients with significant proteinuria.

Ancient origin of mast cells.

The sentinel roles of mammalian mast cells (MCs) in varied infections raised the question of their evolutionary origin. We discovered that the test cells in the sea squirt Ciona intestinalis morphologically and histochemically resembled cutaneous human MCs. Like the latter, C. intestinalis test cells stored histamine and varied heparin·serine protease complexes in their granules. Moreover, they exocytosed these preformed mediators when exposed to compound 48/80. In support of the histamine data, a C. intestinalis-derived cDNA was isolated that resembled that which encodes histidine decarboxylase in human MCs. Like heparin-expressing mammalian MCs, activated test cells produced prostaglandin D2 and contained cDNAs that encode a protein that resembles the synthase needed for its biosynthesis in human MCs. The accumulated morphological, histochemical, biochemical, and molecular biology data suggest that the test cells in C. intestinalis are the counterparts of mammalian MCs that reside in varied connective tissues. The accumulated data point to an ancient origin of MCs that predates the emergence of the chordates >500million years ago, well before the development of adaptive immunity. The remarkable conservation of MCs throughout evolution is consistent with their importance in innate immunity.

Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis.

The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites LTD4 and LTE4, the components of slow-reacting substance of anaphylaxis, are lipid mediators of smooth muscle constriction and inflammation, particularly implicated in bronchial asthma. LTC4 synthase (LTC4S), the pivotal enzyme for the biosynthesis of LTC4 (ref. 10), is an 18-kDa integral nuclear membrane protein that belongs to a superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism that includes 5-lipoxygenase-activating protein, microsomal glutathione S-transferases (MGSTs), and microsomal prostaglandin E synthase 1 (ref. 13). LTC4S conjugates glutathione to LTA4, the endogenous substrate derived from arachidonic acid through the 5-lipoxygenase pathway. In contrast with MGST2 and MGST3 (refs 15, 16), LTC4S does not conjugate glutathione to xenobiotics. Here we show the atomic structure of human LTC4S in a complex with glutathione at 3.3 A resolution by X-ray crystallography and provide insights into the high substrate specificity for glutathione and LTA4 that distinguishes LTC4S from other MGSTs. The LTC4S monomer has four transmembrane alpha-helices and forms a threefold symmetric trimer as a unit with functional domains across each interface. Glutathione resides in a U-shaped conformation within an interface between adjacent monomers, and this binding is stabilized by a loop structure at the top of the interface. LTA4 would fit into the interface so that Arg 104 of one monomer activates glutathione to provide the thiolate anion that attacks C6 of LTA4 to form a thioether bond, and Arg 31 in the neighbouring monomer donates a proton to form a hydroxyl group at C5, resulting in 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTC4). These findings provide a structural basis for the development of LTC4S inhibitors for a proinflammatory pathway mediated by three cysteinyl leukotriene ligands whose stability and potency are different and by multiple cysteinyl leukotriene receptors whose functions may be non-redundant.

Oxidative stress suppresses cysteinyl leukotriene generation by mouse bone marrow-derived mast cells.

Cysteinyl leukotrienes and oxidative stress have both been implicated in bronchial asthma; however, there is no previous study that focused on the ability of oxidative stress to alter cysteinyl leukotriene generation. In this study, treatment of bone marrow-derived mast cells with prostaglandin D(2) reduced their ability to generate leukotriene (LT) C(4) upon calcium ionophore stimulation but had little effect on LTB(4) generation. This effect could be reproduced by a selective agonist of the DP(2) receptor, 15R-methyl prostaglandin D(2) (15R-D(2)). 15R-D(2) dose-dependently inhibited LTC(4) generation with an IC(50) of 2 µM, and the effect was not altered by a DP(2)/thromboxane antagonist or by a peroxisome proliferator-activated receptor-γ antagonist. 15R-D(2) exerted its suppressive effect via a reduction in intracellular GSH, a mechanism that involved the conjugation of its non-enzymatic breakdown product to GSH. At 10 µM, 15R-D(2) reduced LTC(4) generation to 10%, intracellular GSH to 50%, and LTC(4) synthase (LTC(4)S) activity to 33.5% of untreated cells without altering immunoreactive LTC(4)S protein expression or 5-lipoxygenase activity. The effects of 15R-D(2) on LTC(4)S activity could be partially reversed by reducing reagent. The sulfhydryl-reactive oxidative agent diamide suppressed LTC(4)S activity and induced a reversible formation of covalent dimer LTC(4)S. LTC(4)S bearing a C56S mutation was resistant to the effect of diamide. Covalent dimer LTC(4)S was observed in nasal polyp biopsies, indicating that dimerization and inactivation of LTC(4)S can occur at the site of inflammation. These results suggest a cellular redox regulation of LTC(4)S function through a post-translational mechanism.

The catalytic architecture of leukotriene C4 synthase with two arginine residues.

Leukotriene (LT) C(4) and its metabolites, LTD(4) and LTE(4), are involved in the pathobiology of bronchial asthma. LTC(4) synthase is the nuclear membrane-embedded enzyme responsible for LTC(4) biosynthesis, catalyzing the conjugation of two substrates that have considerably different water solubility; that amphipathic LTA(4) as a derivative of arachidonic acid and a water-soluble glutathione (GSH). A previous crystal structure revealed important details of GSH binding and implied a GSH activating function for Arg-104. In addition, Arg-31 was also proposed to participate in the catalysis based on the putative LTA(4) binding model. In this study enzymatic assay with mutant enzymes demonstrates that Arg-104 is required for the binding and activation of GSH and that Arg-31 is needed for catalysis probably by activating the epoxide group of LTA(4).

Neutrophil-derived leukotriene B4 is required for inflammatory arthritis.

Neutrophils serve as a vanguard of the acute innate immune response to invading pathogens. Neutrophils are also abundant at sites of autoimmune inflammation, such as the rheumatoid joint, although their pathophysiologic role is incompletely defined and relevant effector functions remain obscure. Using genetic and pharmacologic approaches in the K/BxN serum transfer model of arthritis, we find that autoantibody-driven erosive synovitis is critically reliant on the generation of leukotrienes, and more specifically on leukotriene B4 (LTB4), for disease induction as well as perpetuation. Pursuing the cellular source for this mediator, we find via reconstitution experiments that mast cells are a dispensable source of leukotrienes, whereas arthritis susceptibility can be restored to leukotriene-deficient mice by intravenous administration of wild-type neutrophils. These experiments demonstrate a nonredundant role for LTB4 in inflammatory arthritis and define a neutrophil mediator involved in orchestrating the synovial eruption.

Impact of nephrotic edema of the lower limbs on obstructive sleep apnea: gathering a unifying concept for the pathogenetic role of nocturnal rostral fluid shift.

BACKGROUND: Nocturnal rostral fluid shift has been suggested to be a risk factor for obstructive sleep apnea (OSA) in healthy subjects after lower body positive pressurization. It remains unclear whether this may apply to subjects with nephrotic lower limb edema and, if so, whether disease remission may reverse the accompanying OSA. METHODS: Patients who presented with steroid-responsive primary nephrotic syndrome with lower limb edema as the predominant presenting clinical feature were recruited. They underwent one overnight polysomnography (PSG) before treatment and a repeat testing after achieving remission of the nephrotic edema. RESULTS: Among 23 consecutive nephrotic subjects, 11 (48%) had polysomnographic evidence of sleep apnea [apnea-hypopnea index (AHI)≥5] upon presentation. After steroid-based treatment, there was remission of proteinuria associated with complete disappearance of lower limb edema, significant reduction of body mass index, waist, hip and calf circumferences and total body water mainly in the extracellular compartment. Repeat PSG, performed 8.1±2.6 months later, showed that the overall (N=23) respiratory disturbance index (RDI) and AHI fell from 17.3±5.0 to 8.7±2.5 (P<0.05) and from 16.3±5.1 to 7.8±2.3 (P=0.057), respectively. Among the 11 subjects with sleep apnea detected at baseline, their AHI and RDI fell from 33.4±7.8 to 15.0±3.7 (P<0.05) and from 34.8±7.6 to 16.5±4.0 (P<0.05), respectively. There was also concomitant improvement in sleep efficiency, mean nocturnal oxygen saturation, shorter duration during sleep with oxygen saturation<95 and <90% and reduced desaturation index. There was also subjective improvement in self-reported daytime sleepiness. CONCLUSIONS: Nephrotic lower limb edema is associated with disturbed respiratory breathing and increased propensity to OSA, which was reversed upon remission of the nephrosis. This gathers a unifying concept for the role of nocturnal rostral fluid shift in the pathogenesis of OSA.

Joint tissues amplify inflammation and alter their invasive behavior via leukotriene B4 in experimental inflammatory arthritis.

Mechanisms by which mesenchymal-derived tissue lineages participate in amplifying and perpetuating synovial inflammation in arthritis have been relatively underinvestigated and are therefore poorly understood. Elucidating these processes is likely to provide new insights into the pathogenesis of multiple diseases. Leukotriene B(4) (LTB(4)) is a potent proinflammatory lipid mediator that initiates and amplifies synovial inflammation in the K/BxN model of arthritis. We sought to elucidate mechanisms by which mesenchymal-derived fibroblast-like synoviocytes (FLSs) perpetuate synovial inflammation. We focused on the abilities of FLSs to contribute to LTB(4) synthesis and to respond to LTB(4) within the joint. Using a series of bone marrow chimeras generated from 5-lipoxygenase(-/-) and leukotriene A(4) (LTA(4)) hydrolase(-/-) mice, we demonstrate that FLSs generate sufficient levels of LTB(4) production through transcellular metabolism in K/BxN serum-induced arthritis to drive inflammatory arthritis. FLSs-which comprise the predominant lineage populating the synovial lining-are competent to metabolize exogenous LTA(4) into LTB(4) ex vivo. Stimulation of FLSs with TNF increased their capacity to generate LTB(4) 3-fold without inducing the expression of LTA(4) hydrolase protein. Moreover, LTB(4) (acting via LTB(4) receptor 1) was found to modulate the migratory and invasive activity of FLSs in vitro and also promote joint erosion by pannus tissue in vivo. Our results identify novel roles for FLSs and LTB(4) in joints, placing LTB(4) regulation of FLS biology at the center of a previously unrecognized amplification loop for synovial inflammation and tissue pathology.

Characterization of a novel human mast cell line that responds to stem cell factor and expresses functional FcεRI.

BACKGROUND: Studies of human mast cells (MCs) are constrained by the paucity of functional cell lines, the expense of maintaining MCs in culture, and technical complexities. OBJECTIVE: We derived and characterized a human MC line that arose spontaneously from a culture of nontransformed hematopoietic progenitor cells. METHODS: CD34(+) enriched mononuclear cells derived from a donor with aspirin-exacerbated respiratory disease were cultured for 8 weeks with stem cell factor and IL-6 and with IL-3 for the first week only. The cells (termed LUVA cells) survived and proliferated without further addition of any growth factors and have been maintained in culture for approximately 2 years. RESULTS: LUVA cells possess metachromatic cytoplasmic granules that are immunoreactive for tryptase, cathepsin G, and carboxypeptidase A3. They express transcripts encoding FcεRI, c-kit, chymase, tryptase, histidine decarboxylase, carboxypeptidase A3, and the type 1 receptor for cysteinyl leukotrienes. Flow cytometry confirmed uniform expression of FcεRI, c-kit, and FcγRII. FcεRI cross-linkage induced the release of ß-hexosaminidase, prostaglandin D(2), thromboxane A(2), and macrophage inflammatory protein 1ß. Immortalization was not associated with either a known genomic mutation of c-kit in the donor or a somatic mutation of c-kit within the cells, and it was not associated with c-kit autophosphorylation. CONCLUSIONS: LUVA cells are an immortalized human MC line that can be maintained without stem cell factor and display high levels of normally signaling c-kit and FcεRI. These cells will prove valuable for functional human MC studies.

Clinical Evaluation of Fiducial Marker Pre-Planning for Virtual Bronchoscopic Navigation Implantation in Lung Tumour Patients Treated With CyberKnife.

Purpose: For the treatment of invisible lung tumours with CyberKnife (CK), fiducial markers (FMs) were implanted as an internal surrogate under virtual bronchoscopic navigation (VBN). This research aims to study the benefits of introducing an additional procedure in assigning the optimal FM positions using a pre-procedure planning system and performing virtual simulation before implantation. The objectives were 1) to reduce the duration of the FM implantation procedure, 2) to reduce the radiation exposure in dose area product (DAP) (dGy*cm2) to patients, and 3) to increase the number of FMs implanted around the tumour. Methods and Materials: This study is retrospective, single-centre, and observational in nature. A total of 32 patients were divided into two groups. In Group 1, 18 patients underwent conventional VBN FM implantation. In Group 2, 14 patients underwent additional pre-procedure planning and simulation. The steps of pre-procedure planning include 1) importing CT images into the treatment planning system (Eclipse, Varian Medical Systems, Inc.) and delineating five to six FMs in their ideal virtual positions and 2) copying the FM configuration into VBN planning software (LungPoint Bronchus Medical, Inc.) for verification and simulation. Finally, the verified FMs were deployed through VBN with the guidance of the LungPoint planning software. Results: A total of 162 FMs were implanted among 35 lesions in 32 patients aged from 37 to 92 (median = 66; 16 men and 16 women). Results showed that 1) the average FM insertion time was shortened from 41 min (SD = 2.05) to 23 min (SD = 1.25), p = 0.00; 2) the average absorbed dose of patients in DAP was decreased from 67.4 cGy*cm2 (SD = 14.48) to 25.3 cGy*cm2 (SD = 3.82), p = 0.01 (1-tailed); and 3) the average number of FMs implanted around the tumour was increased from 4.7 (SD = 0.84) to 5.6 (SD = 0.76), p = 0.00 (1-tailed). Conclusion: Pre-procedure planning reduces the FM implantation duration from 41.1 to 22.9 min, reduces the radiation exposure in DAP from 67.4 to 25.3 dGy*cm2, and increases the number of FMs inserted around the tumour from 4.7 to 5.6.

The efficacy of oral appliances in the treatment of severe obstructive sleep apnea.

OBJECTIVES: The purpose of this study is to evaluate the efficacy of oral appliance (OA) treatment for subjects with severe obstructive sleep apnea (OSA) and to determine the dental parameters associated with treatment outcomes. STUDY DESIGN: This study uses a prospective longitudinal design. METHODS: Consecutive Chinese subjects with severe OSA who refused continuous positive airway pressure treatment were recruited. Their dental measurements were taken from lateral cephalometric radiographs. Polysomnograms with OA were repeated at 3 months and 1 year. Blood pressure was taken in the morning after sleep studies. RESULTS: Thirty-four subjects were evaluated at 3 months and 1 year according to the principle of intention-to-treat analysis. OA reduced AHI significantly in subjects with favorable responses, from 49.3 (37.4-67) to 12.5 (6.1-15.7), p < 0.001 at 3 months and from 47.5 (41.1-72.9) to 13.1 (6.0-14.0), p < 0.001 at 1 year. These OSA subjects had an increased overjet at baseline compared to those with unfavorable responses (p ≤ 0.05). Systolic blood pressure was significantly reduced in those hypertensive OSA subjects after 3 months and 1 year of treatment. CONCLUSIONS: OA reduces the severity of sleep apnea, and the effect is maintained at 1 year in subjects with retrognathism. OA appears to reduce systolic blood pressure in hypertensive OSA subjects at 3 months and 1 year.

Sleep apnea is a novel risk predictor of cardiovascular morbidity and death in patients receiving peritoneal dialysis.

Sleep apnea syndrome is increasingly recognized in peritoneal dialysis patients; however, its prognostic implication in this population is unknown. To study this, we prospectively followed the clinical outcome of 93 peritoneal dialysis patients with baseline polysomnography. Of these, 51 were diagnosed with the syndrome defined by an apnea-hypopnea index (AHI) of at least 15 per hour. During a median follow-up of 41 months, there were 30 deaths, of which 17 were due to cardiovascular causes. Kaplan-Meier analysis for the entire follow-up period indicated that patients with sleep apnea at baseline had significantly higher all-cause and cardiovascular mortality during follow-up than those without. Minimal nocturnal saturation and desaturation indices were predictors of mortality and cardiovascular events at univariate analysis. Multivariable Cox regression analysis identified significant sleep apnea syndrome at baseline as an independent predictor of increased all-cause mortality independent of age, male gender, and diabetic status. Further, an absolute increase in the AHI was associated with an incremental risk of cardiovascular events. Thus, sleep apnea syndrome, detected at the start of peritoneal dialysis, is a novel risk predictor for subsequent mortality and cardiovascular events.

Obstructive sleep apnoea: definitions, epidemiology & natural history.

Obstructive sleep apnoea (OSA) is increasingly being recognized as an important health issue in the last two to three decades. It is characterized by frequent episodes of upper airway collapse during sleep, causing recurrent arousals, intermittent hypoxaemia, sleep fragmentation and poor sleep quality. There is accumulating evidence that OSA is being considered as an independent risk factor for hypertension, glucose intolerance / diabetes mellitus, cardiovascular diseases and stroke, leading to increased cardiometabolic morbidity and mortality. The prevalence rates of OSA have been estimated in the range of 2 to 10 per cent worldwide, and the risk factors for obstructive sleep apnoea include advanced age, male sex, obesity, family history, craniofacial abnormalities, smoking and alcohol consumption. The common clinical presenting symptoms are heavy snoring, witnessed apnoeas and daytime hypersomnolence, which would help to identify the affected individuals. With increasing awareness of this disease entity and associated complications in our society, there have been increased referrals to sleep physicians or expertise for further investigations and diagnostic evaluation. Early recognition and treatment of obstructive sleep apnoea may prevent from adverse health consequences. Some of the epidemiological aspects of obstructive sleep apnoea in adults are reviewed.

Determinants of daytime blood pressure in relation to obstructive sleep apnea in men.

This study investigated the roles of different potential pathophysiological mechanisms in the determination of blood pressure in relation to obstructive sleep apnea. The study was designed as a cross-sectional study. Consecutive healthy male subjects who were to undergo polysomnography were recruited. Demographic and anthropometric data were collected. Blood pressure measurements were taken in the evening before sleep and the next morning on waking. Overnight urinary samples for catecholamines and fasting blood for cortisol, insulin, glucose, and lipids were taken. Ninety-four men were analyzed, with a mean age of 43.7 +/- 9.3 years and mean apnea-hypopnea index (AHI) of 27.5 +/- 26.2 events/h. Sixty-nine patients (73%) had obstructive sleep apnea (AHI >or= 5). Urinary catecholamines were positively correlated with severity of sleep apnea, independent of obesity. Blood pressure measurements correlated with age, obesity, severity of sleep apnea, and urinary catecholamines. Regression analysis showed that sleep indices and urinary catecholamines were independent determinants of morning systolic and diastolic blood pressure, respectively, while total cholesterol and waist circumference were respective additional factors. Urinary catecholamines and waist circumference were determinants of evening blood pressure, with morning cortisol being an additional determinant for diastolic blood pressure. Obstructive sleep apnea and related sympathetic activity contributed significantly to the determination of daytime blood pressure in overweight middle-aged men without overt cardiometabolic diseases, and other contributing factors include abdominal obesity, total cholesterol, and cortisol levels.

Hypoadiponectinemia is related to sympathetic activation and severity of obstructive sleep apnea.

STUDY OBJECTIVES: Hypoadiponectinemia is associated with cardiovascular morbidity and diabetes mellitus. We hypothesize that adiponectin may be downregulated in sleep apnea through various mechanisms, contributing to cardiometabolic risks. This study investigated the relationship between serum adiponectin and sleep disordered breathing and its potential determinants. DESIGN: Cross-sectional study. SUBJECTS AND SETTING: Adult men without prevailing medical comorbidity from the sleep clinic in a teaching hospital. MEASUREMENTS & RESULTS: One hundred thirty-four men underwent polysomnography, with mean age of 43.9 (9.8) years, and median apnea-hypopnea index (AHI) of 17.1 (5.7, 46.6). Overnight urine samples for catecholamines and blood samples for analyses of insulin, glucose and adiponectin levels from fasting subjects were taken. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). Magnetic resonance imaging was performed to quantify the amount of abdominal visceral fat. Serum adiponectin level, adjusted for age, body mass index, and visceral fat volume, was significantly lower in subjects with severe obstructive sleep apnea (AHI > or =30) compared with those with an AHI of less than 30: 4.0 (3.1, 5.4) versus 5.4 (3.6, 7.9) microg/mL, P = 0.039. After we adjusted for adiposity, adiponectin levels remained negatively correlated with AHI (P = 0.037), arousal index (P = 0.022), HOMA-IR/fasting insulin (P < 0.001), and urinary norepinephrine and normetanephrine (P < 0.008). In a multiple stepwise regression model, the independent determinants of adiponectin after adjustment for adiposity were HOMA-IR (P < 0.001) and urinary norepinephrine and normetanephrine (P = 0.037). CONCLUSIONS: Adiponectin was suppressed in subjects with severe obstructive sleep apnea, independent of obesity. Adiponectin levels were determined by insulin resistance and sympathetic activation, factors that may be totally or partially attributed to sleep disordered breathing.

Alleviation of pulmonary hypertension by cardiac resynchronization therapy is associated with improvement in central sleep apnea.

BACKGROUND: Recent studies have demonstrated that cardiac resynchronization therapy (CRT) reduces sleep apnea in heart failure (HF); however, the mechanism of benefit remains unclear. METHODS: Overnight polysomnography (PSG) was performed in consecutive HF patients who were scheduled for CRT implant. Patients with sleep apnea defined by an apnea-hypopnea index (AHI) of >10/hour were recruited and underwent echocardiogram examination at baseline and 3 months after CRT. RESULTS: Among 37 HF patients screened, 20 patients (54%) had sleep apnea and 15 of them consented for the study. After 3 months of CRT, there was a significant improvement in New York Heart Association functional class (3.1+/-0.1 vs 2.1+/-0.1, P<0.01), quality-of-life (QoL) score (62.9+/-3.3 vs 56.1+/-4.5, P=0.02), left ventricular ejection fraction (LVEF, 28.8+/-2.5% vs 38.1+/-2.3%, P<0.01), and reduction in pulmonary artery systolic pressure (PASP, 41.0+/-2.7 vs 28.6+/-2.2 mmHg; P<0.01) compared with baseline. Repeated PSG after CRT demonstrated a reduction in the duration of arterial oxygen desaturation

A cluster of cases of severe acute respiratory syndrome in Hong Kong.

BACKGROUND: Information on the clinical features of the severe acute respiratory syndrome (SARS) will be of value to physicians caring for patients suspected of having this disorder. METHODS: We abstracted data on the clinical presentation and course of disease in 10 epidemiologically linked Chinese patients (5 men and 5 women 38 to 72 years old) in whom SARS was diagnosed between February 22, 2003, and March 22, 2003, at our hospitals in Hong Kong, China. RESULTS: Exposure between the source patient and subsequent patients ranged from minimal to that between patient and health care provider. The incubation period ranged from 2 to 11 days. All patients presented with fever (temperature, >38 degrees C for over 24 hours), and most presented with rigor, dry cough, dyspnea, malaise, headache, and hypoxemia. Physical examination of the chest revealed crackles and percussion dullness. Lymphopenia was observed in nine patients, and most patients had mildly elevated aminotransferase levels but normal serum creatinine levels. Serial chest radiographs showed progressive air-space disease. Two patients died of progressive respiratory failure; histologic analysis of their lungs showed diffuse alveolar damage. There was no evidence of infection by Mycoplasma pneumoniae, Chlamydia pneumoniae, or Legionella pneumophila. All patients received corticosteroid and ribavirin therapy a mean (+/-SD) of 9.6+/-5.42 days after the onset of symptoms, and eight were treated earlier with a combination of beta-lactams and macrolide for 4+/-1.9 days, with no clinical or radiologic efficacy. CONCLUSIONS: SARS appears to be infectious in origin. Fever followed by rapidly progressive respiratory compromise is the key complex of signs and symptoms from which the syndrome derives its name. The microbiologic origins of SARS remain unclear.

HDL dysfunction in obstructive sleep apnea.

OBJECTIVE: HDL is anti-atherogenic and has antioxidant property. HDL dysfunction has been reported in patients with coronary heart disease and we hypothesize that HDL may also be dysfunctional in obstructive sleep apnea (OSA), a condition associated with increased oxidative stress. METHODS: 128 OSA patients and 82 controls were recruited. HDL dysfunction was determined by evaluating the ability of HDL to inhibit LDL oxidation ex vivo. Plasma HDL was incubated with native LDL in the presence of dichlorofluorescein which fluoresced upon interaction with lipid oxidation products. Plasma levels of oxidized LDL and 8-isoprostane were measured by ELISA and a specific enzyme immunoassay, respectively. RESULTS: Plasma total 8-isoprostane levels were elevated in OSA subjects (p<0.01). Despite having similar concentrations of plasma lipids and apolipoproteins as controls, OSA subjects had greater degree of HDL dysfunction (p<0.01) and increased oxidized LDL levels (p<0.05). The apnea-hypopnea index was the main determinant of HDL dysfunction in OSA, accounting for 30% of its variance, with oxidized LDL and apolipoprotein AI contributing to 8% and 5% of its variance respectively (p<0.001). CONCLUSION: HDL is dysfunctional in preventing the formation and inactivation of oxidized lipids in OSA subjects and may partly contribute to their increased cardiovascular risk.

Advanced glycation endproducts in nondiabetic patients with obstructive sleep apnea.

SUBJECT OBJECTIVE: The formation and accumulation of advanced glycation endproducts (AGEs) has been implicated in the progression of age-related diseases such as diabetes mellitus and atherosclerosis. We hypothesize that AGE concentrations may be increased in subjects with obstructive sleep apnea (OSA), a condition associated with increased oxidative stress. METHODS: One hundred nineteen nondiabetic patients with OSA and 234 age-matched healthy controls and 134 patients with type 2 diabetes were recruited for participation in the study. Serum AGEs were assayed by competitive enzyme-linked immunosorbent assay using a polyclonal rabbit antisera raised against AGE-RNase. RESULTS: Serum AGEs were increased in OSA subjects, as compared with controls, but were less increased than the AGEs of patients with type 2 diabetes (control: 3.22 +/- 0.54 unit per mL; OSA: 3.68 +/- 0.39; diabetes mellitus: 4.11 +/- 0.99; analysis of variance p < .01). In the subjects with OSA, serum AGEs correlated with the duration of nocturnal desaturation (r = 0.21, p = .025) and plasma total 8-isoprostane concentration, a biochemical marker of oxidative stress (r = 0.22, p = .015), but not with fasting glucose level. On general linear model univariate analysis, the association between serum AGEs and 8-isoprostane was independent of age, sex, body mass index, smoking status, and glucose. CONCLUSION: Serum levels of AGEs were increased in nondiabetic subjects with OSA and were associated with the severity of OSA. Whether increased AGE formation contributes significantly to the high cardiovascular risk associated with OSA remains to be determined.