Identification and quantification of apneas by computer-based analysis of oxygen saturation

Manual detection and quantitation of apneas from an all-night polysomnogram is very time-consuming. Because SaO2 changes with virtually every apnea event, we reasoned that by identifying cyclical SaO2 changes, we could calculate (1) an apnea-hypopnea index that would correlate very well with the manually derived apnea-hypopnea index, and (2) the duration of apnea-hypopnea events. We developed a computer algorithm to scan and detect dips in SaO2 data digitally stored as a time series by computer throughout overnight studies. Desaturations detected by computer were compared with the events detected manually in 9 all-night polysomnograms from 6 patients with typical obstructive sleep apnea. Events detected by one method but not the other were subsequently verified to determine the overall number of apnea-hypopnea events present and to determine false positive and false negative rates for the 2 methods of detection. The total number of apneas was 4,008. Both methods agreed on 3,639 of them. Of 77 manually recorded apneas not detected by computer, 24 were subsequently discounted (manual false positives, 24 of 4,007 = 0.6%) and 53 confirmed (computer false negatives, 1.32%). Of 358 events not detected manually, 316 were confirmed (manual false negatives, 7.9%) and 42 discounted (computer false positives, 1.1%). Using the final manual scoring as the reference, the computer program detected apneas with a sensitivity of 97.9%, and the predictive value of a computer-detected event was 90.8%. For event duration, a regression was performed on 3,623 matched apneas-hypopnea events, giving a coefficient of r = 0.9431, p less than 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)     

The sialylation of plasma lipoproteins

Sialic acids are a family of amino sugars that are commonly found as terminal oligosaccharide residues on glycoproteins and glycolipids. Plasma lipoproteins are sialylated on their apolipoprotein and glycolipid constituents. The function of sialic acid on apolipoproteins is not completely understood but has been associated with secretion, lipid-binding, and plasma clearance for some apolipoproteins. The sialic acid content of individual apolipoproteins can vary in response to physiological conditions while the sialic acid content of individual sialylated glycolipids (gangliosides) is constant. Thus, the sialic acid content of plasma lipoproteins can differ considerably as a result of (1) variations in the sialylation of their apolipoprotein constituents, (2) variations in their content of sialylated apolipoproteins and gangliosides, and (3) modifications of the sialic acid on lipoprotein constituents while circulating in plasma. The significance of sialic acid on lipoproteins is not fully understood although associations have been made between sialic acid and charge (very low density lipoprotein), lipoprotein solubility, receptor binding and uptake, and interactions with vascular matrix (low density lipoprotein and Lp(a)) and with cholesterol efflux (high density lipoprotein). Further studies identifying sites of sialylation on apolipoproteins and characterizing the structures of sialylated oligosaccharides will aid in determining the enzymes responsible for their sialylation. Manipulations of the sialylation of apolipoproteins and of the quantity of apolipoproteins and gangliosides on lipoproteins will be useful methods in determining the role of lipoprotein sialic acid in the development of atherosclerosis.     

The effect of oxygen on respiration and sleep in patients with congestive heart failure

STUDY OBJECTIVE: To determine the effect of supplemental oxygen on Cheyne-Stokes respiration, nocturnal oxygen saturation (SaO2), and sleep in male patients with severe, stable congestive heart failure. DESIGN: Randomized, single-blind, placebo-controlled crossover study. SETTING: Patients referred from outpatient cardiology clinics of two teaching hospitals. PATIENTS: Sequential sample of nine outpatients with severe, stable congestive heart failure. INTERVENTIONS: For each patient, sleep studies (after an adaptation night) from two consecutive randomized nights were compared; one study was done while the patient breathed compressed air and the other while the patient breathed oxygen (O2). Compressed air and oxygen were both administered through nasal cannulae at 2 to 3 L/min. MEASUREMENTS AND MAIN RESULTS: Cheyne-Stokes respiration, defined as periodic breathing with apnea or hypopnea, was found in all patients. Low-flow oxygen significantly reduced the duration of Cheyne-Stokes respiration (50.7% +/- 12.0% to 24.2% +/- 5.4% total sleep time), mainly during stage 1 NREM (non-rapid eye movement) sleep (21.3% +/- 7.1% to 6.7% +/- 2.3% total sleep time) with no significant change during stage 2 sleep, slow-wave sleep, or REM (rapid eye movement) sleep. Although patients had normal SaO2 (96.0% +/- 1.7%) while awake, severe sleep hypoxemia was common; breathing oxygen reduced the amount of time that SaO2 was less than 90% from 22.3% +/- 8.0% to 2.41% +/- 1.93% of total sleep time. Sleep, disrupted to a variable extent in all patients, improved with oxygen therapy: There was an increase in total sleep time from 275.3 min +/- 36.6 to 324.6 min +/- 23.3; a reduction in the proportion of stage 1 sleep (27.6% +/- 5.8% total sleep time to 15.2% +/- 2.6% total sleep time); and a reduction in the number of arousals (30.4/h +/- 8.0 to 13.8/h +/- 1.9). The apnea-hypopnea index was reduced from 30.0 +/- 4.7 to 18.9 +/- 2.4 with oxygen breathing. CONCLUSION: In severe, stable congestive heart failure, nocturnal oxygen therapy reduces Cheyne-Stokes respiration, corrects hypoxemia, and consolidates sleep by reducing arousals caused by the hyperpneic phase of Cheyne-Stokes respiration. Correction of nocturnal hypoxemia and sleep disruption may improve the clinical status of these patients.     

Human triglyceride-rich lipoprotein apo E kinetics and its relationship to LDL apo B-100 metabolism

Apolipoprotein (apo) E is a multifunctional protein that can act as a ligand for lipoprotein receptors. The receptor-mediated clearance of the triglyceride-rich lipoproteins (TRL) chylomicrons and VLDL from plasma is, in part, dependent on apo E. Enrichment of VLDL with apo E is thought to enhance receptor-mediated clearance of VLDL resulting in a low rate of conversion of VLDL to LDL. However, the kinetic mechanism controlling the concentration of apo E in VLDL is not known. We conducted kinetic studies on apo E in the TRL fraction (d < 1.006 g/ml) and apo B-100 in the TRL and LDL (d = 1.019-1.063 g/ml) fractions to assess the kinetic determinants of apo E concentration in TRL and to determine the effects that TRL apo E production and clearance rates have on the production rate of LDL apo B-100. Nineteen males between the ages of 24 and 73 underwent a primed-constant infusion with deuterated leucine tracer in the constantly-fed state. Apo B-100 from TRL and LDL, and apo E from TRL were isolated and their tracer incorporation measured by gas chromatography/mass spectrometry. The residence time and production rates of each protein were determined from the kinetic data using the SAAM II modeling program. The residence time and production rate of TRL apo E were about one-half that of TRL apo B-100 (1.8 +/- 1.0 vs. 2.9 +/- 2.1 h and 14.5 +/- 11.0 vs. 27.6 +/- 17.3 mg/kg per day, respectively). The production rate of TRL apo E was weakly correlated with the production rate of TRL apo B-100 (r = 0.424, P = 0.07). Multiple regression analysis showed that the residence time of TRL apo B-100 and the relative TRL apo E production rate (relative to the TRL apo B100 production rate) were negatively associated with LDL apo B-100 production rate, accounting for 68% of its variability. We conclude that (1) the concentration of apo E in TRL is highly correlated to its production rate, suggesting that production rate regulates the TRL apo E concentration, and (2) individuals with a relatively short TRL apo B-100 residence time and those producing TRL with a relatively low apo E content have the highest LDL apo B-100 production rates.     

Over- and Ectopic Expression of Wnt3 Causes Progressive Loss of Ameloblasts in Postnatal Mouse Incisor Teeth

Intercellular signaling is essential for the development of teeth during embryogenesis and in maintenance of the continuously growing incisor teeth in postnatal rodents. WNT intercellular signaling molecules have been implicated in the regulation of tooth development, and the Wnt3 gene shows specific expression in the enamel knot at the cap stage. We demonstrate here that Wnt3 also is expressed in specific epithelial cell layers in postnatal incisor teeth. To begin to delineate the functions of Wnt3 in developing and postnatal teeth, we determined the effects of over- and ectopic expression of Wnt3 in the tooth epithelium of mice carrying a keratin 14- Wnt3 transgene. Expression of the transgene caused a progressive loss of ameloblasts from postnatal lower incisor teeth. Loss of ameloblasts may be due to defective proliferation or differentiation of ameloblast precursors, progressive apoptosis of ameloblasts, or loss of ameloblast stem cells.     

Nasal CPAP reduces gastroesophageal reflux in obstructive sleep apnea syndrome.

Anecdotal reports suggest that obstructive sleep apnea syndrome (OSAS) patients may suffer from frequent nocturnal gastroesophageal reflux (GER) and that nasal continuous positive airway pressure may be an effective form of antireflux therapy in this population. To confirm these clinical impressions, we performed two consecutive days of 24-h esophageal pH monitoring, nocturnal esophageal pressure recording, and polysomnography on six OSAS patients complaining of regular nocturnal GER. On night one, the patients were untreated. Five of six subjects had abnormal amounts of nocturnal GER. Arousal, movement and swallowing were more frequent (p less than 0.043) and nadir intrathoracic pressure lower (p less than 0.005) in the 30 s prior to precipitous drops in esophageal pH (greater than or equal to 2 pH units) than during random control periods. A direct association between obstructive apneas and GER was not identified. On night two, nasal CPAP was administered and successfully treated apnea in five of six subjects. In these patients, there was also dramatic reduction in GER frequency and duration on CPAP. The mean percentage of time pH less than 4 dropped from 6.3 +/- 2.1 to 0.1 +/- 0.1 percent (p less than 0.025). We believe that OSAS may predispose to nocturnal GER by lowering intrathoracic pressure and increasing arousal and movement frequency. Nasal CPAP can correct these predisposing factors and reduce GER.     

Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects

BACKGROUND. Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.METHODS. We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).RESULTS. Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.CONCLUSION. These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00990808","term_id":"NCT00990808"}}NCT00990808.FUNDING. Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).