Laryngeal and velopharyngeal sensory impairment in obstructive sleep apnea

STUDY OBJECTIVE: To determine whether mucosal sensory dysfunction is present at multiple upper-airway sites in patients with obstructive sleep apnea (OSA). DESIGN: Physiologic testing of consecutive patients with OSA and nonsnoring controls. SETTING: University hospital sleep center. PARTICIPANTS: Thirty-nine subjects with OSA and 17 controls. INTERVENTIONS: Endoscopic testing was used to determine sensory detection thresholds for air-pressure pulses delivered to the oropharynx, velopharynx, hypopharynx, and larynx (aryepiglottic eminence). The air-pulse stimulus intensity required to elicit the protective laryngeal adductor reflex was also determined. MEASUREMENTS AND RESULTS: There was a significant impairment in sensory detection threshold for OSA versus control subjects in the oropharynx, as previously described by ourselves using other techniques, as well as at the velopharynx (median 11 mm Hg [confidence interval 9-11] for subjects with OSA vs 8 mm Hg [confidence interval 4-11] for controls, P = .03) and, at the larynx, 4 mm Hg [confidence interval 2-9] for subjects with OSA vs 2 mm Hg [confidence interval 2-3] for controls, P < .001). The threshold stimulus intensity for the laryngeal adductor reflex was also significantly higher for OSA subjects. For OSA patients with abnormal laryngeal sensation (61% of OSA subjects), there were significant correlations between laryngeal sensory values and measures of apnea severity, including apnea-hypopnea index (r = 0.82, P < .001) and nadir SaO2 (r = -0.48, P < .05). CONCLUSION: Mucosal sensory function is impaired at multiple upper-airway sites in OSA.     

Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD

BACKGROUND: Enzymatic and histochemical abnormalities of the peripheral muscle may play a role in exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to measure the mitochondrial enzyme activity of the vastus lateralis muscle in patients with COPD and to evaluate the relationship between enzyme activities and functional status. METHODS: Fifty seven patients with COPD of mean (SD) age 66 (7) years with forced expiratory volume in one second (FEV(1)) 39 (15)% predicted and peak oxygen uptake (VO(2)) of 14 (4) ml/min/kg and 15 normal subjects of similar age were included in the study. Each subject performed a stepwise exercise test up to maximal capacity during which five-breath averages of VO(2) were measured. Muscle specimens were obtained by percutaneous needle biopsy of the vastus lateralis muscle and the activity of two mitochondrial enzymes (citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH)) was measured. The functional status of the patients was classified according to peak VO(2). RESULTS: CS and HADH activities were markedly reduced in patients with COPD compared with normal subjects (22.3 (2.7) versus 29.5 (7.3) micromol/min/g muscle (p<0.0001) and 5. 1 (2.0) versus 6.7 (1.9) micromol/min/g muscle (p<0.005), respectively). The activity of CS decreased progressively with the deterioration in the functional status while that of HADH was not related to functional status. Using a stepwise regression analysis, percentage predicted functional residual capacity (FRC), the activity of CS, oxygen desaturation during exercise, age, and inspiratory capacity (% pred) were found to be significant determinants of peak VO(2). The regression model explained 59% of the variance in peak VO(2) (p<0.0001). CONCLUSIONS: The oxidative capacity of the vastus lateralis muscle is reduced in patients with moderate to severe COPD compared with normal subjects of similar age. In these individuals the activity of CS correlated significantly with peak exercise capacity and independently of lung function impairment.     

Regulation of stretch reflex threshold in elbow flexors in children with cerebral palsy: a new measure of spasticity

The tonic stretch reflex threshold in children with cerebral palsy (CP) was measured to determine its test-retest reliability and its concurrent validity as a potential measure of spasticity. Fourteen children with spastic CP aged 6 to 18 years were tested on three separate occasions for clinical spasticity and stretch reflex thresholds of affected elbow flexors. Electromyographic (EMG) recordings were obtained by surface electrodes for elbow flexors and extensors during mechanical displacements of the passive joint towards extension. Displacements were produced by a torque motor at seven velocities which randomly varied from trial to trial. EMG activity was measured in the stretched flexor muscles to determine threshold angles and velocities for each velocity of stretch. These were plotted on a velocity-angle-phase diagram and regression analysis was used to determine the static stretch reflex threshold for each participant. The measure showed good test-retest reliability for the group (ICC 0.73, p<0.001) whereas a significant correlation between the measure and the clinical spasticity scale was not found. This technique is a potential outcome variable for measuring the efficacy of treatments aimed at decreasing spasticity in children with CP.     

Usefulness of the indexed effective orifice area at rest in predicting an increase in gradient during maximum exercise in patients with a bioprosthesis in the aortic valve position

This study examines the hemodynamic behavior of aortic bioprosthetic valves during maximum exercise. Nineteen patients with a normally functioning stented bioprosthetic valve and preserved left ventricular function were submitted to maximum ramp bicycle exercise. In 14 of the 19 patients, valve effective orifice area and mean gradient were measured at rest and during exercise using Doppler echocardiography. At peak exercise (mean maximal workload 118 +/- 53 W), the cardiac index increased by 122 +/- 34% (+3.18 +/- 0.71 L/min/ m2, p <0.001), whereas mean gradient increased by 94 +/- 49% (+12 +/- 8 mm Hg, p <0.001), and effective orifice area by 9 +/- 13% (+0.15 +/- 0.22 cm2, p = 0.02). A strong correlation was found between the increase in mean gradient during maximum exercise and the valve area at rest indexed for body surface area (r = 0.84, p <0.0001). Due to the increase in valve area, the increase in gradient was less (-9 +/- 7 mm Hg, -41 +/- 33%, p = 0.0006) than theoretically predicted assuming a fixed valve area. These results suggest that the effective orifice area of the bioprostheses has the capacity to increase during exercise; therefore, limiting the increase in gradient. The relation found between the indexed effective orifice area at rest and the increase in gradient during exercise should be useful in predicting the hemodynamic behavior of a stented bioprosthesis during exercise.     

Usefulness of measuring net atrioventricular compliance by Doppler echocardiography in patients with mitral stenosis

Twenty-six patients with severe pure mitral stenosis underwent Doppler echocardiographic examination and cardiac catheterization within the same day before the realization of mitral valve balloon valvuloplasty. Net atrioventricular compliance estimated by Doppler echocardiography from the ratio of mitral valve effective orifice area and E-wave downslope was a major independent determinant of left atrial and pulmonary arterial pressures measured by catheterization.     

Contractile fatigue, muscle morphometry, and blood lactate in chronic obstructive pulmonary disease

We hypothesized that patients with chronic obstructive pulmonary disease developing contractile fatigue of the quadriceps during cycle exercise may have characteristic metabolic and muscle features that could increase their susceptibility to fatigue, thus differentiating them from those who do not develop fatigue. We examined, in 32 patients, the fiber-type proportion, enzymatic activities, and capillary density in the vastus lateralis and the arterial blood lactate level during constant work-rate cycling exercise. Contractile fatigue was defined as a postexercise fall in quadriceps twitch force greater than 15% of resting values. Twenty-two patients developed contractile fatigue after exercise. No significant differences were found between fatiguers and non-fatiguers for the endurance time, fiber-type proportion, and oxidative enzyme activities. The lactate dehydrogenase activity was significantly higher (p < 0.05) and muscle capillarization significantly reduced in fatiguers (p < 0.05). Compared with non-fatiguers, the arterial lactate level during exercise was significantly higher in fatiguers (p < 0.001). A significant relationship was found between the fall in quadriceps twitch force and lactate dehydrogenase activity, capillary/fiber ratio, and blood lactate level. We conclude that changes in muscle enzymatic profile and capillarization with a greater reliance on glycolytic metabolism during exercise are associated with contractile fatigue in patients with chronic obstructive pulmonary disease.     

An Amphipathic Alpha-Helix Domain from Poliovirus 2C Protein Tubulate Lipid Vesicles

Positive-strand RNA viruses universally remodel host intracellular membranes to form membrane-bound viral replication complexes, where viral offspring RNAs are synthesized. In the majority of cases, viral replication proteins are targeted to and play critical roles in the modulation of the designated organelle membranes. Many viral replication proteins do not have transmembrane domains, but contain single or multiple amphipathic alpha-helices. It has been conventionally recognized that these helices serve as an anchor for viral replication protein to be associated with membranes. We report here that a peptide representing the amphipathic α-helix at the N-terminus of the poliovirus 2C protein not only binds to liposomes, but also remodels spherical liposomes into tubules. The membrane remodeling ability of this amphipathic alpha-helix is similar to that recognized in other amphipathic alpha-helices from cellular proteins involved in membrane remodeling, such as BAR domain proteins. Mutations affecting the hydrophobic face of the amphipathic alpha-helix severely compromised membrane remodeling of vesicles with physiologically relevant phospholipid composition. These mutations also affected the ability of poliovirus to form plaques indicative of reduced viral replication, further underscoring the importance of membrane remodeling by the amphipathic alpha-helix in possible relation to the formation of viral replication complexes.     

Gut Commensal Bacteria and Regional Wnt Gene Expression in the Proximal Versus Distal Colon

Regional expression of Wingless/Int (Wnt) genes plays a central role in regulating intestinal development and homeostasis. However, our knowledge of such regional Wnt proteins in the colon remains limited. To understand further the effect of Wnt signaling components in controlling intestinal epithelial homeostasis, we investigated whether the physiological heterogeneity of the proximal and distal colon can be explained by differential Wnt signaling. With the use of a Wnt signaling-specific PCR array, expression of 84 Wnt-mediated signal transduction genes was analyzed, and a differential signature of Wnt-related genes in the proximal versus distal murine colon was identified. Several Wnt agonists (Wnt5a, Wnt8b, and Wnt11), the Wnt receptor frizzled family receptor 3, and the Wnt inhibitory factor 1 were differentially expressed along the colon length. These Wnt signatures were associated with differential epithelial cell proliferation and migration in the proximal versus distal colon. Furthermore, reduced Wnt/β-catenin activity and decreased Wnt5a and Wnt11 expression were observed in mice lacking commensal bacteria, an effect that was reversed by conventionalization of germ-free mice. Interestingly, myeloid differentiation primary response gene 88 knockout mice showed decreased Wnt5a levels, indicating a role for Toll-like receptor signaling in regulating Wnt5a expression. Our results suggest that the morphological and physiological heterogeneity within the colon is in part facilitated by the differential expression of Wnt signaling components and influenced by colonization with bacteria.One of the fundamental aspects in the development of the gastrointestinal tract is the spatiotemporal expression of signaling molecules that regulate cell fate and differentiation. Previous studies have highlighted a central role of the evolutionarily conserved Wingless/Int (Wnt) signaling pathways as key regulators of embryonic development and epithelial homeostasis in the gut.^1–3 In development, local expression patterns of Wnt signaling components play an important role in organogenesis.^4,5 Wnt signals control important biological processes required for cell proliferation, differentiation, polarity, and movement, depending on the target cell and the cellular environment.Recent reports have highlighted the importance of understanding the role of Wnt signaling in the intestinal tract. The intestinal epithelium is highly dynamic and, depending on the species and location, is actively turned over in <1 week.⁶ Wnt/β-catenin signaling regulates intestinal epithelial cell (IEC) homeostasis and proliferation by increasing β-catenin stability in crypt epithelial cells, whereas IEC migration and differentiation are believed to be in part facilitated through noncanonical (Wnt) signaling pathways independent of β-catenin.^6,7 The renewal of intestinal epithelia requires a delicate balance of signaling proteins to control epithelial cell proliferation and migration that in turn is vital for maintaining mucosal homeostasis. Interestingly, regional differences in Wnt gene expression in small versus large intestine are observed in adult mice, suggesting the importance of differential local Wnt expression in regulation of intestinal mucosal homeostasis.⁷Although the entire colon exhibits considerable morphological and physiological heterogeneity along its length,^8–11 the expression pattern of Wnt signaling components in the different regions of the adult colon remains poorly understood. Embryologically, the cecum, ascending colon, and the proximal two-thirds of the transverse colon are derived from the midgut, whereas the distal colon originates from the hindgut. Such distinct origins of the colonic segment support specific biological characteristics and suggest that distinct regulatory factors are likely to control epithelial homeostasis in the proximal versus distal colon. In addition, important contributing factors that influence Wnt/β-catenin signaling and intestinal epithelial proliferation might be microbial communities that localize in the intestine in distinct regions.^6,12 Such a delicate physiological balance of Wnt signaling and intestinal epithelial homeostasis is further perturbed in mucosal inflammatory and neoplastic diseases,^3,13 which also indicate regional differences in the proximal versus distal colonic segments.^14–17In the present study, we investigate the regional heterogeneity of Wnt genes in the proximal versus distal colon. Given the importance of luminal microbiota in influencing intestinal epithelial homeostasis¹⁸ and to determine whether the Wnt signatures are influenced by microflora colonization, we examined expression of Wnt proteins in the colonic segments of mice raised under germ-free (GF) conditions.