Disease marker combination enhances patient characterization in the Finnish sarcoidosis patients.

Sarcoidosis is an inflammatory disease of unknown etiology and multiple clinical phenotypes. Clinical manifestations range from asymptomatic disease to severe loss-of-function leading to the hypothesis that sarcoidosis might not be just one disease, but consists of several distinct disease entities each with potentially distinct genetic associations. We have previously demonstrated that in our series HLADRB1* 03:01 and haplotype HLA-DRB1*04:01-DPB1*04:01 are associated with good prognosis sarcoidosis. In our recent work, we found a novel SNP (rs9905945) in the 5'upstream region of the ACE gene to be associated with favorable disease prognosis as well. The main objective of this study was to expand the previous results and analyse combined influence of the found ACE SNP rs9905945 with the protective HLA markers HLADRB1* 03:01 and HLA-DRB1*04:01-DPB1*04:01 in 188 Finnish sarcoidosis patients (resolved disease, n = 90; persistent disease, n = 98). When combining the frequencies of the rs9905945 and of the HLA markers, the strongest association was found for a combination of either/or both HLA markers and rs9905945 for good disease prognosis (37.1% in resolved vs. 11.3% in persistent, p < 0.001, OR = 4.61, (95%CI 2.15-9.86)). In conclusion, we discovered that a combination of the ACE SNP rs9905945 and HLA markers enhance the accuracy for predicting disease course in Finnish sarcoidosis patients further characterizing genetic differences between Finnish sarcoidosis patients with different prognosis.

Inhaled furosemide attenuates hyperpnea-induced obstruction and intra-airway thermal gradients.

Inhaled furosemide attenuates exercise- and isocapnic hyperventilation-induced asthma; however, the mechanism for this phenomenon is unknown. Because the magnitude of the intra-airway thermal gradient that develops between the cooling of hyperpnea and the rewarming that occurs once hyperventilation ceases is directly related to the severity of thermally induced obstruction in humans, we wondered if furosemide blunted these temperature changes. To explore this issue, eight asthmatic subjects had tracheobronchial airstream temperature measures as they performed isocapnic hyperventilation with frigid air alone (HV) or with pretreatment with inhaled saline (S + HV) or 45 +/- 3 (SE) mg of furosemide (F + HV). HV and S + HV resulted in similar degrees of obstruction, whereas the mechanical decrements after F + HV were significantly less. In concert with this protective effect, F + HV resulted in less airstream cooling during hyperventilation and slower rewarming in the recovery period. Because the major source of heat to the airways is provided by its microcirculation, inhaled furosemide may be acting as a topical vasodilator serving to enhance heat availability and thus reducing the effective thermal burden of hyperpnea.

Effects of ozone on lung mechanics and cyclooxygenase metabolites in dogs.

To determine if acute exposure to ozone can cause changes in the production of cyclooxygenase metabolites of arachidonic acid (AA) in the lung which are associated with changes in lung mechanics, we exposed mongrel dogs to 0.5 ppm ozone for two hours. We measured pulmonary resistance (RL) and dynamic compliance (Cdyn) and obtained methacholine dose response curves and bronchoalveolar lavagate (BAL) before and after the exposures. We calculated the provocative dose of methacholine necessary to increase RL 50% (PD50) and analyzed the BAL for four cyclooxygenase metabolites of AA: a stable hydrolysis product of prostacyclin, 6-keto-prostaglandin F1 alpha (6-keto-PgF1 alpha); prostaglandin E2 (PgE2); a stable hydrolysis product of thromboxane A2, thromboxane B2 (TxB2); and prostaglandin F2 alpha (PgF2 alpha). Following ozone exposure, RL increased from 4.75 +/- 1.06 to 6.08 +/- 1.3 cm H2O/L/sec (SEM) (p less than 0.05), Cdyn decreased from 0.0348 +/- 0.0109 TO .0217 +/- .0101 L/cm H2O (p less than 0.05), and PD50 decreased from 4.32 +/- 2.41 to 0.81 +/- 0.49 mg/cc (p less than 0.05). The baseline metabolite levels were as follows: 6-keto PgF1 alpha: 96.1 +/- 28.8 pg/ml; PgE2: 395.8 +/- 67.1 pg/ml; TxB2: 48.5 +/- 11.1 pg/ml; PgF2 alpha: 101.5 +/- 22.6 pg/ml. Ozone had no effect on any of these prostanoids. These studies quantify the magnitude of cyclooxygenase products of AA metabolism in BAL from dog lungs and demonstrate that changes in their levels are not prerequisites for ozone-induced changes in lung mechanics or airway reactivity.

Effect of facial cooling on mucosal blood flow in the mouth in humans.

1. To determine the effects of facial cooling on intraoral thermal events, we placed a thermal conductivity sensor on the buccal surface of the left cheek in six normal and six asthmatic subjects. Room temperature and cold stimuli were then applied to the integument surface of both sides of the face while mucosal surface temperature and thermal conductivity, as an index of blood flow, were recorded. 2. The room temperature challenge had no effect. Application of the cold stimulus to the exterior of the left cheek caused a monotonic decrease in temperature in the mouth in all subjects and was associated with a change in thermal conductivity in which blood flow increased and then fell to baseline despite a continued drop in temperature. These responses were purely local in that cooling of the right side of the face did not change the temperature or blood flow on the left side. No differences were noted between the asthmatic and normal subjects. 3. The data indicate that lowering the temperature of the skin of the face produces significant alterations in the thermal environment within the mouth. With facial cooling, buccal temperature falls and mucosal blood supply transiently rises. This effect appears to be a purely local thermally mediated event. Facial pressure and cutaneous reflexes do not play a role. The above changes may contribute to the conditioning of inspired air during oral breathing.

Responses to negative pressure surrounding the neck in anesthetized animals.

Continuous positive pressure applied at the nose has been shown to cause a decrease in upper airway resistance. The present study was designed to determine whether a similar positive transmural pressure gradient, generated by applying a negative pressure at the body surface around the neck, altered upper airway patency. Studies were performed in nine spontaneously breathing anesthetized supine dogs. Airflow was measured with a pneumotachograph mounted on an airtight muzzle placed over the nose and mouth of each animal. Upper airway pressure was measured as the differential pressure between the extrathoracic trachea and the inside of the muzzle. Upper airway resistance was monitored as an index of airway patency. Negative pressure (-2 to -20 cmH2O) was applied around the neck by using a cuirass extending from the jaw to the thorax. In each animal, increasingly negative pressures were transmitted to the airway wall in a progressive, although not linear, fashion. Decreasing the pressure produced a progressive fall in upper airway resistance, without causing a significant change in respiratory drive or respiratory timing. At -5 cmH2O pressure, there occurred a significant fall in upper airway resistance, comparable with the response of a single, intravenous injection of sodium cyanide (0.5-3.0 mg), a respiratory stimulant that produces substantial increases in respiratory drive. We conclude that upper airway resistance is influenced by the transmural pressure across the airway wall and that such a gradient can be accomplished by making the extraluminal pressure more negative.(ABSTRACT TRUNCATED AT 250 WORDS)

A model of muscular control of upper airway geometry.

Some disorders of the upper airway in humans are marked by decreased cross-sectional area and increased airway wall compliance. Based on our observations from studies performed in the isolated upper airway of dogs, we hypothesized that the size, and perhaps the geometry, of the airway was altered by changes in the relative activation levels of various muscle pairs. This could be accomplished either by altering the intensity of the neuromuscular input, or by activating muscle pairs which have different geometric orientation to the airway. We developed an analytic relationship to allow us to vary the stimulus level driving any one of six muscle pairs, each with a different anatomic orientation, to evaluate the relationship between those parameters and upper airway volume. With data generated from bilateral electrical stimulation of upper airway muscles, we described a shape factor which allowed us to predict the maximum force produced at optimal length. These findings were applied to a length/tension curve common to striated muscle to allow us to examine the muscle behavior at lengths other than optimal. The position of each muscle was described in spherical coordinates relative to an elastic cylinder, which represented the isolated, sealed upper airway. These coordinates defined the direction in which the force generated by each muscle pair would be applied. Three compliance constants determined the change in airway dimensions produced by the muscle force. This system and its variables were used to calculate the change in volume of the sealed upper airway chamber resulting from muscle contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Instrumentation for estimating pulmonary function in patients on positive end-expiratory pressure.

For patients requiring PEEP during ventilation, e.g., patients with respiratory distress syndrome, performing traditional tests of lung function is a complicated problem. The pulmonary mechanics of these patients can change rapidly with potential for a negative impact on oxygenation. In an effort to address these problems, we designed a system with a three-way valve that permits the patient to be switched from the ventilator to a data collection system for the assessment of changes in the disease state. The short periods required for data collection (20 to 30 sec) do not interfere with patient care and are well within the limits of safety. A unique feature of the valved system is that it serves to maintain positive airway pressure during data collection. Tests show that, within the frequency range of interest, the mechanics of the measurement system are not altered by the DC pressures applied to the speaker and the valve itself does not contribute significantly to the serial impedance of the system.

Elastic characteristics of the airway wall.

To examine the elastic behavior of the upper airway, we obtained pressure-area plots from data gathered from acoustic images of the airway and measurements of mouth pressure during tidal breathing in 10 adult human volunteers (dA/dP). These plots revealed both tidal hysteresis and a change in slope as a function of distance along the airway. The slope of the regression line of the dA/dP plots decreased from the pharyngeal region to the trachea and became 0 at the thoracic inlet, the location of which was independently assessed. In most subjects the slope became negative distal to the thoracic inlet. Correlation coefficients between pressure and area approached 1 in the pharyngeal region and 0 at the thoracic inlet. When subjects breathed against a small resistive load (10 cmH2O.1(-1).s) pharyngeal, extrathoracic, and intrathoracic pressure-area plots were exaggerated but the slope at the thoracic inlet was unchanged. We conclude that this pressure-area characteristic defines regional differences in upper airway elasticity and delineates the transition point between the intra- and extrathoracic airways.

Nasal and tracheal responses to chemical and somatic afferent stimulation in anesthetized cats.

Respiratory chemical and reflex interventions have been shown to affect nasal resistance or tracheal tone, respectively. In the present study, nasal caliber (assessed from pressure at a constant flow) and tracheal tone (assessed from pressure in a fluid-filled balloon within an isolated tracheal segment) were monitored simultaneously in anesthetized, paralyzed, artificially ventilated (inspired O2 fraction = 100%) cats. We examined the effect of CO2 inhalation and sciatic nerve stimulation as well as the application of nicotine (6 X 10(-4) mol/l) or lidocaine (2% solution) to the intermediate area of the ventral medullary surface (VMS). CO2 and VMS nicotine resulted in a significant increase in tracheal pressure [147 +/- 73 and 91 +/- 86% (SD), respectively]; and a significant reduction in nasal pressure (-35 +/- 10 and -20 +/- 13%, respectively). In contrast, sciatic nerve stimulation resulted in a significant fall in both tracheal (-50 +/- 36%) and nasal pressure (-21 +/- 13%). Application of 2 or 4% lidocaine to the VMS reduced tracheal pressure but did not significantly affect nasal pressure. After VMS lidocaine, nasal and tracheal responses to CO2, sciatic nerve stimulation, or VMS nicotine, when present, were negligible. These results suggest a role for the VMS in the regulation and coordination of nasal and tracheal caliber responses.

Assessment of muscle action on upper airway stability in anesthetized dogs.

Skeletal muscle activation is believed to be important in the maintenance of upper airway patency. To determine where and how muscles affect pharyngeal stability, we assessed in heavily anesthetized, ventilated dogs, the negative pressure required to close the nasopharynx and the passage from the oral to the pharyngeal airway before and after electrical stimulation of six pairs of upper airway muscles: the sternohyoid, sternothyroid, ceratohyoid, thyrohyoid, genioglossus, and geniohyoid. Before muscle stimulation, the pressures required to close the nasopharynx and the oral passage were -9.8 +/- 2.3 (mean +/- SEM) and -4.9 +/- 1.9 cm H2O, respectively. Submaximal electrical stimulation of each of the six muscle pairs caused consistent and substantial improvements in nasopharynx closing pressure. In contrast, the stabilizing actions of these muscles on the oral passage was less consistent and smaller in magnitude. Using pressure in the sealed upper airway as an index of forces acting on the airway, we found a strong association between the effect of muscle stimulation on the closing pressure and the effect of muscle stimulation on producing a dilating force on the airway. We conclude that muscles in the anterior and lateral pharyngeal wall improve nasopharynx stability to a greater extent than oral passage stability and that the action by any of these six muscle pairs improves airway stability through their ability to dilate the upper airway.