Plasma elastin-derived peptide levels in normal adults, children, and emphysematous subjects. Physiologic and computed tomographic scan correlates.

Pulmonary emphysema is likely to be the result of elastic tissue digestion by unrestrained elastase activity in the lung. Elastin breakdown by elastases results in the release of soluble elastin fragments (EDP), which may be measured in plasma by an ELISA. Plasma EDP levels measured using an ELISA were determined in the following groups: disease-free children (n = 24), 0.162 +/- 0.082 ng/ml; disease-free adult nonsmokers (n = 114), 1.74 +/- 0.8 ng/ml; smokers (n = 68), 2.76 +/- 4.59 ng/ml; reformed smokers (n = 43), 1.91 +/- 1.14 ng/ml. Adults with established pulmonary emphysema (n = 50), as defined by bullous formation on the chest radiograph, had levels of 50.83 +/- 24.8 ng/ml, significantly higher than the disease-free groups at p < 0.01. Pulmonary emphysema can be reflected by pulmonary function tests, especially those that measure the pulmonary elastic properties, and by computed tomographic (CT) scan percent emphysema score. We therefore examined the relationship of plasma EDP to these other indicators of pulmonary emphysema in a separate group of 26 subjects using elastic recoil measurements (K), and a further group of 30 subjects with CT scan percent emphysema score. A significant correlation of p < 0.001 was shown for plasma EDP and K and a significant correlation of p < 0.01 was shown for plasma EDP and CT scan percent emphysema score, these correlations suggesting that plasma EDP levels are indicators of the loss of pulmonary distensibility and of mild to moderate pulmonary emphysema. These findings suggest that pulmonary emphysema is characterized by active elastin breakdown.


Formoterol compared with beclomethasone and placebo on allergen-induced asthmatic responses.

Formoterol is a new long-acting beta 2-agonist. We compared the protective effect of 24 micrograms formoterol with 200 micrograms beclomethasone and placebo on inhaled allergen-induced asthmatic responses in mild stable asthmatic subjects. We measured airflow rates, histamine airway responsiveness, cell counts from sputum and peripheral blood, and markers of lymphocyte and eosinophil activation. Adjustments were made for the confounding effect of bronchodilatation produced by formoterol in comparisons using a control inhalation of normal saline. Formoterol caused bronchodilation and inhibition of histamine airway responsiveness for at least 24 h. It completely inhibited the early asthmatic responses when beclomethasone had no effect. Control comparisons of the effect of formoterol and beclomethasone on the allergen-induced late asthmatic response and increase in histamine responsiveness showed each to be equally effective but not to inhibit the responses completely. Formoterol caused bronchodilation in addition to preventing bronchoconstriction. Both drugs inhibited the rise in serum eosinophil cationic protein 24 h after allergen, but neither inhibited the allergen-induced increases in sputum or blood eosinophils or CD25+ lymphocytes. These results suggest that formoterol modifies allergen-induced airway responses through functional antagonism rather than the inhibition of inflammatory cell infiltration.


Increased oxygen species generation in blood monocytes of asthmatic patients.

Besides eosinophils, inflammatory processes in asthma are characterized by an infiltration of inflammatory cells, including mononuclear phagocytes, such as alveolar macrophages (AM) and blood monocytes, in the airways. Monocyte activation has been observed in the blood after exercise or allergen-induced asthma. Stimulated AM in chronic and stable asthmatic patients have been shown to release oxygen species. We thus investigated the intensity of the activation of monocytes from 18 asthmatic patients compared with 18 healthy subjects. Oxygen species release was analyzed for monocytes in suspension by chemiluminescence using a luminometer and for monocytes maintained in adherence using conventional assay and video imaging camera. Circulating blood monocytes in suspension from asthmatic patients and control subjects showed the same baseline free radical release. Monocytes in suspension from asthmatic patients were more stimulatable by PMA: specifically, monocytes release more H2O and peaks of O2-. are sooner; moreover, peaks of total free radical release are higher, and this plateau is sustained. Compared with monocytes from control subjects, those from asthmatic patients evaluated after adherence show a higher baseline for O2-. and higher total free radical release. Monocytes from asthmatic patients spontaneously release more O2-. over time in nonstimulated cells and release more O2-. with PMA stimulation; they show the same peak level total free radical release as those from control subjects after stimulation. SOD activity analysis on adherent monocytes was lower in asthmatic compared with control subjects. These data show that monocytes from asthmatic patients were activated compared with control monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)


Impairment of airway mucociliary transport by Pseudomonas aeruginosa products. Role of oxygen radicals.

We previously showed that the supernatant of a Pseudomonas aeruginosa (PA) culture and its constituents pyocyanin and 1-hydroxyphenazine inhibit ciliary activity of dispersed tracheal epithelial cells in vitro via the generation of oxygen radicals by phagocytes. In the present study, we wished to determine if tracheal mucus velocity (TMV) is also impaired by PA supernatant and if oxygen radicals have a mediating role. In conscious sheep, TMV (measured with a radiographic method) was determined before and serially following aerosol challenge with the cell-free supernatant of a PA culture or unconditioned culture medium (control). TMV decreased from a mean (+/- SEM) baseline of 6.7 +/- 1.1 mm/min (n = 6) by 29, 35, and 25% at 0.5, 3, and 24 h after challenge, respectively (p < 0.05), and returned to baseline 1 wk later (-6%, p = NS). Control medium had no effect on TMV (maximum decrease by 15% at 0.5 h). Aerosolized catalase blunted the effect of PA supernatant on TMV. To determine if the impairment of TMV involved ciliary inhibition, tissues were mounted in a chamber and ciliary beat frequency (CBF) and surface liquid velocity (SLV) were measured with a microscopic method. PA supernatant decreased both CBF (maximum mean decrease 12%; n = 5, p < 0.05) and SLV (maximum mean decrease 78%; n = 5, p < 0.05) in a dose-dependent fashion, with a correlation between the two parameters; these effects were blocked by catalase.(ABSTRACT TRUNCATED AT 250 WORDS)


Prostanoids inhibit release of endogenous norepinephrine from rat isolated trachea.

Prostanoids, of epithelial origin, are known as modulators of several processes in the airways. The present study examined whether prostanoids are involved in the local control of sympathetic neurotransmission. The release of endogenous norepinephrine from rat isolated tracheae was evoked by electrical field stimulation (3 Hz, 540 pulses) in the presence of yohimbine, desipramine, and tyrosine. In different series of experiments, indomethacin (3 mumol/L) increased the evoked release of endogenous norepinephrine by 70 to 80%. In the presence of indomethacin, prostaglandin E2 (PGE2) and several prostanoid receptor agonists inhibited the evoked release of norepinephrine in a concentration-dependent manner, maximally by 60 to 70%. According to the concentration producing 35% inhibition of norepinephrine release (half-maximal effect), the following rank order of potencies was observed (EC35): nocloprost (8 nmol/L), sulprostone (30 nmol/L), PGE2 (308 nmol/L), iloprost (2 mumol/L), and U46619 (> 10 mumol/L). The EP1 receptor antagonist AH 6809 (3 mumol/L) had no effect on the evoked norepinephrine release and did not affect the inhibitory effect of 1 mumol/L of sulprostone. In the absence of indomethacin, the inhibitory effect of PGE2 was similar to that observed in the presence of indomethacin. After removal of the epithelium, the evoked norepinephrine release was markedly reduced. However, no significant effect of indomethacin was observed in epithelium-denuded tracheae. In conclusion, norepinephrine release in the rat trachea is inhibited via prostaglandin receptors that have the pharmacologic characteristics of the EP3 subtype. Endogenous eicosanoids, most likely of epithelial origin, are involved in the local control of the release of norepinephrine.


Angiotensin II-1 receptor-mediated Cl secretion by canine tracheal epithelium.

To elucidate the effect of angiotensin II (AII) on ion transport function of airway epithelium, we studied the bioelectrical properties of canine cultured tracheal epithelium under short-circuit conditions in vitro. Addition of AII to submucosal solution in Ussing chambers increased the short-circuit current (ISC) in a dose-dependent fashion, the maximal increase from the baseline value and the concentration required to produce a half-maximal effect being 5.2 +/- 0.5 microA/cm2 (p < 0.001) and 10(-6) M, respectively. In contrast, mucosal AII had little effect. The AII-induced increase in ISC was not altered by the AII-2 receptor antagonist EXP655 but was depressed by the AII-1 receptor antagonist DuP 753. Diphenylamine-2-carboxylate, Cl-free medium, indomethacin, the phospholipase A2 inhibitor mepacrine, and the methyltransferase inhibitor 3-deazaadenosine reduced the change in ISC, whereas amiloride and the lipoxygenase inhibitor AA-861 did not. Addition of AII to the submucosal but not the mucosal side increased the release of prostaglandin E2, an effect that was abolished by DuP 753. These results suggest that AII may interact with the submucosal AII-1 receptor and stimulate Cl secretion across tracheal epithelium through the mobilization of arachidonic acid and the release of prostaglandin E2.


Furosemide differentially relaxes airway and vascular smooth muscle in fetal, newborn, and adult guinea pigs.

Furosemide, an inhibitor of Cl-dependent Na+,K+ cotransport, is the most frequently used diuretic in newborns. Recently, furosemide was also demonstrated to decrease bronchial hyper-responsiveness in adults, although little is known about the direct effect of furosemide on smooth muscle of immature animals. This in vitro study was designed to determine the action of furosemide on airway and vascular smooth muscle during ontogeny. Extrathoracic trachea (ET), main stem bronchi, main pulmonary artery, and thoracic aorta ring segments from fetal, newborn, and adult Hartley albino guinea pigs were suspended in HEPES solution for measurement of isometric tension. Furosemide (30 or 300 microM) was administered after preconstriction with an ED35-70 concentration of histamine or acetylcholine for airway and ED40-100 concentration of norepinephrine for vessels. Furosemide (30 microM) caused significant relaxation of airway smooth muscle at all ages. After histamine-induced preconstriction, fetal airway segments exhibited greatest relaxation (183 +/- 28%), with newborn airway demonstrating 123 +/- 15% relaxation and modest relaxation seen in adults (40 +/- 4%). This pattern was similar for both ET and bronchus and appeared greater for histamine compared with ACh preconstriction. Epithelial removal slightly enhanced relaxation. Furosemide also relaxed pulmonary artery segments, but at a 10-fold higher concentration. In striking contrast to the pattern seen in airway, adult pulmonary artery relaxed more than newborn and newborn, more than fetus. Cyclooxygenase blockade and endothelium removal did not change pulmonary artery relaxation. Furosemide did not significantly relax aorta after NE preconstriction. Taken together, these results suggest that furosemide may be more effective in relaxing airway compared with vascular smooth muscle, and the ontogeny of these responses indicates a greater efficacy and selectivity in airways of immature animals.


Effects of natriuretic peptides and neutral endopeptidase 24.11 inhibition in isolated perfused rat lung.

We have studied the acute effect of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) on pulmonary vascular tone in normoxia and acute hypoxia in the absence and presence of a specific inhibitor of neutral endopeptidase 24.11 (NEI, UK 73, 967, candoxatrilat; Pfizer) in the isolated and blood-perfused rat lung preparation. Baseline pulmonary artery pressure (Ppa) was 16.4 +/- 0.3 mm Hg in lungs from normoxic control rats and 22.5 +/- 0.3 mm Hg in lungs from rats kept in hypoxia (FIO2 = 10%) for 7 days. Acute hypoxic pulmonary vasoconstriction (HPV delta Ppa) was similar in normoxic control rats (9.5 +/- 0.6 mm Hg) and chronically hypoxic rats (9.8 +/- 0.9 mm Hg). NEI at 0.07 and 0.2 mg had no effect on baseline Ppa or HPV delta Ppa. Synthetic BNP at 10 nM had no effect on baseline Ppa but produced a 2.8 +/- 0.2 mm Hg reduction in HPV delta Ppa alone and 2.7 +/- 0.2 mm Hg reduction in the presence of 0.07 mg NEI in normoxic control rats. In contrast, ANP at 10 nM produced a significantly greater decrease in HPV delta Ppa in the presence of 0.07 mg NEI (4.8 +/- 0.3 mm Hg, p < 0.05) compared with ANP alone (2.9 +/- 0.4 mm Hg), and similar results were also observed in chronically hypoxic rats. Thus, BNP has a vasodilator effect similar to that of ANP in the pulmonary circulation. Inhibition of neutral endopeptidase 24.11 augments the effects of ANP on HPV but does not influence the pulmonary vascular responses to BNP.


Effects of in utero phrenic nerve section on the development of collagen and elastin in lamb lungs.

Interference with fetal breathing movements is known to retard morphologic development of the lung and to reduce compliance. We hypothesized that the lower compliance might be in part due to effects on lung structural proteins. We studied the effects of phrenic nerve section in utero on lung compliance and on the lung contents of collagen, elastin, and DNA. At 110 to 112 days of gestation, one fetal lamb in each of 12 twin pregnancies had either both phrenic nerves cut (PX) or a sham operation (S). The other twin was left unoperated (Upx, Us) as a control. They were killed 14 to 22 days later, and the concentrations in lung parenchyma of collagen (as hydroxyproline HPro), elastin, and DNA were measured, together with lung compliance and dry and wet weight. Paired comparisons were made (PX versus Upx and S versus Us). Both operated groups (PX, S) had smaller lungs with lower water content than did their unoperated twins. Absolute static compliance in PX was reduced, but compliance relative to lung weight was unchanged, and there was no significant difference between S and Us. There were no significant effects of PX on the concentrations of HPro, elastin, and DNA, or on the elastin/collagen ratio. Compliance was not correlated with either HPro or elastin content. HPro content increased significantly with gestational age in all groups. It is concluded that phrenic nerve section retards the increase of lung compliance and possibly air space, but it does not affect the overall rate of lung cell proliferation or of deposition of elastin or collagen.(ABSTRACT TRUNCATED AT 250 WORDS)


Ventilation and gaseous metabolism in infants born at high altitude, and their responses to hyperoxia.

Hyperventilation and decreased metabolic rate are commonly observed in newborns during acute hypoxia; whether these responses are also present during sustained hypoxia is not known. We asked whether infants at high altitude had higher ventilation and lower metabolism than lowlanders. Ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2) were measured in newborn (< 1 day old) full-term infants in La Paz (altitude 3,800 m; inspired oxygen pressure [PIO2], 92 mm Hg) and in Santa Cruz (altitude, 400 m; PIO2, 141 mm Hg), Bolivia. Each group consisted of 30 infants selected to have similar body weight. The mothers, Amerindians and mestizos, were born in the corresponding cities or at equivalent altitudes. Despite the lower inspired oxygen concentration in La Paz (0.107 ml STPD O2/ml BTPS air) than in Santa Cruz (0.164), neither VE nor VO2 or VCO2 differed between the two groups. The breathing pattern was deeper and slower at high altitude. From the values of VE and VO2 it was calculated that high-altitude infants extracted more O2 (+62%) from the inspired air than did the lowlanders. When given pure O2 to breathe, both groups of infants similarly increased VE and gaseous metabolism; even during hyperoxia, however, the ventilatory O2 extraction was higher (+50%) in the highlanders. We conclude that, contrary to what is observed in acute hypoxia, infants at high altitude maintain metabolic rate with no major alterations in VE. The ability to use a greater fraction of the inspired O2 at high altitude probably results from functional and structural alterations stimulated by fetal hypoxia.


Characterization of gamma/delta T-lymphocytes in the peripheral blood of patients with active tuberculosis. A comparison with normal subjects and patients with sarcoidosis.

Studies in experimental animals have suggested that gamma/delta T-cells play an important role in the immune response against mycobacteria, but evidence for the participation of these cells in the course of human tuberculosis remains fragmentary. We have evaluated the number and state of activation of gamma/delta T-cells in the peripheral blood of patients with active tuberculosis using two-color cytofluorometry, and we have sought evidence that these cells might play a role in the impaired responses to recall antigens seen in some patients by comparing the proliferation of blood T-lymphocytes before and after removing gamma/delta T-cells by panning. Results were compared with those obtained for cells from normal subjects and from patients with sarcoidosis. The proportion and absolute number of circulating CD3+ gamma/delta T-cells were not significantly different comparing blood from patients with tuberculosis and that from control subjects [54.6 +/- 39.9 (n = 17) and 59.1 +/- 30.2 cells/microliters (n = 10), respectively, p > 0.2], and the proportion of cells expressing receptors using the V delta 1 variable region remained unchanged in patients with tuberculosis. Few gamma/delta T-cells from patients with tuberculosis expressed surface antigens associated with activation (IL-2R, < 1%; HLA-DR, 2.6 +/- 3.4%). Four of 15 patients with sarcoidosis had a proportion of gamma/delta T-cells that was outside the range observed in normal subjects, but the absolute number of CD3+ gamma/delta T-lymphocytes was not different comparing the two groups (p > 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)


Dissociation between dyspnea and respiratory effort.

Breathlessness induced by hypercapnia may be related to the sensation of respiratory effort or to the central or peripheral effects of CO2. To examine the relationship among breathlessness, respiratory effort, and hypercapnia, we studied eight normal naive subjects. By using a visual feedback system, subjects maintained a constant ventilation of 50-60 L/min. PETCO2 was held at 40 mm Hg during the first 2 min of each trial (control period), then for 4 min (test period) was either kept at 40 mm Hg or elevated to 50 mm Hg. At the end of each control and test period, subjects were asked to give separate ratings for dyspnea (an unpleasant urge to breathe) and for the sense of respiratory effort (analogous to lifting a weight) on a 50-cm visual analog scale. Hypercapnia was associated with a significant reduction in effort ratings (-7.3 +/- 6.4, mean +/- SD, p < 0.05) and a concomitant increase in dyspnea (+6.6 +/- 6.0, p < 0.05). We conclude that dyspnea associated with hypercapnia is dissociated from changes in respiratory effort, and that CO2 has a direct central effect that leads to breathlessness. Our data also suggest that the sense of effort at a given level of ventilation is less when the ventilation is the result of "reflex" stimuli to breathe rather than "voluntary" signals to the respiratory muscles.


Evidence of acute diaphragmatic fatigue in a "natural" condition. The diaphragm during labor.

Acute diaphragmatic fatigue has been experimentally shown to occur in normal healthy subjects and in patients with chronic obstructive pulmonary disease by asking them to modify their pattern of breathing or to breathe against high inspiratory resistances. During the expulsive period of labor women are asked periodically to make strong expulsive efforts and to sustain them isometrically for many seconds; this is likely to produce "natural" diaphragmatic fatigue. To investigate whether this was the case, six women were studied in the delivery room from the moment of the rupture of the amnion until delivery of the infant occurred. The development of diaphragmatic fatigue was assessed both by measuring the static maximal inspiratory pressure (MIP) and by analyzing the electromyographic power spectrum of the diaphragm (H/L ratio). The majority of contractions were concentrated in the expulsive period of labor. MIP, recorded in the supine position, significantly decreased from 103.2 +/- 17.2 cm H2O (at the beginning of the expulsive period) to 73.8 +/- 10.1 cm H2O (after the delivery). The H/L ratio fell progressively during the expulsive period; after the delivery, it was 59.2 +/- 15.7% of the value recorded at the beginning of the expulsive period. This study demonstrates that (1) the diaphragm is active in the expulsive efforts during labor and (2) the tension developed and the time each contraction is maintained may lead to the development of diaphragmatic fatigue. Therefore, we provide evidence of acute diaphragmatic fatigue in a natural condition.


Adult criteria for obstructive sleep apnea do not identify children with serious obstruction.

Although obstructive sleep apnea (OSA) occurs in the pediatric population, diagnostic criteria have not been established. Since criteria for adult OSA are well established, we asked whether commonly used adult criteria, such as the apnea index (based on the number of obstructive apnea [OA] events per hour), would identify children with serious sleep-related upper airway obstruction. Polysomnographic data were analyzed from 20 children (ages 8 months to 16 yr) with clinical evidence of upper airway obstruction during sleep (loud snoring and labored breathing) and who had cyclic oscillations of oxyhemoglobin saturation (SaO2) during sleep. The overnight studies included sleep state (EEG, EOG, and EMG), SaO2, ECG, nasal (end-tidal CO2) and oral (thermistor) airflow, chest and abdominal movement (inductance plethysmography), and video camera and behavioral observations. Measurements included the number of obstructive events > or = 10 s, the number of desaturations (> or = 5% decrease lasting > or = 5 s), the number of desaturation episodes to < 90%, < 85%, and < 80% lasting > 5 s, and the percentage of sleep time with SaO2 values < 90%. Gas exchange was impaired as evidenced by cyclic decreases in SaO2 and elevated PETCO2 values (maximum value 58 +/- 6 mm Hg). The children experienced 175 +/- 168 (range 6 to 609) episodes of decreased SaO2 > 5%, with an average minimum SaO2 of 66 +/- 13% (range 30 to 85%). The average number of apnea events was only 1.9 +/- 3.2 events/h (range 0 to 10.4).(ABSTRACT TRUNCATED AT 250 WORDS)


Normal polysomnographic values for children and adolescents.

Although polysomnography is routinely performed to evaluate children and adolescents with sleep-disordered breathing, normal polysomnographic values for the pediatric age group have not yet been established. We therefore performed overnight polysomnography in 50 normal children and adolescents (mean age 9.7 +/- 4.6 SD yr, range 1.1 to 17.4 yr). Of the children 56% were male. Chest wall motion, ECG, oronasal airflow, end-tidal PCO2 (PETCO2), arterial oxygen saturation (SaO2), and electrooculogram were monitored. Children had 0.1 +/- 0.5 (range 0 to 3.1) obstructive apneas per hour of total sleep time, with only 18% of children having any obstructive apneas. No child had obstructive apneas > 10 s in duration. Of the children 30% had central apneas > or = 10 s in duration, and one child had a central apnea associated with SaO2 < 90%. Peak PETCO2 was 46 +/- 4 mm Hg (range 38 to 53 mm Hg), and hypoventilation (PETCO2 > 45 mm Hg) occurred for 7 +/- 19% total sleep time (range 0 to 91%). The SaO2 nadir was 96 +/- 2% (range 89 to 98%), with only one child desaturating below 90% in association with a central apnea. We conclude that polysomnographic results in the pediatric age group differ from those in adults. Recommendations for normal polysomnographic criteria are given.


A specific and potent pressor effect of hypoxia in patients with sleep apnea.

A hypoxic ramp test (to 75% arterial oxygen saturation) during the awake state was performed in 17 patients with obstructive sleep apnea (OSA). Blood pressure was monitored with an indwelling arterial line (radial artery), and the ventilatory response to eucapnic hypoxia was determined. Eight of the patients were normotensive. The remaining nine hypertensive patients were studied after a 3-wk washout of antihypertensive medication. Compared with a nonmatched group of normotensive nonsnoring control subjects in whom hypoxemia did not affect blood pressure, all OSA patients showed various degrees of pressor responses during hypoxia. The pressor response was of similar magnitude in normotensive and hypertensive patients with OSA. There was a significant relationship between the ventilatory and the pressor responses to hypoxia (p = 0.03) that was similar in both normotensive and hypertensive patients. Although disease severity expressed as apnea index (number of apneas per hour of sleep) or minimum arterial oxygen saturation reached during the overnight recording correlated with the magnitude of the pressor response (p = 0.03 and 0.045, respectively), the ventilatory response to hypoxia was unrelated to disease severity. Hypoxemia induced a similar increase in heart rate in controls and in normotensive patients, but an attenuated heart rate response was seen at the nadir of oxygen saturation in hypertensive subjects (p < 0.05). These data demonstrate that patients with obstructive sleep apneas have a pressor response to hypoxia. This response is likely to be involved in the blood pressure swings seen during apnea in patients with OSA.(ABSTRACT TRUNCATED AT 250 WORDS)


Temperature thresholds in the oropharynx of patients with obstructive sleep apnea syndrome.

The temperature thresholds for warmth and cold were determined on the oropharyngeal mucosa of 15 patients with obstructive sleep apnea syndrome (OSAS) and 15 age-matched nonsnoring control subjects. We found that six of the patients with OSAS were not able to detect either the upper (50 degrees C) or lower (25 degrees C) temperature limits of the test when recording from the tonsillar pillar, whereas all control subjects detected the temperature change within the measuring range. The OSAS patients showed a statistically significant higher threshold for warmth on the anterior tonsillar pillar, 46.8 degrees C (95% confidence interval 45.2-48.4) versus 42.5 degrees C (41.3-43.8) for the control subjects (p = 0.0006). The same was found on the tip of the tongue-40.1 degrees C (38.7-41.6) for OSAS patients and 38.2 degrees C (37.1-39.4) for the control subjects (p = 0.036). Determination of temperature thresholds on the skin is an established method of detecting a neuropathy. We speculate that patients with OSAS suffer from a neuropathy in the pharynx caused by prolonged and progressive trauma to the pharyngeal structures from vibration induced by snoring and/or stretching of the structures during apneas. A neuropathy may interfere with the normal stabilizing function of the pharyngeal muscles and with the local reflex mechanism preventing the upper airway from collapsing during inspiration. It is thus possible that snoring itself, by inducing a neuropathy in the pharynx, may contribute to the sequence of events that transform a snorer into a patient suffering from OSAS.


Respiratory short-term poststimulus potentiation (after-discharge) in patients with obstructive sleep apnea.

In conscious normal humans after a brief hypoxic ventilatory stimulus, ventilation slowly decays to baseline and does not undershoot though the subjects are hyperoxic and hypocapnic. This phenomenon is attributed to short-term poststimulus potentiation (STP), which may be an important factor promoting ventilatory stability by preventing periodic breathing. It has been proposed that obstructive sleep apnea (OSA) is a variant of periodic breathing, with obstruction occurring when ventilatory drive is low. If this were the case, patients with OSA might have reduced STP. To test this, seven normal adults and 12 patients with OSA (mean apnea index, 52.4 +/- 6.9 SE events/h) were studied. Ventilation (VI) was measured in awake seated subjects during 30 to 45 s of exposure to hypoxia (end-tidal O2: 50 mm Hg) followed by hyperoxia. A total of 57 hypoxic-hyperoxic runs were analyzed (36 in the patients and 21 in the normal subjects). During hypoxia VI increased and end-tidal CO2 decreased by similar amounts in both groups. In normal subjects after hypoxia there was a gradual decay in VI to prehypoxic levels without an undershoot. In patients, there was on average a ventilatory undershoot at 35 s of hyperoxia, with a mean VI of 83% of baseline. The undershoot was due mainly to a decrease in tidal volume, which was significantly lower than that of the normal subjects for several seconds. These changes were particularly prominent in seven patients who were not different from the others in terms of baseline characteristics, hypoxic responses, and OSA severity.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of triazolam on the arousal response to airway occlusion during sleep in normal subjects.

The purpose of this study was to assess the effect of triazolam (0.25 mg) on the arousal response to airway occlusion during nonrapid eye movement sleep in normal subjects. Six male subjects (mean age +/- SD, 28.1 +/- 7.1 yr) had their arousal response tested by occluding a mask covering the nose with the mouth sealed. After an adaptation night, subjects were studied on two consecutive nights. They ingested triazolam (0.25 mg) or placebo one-half hour before bedtime in a randomized double-blind crossover manner. Mask occlusion was performed 1 to 4 h after triazolam/placebo ingestion while the subjects breathed a mixture of air and oxygen adjusted to produce an arterial oxygen saturation of 98%. The maximal deflections in airway pressure were measured at a supraglottic location during airway occlusion to reflect the degree of inspiratory effort. The time to arousal (mean +/- SEM) was significantly longer on triazolam nights (32.0 +/- 5.2 versus 22.6 +/- 3.2 s, p < 0.01). The maximal airway suction pressure preceding arousal was higher on triazolam nights (26.5 +/- 2.0 cm H2O versus 20.0 +/- 1.2 cm H2O, p < 0.02). Conversely, the rate of increase in inspiratory effort (maximal pressure) during occlusion was not decreased by triazolam. We conclude that triazolam prolongs the time to arousal following airway occlusion by increasing the arousal threshold.


Effects of surgical correction of nasal obstruction in the treatment of obstructive sleep apnea.

Negative upper airway pressure is thought to play a key role in the pathophysiology of obstructive sleep apnea. Because nasal resistance contributes to the increase of the transpharyngeal pressure gradient, we evaluated the effects of nasal surgery on sleep-related breathing abnormalities in 20 adults with obstructive sleep apnea. Polysomnographic studies were done before (baseline), and 2 to 3 mo after surgery (septoplasty, turbinectomy, and/or polypectomy). Nasal resistances were measured at these visits in 14 patients. Cephalometric measurements were obtained before surgery. Cephalometric abnormalities consisted in an increase in the distance from the mandibular plane to the hyoid bone (MP-H), a decrease in the space between the base of the tongue and the posterior soft tissues (PAS), a retroposition of the mandibule, and an increase in the length of the soft palate. Body weight did not change between the two studies. Nasal resistance decreased significantly after nasal surgery. The composition of the total sleep time spent in the rapid eye movement stage increased from 11.5 +/- 1.3% (mean +/- SEM) to 14 +/- 1.2% after surgery. For the group as the whole, there was no difference between baseline and postsurgical values in the frequency of respiratory disturbances (39.8 +/- 6.1, 36.8 +/- 5.9 n/h), the total apnea time (17.8 +/- 4.2, 15.4 +/- 2.8), the distribution of the apnea time within the different apnea types (obstructive and nonobstructive), and the severity of the nocturnal desaturations. Interestingly, apnea and apnea plus hypopnea indices returned to normal values (< 5 and 10, respectively) in four subjects with normal posterior soft tissues and mandibular plane to the hyoid bone distances.(ABSTRACT TRUNCATED AT 250 WORDS)


Fiber type and regional differences in oxidative capacity and glycogen content in the hamster diaphragm.

The purpose of this study was to define variability of the oxidative capacity and glycogen content between different fiber types and regions of the hamster diaphragm. Using histochemical and microphotometric techniques, the oxidative capacity (identified by nicotinamide-adenine dinucleotide tetrazolium reductase reaction end product) and glycogen levels (identified by the periodic acid-Schiff stain test) were examined in three myofibrillar ATPase (M-ATPase) fiber types and four diaphragmatic regions: sternal, anterior costal, thoracic surface of the crural (thor/crur), and abdominal surface of the crural (abd/crur). Most regional differences were found between the crus and the rest of the diaphragm. There were no differences in the oxidative capacity between diaphragmatic regions in the types 1 and 2a fibers, but the type 2b fibers in the thor/crur region had the greatest oxidative capacity and the 2b fiber in the sternal region had the lowest oxidative capacity. There were differences in glycogen content between diaphragmatic regions for all of the three M-ATPase fiber types. Variability in oxidative capacity between fiber types was demonstrated in all regions except the thor/crur region. Variation in glycogen content between fiber types was only demonstrated in the two surfaces of the crus. The type 2b fiber demonstrated the most differences from types 1 and 2a fibers in oxidative capacity and glycogen content in the different diaphragmatic regions, whereas the types 1 and 2a fibers demonstrated few differences from each other in these features across the different diaphragmatic regions.(ABSTRACT TRUNCATED AT 250 WORDS)


Lung oxidant changes after zymosan peritonitis: relationship between physiologic and biochemical changes.

Our purpose was to determine the effect of non-bacteria-dependent systemic inflammation on the degree and time course of lung oxidant activity and antioxidant defenses, comparing these changes with lung, physiologic, and histologic alterations. Adult male rats were given intraperitoneal zymosan (0.7 mg/g body weight) and were fluid resuscitated. Oxidant changes were measured as lung tissue oxidized glutathione (GSSG) and malondialdehyde (MDA) content, antioxidant defenses as tissue reduced glutathione (GSH), and catalase. Animals were killed at 4, 12, and 24 h, and at 5, 10, and 30 days. Lung data were compared with that found in liver. We noted a 45% mortality in the first 18 to 36 h with all remaining animals surviving. In the first 24 h, we noted a doubling of lung MDA and an 80% conversion of tissue GSH to GSSG compared with less than 5% in control animals, indicating a severe oxidant stress. These findings corresponded with marked increase in lung neutrophils. Arterial pressure (PaO2) was significantly decreased from a control of 95 +/- 4 mm Hg to 80 +/- 5 mm Hg and 75 +/- 4 mm Hg at Days 5 and 10, respectively, but returned toward control by 30 days. Lung GSSG and MDA remained significantly increased for the 30-day period, whereas amounts of the antioxidants, catalase, and GSH returned to control after 24 h. The ongoing oxidant stress corresponded with marked mononuclear cell infiltration and interstitial thickening, which persisted over the 30-day period even after peritonitis had completely resolved.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of aerosolized recombinant human granulocyte macrophage colony-stimulating factor on lung leukocytes in nonhuman primates.

The number and function of myeloid cells in the lungs are critical determinants of health and disease. To examine whether these cells can be modulated in vivo by a colony-stimulating factor (CSF), recombinant human granulocyte macrophage-CSF (GM-CSF) was given to cynomolgus monkeys by either continuous intravenous infusion (7,200 U/kg/day) for 2 wk or by aerosol exposure to 10(7) U on 1 or 2 consecutive days. At intervals after the initiation of GM-CSF administration, animals underwent bronchoalveolar lavage (BAL) and had peripheral blood sampled to characterize changes in lung and circulating phagocytic cells. Compared with animals exposed to bovine serum albumin, there was an increase in the total number of BAL cells retrieved. This increase was greatest in animals receiving aerosolized GM-CSF, and it was the result of more macrophages and neutrophils. Both lung macrophages and blood neutrophils from animals exposed to aerosolized GM-CSF exhibited an augmented respiratory burst in response to phorbol myristate acetate. Lung macrophages from GM-CSF-exposed animals exhibited increased capacity to bind and/or ingest opsonized and unopsonized Staphylococcus aureus. Despite functional activation of lung phagocytic cells, biochemical analyses of BAL fluid for markers of lung injury revealed an increase in only some parameters in the GM-CSF group. Intravenous administration of GM-CSF had the expected effect on augmenting the number of myeloid cells in the bloodstream. Aerosolized GM-CSF produced a transient effect on circulating myeloid cell number between 3 and 5 days after exposure.(ABSTRACT TRUNCATED AT 250 WORDS)


Hyperoxia-induced airway remodeling in immature rats. Correlation with airway responsiveness.

We recently found that exposure of 21-day-old rats to hyperoxia (> 95% O2 for 8 days) significantly increased in vivo airway cholinergic responsiveness and that O2 exposure also increased airway epithelial and smooth muscle layer thicknesses in a separate cohort of animals. There was substantial variation in the magnitude of both the functional and structural responses to hyperoxia. The present study was designed to test whether the magnitude of O2-induced airway remodeling could account for individual differences in airway responsiveness after O2 exposure, as well as for the difference in responsiveness between air- and O2-exposed animals. We assessed in vivo airway responsiveness to aerosolized acetylcholine (ACh) and airway architecture in 14 O2- and 5 air-exposed, immature rats. Total respiratory system resistance was determined using a plethysmographic method. The mean thicknesses and fractional areas of the airway epithelial and smooth muscle layers were determined by contour tracing using a digitizing pad and microcomputer. Both the small (circumference < 1,000 microns) and central (circumference 1,000 to 4,000 microns) airways were studied. For O2-exposed rats, individual values of EC200 ACh correlated negatively with small airway smooth muscle layer thickness (r = -0.59, p < 0.05; ANOVA), small airway smooth muscle layer fractional area (r = -0.75, p < 0.01), small airway epithelial thickness (r = -0.54, p < 0.05), small airway epithelial fractional area (r = -0.69, p < 0.01), and central airway smooth muscle layer thickness (r = -0.53, p < 0.05). When both air- and O2-exposed animals were considered, EC200 ACh correlated negatively with all eight parameters of airway layer thickness and fractional area.(ABSTRACT TRUNCATED AT 250 WORDS)


Bradykinin causes airway hyperresponsiveness and enhances maximal airway narrowing. Role of microvascular leakage and airway edema.

The relationship between bronchial edema and airway responsiveness was studied in cats in situ. Five cats were exsanguinated, and the bronchial arteries were perfused. We monitored pulmonary resistance (RL), and the provocative dose of acetylcholine (ACh) required to produce a 300% increase in RL (PD300) was determined. Bronchial vascular permeability was measured by quantifying extravasation of Evans blue (EB) dye. Bradykinin (BK) and ACh were administered via the bronchial arteries to increase leakage and bronchoconstriction, respectively. BK preperfusion (for 30 min) significantly increased bronchial vascular permeability to four times the control values (p < 0.05). BK preperfusion did not alter baseline RL but caused hyperresponsiveness to ACh, with log [PD300 (mole)] of -6.53 +/- 0.42 (mean +/- SD) and -6.90 +/- 0.30, before and after BK, respectively (p < 0.01). Furthermore, the maximal airway narrowing after BK was 58% higher than before BK (p < 0.01). Histologic study showed peribronchial edema after BK. The enhancement of maximal airway narrowing was significantly correlated with the degree of EB dye extravasation. These results suggest that BK causes airway hyperresponsiveness to ACh and increases maximal airway narrowing, possibly because of airway edema.


Bronchoconstriction and airway microvascular leakage in guinea pigs sensitized with trimellitic anhydride.

We have developed a guinea pig model of immediate airway responses following intradermal sensitization with free trimellitic anhydride (TMA). Guinea pigs were given an intradermal injection with either 0.1 ml of 0.3% TMA in corn oil (n = 8) or 0.1 ml of corn oil alone (n = 6). A guinea pig serum albumin conjugate of trimellitic anhydride (TMA-GPSA) was prepared with a substitution ratio of 21:1. All sensitized guinea pigs had raised specific serum IgG1 antibodies (ELISA), and IgE antibodies were detected in six of the eight sensitized guinea pigs by passive cutaneous anaphylaxis. On Days 21 to 28, guinea pigs were anesthetized, tracheostomized, and ventilated. Evans blue dye (20 mg/ml), an albumin marker, was injected intravenously to quantify airway microvascular leakage (MVL). TMA-GPSA (50 microliters; 1%) in saline was instilled into the trachea. Lung resistance (RL) was measured for 6 min. The guinea pigs were killed, and the lungs were removed. Peak RL (cm H2O/ml x s-1) was significantly increased in sensitized guinea pigs from 0.26 +/- 0.01, mean +/- SEM to 21.3 +/- 6.9 (p < 0.05), compared with nonsensitized guinea pigs. There was a significant increase in Evans blue at all levels of the tracheobronchial tree in sensitized guinea pigs compared with the controls (p < 0.005). The site of MVL was localized to the postcapillary venules as assessed by extravasation of intravascular Monastral blue dye. We conclude that intradermal sensitization of guinea pigs to TMA induces a polyclonal immune response, associated with bronchoconstriction and airway microvascular leakage, when challenged specifically with TMA-GPSA.(ABSTRACT TRUNCATED AT 250 WORDS)


Bronchial hyperreactivity after inhalation of trimellitic anhydride dust in guinea pigs after intradermal sensitization to the free hapten.

We have developed in the guinea pig, an animal model of bronchial hyperreactivity provoked by inhalation of trimellitic anhydride (TMA) dust, a known cause of occupational asthma in humans, after intradermal sensitization to the free hapten. Male Dunkin-Hartley guinea pigs (n = 6) were injected intradermally with 0.1 ml of 30% TMA in corn oil. Control animals (n = 7) were injected with 0.1 ml corn oil alone. On Days 21 to 28 after sensitization, guinea pigs were challenged (nose only) to 12 mg/m3 of inhalable TMA dust for 30 min. Bronchial reactivity was measured in sensitized animals and in control animals at 8 h after exposure to the dust. We also measured bronchial reactivity in sensitized exposed guinea pigs at 2 h (n = 5) and at 24 h (n = 5). Pulmonary inflation pressure (PIP) was used to assess bronchopulmonary response. Blood samples were taken for assessment of IgG-1 antibodies to TMA conjugated to guinea-pig albumin. The concentration of acetylcholine required to induce a 100% increase in PIP was used to assess bronchial reactivity. The lungs were eviscerated for histologic examination. All guinea pigs injected intradermally with TMA had high titers of specific IgG-1 antibodies to TMA conjugated to guinea-pig albumin. There was a significant increase in bronchial reactivity in sensitized guinea pigs 8 h after exposure to the TMA dust compared with that in the control animals. There was also a significant eosinophilic inflammatory influx in the subepithelium of the sensitized groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Relationship among mediators, inflammation, and volume history with antigen versus hyperpnea challenge in guinea pigs.

Paralyzed mechanically ventilated guinea pigs constricted to a similar degree by either isocapnic hyperpnea or antigen challenge display significantly different lung resistance (RL) volume history responses to a deep breath. We compared bronchoalveolar lavage (BAL) mediator profiles, BAL total protein concentrations, and tissue histopathology of antigen-constricted (AC), hyperpnea-constricted (HC), and control guinea pigs to determine whether patterns of volume history near peak constriction could be related to specific patterns of lung mediators, indices of microvascular leakage, or severity of tissue inflammation assessed pathologically. Methacholine constricted (MC) animals served as a second control group for assessing the effects of direct smooth-muscle contraction on indices of inflammation and volume history responses. Our results show that despite similar baseline and postchallenge RL, HC and MC animals displayed significant constriction reversal after a deep lung inflation, whereas AC animals did not. BAL concentrations of prostaglandin D2(PGD2), thromboxane B2 (TxB2), and leukotriene C4/D4/E4 (slow reacting substance of anaphylaxis, SRSA) were significantly elevated in both AC and HC animals compared with control and MC animals, with AC and HC BAL differing only with respect to PGD2 values (AC 2.4-fold higher). BAL total protein in AC animals was significantly greater than in HC, MC, and control animals. Histopathology showed significant peribronchial and interstitial cellular inflammation in AC animal specimens, whereas specimens from HC animals had little or no inflammation. Differences in volume history responses observed between equally constricted AC, HC, and MC animals may be due to differences in airway and/or parenchymal microvascular leak and cellular inflammation.


Increased expression of endothelin in bronchial epithelial cells of asthmatic patients and effect of corticosteroids.

We have previously demonstrated that human bronchial smooth muscle cells possess specific binding sites for the potent bronchoconstrictive peptide endothelin 1 and that primary cultures of human bronchial epithelial cells constitutively produce an endothelin-like material that binds to smooth muscle cell receptors with a kinetic ability analogous to that shown by the authentic peptide. To evaluate the potential role of airway epithelium-derived endothelin in the pathogenesis of asthma, we have examined here the expression of endothelin in the bronchial epithelial cells of 6 patients with symptomatic asthma and reversible airflow obstruction. The epithelial cells of 5 normal volunteers and 5 patients with chronic bronchitis and airflow obstruction unaffected by bronchodilators were tested as controls. The bronchial epithelial cells of all the asthmatic patients expressed preproendothelin 1 mRNA, as assessed by in situ hybridization, and released high amounts of mature and biologically active endothelin during a 48-h period of incubation (radioimmunoassay). By contrast, the epithelial cells from normal donors did not contain preproendothelin 1 transcripts, and the endothelin-like material in their supernatants was invariably below the detection limit of the assay. Only a few cells from 2 patients with chronic bronchitis expressed preproendothelin mRNA and endothelin immunoreactivity. When hydrocortisone (10(-6)M) was added to the culture medium of asthmatic bronchial epithelial cells for 48 h, the release of immunoreactive endothelin significantly decreased (p < 0.025), but the numbers of cells expressing preproendothelin 1 mRNA did not change to the same extent.


Miliary Mycobacterium bovis induced by intravesical bacille Calmette-Guérin immunotherapy.

Intravesical instillation of bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the treatment of choice for many patients with bladder cancer. In a small percentage, this therapy is associated with systemic side effects including pneumonitis. It is uncertain whether these systemic manifestations are due to dissemination of infection or due to hypersensitivity, an etiologic distinction that has important therapeutic implications. We report the first case in which miliary M. bovis was proven to be the responsible mechanism, by culture of M. bovis biovar BCG from a transbronchial lung biopsy and complete resolution on anti-tuberculous chemotherapy.


Effects of cigarette smoking on rate of loss of pulmonary function in adults: a longitudinal assessment.

Data from a random sample of 8,191 men and women selected in six U.S. cities and examined on three occasions over a 6-yr follow-up period were analyzed by longitudinal methods to describe the effects of smoking history and current smoking behavior on rate of loss of pulmonary function during adult life. Former smokers had age- and height-adjusted rates of decline (34.3 ml/yr for men and 29.6 ml/yr for women) comparable with those of never smokers (37.8 ml/yr for men and 29.0 ml/yr for women) but much smaller than those of continuing smokers (52.9 ml/yr for men and 38.0 ml/yr for women). The accelerated rate of loss of FEV1 among smokers depended linearly on the number of cigarettes smoked per day during the interval between examinations. The estimated increase in rate of loss associated with smoking was 12.6 ml/yr per pack/day for men and 7.2 ml/yr per pack/day for women. These longitudinal estimates of the effects of smoking were approximately 50% larger than estimates obtained from cross-sectional analysis of the initial pulmonary function examination. Men who started smoking had accelerated rates of loss (55.9 ml/yr) as did women (43.1 ml/yr). Smokers who stopped smoking between examinations had reduced declines (41.2 ml/yr for men and 28.7 ml/yr for women) compared with continuing smokers. The age-specific rates of loss suggest that the benefits of cessation may be greatest among the youngest smokers.(ABSTRACT TRUNCATED AT 250 WORDS)


Adrenergic and cholinergic regulation of bronchial vascular tone.

The autonomic nervous system plays a vital role in the regulation of vasomotor tone. Previous studies of systemic arteries and veins have shown that the classic autonomic neurotransmitters, norepinephrine and acetylcholine, act on smooth muscle, adrenergic nerve endings, and endothelial cells in the blood vessel wall to regulate vasomotor tone. Similar studies with isolated tissues indicate that bronchial arteries are innervated by adrenergic neurons and that norepinephrine activates postjunctional alpha 1-adrenoceptors to cause smooth muscle contraction. Isolated canine bronchial arteries fail to relax in response to beta-adrenoceptor agonists, and they do not contract when exposed to acetylcholine. This lack of responsiveness may be species-specific, however, since isolated bronchial arteries from other species respond to these agonists. Acetylcholine causes endothelium-dependent relaxation of bronchial arteries in vitro; this response is mediated by endothelial M3-muscarinic receptors. The role of the endothelium in mediating responses to adrenergic agonists, as well as the prejunctional effects of norepinephrine and acetylcholine on adrenergic nerve endings, remain to be explored in isolated bronchial arteries.


Lymph and blood flow responses in central airways.

The lymphatic drainage of the lung has been used as a quantitation of pulmonary microvascular fluid flux in normal animals and after various forms of injury. This review supports the importance of the bronchial microvasculature in the formation of lung lymph. Proof that the lymph drainage of the lung comes from the pulmonary circuit has been based on the finding of an elevation of lymph flow when the pulmonary venous pressure is elevated. This proof is wanting since recent work demonstrates that the venous drainage of the intrapulmonary bronchi flows into the pulmonary vascular system at the precapillary level. The administration of endotoxin induces an elevation of lung lymph. The bronchial circuit may play a role in this response since it is likewise exposed to the high pulmonary pressures induced by endotoxin, and there is evidence that ischemia/reperfusion injury to the airway occurs with endotoxin administration. After acute lung injury from smoke inhalation, lung lymph flow is markedly elevated. The lymph drainage from the airway may play an important role in this response. Bronchial blood flow is markedly increased after inhalation injury and there is airway edema. The increases in lung lymph flow and extravascular lung water are markedly reduced by occlusion of the bronchial artery. These data support the need for additional study of the role of the bronchial circulation in the formation of lung lymph.


Effect of airway blood flow on airflow.

Resistance to gas flow of an airway is a function of both airway smooth muscle tone and thickness of the airway wall internal to the outer ring of airway smooth muscle. Schematically, the increase in airway resistance caused by shortening of airway smooth muscle may be potentiated by a concomitant increase in airway wall thickness caused by vasodilation of the bronchial vessels and/or microvascular leakage. Conversely, bronchial vasoconstriction may limit to some extent the increase in resistance to gas flow caused by airway smooth muscle shortening and/or congestion and edema of the airway wall. Many endogenous paracrine mediators, putatively involved in asthma and bronchial hyperresponsiveness, have both bronchomotor and vascular effects. The overall effects on resistance to airflow of endogenous or exogenous agents depend not only upon pre-existing airway smooth muscle tone and pre-existing condition of bronchial vessels but also upon two factors that facilitate microvascular leakage, namely, inflammation of the airway wall and outflow pressure of the bronchial circulation, which is close to left atrial pressure.


Microvascular function. Transvascular exchange of fluid in the airways.

Fluid exchange in the airway microcirculation is presented relative to whether the airway epithelium is in an absorbing or a secreting state. The effects of increasing microvascular pressures and damaging the endothelial barrier are also examined relative to fluid dynamics and lymph flow, especially with regard to "filtration secretion." The microvessel pressure profile of the tracheal circulation is discussed relative to our recent data and to the published literature. These micropuncture data indicate that the major resistance to tracheal blood flow resides in arterioles with diameters less than 50 microns. It is hoped that this review will stimulate research on the airway microcirculation since the available data on the physiology and biophysics of circulation in the large and small airways are insufficient to define the microcirculatory exchange characteristics in this capillary bed.


Cellular and intercellular transport pathways in exchange vessels.

The endothelium of lung alveolar capillaries is of the continuous type, that of airway exchange vessels (capillaries and pericytic venules) includes both continuous and fenestrated types. Water and small lipophilic solutes penetrate via the endothelial cells (cell membrane pathway) as well as through intercellular junctions. Hydrophilic solutes are limited to junctional pathways and cytoplasmic vesicles. Permeation of hydrophilic solutes is progressively restricted with increasing molecular size, as by a sieve, with many openings 8 nm and a few 40 to 60 nm wide. In response to local tissue injury or to certain chemical mediators, larger junctional pathways may be opened, greatly increasing permeability to large molecules. Both alveolar capillaries and airway exchange vessels exhibit this response, but the effective stimuli may differ (e.g., alveolar capillaries are insensitive to histamine and bradykinin). Hydrophilic solutes are transported by diffusion, convection, and vesicular exchange (transcytosis). For small ions and molecules (radii < 2 nm), diffusion is the dominant transport mode; contributions of convection and transcytosis are negligibly small. Because diffusion decreases with increasing molecular size, all three mechanisms may contribute substantially to transport of large molecules (radii > 2 nm). Fenestrated endothelia have higher hydraulic conductivities and are more permeable to small ions and molecules than are continuous endothelia. However, their permeabilities to plasma proteins are about the same. Lung alveolar capillary endothelium has lower hydraulic conductivity and lower solute permeabilities than do other continuous endothelia (heart, skeletal muscle). Airway exchange vessel endothelium has about the same permeability to serum albumin as alveolar capillary endothelium.


Physiologic control. Anatomy and physiology of the airway circulation.

Both for the nose and the lower airways there is an extensive subepithelial capillary network. That for the nose is fenestrated, and this is true for the tracheobronchial tree of rats, guinea pigs, and hamsters, and for that of human asthmatics. However, healthy humans, dogs, and sheep have capillaries without fenestrations except for those close to neuroepithelial bodies and submucosal glands. Deeper in the mucosa there is a capacitance system of vessels, conspicuous in the nose but present also in the lower airways of rabbits and sheep and, to a lesser extent, in those of dogs and humans. Both for the nose and the lower airways, parasympathetic nerves are vasodilator, sympathetic nerves are vasoconstrictor, and sensory nerves are able to release dilator neuropeptides. Most inflammatory and immunologic mediators are vasodilator. A conspicuous difference between the nasal and lower airway vasculatures is the presence of arteriovenous anastomoses only in the former. Countercurrent mechanisms also exist in the nose to increase its efficiency in air conditioning, but they have not been established for the trachea. The pulmonary vasculature could be part of such a system for the bronchi. Distension of the airway vasculature thickens the mucosa, probably both by vascular distension and by edema formation. The latter can lead to exudation into the airway lumen. These processes have not been well quantitated, and the balance sheet of capillary and capacitance vessel volumes, interstitial liquid volume, and exudate volume needs to be worked out in physiologic and pathologic conditions.


The transport of albumin: a critique of the vesicular system in transendothelial transport.

Although albumin circulating in the plasma can exchange with the contents of the extensive vesicular system of microvascular endothelium, the mechanism and quantitative significance of vesicular transport remains unclear. It has recently been shown that transport of electron opaque tracers can occur via the vesicular system, but the detailed ultrastructure is inconsistent with the transcytotic shuttling of single vesicles. Although most physiologic measurements show a major degree of convective coupling in the microvascular permeation of perfused tissues, recent reports suggest that convective coupling is low when albumin escapes from the intact circulation. Because albumin clearance in these studies is consistent with values calculated from ferritin-labeling of vesicles in perfused microvessels, the possibility remains that macromolecular transendothelial transport occurs through transient communications within the vesicular system.


Turnover of hyaluronan in the microcirculation.

Hyaluronan in skin, lung, and intestine turns over within a few days and catabolism takes place locally in the tissues, in local lymph nodes, and in the liver. Hyaluronan will affect microcirculatory exchange through its influence on interstitial volume exclusion, hydraulic conductivity, and diffusivity of macromolecules. Prolonged increase in interstitial fluid flux in intestine has been shown to reduce the hyaluronan content, which in turn increases hydraulic conductivity and diffusivity of macromolecules.


Infections intensify neurogenic plasma extravasation in the airway mucosa.

Stimulation of sensory nerves in the airway mucosa of the rat evokes the release of inflammatory peptides such as substance P, which can increase microvascular permeability, resulting in a phenomenon known as neurogenic plasma extravasation. The change in vascular permeability is mediated by NK-1 receptors and is caused by the formation of gaps between endothelial cells of postcapillary venules and small collecting venules, which are the same vessels as are affected by inflammatory mediators such as histamine and bradykinin. Respiratory tract infections caused by Sendai virus or Mycoplasma pulmonis can intensify neurogenic plasma extravasation in the airway mucosa, as indicated by the amount of microvascular leakage evoked by substance P or capsaicin. M. pulmonis infections can produce a 30-fold increase in the magnitude of neurogenic plasma extravasation, which is evident 4 wk after infection and may be permanent. A proliferation of venules in the airway mucosa and heightened sensitivity of these vessels to inflammatory mediators are key elements of the increase in plasma extravasation. Exposure of M. pulmonis-infected rats to ammonia exacerbates the infections and further augments the responsiveness of mucosal venules to inflammatory mediators. Despite this increased responsiveness, the vessels are not abnormally leaky in the absence of inflammatory stimuli. These findings emphasize the importance of airway infections as factors that can cause a potent, long-lasting increase in the sensitivity of the microvasculature of the airway mucosa to inflammatory mediators.


Endothelial cell biology. Adhesion molecules involved in the microvascular inflammatory response.

Accumulation of leukocytes in tissues is essential for effective host defense. To fulfill this role the cell must interact with and penetrate the vessel wall and migrate in the tissue. It is now clear that cell adhesion molecules play a crucial role in orchestrating these processes. A number of families of such adhesion molecules that mediate the interaction of circulating leukocytes and vascular endothelial cells have been identified. These include the leukocyte integrins, the selectins, members of the immunoglobulin family, and certain carbohydrates. Studies in vitro have elucidated which of these adhesion molecules are important in the interaction of different leukocyte classes with the endothelium under both basal and stimulated conditions. With the aid of monoclonal antibodies, the role that these molecules play in the interaction of inflammatory cells in the microvasculature in vivo is being assessed. Studies to date have demonstrated the key role of cell adhesion molecules in inflammation.


The role of the endothelial cell in leukotriene biosynthesis.

Endothelial cells do not contain 5-lipoxygenase and thus are unable to generate LTA4 from arachidonate. Nonetheless, endothelial cells may play an important role in leukotriene synthesis by virtue of their ability to metabolize LTA4 derived from activated polymorphonuclear leukocytes (PMNL) and to modulate PMNL 5-lipoxygenase activity. Porcine aortic endothelial cells were found to metabolize exogenous LTA4 to LTC4, and under some conditions human umbilical vein endothelial cells have been found to generate LTB4. Production of LTB4 by these cells appears to be under poorly understood cellular control, and it remains a controversial area of research. Under physiologic conditions, endothelial cells are in constant contact with circulating PMNL, which are known to generate substantial amounts of LTA4. When these two cell types are coincubated in vitro, clear evidence of transcellular metabolism of PMNL-derived LTA4 to LTC4 by endothelial cells is found. Coincubations produce from two to greater than 10 times more LTC4 than either cell alone. In contrast to these findings, when these cells were activated by the receptor-mediated agonist fMLP, evidence for an endothelial cell inhibition of PMNL 5-lipoxygenase was obtained. Rather than augmentation of LTC4 production, as seen with A23187 activation, coincubation activated by fMLP generated significantly less LTC4 (0.23 +/- 0.08 versus 0.75 +/- 0.39 pmol/10(7) cells). The endothelial cell inhibition was removed when these cells were pretreated with aspirin, suggesting that their major cyclooxygenase product, prostacyclin, acts as a feedback regulator of LT synthesis. When cyclooxygenase was blocked, significant transcellular LTC4 synthesis was once again apparent (1.66 +/- 0.44 pmol/10(7) cells).


Heat and water exchange in human airways.

The intrathoracic airways of humans play a prominent part in conditioning inspired air. During inspiration the air is warmed and humidified by the movement of heat and water from the mucosa as a direct function of the temperature and vapor pressure gradients that exist. In this process, the mucosa is cooled. During expiration, the gradients are reversed, and heat and water are given back into the airways. At low levels of ventilation, most of the conditioning process takes place in the upper air passages; however, as ventilation rises, more and more of the tracheobronchial tree becomes involved, and incompletely conditioned air penetrates deeply into the distal airways before it is brought to equilibrium with body conditions. It is likely that the heat required to condition the inspired air is derived from the bronchial circulation, but this has not yet been definitely proved. In normal persons, the thermal events associated with the conditioning of inspired air do not produce any changes in pulmonary mechanics. In contrast, in asthmatics, the airway cooling of hyperpnea and the rapid rewarming that develops when hyperpnea is terminated evoke bronchoconstriction.


[Pertussis. Study of an epidemic].

Forty-six children seen during 1989 with the clinical diagnosis of Pertussis are reviewed in this study. In 64.5% of the cases the Bordet-Gengou medium nasopharyngeal culture was positive for B. pertussis. Two age groups showed more susceptibility to B. pertussis, children under one year of age (70%) and of more than five years of age (20%). The disease was of more severity among infants younger than two months of age (apnea, choking spells, etc.). Most infants needed to be admitted to the hospital. All patients received therapy with erythromycin, salbutamol (80%) and general supportive medical care. No deaths or other medical sequelae were observed.


[Evaluation of microalbuminuria in children].

Microalbuminuria has been shown to be important for the diagnosis and prognosis of glomerular nephropathy. A few studies in normal healthy children were performed. The concentration of albumin was determined in 171 samples of the first morning urine by an immunoturbidimetric method. Microalbumin/creatinine ratio values were 4.07 +/- 0.11 mg/mmol, 1.16 +/- 0.10 mg/mmol and 0.88 +/- 0.11 mg/mmol in children of ages 4 days-1 year, 1-7 years and 7-15 years, respectively. We found a negative inverse correlation (r = 0.31; p < 0.05) between age and microalbumin/creatinine ratio.


[Modification of the calculation of risk factors in women, possible carriers of Duchenne muscular dystrophy, based on CPK levels].

We have analyzed the CPK levels in 44 carriers of DMD women, previously diagnosed by using molecular techniques (from a risk population of 133 women), and compare them with the CPK levels of 138 women of a control population. The results obtained show that values higher than the normal level (> 250 mU/ml) are compatible compatible in 99% of the cases with the carrier status (21 women of the carrier population and 1 women of the control population showed values higher than 250 mU/ml). On the other hand, normal values do not distinguish between the healthy and carrier populations (22 women of the carrier population showed normal CPK levels). These results can be very useful in genetic counselling, especially in centers where it is not possible to apply recombinant-DNA techniques.


[A new method for the measurement of the anatomical development of the muscle complex of the anus in children with anorectal malformations].

We present a new method for the measurement of the anorectal muscle complex. We studied 40 children with anorectal malformation (14 low and 16 high). Taking the perineal TAC with a rectal probe and quotient called "C": [formula: see text] A "C" value less than 0.31 indicates little development of the anus muscle complex. In 10/26 patients with high malformation, "C" was less than 0.31. All of these patients had fecal incontinence.


[Intussusception in the Pediatric Hospital of Coimbra. 13-year results].

We present the results from 233 consecutive patients treated for intussusception at the Children's Hospital of Coimbra over a 13-year period (between 1/6/77 and 31/5/90). Males outnumbered females (66.5% vs 33.5%) and 87.9% of the cases occurred within the first year of life. Among the presenting signs and symptoms, abdominal pain occurred in 87.9% and vomiting in 81.5%. The presence of currant-jelly stools was less common, but noted in 67.3%. Hydrostatic barium enema was performed in 94.4% of the patients with the aim being both diagnostic and therapeutic, successful reduction was achieved in 57.7%. One hundred and twenty-one patients were operated on with specific pathologic lesion found in 11.5% of them. Complications occurred only in the group submitted to surgery. Six children were reoperated on. Most intussusceptions were of the ileocecocolic variety. The overall recurrence rate was 3.8% (3% recurrent intussusceptions followed barium enema reduction and 0.8% followed manual reduction). Mortality rate was 2.5% (1.7% related to intussusception).


[Lipid profiles of children and adolescents in Madrid].

We have studied 2,224 children and adolescents of both sexes, ranging between 2 and 18 years of age, at five schools in the city of Madrid. We determined the lipid profile: total cholesterol (T-C), cholesterol bound to high density lipoproteins (HDL-C), cholesterol bound to low density lipoproteins (LDL-C), cholesterol bound to very low density lipoproteins (VLDL-C), triglycerides (TG), apolipoprotein AI and apolipoprotein B100 (Apo A1 and Apo B100, respectively). In relationship to age and sex, in males, as age increases, there is an elevation in LDL-C and TG and a diminution in T-C, HDL-C, Apo AI and Apo B100. There are no changes in VLDL-C. In females, there is a diminution in LDL-C, TG, Apo-B100 and an increase in HDL-C, Apo AI and T-C, with the increase in T-C being found only in those older than 15 years.


[Breast feeding in a metropolitan area: (I). Analysis of the current situation].

In order to elaborate a program to promote breast-feeding, it is necessary to know in advance the difficulties encountered by the mothers in the target population. For this purpose, we surveyed a sample of 400 mothers who were representative of those who gave birth in Móstoles in 1989. We found that 56% of the mothers did not exceed two months of breast-feeding. Breast-feeding was shorter in low-income families. Its duration was influenced by the husband's and grandmother's opinions and also by previous failure with elder siblings. Mothers made their choice of feeding method before getting pregnant. We also found that most health professionals acted unsatisfactorily. Other unfavorable factors included excessive insecurity of the mother and misinformation.


[Breast feeding in a metropolitan area: (II). Design for a promotion program].

Because of the importance of breast-feeding in the health of both the mother and child, and taking into consideration its poor situation at the present time, it seems fully justified to start a program to promote breast-feeding. This program basically will consist of training health professionals and in the improvement of both the mother's and hospital's practices. It is necessary to motivate health authorities and to curb the excess in formula promotion. Mass-media should be employed for the promotion of breast-feeding and a system should be implemented to obtain a proper record of the duration of breast-feeding.


[Children at risk. Our experience].

Seventy children in a situation of risk, evaluated and treated in the Social Work Unit of the Children's Hospital "Virgen del Rocío" over a period of 22 months, were analyzed. Of these children, 89% corresponded to low-middle, low or very low social classes. The most common problems included those of the family (77.1%) with history of maltreatment and unwanted pregnancies being the most prevalent problems. In second place was the personal pathology of the parents (74.2%), with mental disorders and alcoholism being the main causes, followed by drug addiction and delinquency. Social factors (57.1%), which included predominantly unemployment and illiteracy, were the next most common finding. The final factor was the personal pathology of the child (10%). The consequences of the risk situation are described, emphasizing the psychic and treatment carried out. Final comments are made underlining the importance of awareness and professional training, multiprofessional teams, means of detecting and intervention into the problems, manpower and material as well as how to carry out studies in this area.


[Early diagnosis of HIV infection in children born to seropositive mothers].

We have studied 70 children, born to HIV seropositive mothers, since the first trimester of life and every three months thereafter. The virological markers we used in the diagnosis included: 1) p24 antigen detection. 2) Autochthonous production of antibodies detected by Western Blot technique. 3) HIV isolation. 4) Specific determination of IgM antibodies. In infected children under 15 months of age, p24 antigen was positive in 78%, HIV was isolated in 75% and autochthonous production of antibodies occurred in 50%. IgM specific antibodies were detected in 92%, but these were also detected in the 33% of the children who seroreverted. In seroreverted children, the other three virological markers were negative. The problems due to the low sensitivity in p24 antigen detection, HIV isolation and the detection of autochthonous production of antibodies, as well as the low specificity of the IgM detection, means that it is necessary to simultaneously use several techniques in the diagnosis of these children.


[Neurofibromatosis as a cause of arterial hypertension in children].

Hypertension can complicate the course of neurofibromatosis. When it appears in adulthood (after 18 years of age) it is usually due to pheochromocytoma, but in children the cause is a stenotic lesion of the renal arteries or the suprarenal aorta. Its treatment follows the general principles used in the treatment of the more common forms of renovascular hypertension. We report four patients that developed renovascular hypertension after being diagnosed of neurofibromatosis, they had different localizations of the stenotic lesion, and the diverse types of surgical treatment are analyzed.


[Diagnostic evaluation of cervical adenopathies in childhood].

Between 1985 and 1990, 45 children were studied in an inpatient basis hospital because of cervical lymphadenopathy. This was the most important clinical sign in these patients. Forty-three had true adenitis. In the others, one was submaxillitis and one a sarcoma. The age range was from 2.1 to 13.3 years. Seven children (16%) had neoplastic adenitis (2 papillary carcinoma of the thyroid, 4 Hodgkin's lymphoma and one non-Hodgkin's lymphoma). Thirty-six patients had benign disorders (18 mononucleosis infections, 7 nonspecific adenitis, 5 infections of mycobacteria, 2 of toxoplasma and 2 of rickettsia, one cervical Whipple and one desmopathic adenitis). We did no find any differences related to age or morphological characteristics of the lymph nodes. The evolution time in patients with malignant tumors was 16.4 weeks and 9.6 weeks in the benign group. All of the cases with supraclavicular location had a lymphoma. The mean LDH in patients with malignant tumors was 214 U/L and 614 U/L in those with non-malignant tumors (p < 0.01).


[Primary dyslipoproteinemias in a child-adolescent population of Aragón detected by two methods: selective search and targeted search].

A series of 439 children (245 boys and 194 girls) ranged between 2.0 and 18.0 years of age have been studied January 1987 to April 1990. They belonged to four groups: I) 306 children (163 boys and 143 girls), "control group"; II) 31 children (22 boys and 9 girls) whose parents had some type of dyslipoproteinemia (HPDLP); III) 38 children (24 boys and 14 girls) whose fathers were survivors of myocardial infarction occurred before 55 years of age (HPCI); and IV) 43 children (23 boys and 20 girls) who had, at least in two occasions, more than three months of time separated between then, over 200 mg/dL of total serum cholesterol levels detected by opportunist search (HDC). For children's identification of risk factors to develop atherosclerotic disease during adult life, two different types of strategy has been utilised. One, "selective search", taking into account children of groups II (HPDLP) and III (HPCI). Other, "opportunist search", taking into consideration children of group IV (HDC). The most frequent primary dyslipoproteinemia between the families of children with high serum levels has been Polygenic Hypercholesterolemia (HP). In the second place were both Familial Hypercholesterolemia (HF) an Familial Combined Hyperlipidemia (HFC). A family with Mixed Hyperlipidemia (HM) was also identified. Familial aggregation, with relation to serum lipid levels, were detected in children of the three groups: HPDLP, HPCI and HDC, as it is reported by another authors. Our results suggest the genetic alterations may contribute to the presence of different types of dyslipoproteinemia in children.


[Poliomyelitis vaccination and immunization status of school children. School Health Team of the Center of Health Promotion].

This study presents the results of a vaccination inquire in 2,078 schoolchildren: 807 students in the first year of General Basic Education (G.B.E.) and 1,227 students in the last year of G.B.E. attending public and private schools of the Council of Madrid. The presence of antibodies against the three polio-viruses was determined in 1,509 schoolchildren. About 68.3% of the students received the complete schedule of vaccinations, with 84.7% belonging the group of children in the first year of G.B.E. and 51.2% belonging to that in the last year of G.B.E. (p < 0.01). The percentage of children immunized against the three polioviruses was 92.7%, with 94% of the students in the first year of G.B.E. being immunized and 92% of those in the last year of G.B.E. (p < 0.01). We found differences in the immunization rate between those students receiving more or less than three doses of vaccine. We compared our study with other seroepidemiologic studies undertaken in our country.


[Neonatal care in a primary health care center].

Small Madrid community hospitals (less than 100 deliveries annually) were the site of approximately 14% of the hospital births in 1990. The quality and quantity of services provided by our unit, considered to be of the first of primary level, are presented. The study period was 2.5 years long and 1,339 newborns were attended. The mean stay in the neonatal unit was 4.44 days (+/- 3.8 days). The cesarean section rate was 17%. The incidence of newborns with a weight less than 2,000 g was 1.5%, while those with a weight of more than 4,000 g was 5.47%. Almost 25% of the newborns were transferred to the neonatal ward and 1.79% were transferred to a third level hospital (neonatal intensive care), where three of them died. The mortality rate in our hospital was null. With rational guidelines, the primary centers can provide valuable services in a community perinatal care system.


[Dog bites in children. Epidemiologic and clinical study of 144 cases].

We have done a prospective study of 144 cases of dog bites in children between 1 and 13 years of age that were attended at the Emergency Department of the "Miguel Servet" Children's Hospital of Zaragoza over a period of 30 months. The average child is an 8 year old boy who is bitten at 4 p.m. in the lower limbs by a dog belonging to either the family, a neighbor, or to some friends. The dog of unknown breed and the German shepherd are those most frequently involved (39.5% and 22.2%, respectively). There is a low incidence of infection (4.8%). The attacks were provoked by petting in 52.7%; therefore, we recommend not to get close to the animals even if they are known. In our area, 83.3% of the children are correctly vaccinated. Finally, we compare our results with other studies and we suggest that it is of great interest to establish measures in order to reduce the incidence of dog bites.


[Radiological parameters indicating normalization of bone lesions in Langerhans-cell histiocytosis].

The signs predicting radiological healing were studied in 35 bone lesions of 12 children with Langerhans' cell histiocytosis. The earliest and more frequent radiological signs predicting healing were a decrease in size (52%), the change from a non-sclerotic lesion to one with sclerosis (41%) and the loss of distinct margins of the lesions (29%) three months after diagnosis. The first of these signs was statistically significant after three months of follow-up, the last two after 12 months. The trabecular pattern was a late (one case after 2 years) and infrequent (observed in only 24% of lesions) sign of radiological healing.


[Cardiovascular risk in the pediatric population. Plasma fatty acid levels].

Thirty-seven offspring of patients who had acute myocardial infarctions were investigated. Serum fatty acids of the whole plasma lipids were evaluated within the frame of a full biochemical assessment. Baseline values were obtained and the children were subsequently put on appropriate diets and advised to cut-out smoking and alcohol. The same values were obtained following one year on such a regimen. Results were compared with those found in a control group. Baseline palmitoleic and dihomogammalinolenic acid serum levels were significantly raised in the study group. Values of palmitoleic, but not of dihomogammalinolenic acid, had returned to normal by the reassessment one year later.


[Blood lipids in children up to 12 years of age in a rural population from Extremadura].

We have studied the levels of total cholesterol and triglycerides in 398 children of both sexes, ranging in age from birth until 12 years, in a rural population from Extremadura (Spain). The measurements have been made when analyses were indicated for other reasons. We obtained the following mean values: Total cholesterol = 170.8 +/- 37.0 mg/dl in boys and 172.6 +/- 31.7 mg/dl in girls. Of these children, 43.5% had levels over the limit of 175 mg/dl. Triglycerides = 75.1 +/- 33.5 mg/dl in boys and 71.1 +/- 36.2 mg/dl in girls. In 14.2% of the children this value was over 100 mg/dl. The lipoprotein levels did not present any significant differences with respect to sex until 12 years of age. We compare our results to those of other authors.


[Celiac disease and short stature in children].

Celiac disease (CD) is a known cause of short stature and sometimes, this is its only symptom. The aim of this work was to determine the incidence of CD in children with short stature. We studied 178 infants with short stature and with no gastrointestinal symptoms. Serum IgA antigliadin antibodies were determined in all of them. We found a pathological titer in ten of these patients. Peroral intestinal biopsy was performed on these children, with nine showing no alterations and only one having subtotal villus atrophy that was compatible with CD. Therefore, the incidence of CD in this population is about 0.56%, which is much lower than the incidence shown by other authors.


[Dermatitis herpetiformis vs. celiac disease].

Twenty-nine patients affected with dermatitis herpetiformis (HD), all of whom were on a diet including gluten, were investigated for symptoms of enteropathy. Of these patients, 71% presented severe intestinal lesions, indistinguishable from those found in coeliac disease (CD). However, there were little other clinical manifestations of this finding since only three children in this group had weight and height < or = P3. Of the remaining children, 18% had moderate intestinal atrophy and 10% had normal mucosa or mucosa with negligible changes. When changed to a gluten free diet, the intestinal lesions subsided, dermic lesions disappeared in 17 patients, improved in 8 others and remained the same in the other three patients that were still on variable diets. A study of human leukocyte antigens (HLA) class II showed a total association with Dqw2 and 85% association to DR3, which was identical to the coeliac disease control group. These findings lead one to conclude that HD and CD are different clinical expressions of the same sensitivity to gluten which is associated to an immunological disorder with a common genetic base linked to certain HLA molecules.


[Objective evaluation of a pediatric intensive care unit without continuous attendance (I)].

Eight-hundred and nine consecutive admissions have been reexamined by means of analysis of record cards made out at the moment of discharge from the ICU, in which, among other data, the TISS and PSI maximum for the first six hours from admission are included. The results obtained are the following: 50% of the admissions were classified as medium care (PSI < 5, TISS < 20), 28% were grade IV (PSI > 12, TISS > 40), and half were of grade III with a PSI of 9.38 and a TISS of 20.29. The overall mortality was 8.9%. However, the mortality for grades III+IV was 13.4% and gave a good correlation with the PSI, but not with the TISS. The PSI/TISS ratio was 0.45 and the predicted mortality rate according to the PSI was 6.1% for grade III and greater than 12% for grade IV. We conclude the following: (1) Of the illness, 28% were grade IV. (2) We observed a deficient PSI/TISS ratio. (3) The evaluation has to be done by objective means in which the capability of carrying out different methodologies has not been taken into account.


Postoperative hyponatremic encephalopathy in menstruant women.

To determine factors associated with the development of encephalopathy and with its clinical course in patients with postoperative hyponatremia. Consultation and referral services of two university medical centers and community hospitals. Case-control study (risk factors for encephalopathy) and cohort study (clinical course among patients with encephalopathy). Case patients included 65 adults with postoperative hyponatremic encephalopathy; controls included 674 adult patients who had postoperative hyponatremia without encephalopathy and who were selected from 76,678 consecutive adult surgical inpatients. Age, gender, menstrual status, neurologic symptoms, time to development and degree of hyponatremia, arterial blood gas determinations, serum chemistries, morbidity and mortality. Case patients included 40 women (62%) and 25 men (38%) (P > 0.05); controls included 367 women (54%) and 307 men (46%) (P > 0.1). Of the 34 case patients who developed permanent brain damage or died, 33 (97%) were women (P < 0.001). Among the women with brain damage, 25 (76%) were menstruant (P < 0.001). The relative risk for death or permanent brain damage from hyponatremic encephalopathy in women compared with men was 28 (95% Cl, 5 to 141) and in menstruant women compared with postmenopausal women, 26 (Cl, 11 to 62). Arterial PO2 at diagnosis was significantly lower in female than in male case patients (34 +/- 5 compared with 91 +/- 3 mm Hg; P < 0.001). Further, of the 38 case patients who had respiratory arrest before the diagnosis of hyponatremic encephalopathy, 36 (95%) were women. Extent of or time to development of hyponatremia did not correlate with subsequent brain damage (P > 0.1). Women and men are equally likely to develop hyponatremia and hyponatremic encephalopathy after surgery. However, when hyponatremic encephalopathy develops, menstruant women are about 25 times more likely to die or have permanent brain damage compared with either men or postmenopausal women.


Causes of persistent dizziness. A prospective study of 100 patients in ambulatory care.

To determine the causes of persistent dizziness in outpatients. Consecutive adult outpatients presenting with a chief complaint of dizziness. Four clinics (internal medicine, walk-in, emergency room, and neurology) in a teaching hospital. Of 185 patients presenting during the 10-month study period, 51 (28%) had minimal or no dizziness at 2-week follow-up. Of the remaining 134 patients, 100 completed the study protocol (mean age, 62 years; range, 20 to 85 years). Evaluation included a detailed study questionnaire, standardized physical examination, vestibular testing by a neuro-ophthalmologist, laboratory tests, audiometry, and a structured psychiatric interview. Data were abstracted onto a standard form and reviewed by three raters. Raters independently assigned diagnoses using explicit criteria, with the final cause determined by consensus. Primary causes of dizziness included vestibular disorders (54 patients), psychiatric disorders (16 patients), presyncope (6 patients), dysequilibrium (2 patients), and hyperventilation (1 patient); dizziness was multicausal in 13 patients and of unknown cause in 8 patients. Many of those with a single primary cause, however, had at least one other condition contributing to their dizziness; only 52% of patients had a single "pure" cause. Thirty patients had a potentially treatable primary cause, the most common being benign positional vertigo (BPV) (16%) and psychiatric disorders (6%). Central vestibulopathies detected in 10 patients were presumably vascular or idiopathic in origin. No brain tumors or cardiac arrhythmias were found. Vestibular disease and psychiatric disorders are the most common causes of persistent dizziness in outpatients. In about 50% of patients with dizziness, more than one factor causes or aggravates symptoms. Life-threatening causes were rare, even in our elderly population.


Effect of HIV antibody testing and AIDS education on communication about HIV risk and sexual behavior. A randomized, controlled trial in college students.

To evaluate the effects of human immunodeficiency virus (HIV) antibody testing and education about HIV infection on communication about sexual risk behaviors for HIV transmission. Randomized, controlled trial with three arms. University student health center. Of 2196 heterosexual university students attending the student health clinic for medical care, 435 were interested in education about HIV and HIV testing and were randomly assigned to three groups. Follow-up at 6 months was done in 370 subjects (85%): 90 control subjects, 144 subjects who received education alone, and 136 subjects who received education plus HIV testing. Subjects who received HIV testing plus education questioned sexual partners about their HIV status more than subjects receiving education alone or those in the control group (56%, 42%, and 41% of subjects, respectively; P = 0.01). No consistent differences among groups in the number of sexual partners or in the use of condoms were found at follow-up. Heterosexual university students who received education about HIV infection plus HIV testing had increased communication with sexual partners about the risk for HIV infection after 6 months. Further reduction in risk behaviors for HIV transmission may require additional interventions in this population.


Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic effectiveness?

To compare clinicians' ratings of therapeutic effectiveness when different trial end points were presented as percent reductions in relative compared with absolute risk and as numbers of patients treated to avoid one adverse outcome. Survey, with random allocation of two questionnaires. Toronto teaching hospitals. Convenience sample of 100 faculty and housestaff in internal medicine and family medicine. One questionnaire presented results for three end points of the Helsinki Heart Study as separate drug trials using only absolute differences in events; the other showed the same end points as relative differences. Both questionnaires included a fourth "trial," showing person-years of treatment needed to prevent one myocardial infarction. The "trials" were each rated on an 11-point scale, from treatment "harmful" to "very effective." Respondents' ratings of effectiveness varied with the end point. Controlling for end point, ratings of effectiveness by the 50 participants receiving absolute event data were lower than those by 50 participants responding to relative risk reductions (P < 0.001); however, no end-point difference was more than 0.6 scale points. For a "trial" reporting that 77 persons were treated for 5 years to prevent one myocardial infarction, mean ratings were 2.3 or 1.8 scale points lower, respectively (both P < 0.001), than when the same data were shown as relative or absolute risk reductions. Clinicians' views of drug therapies are affected by the common use of relative risk reductions in both trial reports and advertisements, by end-point emphasis, and, above all, by underuse of summary measures that relate treatment burden to therapeutic yields in a clinically relevant manner.


Transesophageal echocardiography in the evaluation of stroke.

To review the current role of transesophageal echocardiography in the evaluation of stroke. Articles examining the role of transesophageal echocardiography for evaluation of patients with stroke were identified using computer and bibliography searches. All English-language articles that provided full details on patient selection criteria, methods, and study design were reviewed. Cardiogenic embolism is frequently an uncertain diagnosis merely inferred by finding a potential cardiac source. Transthoracic echocardiography has had a low yield in screening unselected patients with stroke. Several series of patients with stroke have been reported comparing transthoracic and transesophageal echocardiography. Potential cardiac sources of embolism were consistently identified in many more patients by transesophageal echocardiography. Many findings are, however, of uncertain significance; these include spontaneous echo contrast, patent foramen ovale, filamentous strands on the mitral valve, and atrial septal aneurysm. Transesophageal echocardiography is most helpful in patients with stroke who are less than 45 years of age and in those without clinical evidence of heart disease. The indications for its use in the evaluation of stroke remain controversial. Further studies are needed using transesophageal echocardiography in patients with stroke and in control groups, not only to determine the natural history of transesophageal, echocardiographically detected abnormalities but also to evaluate treatment options.


Chronic myelopathy associated with human T-lymphotropic virus type I (HTLV-I).

To review the clinical, epidemiologic, immunologic, and virologic aspects of the chronic myelopathy associated with human T-cell leukemia/lymphoma virus type I (HTLV-I), currently called tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). Studies done after 1985, when TSP/HAM was first recognized, were identified by a computer search using MEDLARS II and CANCERLIT. Additional information was acquired from personal files and bibliographies of existing literature. A total of 400 articles, 90 book chapters, and 150 abstracts from meetings covering all aspects of HTLV-I and neurologic diseases were critically analyzed, and information from 250 publications was included. TSP/HAM is present in most HTLV-I endemic areas, with a prevalence ranging from 5.1 to 128 per 100,000 inhabitants. Up to 20% of patients develop TSP/HAM after transfusion of HTLV-I contaminated blood. Pathologic characteristics indicate a chronic meningomyelitis. The clinical features consist of a chronic progressive spastic paraparesis or paraplegia, sphincter disturbances, and minimal sensory loss. Supraspinal and peripheral nerve involvement is sometimes observed. High titers of HTLV-I-specific antibodies are present in the serum and cerebrospinal fluid. The high level of humoral and cellular immunologic response and the association of TSP/HAM with other immunologic diseases suggest an immune-mediated process. Corticosteroids and immunosuppressor treatment usually result in only short-term improvement. TSP/HAM is a common neurologic disease in many parts of the world. All patients with chronic progressive myelopathies should be tested for serum and cerebrospinal fluid HTLV-I-specific antibodies. Systematic screening of blood donors for HTLV-I is necessary to help prevent the dissemination of the virus and the occurrence of post-transfusional cases.