Sequential chemoimmunotherapy for advanced non-small cell lung cancer using cisplatin, etoposide, thymosin-alpha 1 and interferon-alpha 2a.

A phase II study was performed to evaluate the clinical and immunological effects of a regimen of cisplatin (DDP) and etoposide (VP-16) combined with thymosin-alpha 1 (TA1) and low-dose interferon-alpha 2a (IFN) in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Chemoimmunotherapy cycles were repeated every 3 weeks. There were 24 responses (two complete, 22 partial) among 56 assessable patients. Median survival was 12.6 months. Overall, treatment was well tolerated. Natural killer cell activity and lymphocyte subtypes were depressed by chemotherapy, but this effect was less prominent in patients receiving TA1 and IFN in comparison with a concomitant group of patients treated with DDP and VP-16 only. The combination of DDP and VP-16 and TA1 and IFN is effective in advanced NSCLC with acceptable toxicity. However, the results of this study need to be confirmed in a randomised trial.

Autonomic cardiac regulation in obstructive sleep apnea syndrome: evidence from spontaneous baroreflex analysis during sleep.

OBJECTIVE: To assess spontaneous baroreceptor-heart rate reflex sensitivity during sleep in patients with obstructive sleep apnea syndrome, a condition associated with increased cardiovascular morbidity and mortality and characterized by marked sympathetic activation, which is believed to originate from hypoxic chemoreceptor stimulation, although little is known of other possible mechanisms such as baroreflex impairment. DESIGN AND METHODS: In 11 patients with severe obstructive sleep apnea syndrome (mean+/-SD age 46.8+/-8.1 years, apnea/hypopnea index 67.9+/-19.1 h), who were normotensive or borderline hypertensive during wakefulness by clinic blood pressure measurements, finger blood pressure was monitored beat-by-beat non-invasively (Finapres) at night during polysomnography. Periods of wakefulness and sleep were identified based on electroencephalographic recordings. Baroreflex sensitivity was assessed by the sequence technique, as the slope of the regression line between spontaneous increases or reductions in systolic blood pressure (SBP) and the related lengthening or shortening in the RR interval, occurring over spontaneous sequences of four or more consecutive beats. The number of these sequences was also computed, as an additional index of baroreflex engagement by the spontaneous blood pressure fluctuations. The controls were age-related normotensive or borderline hypertensive subjects without sleep apnea who had been investigated in previous studies; in these subjects blood pressure was recorded intra-arterially over 24 h in ambulatory conditions and spontaneous baroreflex sensitivity was assessed by the sequence technique. RESULTS: In our patients the lowest nocturnal arterial oxygen saturation was 78.6+/-12.1% (mean+/-SD). During sleep, the number of pooled +RR/+SBP and -RR/-SBP sequences per hour was 20.3+/-2.7 per h in patients with sleep apnea and 27.1+/-2.1 /h in controls (means+/-SEM). The average baroreflex sensitivity during sleep periods was 7.04+/-0.8 ms/mmHg in sleep apnea patients and 10.05+/-2.1 ms/mmHg in controls. Both the pooled number of sequences and baroreflex sensitivity values of the sleep apnea patients were significantly (P < 0.01) less than the corresponding night values of control subjects. In the sleep apnea patients, at variance from controls, baroreflex sensitivity did not show any increase during sleep compared with its values during wakefulness (6.9+/-1.0 ms/mmHg). CONCLUSIONS: Our data provide evidence that spontaneous baroceptor reflex sensitivity is depressed in severe obstructive sleep apnea syndrome. This suggests that in such patients baroreflex dysfunction and not only chemoreceptor stimulation by hypoxia may be involved in the sympathetic activation which occurs during sleep. Such dysfunction may contribute to the higher rate of cardiovascular morbidity and mortality reported in these patients.

Different heart rate patterns in obstructive apneas during NREM sleep.

Both bradycardia and a trend to tachycardia have been reported in obstructive sleep apneas (OSA). Because heart rate (HR) behavior may yield information on parasympathetic activity during OSA, we analyzed HR in samples of consecutive apneic cycles in non-rapid eye movement (NREM) sleep, recorded in normotensive patients breathing room air (n = 7) and supplemental O2 (n = 4). In air, the patients showed different HR trends during apnea, as HR decreased (HR decreased), remained constant (HR=), or increased (HR increased). By multiple regression analysis, development of HR trends correlated with the HR fall in the late interapneic period, HR at first effort, the decrease in esophageal pressure, and the lengthening of inspiration during apnea (R2 = 0.42). O2 abolished HR decreased-OSA, whereas HR= and HR increased-OSA still occurred but at higher HR than in air. In both the air and O2 series, the HR fall preceding apnea correlated significantly with the degree of hypoxia reached in the previous apneic cycle. These data indicate a complex modulation of HR during OSA, with the HR fall in the late interapneic period possibly reflecting the effectiveness of parasympathetic cardiac control in OSA patients during sleep.

Myocardial ischemia during sleep.

The role of sleep in the pathogenesis of coronary ischaemic events such as myocardial infarction, transient myocardial ischaemia, or cardiac sudden death, is unclear. This review will analyse the available data on the subject according to: (i) the autonomic and cardiovascular changes during sleep that may potentially favour myocardial ischaemia; (ii) the evidence of a circadian distribution of coronary events; and (iii) the factors possibly involved in the pathogenesis of nocturnal angina. Available data suggest that myocardial ischaemia may occur by different mechanisms in non-rapid eye movement (NREM) (decreased coronary perfusion pressure) and rapid eye movement (REM) sleep (increased myocardial oxygen demand). Coronary events show a major peak of occurrence between 6.00 a.m. and noon; however, the myocardial ischaemic threshold, defined as the heart rate value at which myocardial ischaemia develops, may be lower at night than during the daytime, suggesting an unexpectedly higher susceptibility to myocardial ischaemia during sleep than during wakefulness. These data warrant further study on the pathophysiology of coronary circulation during sleep. Finally, some evidence is available that sleep disordered breathing may precipitate nocturnal angina especially in REM sleep, through decreased arterial oxygen content secondary to hypoventilation or true apnoeas. More data are needed to better understand the effects of sleep on the coronary circulation, and to improve the therapeutic approach of nocturnal angina.

Airway remodelling in the pathogenesis of asthma.

The inflammatory and remodelling processes that underlie asthma result from a highly complex interaction between various cell types. Apart from inflammatory cells, such as eosinophils, activated T cells, mast cells and macrophages, structural tissue cells such as epithelial cells, fibroblasts and smooth muscle cells can also play an important effector role through the release of a variety of mediators, cytokines and chemokines. This results in an acute inflammatory response that is characterized by vascular leakage, mucus hypersecretion, epithelial shedding and widespread airway narrowing. At the same time, through the release of mediators, cytokines, chemokines and growth factors, epithelial and mesenchymal cells cause persistence of the inflammatory infiltrate and induce structural changes in the airway wall, such as increased thickness of the basement membrane, increased collagen deposition, changes in bronchial microcirculation, and smooth muscle hypertrophy and hyperplasia. The end result of airway inflammation and remodelling is an increased thickness of the airway wall, leading to a reduced baseline airway calibre and exaggerated airway narrowing.

The expression of basic fibroblast growth factor (bFGF) in tumor-associated stromal cells and vessels is inversely correlated with non-small cell lung cancer progression.

Tumor progression results from complex interactions between tumor and tumor-associated host tissue. Basic fibroblast growth factor (bFGF), via activation of its receptor, FGFR-1, has been postulated to be an important inducer of host stromal response and angiogenesis. To assess the putative role of tumor-associated stromal cells and vessels in tumor progression, we studied non-small cell lung cancer (NSCLC) from 84 patients, including 51 squamous cell carcinomas and 33 nonsquamous cell carcinomas, by immunohistochemical detection. bFGF and FGFR-1 immunoreactivity was observed in tumor and in tumor-associated stromal cells and vessels. The expression of bFGF and FGFR-1 in stromal cells was higher in squamous than in non-squamous cell carcinomas (respectively, P = .007 and P = .0004). We found that bFGF and FGFR-1 expression in tumor and tumor-associated stromal cells and vessels was directly correlated with host stromal response, as assessed by intratumoral extension of stroma, but not with angiogenic response, as assessed by microvessel count. Although FGFR-1 expression of tumor cells was directly correlated with T-stage (P = .03), bFGF expressions of tumor-associated stromal cells and vessels were inversely correlated with lymph node metastasis (respectively, P = .0001 and P = .0002) and advanced pathological stage (respectively, P = .03 and P = .01). These findings suggest that bFGF might mediate host stromal response in NSCLC and that the expression of bFGF in tumor-associated stromal cells and vessels might have an inhibitory role in NSCLC progression.

Characteristics and prognostic value of morning dipping of peak expiratory flow rate in stable asthmatic subjects.

Characteristics and prognostic relevance of morning dip of peak expiratory flow rate (PEFR) were evaluated in stable asthmatic subjects. Among 246 outpatients monitored four times daily for two weeks, 38 (group A) showed a significant difference between morning reading of PEFR and each of the others; they were compared to 38 randomly selected patients (group B) not showing morning dip in PEFR. Less frequent seasonal course, extrinsic pathogenesis, and sensitization to mites characterized group A; starting airflow limitation was more severe in those with morning dip, but no significant difference between mean PEFR measured throughout two weeks was found. At 6 to 12 weeks, morning dip was not found in 19 of 38 subjects in group A and appeared in seven of 38 subjects in group B, with no clearcut relationship to treatment being evident. At 25 to 104 weeks, no significant difference between therapeutic requirements and the forced expiratory volume in one second was detected; therefore, unlike the short-term, morning dip is not a risk factor for worse long-term prognosis.

Acute effects of oxygen administration on transmural pulmonary artery pressure in obstructive sleep apnea.

In order to investigate the role of hypoxia on the cyclic oscillation of transmural pulmonary artery pressure (PAP) in obstructive sleep apnea, oxygen was administered during one half of the night to six patients affected by obstructive sleep apnea syndrome during a nocturnal polysomnographic study. In each patient, transmural PAP measurements were performed on 15 randomly selected apneas recorded while breathing room air, and on 15 during O2 administration. During O2 administration in all patients, apneas were associated with a higher oxyhemoglobin saturation (SaO2), a smaller SaO2 swing, and a higher transcutaneous PCO2. The mean highest level of transmural PAP in the apneic episodes, commonly reached at their end, was significantly lower than while breathing room air in only two patients; however, due to a decrease in the mean lowest PAP level (at the beginning of apneas), the extent of the PAP increase within apneas did not differ between air and O2 breathing; these patients showed the smallest increase in transcutaneous PCO2 in our sample. End-apneic transmural PAP during O2 administration was significantly higher in one subject (for systolic values) and was not significantly different in the remaining three subjects. The extent of the increase in transmural PAP within apneas was greater in one patient; it was smaller in another one, but only for the diastolic values; and it did not differ significantly with respect to the value observed while breathing room air in all of the other subjects. The results suggest that hypoxia in obstructive apneas, at least in some patients, may lead to a steady increase in PAP, detectable both at the beginning and at the end of the episodes; conversely, the increase in PAP within apneas does not seem to be influenced by the simultaneous decrease in SaO2.

Effect of age upon airway obstruction and reversibility in adult patients with asthma.

OBJECTIVE: In a cross-sectional study we evaluated the effect of aging (separately from that of duration of disease) on airway obstruction and reversibility by comparing two groups of non-smoker patients with asthma. METHODS: We compared two groups of patients: group A, which had 50 subjects (8 men and 42 women) aged 59.7+/-4.6 years (mean +/- SD), and group B, comprised of 51 subjects (19 men and 32 women) who were 35.7+/-7.4 years old. The groups were selected because of comparable baseline degree of obstruction (FEV1 % of predicted, 67.8+/-20.3 in group A; 73.0+/-19.6 in group B, NS) and duration of the disease (14.0+/-11.7 years vs 11.2+/-9.1, NS). Spirometric examination, with a bronchodilator test, was performed and subjects not reaching 85% of predicted were submitted to a 4-week course of inhaled steroids. RESULTS: Although a higher number of subjects from group B responded to the acute bronchodilator test (p < 0.001), the maximum response achievable with treatment (steroid or bronchodilator) (deltaFEV1 expressed as the percent of predicted) was not statistically different between groups (12.0+/-17.5 vs 16.0+/-23.9). The mean FEV1 attainable after treatment (deltaFEV1%PT) was significantly lower in the older group (p = 0.0006). Within groups, the baseline FEV1% did not correlate with age; it was inversely correlated with the duration of the disease (p < 0.03 and p < 0.01, respectively). In both groups deltaFEV1 was inversely related with the baseline FEV1, whereas FEV1%PT was correlated with the duration of the disease, with a slope nearly doubled in group B (p < 0.001). CONCLUSIONS: Both the process of aging and the prolonged exposure to disease effects are important factors in determining the functional characteristics of chronic asthma: In particular, aging is associated not only with a reduced acute responsiveness to bronchodilators, but also with a reduced slope of the duration-FEV1%PT relationship that suggests a slowing of the rate of loss of reversibility of uncertain biological meaning.

Changes in FVC during methacholine-induced bronchoconstriction in elderly patients with asthma: bronchial hyperresponsiveness and aging.

STUDY OBJECTIVE: We evaluated whether aging may produce changes in bronchial hyperresponsiveness, risk of enhanced bronchoconstriction, and changes of bronchoconstriction perception. SETTING: Each subject underwent a methacholine bronchial challenge. Methacholine challenge was stopped when one of the following conditions occurred: (1) plateau of bronchoconstriction; (2) decrease of FEV(1) > 40%; (3) FEV(1) drop below 1 L; or (4) excessive respiratory discomfort. Methacholine dose-response curves were plotted both for FVC and FEV(1). The provocative dose of methacholine causing a 20% decrease in FEV(1) with respect to baseline (PD(20)) and the fall in FVC (DeltaFVC) at PD(20) were computed. The Borg scale was used for scoring the perception of respiratory discomfort. PATIENTS: We compared 17 young asthmatic patients (aged 22 to 45 years) with 17 older asthmatic patients (aged 63 to 78 years) selected on the basis of similar baseline pulmonary function and disease duration. RESULTS: No significant between-group difference was found in PD(20) and in plateau development. Conversely, DeltaFVC was significantly higher in the older group (mean +/- SD, 15.5 +/- 3.9% vs 11.6 +/- 5.5% in younger patients). In addition, DeltaFVC showed a positive linear relationship with age (p = 0.0026). Elderly subjects were less aware of bronchoconstriction during the methacholine challenge (p = 0.04). CONCLUSIONS: In elderly patients with asthma having comparable pulmonary function and disease duration, bronchial responsiveness is not different from that observed in younger asthmatic patients. Nevertheless, in such patients, an age-related tendency to an enhanced bronchoconstriction and a reduced perception of the degree of bronchoconstriction exist.

Transmural pressure measurements. Importance in the assessment of pulmonary hypertension in obstructive sleep apneas.

Seven patients with OSAS were studied during nocturnal sleep in order to assess the trend of PAP throughout apneas and to identify factors possibly associated with such a trend. All patients underwent a polysomnography including the monitoring of PAP and esophageal pressure. While intravascular PAP decreased during apneas and increased at the resumption of breathing, transmural PAP values (ie, corrected for intrathoracic pressure swings) showed a trend toward a progressive increase throughout apneas and toward a decrease once ventilation had been resumed. The measurement of transmural values allowed a reliable assessment of PAP changes occurring during apneas, and different degrees of such changes shown by different patients may be related to a host of factors relevant to wakefulness and sleep, including individual responsivity to hypoxic stimulus.

Validation of morning dip of peak expiratory flow as an indicator of the severity of nocturnal asthma.

Overnight falls in peak expiratory flow (PEF) (with the morning dip of the index) may be considered the hallmark of nocturnal asthma. To validate the morning dip a quantitative marker of the degree of nocturnal bronchoconstriction, the dip was measured in 11 subjects (six with a history consistent with nocturnal asthma) undergoing all-night monitoring of lower respiratory resistance by a double-catheter method. In six subjects, marked and recurrent increases in resistance were recorded, along with morning dips higher than 20 percent; however, on the following morning, only two of them reported having suffered significant breathlessness and wheeze. Peak and average values for resistance, as well as the duration for which resistance was increased, were closely correlated with the magnitude of morning dips. Therefore, unlike the subjective report, PEF may be considered a reliable quantitative indicator of nocturnal bronchoconstriction.

Lung compartmentalization of increased TNF releasing ability by mononuclear phagocytes in pulmonary sarcoidosis.

The TNF is a monokine with cytotoxic and tumor-necrosing activities; in addition, TNF may play a role in inflammatory processes. The present study evaluates spontaneous and LPS-mediated release of TNF by AMs and autologous peripheral BMs of normal subjects and patients with pulmonary sarcoidosis. A recently developed cytotoxicity assay, specific for detection of TNF activity, was applied. This study demonstrates that (1) unstimulated mononuclear phagocytes released low levels of TNF with no differences between groups; (2) when effector cells were stimulated with LPS, AMs from patients with active pulmonary sarcoidosis released more TNF than AMs recovered from normal subjects and from patients with inactive disease; (3) this increase was compartmentalized to the lungs, since comparisons of TNF production by LPS-stimulated BMs failed to show any difference between study groups. These results suggest that TNF might play a role in the pathogenesis of the alveolitis of pulmonary sarcoidosis.

MUC1 (episialin) expression in non-small cell lung cancer is independent of EGFR and c-erbB-2 expression and correlates with poor survival in node positive patients.

AIM: To examine tumour samples immunohistochemically for MUC1 (episialin), epidermal growth factor receptor (EGFR), and c-erbB-2, since the disruption of the cell-cell adhesion system by MUC1 and the c-erbB oncoprotein family is known to be important in the development of metastasis in human cancers. METHODS: 93 tumour samples from patients with early stage non-small cell lung cancer treated with surgery alone were examined for episialin, EGFR, and c-erbB-2. RESULTS: Episialin depolarised expression did not correlate with any of the histopathological variables examined (T,N stage, grade, histology, Ki67 proliferation index). No correlation was observed between episialin and EGFR or c-erbB-2 expression. Survival analysis showed that episialin depolarised expression correlated with poor prognosis (p = 0.003), especially in squamous cell cases (p = 0.0003). Episialin expression defined a group of patients with poor prognosis in the node positive category (p = 0.003). In multivariate analysis episialin was the most significant independent prognostic factor (p = 0.007), followed by N stage (p = 0.04). CONCLUSIONS: Depolarised expression of episialin is associated with poor outcome in early stage non-small cell lung cancer. Despite the similar activity on the cadherin cell-cell adhesion system, the expression of episialin and c-erbB oncoproteins is likely to be activated within different pathogenic pathways.

Thyroarytenoid muscle activity in sleep apneas.

In normal subjects the thyroarytenoid muscle (TA), a vocal cord adductor, has phasic expiratory activity during wakefulness that disappears during non-rapid-eye-movement (NREM) sleep. Fiber-optic studies have reported absent or irregular vocal cord movements during obstructive apneas and vocal cord adduction during central apneas. This study was designed to investigate TA activity during NREM sleep in 14 subjects with sleep apnea by means of intramuscular wire electrodes. During central apneas, which were recorded in three subjects, continuous TA activity was observed. During obstructive apneas, which were recorded in all subjects, two different patterns of TA activity were observed: 1) absence of any activity until arousal and 2) phasic activity throughout the apnea. The first pattern was detected in six subjects, whereas both patterns were observed in the remaining eight subjects. No correlation was found between obstructive apnea characteristics and presence or absence of TA activity. In all subjects TA underwent a marked activation during arousal. While nasal continuous positive airway pressure was applied during NREM sleep TA activity was always absent. The persistence of TA activity during central apneas suggests that they may represent an extreme prolongation of neural expiratory discharge. We speculate that a variable interaction of different stimuli acting during obstructive apnea may activate TA, which, in turn, may contribute to glottic narrowing.

Respiratory energetics during exercise at high altitude.

The purpose of this study was to assess the effect of high altitude (HA) on work of breathing and external work capacity. On the basis of simultaneous records of esophageal pressure and lung volume, the mechanical power of breathing (Wrs) was measured in four normal subjects during exercise at sea level (SL) and after a 1-mo sojourn at 5,050 m. Maximal exercise ventilation (VEmax) and maximal Wrs were higher at HA than at SL (mean 185 vs. 101 l/min and 129 vs. 40 cal/min, respectively), whereas maximal O2 uptake averaged 2.07 and 3.03 l/min, respectively. In three subjects, the relationship of Wrs to minute ventilation (VE) was the same at SL and HA, whereas, in one individual, Wrs for any given VE was consistently lower at HA. Assuming a mechanical efficiency (E) of 5%, the O2 cost of breathing at HA and SL should amount to 26 and 5.5% of maximal O2 uptake, whereas for E of 20% the corresponding values were 6.5 and 1.4%, respectively. Thus, at HA, Wrs may substantially limit external work unless E is high. Although at SL VEmax did not exceed the critical VE, at which any increase in VE is not useful in terms of body energetics even for E of 5%, at HA VEmax exceeded critical VE even for E of 20%.

Cardiovascular and ventilatory response to isocapnic hypoxia at sea level and at 5,050 m.

To assess the effect of chronic hypoxic conditions on ventilatory, heart rate (HR), and blood pressure (BP) responses to acute progressive isocapnic hypoxia, we studied five healthy Caucasian subjects (3 men and 2 women). Each subject performed one rebreathing test at sea level (SL) and two tests at the Pyramid laboratory at Lobuche, Nepal, at the altitude of 5,050 m, 1 day after arrival (HA1) and after 24 days of sojourn (HA2). The effects of progressive isocapnic hypoxia were tested by using a standard rebreathing technique. BP, electrocardiogram, arterial oxygen saturation, airflow and end-tidal CO2 and O2 were recorded. For each subject, the relationships between arterial oxygen saturation and HR, systolic BP and minute ventilation (VE), respectively, were evaluated. At HA1, the majority of subjects showed a significant increase in VE and BP response and a decrease in HR response to progressive isocapnic hypoxia as compared to SL. At HA2, VE and BP responses further increased, whereas the HR response remained similar to that observed at HA1. A significant relationship between hypoxic ventilatory responses and both systolic and diastolic BP responses to progressive hypoxia was found. No significant correlation was found between hypoxic ventilatory and HR responses.

Blood pressure and heart rate during periodic breathing while asleep at high altitude.

The ventilatory and arterial blood pressure (ABP) responses to isocapnic hypoxia during wakefulness progressively increased in normal subjects staying 4 wk at 5,050 m (Insalaco G, Romano S, Salvaggio A, Braghiroli A, Lanfranchi P, Patruno V, Donner CF, and Bonsignore G; J Appl Physiol 80: 1724-1730, 1996). In the same subjects (n = 5, age 28-34 yr) and expedition, nocturnal polysomnography with ABP and heart rate (HR) recordings were obtained during the 1st and 4th week to study the cardiovascular effects of phasic (i.e., periodic breathing-dependent) vs. tonic (i. e., acclimatization-dependent) hypoxia during sleep. Both ABP and HR fluctuated during non-rapid eye movement sleep periodic breathing. None of the subjects exhibited an ABP increase during the ventilatory phases that correlated with the lowest arterial oxygen saturation of the preceding pauses. Despite attenuation of hypoxemia, ABP and HR behaviors during sleep in the 4th wk were similar to those in the 1st wk. Because ABP during periodic breathing in the ventilatory phase increased similarly to the ABP response to progressive hypoxia during wakefulness, ABP variations during ventilatory phases may reflect ABP responsiveness to peripheral chemoreflex sensitivity rather than the absolute value of hypoxemia, suggesting a major tonic effect of hypoxia on cardiorespiratory control at high altitude.

Endogenous digitalislike factors in obstructive sleep apnea.

Recent studies have provided evidence that hypoxia may stimulate the release of endogenous digitalislike factors (EDLF). Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia during sleep and may be associated with sympathetic activation and a high risk of developing hypertension. This study was designed to measure EDLF in the plasma of patients with OSA diagnosed by polysomnography, with patients being classified by the number of apneic-hypopneic episodes/h sleep (apnea-hypopnea index, AHI). Plasma was obtained in the morning from 8 male normotensive OSA patients (OSA-N) (AHI 70+/-6), 2 untreated hypertensive OSA patients (OSA-HT), and 11 age-matched healthy male controls (C). EDLFs of different hydrophobicities were separated from the same plasma sample by solid-state C18-cartridges with 25% acetonitrile (ACN) (EDLF-1) followed by 40% ACN (EDLF-2). This procedure recovered ouabain in the first fraction and digoxin and digoxigenin in the second. EDLF was quantified in pM ouabain-equivalents by a human placenta radioreceptor assay. EDLF-1 levels were similar for OSA-N and C (231+/-55 vs. 258+/-58), whereas EDLF-2 levels were increased in OSA-N (244+/-51 vs. 110+/-25 in C, p=0.02). Norepinephrine was increased in apneics. The two OSA-HT had EDLF and norepinephrine levels similar to OSA-N. These preliminary results suggest that OSA is associated with an increase in the more hydrophobic EDLF levels in both normotensive and hypertensive states. No significant increase was found for the less hydrophobic ouabain-like EDLF.

Effects of gemcitabine on cell proliferation and apoptosis in non-small-cell lung cancer (NSCLC) cell lines.

We evaluated the antiproliferative and the proapoptotic ability of gemcitabine in three non-small-cell lung cancer (NSCLC) cell lines. NCI-H292 (mucoepidermoid carcinoma), NCI-CorL23 (large-cell carcinoma) and NCI-Colo699 (adenocarcinoma) cells were cultured with and without 0.5, 0.05 and 0.005 microM gemcitabine for 24, 48 and 72 h, respectively. Gemcitabine exerted a stronger and earlier antiproliferative and proapoptotic effect on H292 cells than on CorL23 or Colo699 cells. Fas receptor expression was increased in all three cell lines and was higher in Colo699 than in CorL23 cells. The incubation of NSCLC with anti-Fas agonistic monoclonal antibody (CH11) induced cell apoptosis in H292 cells, demonstrating that the Fas receptor was functionally active. Finally, gemcitabine and CH-11 exerted a synergistic effect on cell apoptosis in H292 cells. This study demonstrates that gemcitabine induces apoptosis in NSCLC and that this effect might be exerted by modulating functionally active Fas expression, and these effects of gemcitabine were stronger in H292 cells than in either CorL23 or Colo699 cells.