Intermittent recruitment with high-frequency oscillation/tracheal gas insufflation in acute respiratory distress syndrome.

In acute respiratory distress syndrome (ARDS), recruitment sessions of high-frequency oscillation (HFO) and tracheal gas insufflation (TGI) with short-lasting recruitment manoeuvres (RMs) may improve oxygenation and enable reduction of subsequent conventional mechanical ventilation (CMV) pressures. We determined the effect of adding HFO-TGI sessions to lung-protective CMV on early/severe ARDS outcome. We conducted a prospective clinical trial, subdivided into a first single-centre period and a second two-centre period. We enrolled 125 (first period, n = 54) patients with arterial oxygen tension (P(a,O(2)))/inspiratory oxygen fraction (F(I,O(2))) of <150 mmHg for >12 consecutive hours at an end-expiratory pressure of ≥ 8 cmH(2)O. Patients were randomly assigned to an HFO-TGI group (receiving HFO-TGI sessions with RMs, interspersed with lung-protective CMV; n = 61) or CMV group (receiving lung-protective CMV and RMs; n = 64). The primary outcome was survival to hospital discharge. Pre-enrolment ventilation duration was variable. During days 1-10 post-randomisation, P(a,O(2))/F(I,O(2))), oxygenation index, plateau pressure and respiratory compliance were improved in the HFO-TGI group versus the CMV group (p < 0.001 for group × time). Within days 1-60, the HFO-TGI group had more ventilator-free days versus the CMV group (median (interquartile range) 31.0 (0.0-42.0) versus 0.0 (0.0-23.0) days; p < 0.001), and more days without respiratory, circulatory, renal, coagulation and liver failure (p ≤ 0.003). Survival to hospital discharge was higher in the HFO-TGI group versus the CMV group (38 (62.3%) out of 61 versus 23 (35.9%) out of 64 subjects; p = 0.004). Intermittent recruitment with HFO-TGI and RMs may improve survival in early/severe ARDS.

Nasal inflammation in sleep apnoea patients using CPAP and effect of heated humidification.

Nasal continuous positive airway pressure (CPAP) can cause undesirable nasal symptoms, such as congestion to obstructive sleep apnoea (OSA) patients, whose symptoms can be attenuated by the addition of heated humidification. However, neither the nature of nasal symptoms nor the effect of heated humidification on nasal pathophysiology and pathology are convincingly known. 20 patients with OSA on nasal CPAP who exhibited symptomatic nasal obstruction were randomised to receive either 3 weeks of CPAP treatment with heated humidification or 3 weeks of CPAP treatment with sham-heated humidification, followed by 3 weeks of the opposite treatment, respectively. Nasal symptom score, nasal resistance, nasal lavage interleukin-6, interleukin-12 and tumour necrosis factor-α and nasal mucosa histopathology were assessed at baseline and after each treatment arm. Heated humidification in comparison with sham-heated humidification was associated with decrease in nasal symptomatology, resistance and lavage cytokines, and attenuation of inflammatory cell infiltration and fibrosis of the nasal mucosa. In conclusion, nasal obstruction of OSA patients on CPAP treatment is inflammatory in origin and the addition of heated humidification decreases nasal resistance and mucosal inflammation.

Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD.

It is known that non-cachectic patients with chronic obstructive pulmonary disease (COPD) respond well to pulmonary rehabilitation, but whether cachectic COPD patients are capable of adaptive responses is both important and unknown. 10 cachectic and 19 non-cachectic COPD patients undertook high-intensity cycling training, at the same relative intensity, for 45 min x day(-1), 3 days x week(-1) for 10 weeks. Before and after rehabilitation vastus lateralis muscle biopsies were analysed morphologically and for the expression of muscle remodelling factors (insulin-like growth factor (IGF)-I, myogenic differentiation factor D (MyoD), tumour necrosis factor (TNF)-alpha, nuclear factor (NF)-kappaB and myostatin) and key components of ubiquitin-mediated proteolytic systems (muscle ring finger protein (MURF)-1 and Atrogin-1). Rehabilitation improved peak work-rate and the 6-min walk distance similarly in non-cachectic (18+/-3% and 42+/-13 m, respectively) and cachectic (16+/-2% and 53+/-16 m, respectively) patients, but quality of life only improved in non-cachectic COPD. Mean muscle fibre cross-sectional area increased in both groups, but significantly less in cachectic (7+/-2%) than in non-cachectic (11+/-2%) patients. Both groups equally decreased the proportion of type IIb fibres and increased muscle capillary/fibre ratio. IGF-I mRNA expression increased in both groups, but IGF-I protein levels increased more in non-cachectic COPD. MyoD was upregulated, whereas myostatin was downregulated at the mRNA and protein level only in non-cachectic patients. Whilst rehabilitation had no effect on TNF-alpha expression, it decreased the activation of the transcription factor NF-kappaB in both groups by the same amount. Atrogin-1 and MURF-1 expression were increased in cachectic COPD, but it was decreased in non-cachectic patients. Cachectic COPD patients partially retain the capacity for peripheral muscle remodelling in response to rehabilitation and are able to increase exercise capacity as much as those without cachexia, even if they exhibit both quantitative and qualitative differences in the type of muscle fibre remodelling in response to exercise training.

Carbapenem-resistant versus carbapenem-susceptible Acinetobacter baumannii bacteremia in a Greek intensive care unit: risk factors, clinical features and outcomes.

BACKGROUND: There has been an increasing incidence of carbapenem-resistant Acinetobacter baumannii (CRAB) infections in recent years. The objective of this study was to determine specific risk factors for and outcome of bacteremia due to CRAB isolates among our ICU patients with A. baumannii bacteremia. PATIENTS AND METHODS: Among 96 patients with ICU-acquired A. baumannii bacteremia, 30 patients with CRAB were compared with the remaining 66 with carbapenem-susceptible A. baumannii (CSAB) isolates. RESULTS: Recent ventilator-associated pneumonia (VAP) due to CRAB (OR 16.74, 95% CI 3.16-88.79, p = 0.001) and a greater number of intravascular devices (OR 3.93, 95% CI 1.9-13.0, p = 0.025) were independently associated with CRAB bacteremia acquisition. Patients with CRAB bacteremia had a lower severity of illness on admission than those with CSAB. Although, by univariate analysis, patients with CRAB were more likely to have had exposure to colistin, carbapenems and linezolid, multivariate analysis did not revealed any significant association. The mortality was not different between patients with CRAB and CSAB bacteremia (43.3 vs. 46.9%, p = 0.740). Severity of organ failure (OR 1.42, 95% CI 1.20-1.67, p = 0.001), and increased white blood cell (WBC) count (OR 1.09, 95% CI 1.01-1.19, p = 0.036), at bacteremia onset were independently associated with mortality. CONCLUSION: VAP due to CRAB and excess use of intravascular devices are the most important risk factors for CRAB bacteremia in our ICU. Severity of organ failure and WBC count at A. baumannii bacteremia onset are independently associated with mortality.

Effect of heliox breathing on flow limitation in chronic heart failure patients.

Patients with chronic heart failure (CHF) exhibit orthopnoea and tidal expiratory flow limitation in the supine position. It is not known whether the flow-limiting segment occurs in the peripheral or central part of the tracheobronchial tree. The location of the flow-limiting segment can be inferred from the effects of heliox (80% helium/20% oxygen) administration. If maximal expiratory flow increases with this low-density mixture, the choke point should be located in the central airways, where the wave-speed mechanism dominates. If the choke point were located in the peripheral airways, where maximal flow is limited by a viscous mechanism, heliox should have no effect on flow limitation and dynamic hyperinflation. Tidal expiratory flow limitation, dynamic hyperinflation and breathing pattern were assessed in 14 stable CHF patients during air and heliox breathing at rest in the sitting and supine position. No patient was flow-limited in the sitting position. In the supine posture, eight patients exhibited tidal expiratory flow limitation on air. Heliox had no effect on flow limitation and dynamic hyperinflation and only minor effects on the breathing pattern. The lack of density dependence of maximal expiratory flow implies that, in CHF patients, the choke point is located in the peripheral airways.

Predictors of residual sleepiness in adequately treated obstructive sleep apnoea patients.

Some patients with obstructive sleep apnoea syndrome (OSAS; respiratory distress index (RDI) of >5 events.h(-1)) experience residual excessive daytime subjective sleepiness (Epworth Sleepiness Scale (ESS) score of >10), despite adequate use of continuous positive airway pressure (CPAP) therapy. The aim of the present study was to identify clinical and polysomnographic predictors of this sleepiness. Clinical and polysomnographic variables and ESS score were evaluated in 208 OSAS patients with an ESS score of >10 before (initial assessment) and after > or =6 months of adequate (> or =4 h.day(-1)) CPAP use. Following CPAP treatment, 114 (55%) patients showed an abnormal ESS score (>10; CPAP nonresponders), whereas 94 (45%) showed a normal ESS score (<11; CPAP responders). Of the CPAP responders, none had a history of depression, whereas the converse was true for 38.8% of CPAP nonresponders. In addition, multivariate logistic regression analysis revealed that the independent predictors of residual excessive daytime sleepiness following CPAP therapy were a history of diabetes and heart disease, and a higher ESS score and lower RDI on initial assessment. In conclusion, predictors of residual excessive sleepiness in adequately CPAP-treated OSAS were a history of depression, diabetes and heart disease, and a higher ESS score and lower RDI on initial assessment.

Thoracoabdominal motion in ankylosing spondylitis: association with standardised clinical measures and response to therapy.

OBJECTIVES: To assess the relationship between thoracoabdominal motion during quiet breathing and standardised indices of disease severity in patients with ankylosing spondylitis (AS); also to evaluate whether thoracoabdominal motion improves after institution of biological agents in these patients. METHODS: Displacement of the rib cage (RC) and abdomen (Abd) during quiet breathing in the sitting, standing and supine position were recorded by impedance plethysmography in 60 patients (mean (SD) age 41 (10) years, 56 men) and 21 healthy men (mean (SD) 36 (7) years). x-y plots of RC versus Abd displacement during quiet breathing were constructed, and the angle of the slope of the RC-Abd loop was calculated and averaged for five consecutive breaths. In 13 patients treated with anti-tumour necrosis factor alpha (TNFalpha), measurements were made before and at 3, 6 and 12 months after the start of treatment. RESULTS: In the entire AS group, the angle of the slope of the RC-Abd loop correlated with Bath Ankylosing Spondylitis Functional Index (BASFI) in the sitting (R = -0.50, p<0.0001), standing (R = -0.36, p = 0.004) and supine (R = -0.47, p = 0.0001) position, but not with Bath Ankylosing Spondylitis Disease Activity (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI) or the modified Schober's test. In 13 patients treated with anti-TNFalpha, the angle of the RC-Abd slope improved significantly (35-69% over baseline at 3 months) in all body positions and in a nearly parallel fashion with the improvements in standardised clinical measurements. CONCLUSIONS: The pattern of thoracoabdominal motion during quiet breathing correlates with BASFI, and its response to anti-TNFalpha treatment is large. This variable may be an appropriate target for evaluating potential usefulness in monitoring thoracic spine involvement and response to treatment in AS.

Exercise-induced skeletal muscle deoxygenation in O-supplemented COPD patients.

This study was designed to assess quadriceps oxygenation during symptom-limited and constant-load exercise in patients with chronic obstructive pulmonary disease (COPD) and healthy age-matched controls. Thirteen male COPD patients [FEV(1): 43 +/- 5% predicted (mean +/- SEM)] and seven healthy male controls performed an incremental exercise test at peak work rate (WR) and a constant-load test at 75% peak WR on a cycle ergometer. Quadriceps hemoglobin saturation (StO2) was measured by continuous-wave near-infrared spectrophotometry throughout both exercise tests. StO2 is the ratio of oxygenated hemoglobin to total hemoglobin and reflects the relative contributions of tissue O2 delivery and tissue O2 utilization. Oxygen was supplemented to all patients in order to maintain arterial O2 saturation normal (> 95%). The StO2 decreased during symptom-limited exercise, reaching the nadir at peak WR. The decrease in StO2 was greater (P < 0.05) in healthy subjects (from 74 +/- 2% to 38 +/- 6%) compared with that in COPD patients (from 61 +/- 5% to 45 +/- 4%). However, when StO2 was normalized relative to the WR, the slope of change in StO2 during exercise was nearly identical between COPD patients and healthy subjects (0.47 +/- 0.10%/W and 0.51 +/- 0.04%/W, respectively). During constant-load exercise, the kinetic time constant of StO2 desaturation after the onset of exercise (i.e., equivalent to time to reach approximately 63% of StO2 decrease) was not different between COPD patients and healthy subjects (19.0 +/- 5.2 and 15.6 +/- 2.5 s, respectively). In O2-supplemented COPD patients, peripheral muscle oxygenation for a given work load is similar to that in healthy subjects, thus suggesting that skeletal muscle O2 consumption becomes normal for a given O2 delivery in COPD patients

Use of extracorporeal circulation and selective renal perfusion during the surgical correction of abdominal aortic coarctation.

Coarctation of the abdominal aorta is a rare pathology. Stenosis of visceral and renal arteries may present together with coarctation, which requires specific operation techniques. We present the case of a patient with coarctation of the abdominal aorta associated with stenosis of the celiac trunk, the superior mesenteric and the right renal arteries. Distal aortic perfusion by extracorporeal circulation and selective right renal perfusion techniques were used during the operation to protect the spinal cord and kidney against hypoperfusion and ischemia.

Randomised trial of nasal surgery for fixed nasal obstruction in obstructive sleep apnoea.

Although nasal surgery has limited efficacy in obstructive sleep apnoea (OSA) treatment, some patients experience improvement. The present study tested the hypothesis that post-surgery improvement is associated with increased nasal breathing epochs. A total of 49 OSA patients (mean apnoea/hypopnoea index (AHI) 30.1+/-16.3 events x h(-1)) with symptomatic fixed nasal obstruction due to deviated septum were randomly assigned to either septoplasty (surgery group; 27 patients) or sham surgery (placebo group; 22 patients). The breathing route was examined during overnight polysomnography. All patients in the placebo group were nonresponders, whereas in the surgery group four (14.8%) patients were responders and exhibited considerable increase in nasal breathing epochs (epochs containing more than three consecutive phasic nasal signals), and 23 patients were nonresponders, presenting a modest increase in nasal breathing epochs. The change in AHI was inversely related to the change in nasal breathing epochs, with responders exhibiting among the greatest increases in nasal breathing epochs. Baseline nasal breathing epochs were positively related to per cent change in AHI. Responders had among the lowest baseline nasal breathing epochs; a cut-off value of 62.4% of total sleep epochs best separated (100% sensitivity, 82.6% specificity) responders/nonresponders. In conclusion, nasal surgery rarely treats obstructive sleep apnoea effectively. Baseline nasal breathing epochs can predict the surgery outcome.

Chest wall volume regulation during exercise in COPD patients with GOLD stages II to IV.

The present study investigated how end-expiratory ribcage and abdominal volume regulation during exercise is related to the degree of dynamic chest wall hyperinflation in patients with different spirometric severity of chronic obstructive pulmonary disease (COPD) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. In total, 42 COPD patients and 11 age-matched healthy subjects were studied during a ramp-incremental cycling test to the limit of tolerance (W(peak)). Volume variations of the chest wall (at end expiration (EEV(cw)) and end inspiration) and its compartments (ribcage (V(rc)) and abdominal (V(ab))) were computed by optoelectronic plethysmography. At W(peak), only patients in GOLD stages III and IV exhibited a significant increase in EEV(cw) (increase of 454+/-509 and 562+/-363 mL, respectively). These patients did not significantly reduce end-expiratory V(ab), whereas patients in GOLD stage II resembled healthy subjects with significantly reduced end-expiratory V(ab) (decrease of 287+/-350 mL). In patients, the greater the increase in EEV(cw) at W(peak), the smaller the reductions in end-expiratory V(ab) and the greater the increase in end-expiratory V(rc). In chronic obstructive pulmonary disease patients with different spirometric disease severity, greater degrees of exercise-induced dynamic chest wall hyperinflation were accompanied by lower degrees of end-expiratory abdominal volume displacement and larger increases in end-expiratory ribcage volume.

Breath markers of oxidative stress and airway inflammation in Seasonal Allergic Rhinitis.

Oxidative stress (OS) is well documented in asthma, but so far, little data has been reported in nonasthmatic patients with Seasonal Allergic Rhinitis (SAR). The aim of this study is to investigate the degree of OS and airway inflammation in patients with SAR, with and without concomitant asthma (SAR+A), using breath markers in exhaled air and in Exhaled Breath Condensate (EBC). In addition, the effects of natural allergen exposure and intranasal steroid treatment on these markers were evaluated. Exhaled NO (eNO) and CO, combined with measurements of 8-Isoprostane (Iso-8), Leukotriene B4 (LTB4) and nitrate/nitrite in EBC, were performed in 23 patients, 11 with SAR and 12 with SAR+A, and 16 healthy subjects. Iso-8 and LTB4 were significantly increased in both groups of patients (median values 43.6 pg/ ml and 138.4 pg/ml in SAR group; 38.9 pg/ml, and 164.6 pg/ml in SAR+A group respectively; p>0.05) compared to healthy subjects (18.6 pg/ml and 7.8 pg/ml; p<0.05). Nitrate/nitrite and eNO levels were elevated in both groups compared to controls, but were significantly higher in the SAR+A compared to SAR group (nitrate/nitrite 9 microM and 3.9 microM; p=0.025; and eNO 18.5 ppb and 12.5 ppb, respectively; p>0.05). Nasal steroids caused significant reduction in LTB4 and 8-isoprostane levels in both groups of patients (p<0.05), while nitrate levels and eNO concentration were little affected by nasal treatment. OS markers were decreased at normal levels out of pollen season. Natural allergen exposure induces OS and airway inflammation, as assessed by measurements of markers in EBC and exhaled air, in patients with SAR who have no clinical signs of lower airway involvement. Besides, intranasal steroid treatment may have a regulatory role in the OS.

Predisposing factors for critical illness polyneuromyopathy in a multidisciplinary intensive care unit.

OBJECTIVE: To investigate risk factors of critical illness polyneuromyopathy (CIPM) in a general multidisciplinary intensive care unit (ICU). PATIENTS AND METHODS: Prospective observational study in a 28-bed university multidisciplinary ICU. Four hundred and seventy-four (323 M/151 F, age 55 +/- 19) consecutive patients were prospectively evaluated. All patients were assigned admission Acute Physiology and Chronic Health Evaluation (APACHE II; 15 +/- 7) and Sequential Organ Failure Assessment (SOFA; 6 +/- 3) scores and were subsequently evaluated for newly developed neuromuscular weakness. Other potential causes of new-onset weakness after ICU admission were excluded before CIPM was diagnosed. RESULTS: Forty-four (23.8%) of 185 patients developed generalized weakness that met the criteria for CIPM. Patients with CIPM had higher APACHE II (18.9 +/- 6.6 vs 15.6 +/- 6.4, P = 0.004) and SOFA scores (8.4 +/- 2.9 vs 7.1 +/- 2.9, P = 0.013). According to multivariate logistic regression analysis, the following risk factors were independently associated with the development of CIPM: severity of illness at the time of ICU admission, administration of aminoglycoside antibiotics and high blood glucose levels. Analysis according to severity of illness stratification revealed the emergence of Gram (-) bacteremia as the most important independent predisposing factor for CIPM development in less severely ill patients. CONCLUSIONS: CIPM has a high incidence in the ICU setting. Our study revealed the association of aminoglycosides, hyperglycemia and illness severity with CIPM development, as well as the association between Gram (-) bacteremia and development of CIPM in less severely ill patient population.

Histochemical and biochemical correlates of ventilatory muscle fatigue in emphysematous hamsters.

Histochemical and biochemical characteristics of the ventilatory muscles were evaluated in control and elastase-induced emphysematous hamsters. The emphysematous group was divided into sedentary and endurance-trained groups. Endurance training consisted of treadmill running, 1 h a day, 7 d a week. The experimental period lasted 24 wk. Histochemically, the diaphragm from the sedentary emphysematous hamsters revealed a selective fast fiber atrophy which was prevented by endurance training. Training also led to a hypertrophy of the slow, high oxidative fibers. The external intercostals from both emphysematous groups revealed an increased proportion of fast oxidative fibers at the expense of a decreased number of fast glycolytic fibers. However, the fast fibers in both emphysematous groups were significantly atrophied as compared with controls. The internal intercostals revealed no adaptive changes in either size or proportion distribution of the various fiber types. Biochemically, the diaphragm of the emphysematous animals had a significantly improved oxidative potential as measured by citrate synthase, and a reduced glycolytic capacity as indicated by phosphofructokinase activity, compared with controls. The magnitudes of the biochemical changes were similar in both emphysematous groups and were consistent for diaphragmatic samples taken from the costal and crural segments. The combined internal and external intercostals also underwent significant biochemical increases in their oxidative capacity. In addition, training of the emphysematous group led to an increased glycolytic potential of the intercostals.

Regional blood flow distribution in dog during induced hypotension and low cardiac output. Spontaneous breathing versus artificial ventilation.

Respiratory muscle blood flow and organ blood flow was studied in two groups of dogs with radioactively labeled microspheres to assess the influence of the working respiratory muscles on the regional distribution of blood flow when arterial pressure and cardiac output were lowered by pericardial tamponade. In one group (n = 6), the dogs were paralyzed and mechanically ventilated (Mv), while in the other (n = 6), they were left to breathe spontaneously (Sb). Cardiac output fell to 30% of control values during tamponade in both groups and was maintained constant. None of the dogs was hypoxic. Ventilation in the Sb group peaked after 50 min of hypotension, but remained unchanged in the Mv group. Duplicate measurements of blood flow were made during a control period and after 50 min of tamponade (corresponding to the peak ventilation in Sb). Blood flow to the respiratory muscles increased significantly (P less than 0.001) during tamponade in Sb (diaphragmatic flow increased to 361% of control values), while it decreased in Mv. Although the arterial blood pressure and cardiac output were comparable in the two groups, blood flow distribution during tamponade was different. In Sb, the respiratory muscles received 21% of the cardiac output, compared with only 3% in the Mv group. Thus, by muscle paralysis and Mv, a large fraction of the cardiac output used by the working respiratory muscles can be made available for perfusion of other organs during low cardiac output state: blood flows to the liver, brain, and quadriceps muscles were significantly higher during tamponade in the Mv group compared with the Sb group. Similarly, blood lactate at all times after the induction of low cardiac output and hypotension was significantly lower in the Mv animals (P less than 0.005).

Regulation of the expression of soluble guanylyl cyclase by reactive oxygen species.

BACKGROUND AND PURPOSE: Superoxide anions produced during vascular disease scavenge nitric oxide (NO), thereby reducing its biological activity. The aim of the present study was to investigate whether reactive oxygen species (ROS) have a direct effect on soluble guanylyl cyclase (sGC) subunit levels and function and to ascertain the mechanism(s) involved. EXPERIMENTAL APPROACH: Rat aortic smooth muscle cells (RASM) or freshly isolated vessels were exposed to reactive oxygen species (ROS)-generating agents and sGC subunit expression was determined at the mRNA and/or protein level. cGMP accumulation was also determined in RASM exposed to ROS. KEY RESULTS: Incubation of smooth muscle cells with H(2)O(2), xanthine/xanthine oxidase (X/XO) or menadione sodium bisulphite (MSB) significantly decreased protein levels of alpha1 and beta1 subunits of sGC and reduced SNP-induced cGMP formation. Similarly, sGC expression was reduced in freshly isolated vessels exposed to ROS-generating agents. The ROS-triggered inhibition of alpha1 and beta1 levels was not blocked by proteasome inhibitors, suggesting that decreased sGC protein was not due to protein degradation through this pathway. Real time RT-PCR analysis demonstrated a 68% reduction in steady state mRNA levels for the alpha1 subunit following exposure to H(2)O(2). In addition, alpha1 promoter-driven luciferase activity in RASM decreased by 60% after H(2)O(2) treatment. CONCLUSION AND IMPLICATIONS: We conclude that oxidative stress triggers a decrease in sGC expression and activity that results from reduced sGC steady state mRNA levels. Altered sGC expression is expected to contribute to the changes in vascular tone and remodeling observed in diseases associated with ROS overproduction.

Anti-angiogenic properties of a sulindac analogue.

BACKGROUND AND PURPOSE: Angiopoietins (Ang) are crucial for new blood vessel formation and exert their effects by acting on the Tie2 receptor. We have recently described a sulindac analogue 2-((1E,Z)-1-benzylidene-5-bromo-2-methyl-1H-inden-3-yl)acetic acid; termed C-18 from now onwards) that inhibits Tie2 receptor activity in kinase assays in vitro. Here, we have assessed the ability of C-18 to inhibit angiogenesis-related properties of endothelial cells and tested its selectivity for the Tie2 receptor. EXPERIMENTAL APPROACH: For in vitro experiments human umbilical vein endothelial cells (HUVEC) were used. Proliferation was measured using the MTT assay; migration assays were performed in a modified Boyden chamber and tube-like structure formation was determined on matrigel. The effects of C-18 in vivo were evaluated in the chicken chorioallantoic membrane (CAM). KEY RESULTS: Pre-treatment of HUVEC with C-18 blocked Ang-1-stimulated migration, but also abolished vascular endothelial cell growth factor (VEGF)- and fibroblast growth factor 2-induced responses. Incubation with C-18 inhibited serum-induced proliferation in a concentration-dependent manner; C-18 was, however, without effect on Ang-1-induced survival. In addition, we observed that C-18 did not inhibit ligand-induced receptor phosphorylation of Tie2 or VEGFR2. On the other hand, C-18 blocked activation of members of the mitogen-activated protein kinase family and of the Ser/Thr kinase Akt induced by both VEGF and Ang-1. Furthermore, incubation of CAMs with C-18 led to a dose-dependent inhibition of vascular length. CONCLUSIONS AND IMPLICATIONS: C-18 did not act as a Tie2 inhibitor, as originally thought, but rather inhibited growth factor-stimulated signalling pathways that regulate endothelial cell migration and potently reduces neovascularization in vivo.

Biweekly administration of docetaxel and gemcitabine for elderly patients with advanced non-small cell lung cancer: a phase II study.

With 69 years being the median age at diagnosis in the United States, management of elderly patients with advanced non-small cell lung cancer (NSCLC) has become a common problem faced by the oncology practitioner. We evaluated a biweekly administration of the combination regimen using docetaxel (Sanofi Aventis, Athens) and gemcitabine (Eli Lilly, Athens) in a phase II study (objective response rate, median survival, median response duration and safety). A total of 198 cycles were administered to 38 patients with advanced NSCLC with a median age of 72 years (range 65-85 years). Patients received docetaxel 80 mg/m(2 )and gemcitabine 1000 mg/m (2 )on days 1 and 14 of a 28-day cycle. Twenty patients achieved a partial response (PR) (20/34, 58.8%), 4 patients had stable disease (SD) (4/34, 11.7%) and 10 (10/34, 29.4%) had progressive disease (PD). The median time to disease progression was 3 months (range 1-11 months) with a mean survival of 7 months (range 1-29 months). Hematological and non-hematological toxic effects were generally mild to moderate and manageable: grade 3 neurotoxicity and grade 3 allergy occurred in 5 patients (13.1%) and 1 patient (2.6%), respectively. Peripheral neuropathy, mostly grades 1 and 2, was reported in 29 patients (76.3%), which was seen more frequently in patients >70 years of age (P=0.048).We conclude that the biweekly administration of a docetaxel/gemcitabine combination with G-CSF support constitutes a tolerable and convenient regimen for the treatment of elderly patients with advanced NSCLC, with efficacy similar to that reported in other regimens. Hence, this two-drug combination appears promising and warrants further evaluation.

Gender differences on polysomnographic findings in Greek subjects with obstructive sleep apnea syndrome.

BACKGROUND AND PURPOSE: Studies from North American clinics have reported that females with obstructive sleep apnea syndrome (OSAS) are about the same age as males but are heavier, have less severe apnea and make up a much smaller proportion of cases. We examined polysomnographic differences between Greek men and women with OSAS in order to study the influence of gender on clinical presentation and laboratory findings. PATIENTS AND METHODS: This retrospective study included a cohort of 1,010 Greek patients (844 males, 166 females) diagnosed with OSAS by overnight polysomnography (PSG), who were referred to the Sleep Disorders Center of Evangelismos Hospital, Athens Medical School, University of Athens. All patients were studied over a period of three consecutive years, during which time clinical and polysomnography (PSG) findings were compared. RESULTS: Body mass index (BMI) was similar in men and women with OSAS (BMI=31.6+/-5.5kg/m(2) in men versus BMI=32.5+/-8.1 (SD) kg/m(2) in women). Female patients were significantly older than male patients (56.9+/-10.6 versus 50.6+/-11.7 year, P=0.001). The mean apnea-hypopnea index (AHI) during total sleep time was higher in men than in women (42.4+/-28.2 versus 33.2+/-27.7 events/h, P<0.001). The AHI in non-rapid eye movement (NREM) sleep was higher in men than in women (42.9+/-28.9 versus 32.6+/-28.7 events/h, P<0.001), but in rapid eye movement (REM) sleep AHI was similar in men and women (36.0+/-23.3 versus 34.9+/-25.4 events/h). Forty percent of men had AHI-REM sleep >AHI-NREM compared to 62% of women, and the difference between REM and NREM-AHI was significantly less in men than in women (14.21+/-11.18 versus 19.76+/-13.43 events/h, P<0.001)). Several aspects of sleep were worse in women versus men: sleep efficiency index was lower (79.4+/-16.1% versus 85.1+/-12.5%, P<0.001); sleep onset latency (27.7+/-27.7 versus 17.9+/-18.1min, P<0.001), and REM onset latency (161.5+/-76.2 versus 145.7+/-71.4min, P<0.018) were longer; wake time after sleep onset (WASO) was also greater in women (42.6+/-46.5 versus 30.7+/-34.9min, P<0.003). CONCLUSIONS: In Greek subjects with OSAS, there was no difference in BMI, and female patients were significantly older than male patients. OSAS was diagnosed in men five times more often than in women. AHI was greater in men than in women, but women are more likely than men to have a higher AHI in REM than NREM. Sleep quality is worse in female than in male patients.