Biomedical subjects

Charis Roussos

Publications and source records attributed to Charis Roussos.

At least 37 records · Page 2Linked to original sources

PubMed2006

Regulation of Ang2 release by PTEN/PI3-kinase/Akt in lung microvascular endothelial cells.

Angiopoietin-2 (Ang2) is a Tie-2 ligand that destabilizes vascular structures, allowing for neovascularization or vessel regression depending on local vascular endothelial cell growth factor (VEGF) concentrations. Although various stimuli have been shown to affect Ang2 expression, information on the underlying mechanisms involved in Ang2 production in endothelial cells (EC) is just beginning to emerge. In the present study, we have used adenovirus-mediated gene transfer and pharmacological inhibitors to examine the role of the PTEN/PI3-K/Akt pathway on Ang2 release. Inhibition of PI3-kinase with wortmannin led to a stimulation of basal Ang2 release in EC, while overexpression of an active form of Akt reduced Ang2. In addition, adenovirus-mediated gene transfer of the phosphatase PTEN stimulated Ang2 release. Incubation of the cells with Ang1, an agent that activates the PI3-K/Akt pathway in EC, reduced Ang2 release. This effect of Ang1 could be prevented by wortmannin and LY-294002 pretreatment. Similarly, in VEGF-treated EC the increase in Ang2 production observed was greater in the presence of a PI3-K inhibitor. Our observations that PTEN acts as a positive modulator of Ang2 release, while activation of the PI3-K/Akt pathway downregulates Ang2, reveal an additional mechanism through which the PTEN/PI3-K/Akt pathway could affect the angiogenic process.

Androstadienes↗

PubMed2006

Monocytes as a site of production of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the septic host.

The role of blood monocytes in the secretion of soluble triggering receptor expressed on myeloiod cells (sTREM-1) was studied in 90 patients with septic syndrome due to ventilator-associated pneumonia. Blood monocytes were isolated on 7 consecutive d after initiation of symptoms. Monocytes were incubated in the absence or presence of LPS and concentrations of sTREM-1 and TNFalpha in cell supernatants and serum were estimated by an enzyme-immunoassay. sTREM-1 and TNFalpha were consistently present at detectable levels in the cell supernatants. LPS induced increased levels of TNFalpha but not of sTREM-1. Supernatants recovered from monocytes on d 1 showed levels of sTREM-1 higher than those recovered on any of the following 6 d (p<0.05); these levels were higher in non-survivors than in survivors. Supernatants recovered from monocytes on d 1 of patients with severe sepsis had elevated concentrations of sTREM-1 compared to patients with septic shock and similar to patients with sepsis. A negative correlation was found between levels of sTREM-1 in the cell supernatants and the percentage of apoptotic monocytes. In essence, the above results suggest that monocytes contribute to the production of sTREM-1 in the event of septic syndrome.

Cells, Cultured↗

PubMed2006

Effects of exercise rehabilitation program on heart rate recovery in patients with chronic heart failure.

BACKGROUND: Heart rate recovery (HRR1) immediately after exercise reflects parasympathetic activity, which is markedly attenuated in chronic heart failure (CHF) patients. The aim of our study was to examine both continuous and interval exercise training effects on HRR1 in these patients. DESIGN: The population study consisted of 29 stable CHF patients that participated at a rehabilitation program of 36 sessions, three times per week. Of the 29 patients, 24 completed the program. Patients were randomly assigned to interval {n=10 [100% peak work rate (WRp) for 30 s, alternating with rest for 30 s]} and to continuous training [n=14 (50%WRp)]. METHODS: All patients performed a symptom-limited cardiopulmonary exercise test on a cycle ergometer before and after the completion of the program. Measurements included peak oxygen uptake (VO2p), anaerobic threshold (AT), WRp, first degree slope of VO2 during the first minute of recovery (VO2/t-slope), chronotropic response [% chronotropic reserve (CR)=(peak HR - resting HR)x100/(220 - age - resting HR)], HRR1 (HR difference from peak exercise to one minute after). RESULTS: After the completion of the rehabilitation program there was a significant increase of WRp, VO2p, AT and VO2/t-slope (by 30%, P=0.01; 6%, P=0.01; 10%, P=0.02; and 27%, P=0.03 respectively for continuous training and by 21%, P<0.05; 8%, P=0.01; 6%, P=NS; and 48%, P=0.02 respectively for interval training). However, only patients exercised under the continuous training regime had a significant increase in HRR1 (15.0+/-9.0 to 24.0+/-12 bpm; P=0.02) and CR (57+/-19 to 72+/-21%, P=0.02), in contrast with those assigned to interval training (HRR1: 21+/-11 to 21+/-8 bpm; P=NS and CR: 57+/-18 to 59+/-21%, P=NS). CONCLUSIONS: Both continuous and interval exercise training program improves exercise capacity in CHF patients. However, continuous rather than interval exercise training improves early HRR1, a marker of parasympathetic activity, suggesting a greater contribution to the autonomic nervous system.

Adult↗

PubMed2006

A multidisciplinary overview of cardiogenic shock.

Cardiogenic shock complicating acute myocardial infarction (AMI) is reviewed from multidisciplinary viewpoints encompassing both basic and clinical aspects. Insights into the absolute obligate aerobic nature of the heart which possesses neither facultative capability nor functional collateral channels, together with O2 diffusion gradients, mitochondrial O2 sensing and anaerobic ATP deficiencies, are described in some detail. Myocardial adaptive responses against energy crisis, termed the Pasteur Effect, and hypoxia inducible factor (HIF)-1 alpha are implicated for cardiomyocyte viability. Oncosis and/or lysosomal autophagy cause such overwhelming numbers (several billions) of cardiomyocyte death, virtually simultaneously following coronary thrombotic occlusion. Apoptosis is briefly described and cardiogenic shock is discussed in terms of the diagnostic criteria by MIRU, unique hemodynamic manifestations, infarct sizes and border zone extension, and potentially jeopardized myocardium in the remote areas. Reperfusion injury, i.e., reactive oxygen species (ROS), is noted as a double-edged sword. The importance of early revascularization by means of PCI, CABG, and IABP support is emphasized according to current guidelines. For innovative promise in the future, de novo development of collateral channels by growth factors and trials of stem cell implantation aimed at myocardial regeneration are introduced.

Adenosine Triphosphate↗

PubMed2006

The effect of hypoxemic resuscitation of hemorrhagic shock on hemodynamic stabilization and inflammatory response: a pilot study in a rat experimental model.

BACKGROUND: Resuscitation of hemorrhagic shock is associated with tissue injury. The effect of hypoxemia during resuscitation was investigated. METHODS: Shock was induced by withdrawing blood to mean arterial pressure (MAP) 40 mm Hg and maintained for 60 minutes in 25 Wistar rats. Animals were randomly divided to receive either normoxemic (controls, FiO2 = 21%, n = 14) or hypoxemic (HypRes, FiO2 = 12%, n = 11) resuscitation by re-infusing their shed blood. Outcome was assessed through hemodynamic and inflammatory parameters. Another nine rats served to correlate different FiO2 to the corresponding PaO2. RESULTS: At 60 minutes of resuscitation HypRes had higher MAP than control animals (p = 0.008). The respective median (range) malondialdehyde and TNF-alpha levels was 1.7 (1-2.1) versus 3.1 (2.4-4.3) micromol/L, (p = 0.02) and 0 versus 5.8 (0-5.8) pg/mL, (p = 0.025). Glutathione, endotoxin, interferon-gamma, and nitric oxide values were similar between groups. FiO2 of 12% induced only a mild hypoxemia (PaO2 approximately 80 mm Hg). CONCLUSIONS: Even mild hypoxemia during resuscitation of shock leads to effective hemodynamic stabilization.

Animals↗

PubMed2006

Bench-to-bedside review: weaning failure--should we rest the respiratory muscles with controlled mechanical ventilation?

The use of controlled mechanical ventilation (CMV) in patients who experience weaning failure after a spontaneous breathing trial or after extubation is a strategy based on the premise that respiratory muscle fatigue (requiring rest to recover) is the cause of weaning failure. Recent evidence, however, does not support the existence of low frequency fatigue (the type of fatigue that is long-lasting) in patients who fail to wean despite the excessive respiratory muscle load. This is because physicians have adopted criteria for the definition of spontaneous breathing trial failure and thus termination of unassisted breathing, which lead them to put patients back on the ventilator before the development of low frequency respiratory muscle fatigue. Thus, no reason exists to completely unload the respiratory muscles with CMV for low frequency fatigue reversal if weaning is terminated based on widely accepted predefined criteria. This is important, since experimental evidence suggests that CMV can induce dysfunction of the diaphragm, resulting in decreased diaphragmatic force generating capacity, which has been called ventilator-induced diaphragmatic dysfunction (VIDD). The mechanisms of VIDD are not fully elucidated, but include muscle atrophy, oxidative stress and structural injury. Partial modes of ventilatory support should be used whenever possible, since these modes attenuate the deleterious effects of mechanical ventilation on respiratory muscles. When CMV is used, concurrent administration of antioxidants (which decrease oxidative stress and thus attenuate VIDD) seems justified, since antioxidants may be beneficial (and are certainly not harmful) in critical care patients.

Animals↗

PubMed2006

Mastic oil from Pistacia lentiscus var. chia inhibits growth and survival of human K562 leukemia cells and attenuates angiogenesis.

Mastic oil from Pistacia lentiscus var. chia, a natural plant extract traditionally used as a food additive, has been extensively studied for its antimicrobial activity attributed to the combination of its bioactive components. One of them, perillyl alcohol (POH), displays tumor chemopreventive, chemotherapeutic, and antiangiogenic properties. We investigated whether mastic oil would also suppress tumor cell growth and angiogenesis. We observed that mastic oil concentration and time dependently exerted an antiproliferative and proapoptotic effect on K562 human leukemia cells and inhibited the release of vascular endothelial growth factor (VEGF) from K562 and B16 mouse melanoma cells. Moreover, mastic oil caused a concentration-dependent inhibition of endothelial cell (EC) proliferation without affecting cell survival and a significant decrease of microvessel formation both in vitro and in vivo. Investigation of underlying mechanism(s) demonstrated that mastic oil reduced 1) in K562 cells the activation of extracellular signal-regulated kinases 1/2 (Erk1/2) known to control leukemia cell proliferation, survival, and VEGF secretion and 2) in EC the activation of RhoA, an essential regulator of neovessel organization. Overall, our results underscore that mastic oil, through its multiple effects on malignant cells and ECs, may be a useful natural dietary supplement for cancer prevention.

Angiogenesis Inhibitors↗

PubMed2006

Angiopoietin-2 levels are elevated in exudative pleural effusions.

OBJECTIVE: To examine the pleural fluid (PF) and serum levels of angiopoietin (Ang)-1, Ang-2, and vascular endothelial growth factor (VEGF) in patients with pleural effusions (PEs). METHODS: One hundred fifteen patients, 16 with transudative PEs due to heart failure and 99 with exudative PEs (malignant, 40; para-pneumonic, 24; tuberculous, 13; miscellaneous etiologies, 22) were included in the study. PF and serum levels of the growth factors were measured using enzyme-linked immunosorbent assay. RESULTS: PF Ang-2 and VEGF levels but not Ang-1 levels were higher (p < 0.001) in exudates than in transudates. PF Ang-2 levels were higher in tuberculous PEs than in PEs of any other etiology and were lower in heart failure PEs than in PEs of any other etiology. The highest PF VEGF levels were observed in patients with malignant and parapneumonic PEs. The lowest PF VEGF levels were observed in patients with transudates. In PEs, Ang-2 levels correlate with VEGF levels (p < 0.001), RBC count (p = 0.002), nucleated cell count (p < 0.001), total protein levels (p < 0.001), and lactate dehydrogenase levels (p < 0.001). PF Ang-1 levels were lower than serum Ang-1 levels both in patients with exudates (p < 0.001) and in those with transudates (p = 0.001). PF Ang-2 levels were higher than serum Ang-2 levels both in patients with exudates (p < 0.001) and in those with transudates (p = 0.045). PF VEGF levels were higher than serum VEGF levels in patients with malignant PEs (p < 0.001) and parapneumonic PEs (p = 0.003), but lower than serum VEGF levels in heart failure PEs (p < 0.001). In patients with tuberculous PEs and exudative PEs of miscellaneous etiology, PF and serum VEGF levels did not differ significantly. CONCLUSION: Ang-2 levels but not Ang-1 levels are elevated in exudative PEs, and they correlate with levels of VEGF and markers of pleural inflammation. It is thus possible that Ang-2 along with VEGF participate in pleural inflammation and the pathogenesis of exudative PEs.

Adult↗

PubMed2005

Early heart rate recovery after exercise predicts mortality in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) have multiple abnormalities of autonomic regulation that have been associated to their high mortality rate. Heart rate recovery immediately after exercise is an index of parasympathetic activity, but its prognostic role in CHF patients has not been determined yet. METHODS: Ninety-two stable CHF patients (83M/9F, mean age: 51+/-12 years) performed an incremental symptom-limited cardiopulmonary exercise testing. Measurements included peak O2 uptake (VO2p), ventilatory response to exercise (VE/VCO2 slope), the first-degree slope of VO2 for the 1st minute of recovery (VO2/t-slope), heart rate recovery [(HRR1, bpm): HR difference from peak to 1 min after exercise] and chronotropic response to exercise [%chronotropic reserve (CR, %)=(peak HR-resting HR/220-age-resting HR)x100]. Left ventricular ejection fraction (LVEF, %) was also measured by radionuclide ventriculography. RESULTS: Fatal events occurred in 24 patients (26%) during 21+/-6 months of follow-up. HRR1 was lower in non-survivors (11.4+/-6.4 vs. 20.4+/-8.1; p<0.001). All cause-mortality rate was 65% in patients with HRR1 12 bpm (log-rank: 32.6; p<0.001). By multivariate survival analysis, HRR1 resulted as an independent predictor of mortality (chi2=19.2; odds ratio: 0.87; p<0.001) after adjustment for LVEF, VO2p, VE/VCO2 slope, CR and VO2/t-slope. In a subgroup of patients with intermediate exercise capacity (VO2p: 10-18, ml/kg/min), HRR1 was a strong predictor of mortality (chi2: 14.3; odds ratio: 0.8; p<0.001). CONCLUSIONS: Early heart rate recovery is an independent prognostic risk indicator in CHF patients and could be used in CHF risk stratification.

Chronic Disease↗

PubMed2005

VE/VCO2 slope is associated with abnormal resting haemodynamics and is a predictor of long-term survival in chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) present with exercise-induced hyperpnea, but its pathophysiological mechanism has not been thoroughly investigated. We aimed to determine the relationship between exercise-induced hyperpnea, resting haemodynamic measurements and the validity of ventilatory response (V(E)/V(CO(2)) slope) as a mortality predictor in CHF patients. METHODS: Ninety-eight CHF patients (90M/8F) underwent a symptom-limited treadmill cardiopulmonary exercise test (CPET). Right heart catheterization and radionuclide ventriculography were performed within 72 h of CPET. RESULTS: Twenty-seven patients died from cardiac causes during 20+/-6 months follow-up. Non-survivors had a lower peak oxygen consumption (V(O(2)p)), (16.5+/-4.9 vs. 20.2+/-6.1, ml/kg/min, p=0.003), a steeper V(E)/V(CO(2)) slope (34.8+/-8.3 vs. 28.9+/-4.8, p<0.001) and a higher pulmonary capillary wedge pressure (PCWP) (19.5+/-8.6 vs. 11.7+/-6.5 mm Hg, p=0.008) than survivors. By multivariate survival analysis, the V(E)/V(CO(2)) slope as a continuous variable was an independent prognostic factor (chi(2): 8.5, relative risk: 1.1, 95% CI: 1.03-1.18, p=0.004). Overall mortality was 52% in patients with V(E)/V(CO(2)) slope > or =34 and 18% in those with V(E)/V(CO(2)) slope <34 (log rank: 18.5, p<0.001). In a subgroup of patients (V(O(2)p): 10-18 ml/kg/min), V(E)/V(CO(2)) slope was a significant predictor of mortality (relative risk: 6.2, 95% CI: 1.7-22.2, p=0.002). Patients with high V(E)/V(CO(2)) slope had higher resting PCWP (19.9+/-9.1 vs. 11.3+/-5.7 mmHg, p<0.001) and V(E)/V(CO(2)) slope correlated significantly with PCWP (r: 0.57, p<0.001). CONCLUSIONS: The V(E)/V(CO(2)) slope, as an index of ventilatory response to exercise, improves the risk stratification of CHF patients. Interstitial pulmonary oedema may be a pathophysiological mechanism of inefficient ventilation during exercise in these patients.

Adult↗

PubMed2005

Static pressure volume curves and body posture in acute respiratory failure.

OBJECTIVE: In acute respiratory distress syndrome the body posture effects on pressure-volume (PV) curves are still unclear. We examined the effects of prone position on inflation PV curves and their potential relationships with postural alterations in gas exchange. DESIGN AND SETTING: Prospective study with patients serving as their own controls in a university-affiliated 30-bed intensive care unit. PATIENTS AND PARTICIPANTS: Thirteen anesthetized, paralyzed, semirecumbent, mechanically ventilated patients with early/severe/diffuse ARDS. INTERVENTIONS: Sequential body posture changes: preprone semirecumbent, prone, and postprone semirecumbent. MEASUREMENTS AND RESULTS: In each posture hemodynamics, gas exchange, and lung volumes were determined before/during removal and after restoration of positive end-expiratory pressure (PEEP=10.2+/-0.6 cmH2O). At zero PEEP PV curves of respiratory system, lung, and chest wall were constructed. Prone position vs. preprone semirecumbent resulted in significantly reduced pressure at lower inflection point of lung PV curve (2.2+/-0.2 vs. 3.7+/-0.5 cmH2O) and increased volume at upper inflection point (0.87+/-0.03 vs. 0.69+/-0.05 l). Postural reduction in lower inflection point pressure of lung PV curve was the sole independent predictor of pronation-induced increases in PaO2/FIO2 (R2=0.76). PaO2/FIO2 increases were also significantly related with increases in functional residual capacity (R2=0.60). CONCLUSIONS: In early/severe/diffuse ARDS prone position reduces lower inflection point pressure and increases upper inflection point UIP volume of the lung PV curve. Lower inflection point pressure reductions explain oxygenation improvements, which are also associated with a postural increase in functional residual capacity.

Adult↗

PubMed2005

Differential cardiovascular responses during weaning failure: effects on tissue oxygenation and lactate.

OBJECTIVE: To test the following two hypotheses during weaning failure: (a) mixed venous oxygen saturation (SvO2) does not decrease in patients whose oxygen consumption does not increase, and (b) blood lactate may increase in patients who demonstrate substantial decreases in SvO2. DESIGN AND SETTING: A prospective observational and physiological study in a 30-bed university intensive care unit. PATIENTS AND PARTICIPANTS: 18 patients who failed weaning and 12 patients who succeeded weaning (controls). MEASUREMENTS AND RESULTS: Hemodynamics, global tissue oxygenation, cardiovascular response (cardiac index/oxygen extraction diagram), and blood lactate were measured in ventilator-supported patients undergoing a spontaneous breathing trial. In patients who failed without having increased their oxygen consumption (n=9) the increase in oxygen delivery was accompanied by a decrease in oxygen extraction (by 15+/-4%). In patients who failed (n=9) having increased their oxygen consumption (by>10%) this increase was met mainly by an increase in oxygen extraction (by 30+/-7%). SvO2 increased by 2+/-1% in the former patients, whereas it decreased by 20+/-5% in the latter. Arterial lactate increased (range 2.3-3.1 mM/l) in only three patients who failed to have increased oxygen consumption and exhibited heart failure and the highest decreases in SvO2 (by 12-39%). CONCLUSIONS: Patients whose SvO2 does not decrease during weaning failure do not have increased oxygen consumption probably due to respiratory center depression in some of them. Patients whose SvO2 decreases have increased oxygen consumption.

Aged↗

PubMed2005

Soluble guanylyl cyclase expression is reduced in allergic asthma.

Soluble guanylyl cyclase (sGC) is an enzyme highly expressed in the lung that generates cGMP contributing to airway smooth muscle relaxation. To determine whether the bronchoconstriction observed in asthma is accompanied by changes in sGC expression, we used a well-established murine model of allergic asthma. Histological and biochemical analyses confirmed the presence of inflammation in the lungs of mice sensitized and challenged with ovalbumin (OVA). Moreover, mice sensitized and challenged with OVA exhibited airway hyperreactivity to methacholine inhalation. Steady-state mRNA levels for all sGC subunits (alpha1, alpha2, and beta1) were reduced in the lungs of mice with allergic asthma by 60-80%, as estimated by real-time PCR. These changes in mRNA were paralleled by changes at the protein level: alpha1, alpha2, and beta1 expression was reduced by 50-80% as determined by Western blotting. Reduced alpha1 and beta1 expression in bronchial smooth muscle cells was demonstrated by immunohistochemistry. To study if sGC inhibition mimics the airway hyperreactivity seen in asthma, we treated naïve mice with a selective sGC inhibitor. Indeed, in mice receiving ODQ the methacholine dose response was shifted to the left. We conclude that sGC expression is reduced in experimental asthma contributing to the observed airway hyperreactivity.

Animals↗

PubMed2005

Cytogenetic and molecular aspects of lung cancer.

Lung cancer is one of the most common cancers worldwide and its pathogenesis is closely associated with tobacco smoking. Continuous exposure of smoking carcinogens results in the accumulation of several alterations of tumorigenesis related genes leading to neoplastic bronchial lesions. Lung cancer is divided in two main histological groups, non-small cell lung carcinomas (NSCLCs) and small cell lung carcinomas (SCLCs). It seems that lung tumorigenesis is a multistep process in which a number of genetic events including alterations of oncogenes and tumor suppressor genes have been occurred. Cytogenetic abnormalities in lung cancer are very complex. However, a number of recurrent cytogenetic abnormalities have been identified. Many of these changes are common in both major histological groups of lung cancer while certain chromosomal abnormalities have been correlated with the stage or the grade of the tumors. In addition, several molecular alterations have been constantly found. Some of them are common in different histological subtypes of lung cancer and they appear to play an important role in the pathogenesis of lung cancer. A good understanding of the underlying genetic changes of lung tumorigenesis will provide new perspectives for early diagnosis and screening of high-risk individuals. In addition, a number of genetical prognostic factors have been identified as possibly helpful parameters in the evaluation of lung cancer patients. Further research is required in order to systematically investigate genetical alterations in lung cancer contributing to improvement of lung cancer classification and staging and to development of new molecular targeted therapies.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

CD8+ T lymphocytes in lung tissue from patients with idiopathic pulmonary fibrosis.

BACKGROUND: Several studies have implicated a role of inflammation in the pathogenesis of lung damage in idiopathic pulmonary fibrosis (IPF). Parenchymal lung damage leads to defects in mechanics and gas exchange and clinically manifests with exertional dyspnea. Investigations of inflammatory cells in IPF have shown that eosinophils, neutrophils and CD8+ TLs may be associated with worse prognosis. We wished to investigate by quantitative immunohistochemistry infiltrating macrophages, neutrophils and T lymphocytes (TLs) subpopulations (CD3+, CD4+ and CD8+) in lung tissue of patients with IPF and their correlation with lung function indices and grade of dyspnoea. METHODS: Surgical biopsies of 12 patients with IPF were immunohistochemically stained with mouse monoclonal antibodies (anti-CD68 for macrophages, anti-elastase for neutrophils, and anti-CD3, anti-CD4, anti-CD8 for CD3+TLs, CD4+TLs, and CD8+TLs respectively). The number of positively stained cells was determined by observer-interactive computerized image analysis (SAMBA microscopic image processor). Cell numbers were expressed in percentage of immunopositive nuclear surface in relation to the total nuclear surface of infiltrative cells within the tissue (labeling Index). Correlations were performed between cell numbers and physiological indices [FEV1, FVC, TLC, DLCO, PaO2, PaCO2 and P(A-a)O2)] as well as dyspnoea scores assessed by the Medical Research Council (MRC) scale. RESULTS: Elastase positive cells accounted for the 7.04% +/- 1.1 of total cells, CD68+ cells for the 16.6% +/- 2, CD3+ TLs for the 28.8% +/- 7, CD4+ TLs for the 14.5 +/- 4 and CD8+ TLs for the 13.8 +/- 4. CD8+TLs correlated inversely with FVC % predicted (rs = -0.67, p = 0.01), TLC % predicted (rs = -0.68, p = 0.01), DLCO % predicted (rs = -0.61, p = 0.04), and PaO2 (rs = -0.60, p = 0.04). Positive correlations were found between CD8+TLs and P(A-a)O2 (rs = 0.65, p = 0.02) and CD8+TLs and MRC score (rs = 0.63, p = 0.02). Additionally, CD68+ cells presented negative correlations with both FVC % predicted (rs = -0.80, p = 0.002) and FEV1 % predicted (rs = -0.68, p = 0.01). CONCLUSION: In UIP/IPF tissue infiltrating mononuclear cells and especially CD8+ TLs are associated with the grade of dyspnoea and functional parameters of disease severity implicating that they might play a role in its pathogenesis.

CD8-Positive T-Lymphocytes↗

PubMed2005

Interaction between the 90-kDa heat shock protein and soluble guanylyl cyclase: physiological significance and mapping of the domains mediating binding.

The 90-kDa heat shock protein (hsp90) regulates the stability and function of many client proteins, including members of the NO-cGMP signaling pathway. Soluble guanylyl cyclase (sGC), an NO receptor, was recently reported to be an hsp90-interacting partner. In the present study, we show that hsp90 binds to both subunits of the most common sGC form (alpha(1)beta(1)) when these are expressed individually but only interacts with beta(1) in the heterodimeric form of the enzyme. Characterization of the region of hsp90 required to bind each subunit in immunoprecipitation experiments revealed that residues 310 to 456 of hsp90 interact with the sGC subunits. The region of beta(1) responsible for binding to hsp90beta was mapped using in vitro binding assays and immunoprecipitation experiments and was found to lie in the regulatory domain. The physiological importance of the hsp90/sGC interaction was investigated by treating rat smooth muscle cells with the hsp90 inhibitors radicicol and geldanamycin (GA) and determining both sGC activity and protein levels. Long-term (24 or 48 h) inhibition of hsp90 resulted in a strong decrease of both alpha(1) and beta(1) protein levels and sGC activity. Moreover, incubation of smooth muscle cells with the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) blocked the GA-induced down-regulation of sGC. We conclude that the N-terminal region of the beta(1) subunit mediates binding of the heterodimeric form of sGC to hsp90 and that this interaction involves the M domain of hsp90. Hsp90 binding to sGC regulates the pool of active enzymes by affecting the protein levels of the two subunits.

Animals↗

PubMed2005

Cytogenetic aspects of adult primary myelodysplastic syndromes: clinical implications.

Myelodysplastic syndrome (MDS) is a heterogeneous disease from the clinical, biological and morphological point of view. The pathogenesis of MDS is not well established and it appears to occur complex changes in the stem cell biology. Clonal chromosomal aberrations are found in 30-50% of primary MDS and no specific cytogenetic abnormality has as yet been defined. The chromosomal abnormalities are predominantly characterized by partial/total chromosomal losses or chromosomal gains. These chromosomal abnormalities include mainly -5/del(5q), -7/del(7q), del(11q), del(12p), del(20q), -Y, and +8. The role of cytogenetic analysis in the diagnosis, prognosis, taking treatment decisions and follow up of patients with MDS has been clearly defined. Despite its difficulties in obtaining for analysis high quality metaphases conventional cytogenetics continues to be the basic technique for cytogenetic evaluation of a MDS patient. Other molecular cytogenetic methods have been shown to be complementary, without replacing the information obtained with this technique. Further investigations with both conventional and molecular cytogenetics in relation to clinical features as well as other molecular methods will undoubtedly contribute to improve understanding of the underlying genetic events responsible for the development and evolution of MDS leading to more accurate classification and management of MDS patients.

Animals↗

PubMed2005

Non-random structural chromosomal changes in ovarian cancer: i(5p) a novel recurrent abnormality.

Ovarian cancer represents the leading cause of death among patients with gynecological cancer. The genetic changes underlying the initiation and progression of ovarian cancer have not been well defined. However, non-random structural chromosomal changes have been identified with common chromosomal breakpoints. We have studied cytogenetically 15 cases of ovarian adenocarcinomas by a direct culture of cancer cells and a G-banding technique investigating the presence of recurrent structural aberrations with common chromosomal breakpoints. Among very complex structural rearrangements found, we could recognize recurrent structural aberrations involving according to frequency chromosomal regions 3p13-14, 11p15, 19q13, 3q21, 11q23, 11q10, 1p13, 1p36, and 17q24-25. Isochromosomes i(5p), i(17q), i(8q) and i(11q) were also observed. Isochromosome i(5p), rarely reported in ovarian cancer was found in seven cases suggesting that it may be a novel recurrent abnormality. Translocations t(1;11), t(3;19), t(3;17), t(7;11) and t(11;17) were also identified. Conventional cytogenetics continues to be valuable detecting the presence of non-random chromosomal breakpoints and facilitating the identification of genes implicated in tumorigenesis.

Adenocarcinoma↗