Silencing of the DNA damage repair regulator PPP1R15A sensitizes acute myeloid leukemia cells to chemotherapy.

Acute Myeloid Leukemia (AML) is a life-threatening disease whose induction treatment consists of combination chemotherapy with Idarubicin and Cytarabine for fit patients. Treatment failures are frequent, urging the need for novel treatments for this disease. The DNA Damage Response Mechanism (DDR) comprises numerous molecules and pathways intended to arrest the cell cycle until DNA damage is repaired or else drive the cell to apoptosis. AML-derived cell lines after treatment with Idarubicin and Cytarabine were used for studying the expression profile of 84 DDR genes, through PCR arrays. Utilizing de novo AML patient and control samples we studied the expression of PPP1R15A, CDKN1A, GADD45A, GADD45G, and EXO1. Next, we performed PPP1R15A silencing in AML cell lines in two separate experiments using siRNA and CRISPR-cas9, respectively. Our findings highlight that DDR regulators demonstrate increased expression in patients with high cytogenetic risk possibly reflecting increased genotoxic stress. Especially, PPP1R15A is mainly involved in the recovery of the cells from stress and it was the only DDR gene upregulated in AML patients. The PPP1R15A silencing resulted in decreased viability of Idarubicin and Cytarabine-treated cell lines, in contrast to untreated cells. These findings shed light on new strategies to enhance chemotherapy efficacy and demonstrate that PPP1R15A is an important DDR regulator in AML and its downregulation might be a safe and effective way to increase sensitivity to chemotherapy in this disease.

MicroRNA-675-5p Overexpression Is an Independent Prognostic Molecular Biomarker of Short-Term Relapse and Poor Overall Survival in Colorectal Cancer.

Colorectal cancer (CRC) is the main cause of cancer-related deaths globally, highlighting the importance of accurate biomarkers for early detection and accurate prognosis. MicroRNAs (miRNAs) have emerged as effective cancer biomarkers. The aim of this study was to investigate the prognostic potential of miR-675-5p as a molecular prognostic biomarker in CRC. For this reason, a quantitative PCR assay was developed and applied to determine miR-675-5p expression in cDNAs from 218 primary CRC and 90 paired normal colorectal tissue samples. To assess the significance of miR-675-5p expression and its association with patient outcome, extensive biostatistical analysis was performed. miR-675-5p expression was found to be significantly downregulated in CRC tissue samples compared to that in adjacent normal colorectal tissues. Moreover, high miR-675-5p expression was associated with shorter disease-free (DFS) and overall survival (OS) in CRC patients, while it maintained its unfavorable prognostic value independently of other established prognostic factors. Furthermore, TNM stage stratification demonstrated that higher miR-675-5p levels were associated with shorter DFS and OS intervals, particularly in patients with CRC of TNM stage II or III. In conclusion, our findings suggest that miR-675-5p overexpression constitutes a promising molecular biomarker of unfavorable prognosis in CRC, independent of other established prognostic factors, including TNM staging.

Identification of Two Novel Circular RNAs Deriving from BCL2L12 and Investigation of Their Potential Value as a Molecular Signature in Colorectal Cancer.

The utility of circular RNAs (circRNAs) as molecular biomarkers has recently emerged. However, only a handful of them have already been studied in colorectal cancer (CRC). The purpose of this study was to identify new circRNAs deriving from BCL2L12, a member of the BCL2 apoptosis-related family, and investigate their potential as biomarkers in CRC. Total RNA extracts from CRC cell lines and tissue samples were reversely transcribed. By combining PCR with divergent primers and nested PCR followed by Sanger sequencing, we were able to discover two BCL2L12 circRNAs. Subsequently, bioinformatical tools were used to predict the interactions of these circRNAs with microRNAs (miRNAs) and RNA-binding proteins (RBPs). Following a PCR-based pre-amplification, real-time qPCR was carried out for the quantification of each circRNA in CRC samples and cell lines. Biostatistical analysis was used to assess their potential prognostic value in CRC. Both novel BCL2L12 circRNAs likely interact with particular miRNAs and RBPs. Interestingly, circ-BCL2L12-2 expression is inversely associated with TNM stage, while circ-BCL2L12-1 overexpression is associated with shorter overall survival in CRC, particularly among TNM stage II patients. Overall, we identified two novel BCL2L12 circRNAs, one of which can further stratify TNM stage II patients into two subgroups with substantially distinct prognosis.

Risk factors for carbapenem-resistant Gram-negative bacteremia in intensive care unit patients.

PURPOSE: Carbapenem-resistant (CR) Gram-negative pathogens have increased substantially. This study was performed to identify the risk factors for development of CR Gram-negative bacteremia (GNB) in intensive care unit (ICU) patients. METHODS: Prospective study; risk factors for development of CR-GNB were investigated using two groups of case patients: the first group consisted of patients who acquired carbapenem susceptible (CS) GNB and the second group included patients with CR-GNB. Both case groups were compared to a shared control group defined as patients without bacteremia, hospitalized in the ICU during the same period. RESULTS: Eighty-five patients with CR- and 84 patients with CS-GNB were compared to 630 control patients, without bacteremia. Presence of VAP (OR 7.59, 95 % CI 4.54-12.69, p < 0.001) and additional intravascular devices (OR 3.69, 95 % CI 2.20-6.20, p < 0.001) were independently associated with CR-GNB. Presence of VAP (OR 2.93, 95 % CI 1.74-4.93, p < 0.001), presence of additional intravascular devices (OR 2.10, 95 % CI 1.23-3.60, p = 0.007) and SOFA score on ICU admission (OR 1.11, 95 % CI 1.03-1.20, p = 0.006) were independently associated with CS-GNB. The duration of exposure to carbapenems (OR 1.079, 95 % CI 1.022-1.139, p = 0.006) and colistin (OR 1.113, 95 % CI 1.046-1.184, p = 0.001) were independent risk factors for acquisition of CR-GNB. When the source of bacteremia was other than VAP, previous administration of carbapenems was the only factor related with the development of CR-GNB (OR 1.086, 95 % CI 1.003-1.177, p = 0.042). CONCLUSIONS: Among ICU patients, VAP development and the presence of additional intravascular devices were the major risk factors for CR-GNB. In the absence of VAP, prior use of carbapenems was the only factor independently related to carbapenem resistance.

Longitudinal study of PTSD, depression, and quality of life among adolescents after the Parnitha earthquake.

OBJECTIVE: To investigate the course of PTSD, depression, and current quality of life among adolescents 32-months after the 1999 Parnitha earthquake in Greece. METHODS: The follow-up was conducted among 511 adolescents originally evaluated at 3-months post-earthquake using the UCLA PTSD Reaction Index (PTSD-RI), Depression Self-Rating Scale (DSRS), and Quality of Life Questionnaire (QOLQ). RESULTS: Mean PTSD scores for the whole sample had subsided to mild levels; however, 8.8% were still experiencing moderate to severe levels of symptoms, and 13.6% met criteria for clinical depression. Frequency of experiencing reminders of the earthquake in the past month best explained the variance (15%) in PTSD severity, followed by depression at 3-months (8%). The QOLQ domain scores were negatively correlated with PTSD and depression. Depression at 3-months was the best predictor of QOLQ at 32-months, explaining 16% of the variance. LIMITATIONS: Self-report instruments were used; hence the responses may have been over- or under-estimated; also, the findings may not be generalizable to other ethnic groups. CONCLUSION: Ongoing screening is recommended after disaster to identify adolescents who continue to experience moderate to severe levels of PTSD and depressive symptoms. Specific interventions to reduce reactivity to earthquake-related reminders should be a component of post-disaster recovery programs. A quality of life measure can provide important information in addition to traditional scales for monitoring the course of recovery among adolescents after disasters.

Exhaled breath condensate in mechanically ventilated brain-injured patients with no lung injury or sepsis.

BACKGROUND: The inflammatory influence of prolonged mechanical ventilation in uninjured lungs remains a matter of controversy and largely unexplored in humans. The authors investigated pulmonary inflammation by using exhaled breath condensate (EBC) in mechanically ventilated, brain-injured patients in the absence of acute lung injury or sepsis and explored the potential influence of positive end-expiratory pressure (PEEP). METHODS: Inflammatory EBC markers were assessed in 27 mechanically ventilated, brain-injured patients with neither acute lung injury nor sepsis and in 12 healthy and 8 brain-injured control subjects. Patients were ventilated with 8 ml/kg during zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H(2)O PEEP (PEEP group, n = 15). EBC was collected on days 1, 3, and 5 of mechanical ventilation to measure pH; interleukins (IL)-10, 1ß, 6, 8, and 12p70; and tumor necrosis factor-α. RESULTS: EBC pH was lower, whereas IL-1ß and tumor necrosis factor-α were greater in both patient groups compared with either control group; IL-6 was higher, whereas IL-10 and IL-12p70 were sporadically higher than in healthy control subjects; no differences were noted between the two patient groups, except for IL-10, which decreased by day 5 during PEEP. Leukocytes, soluble IL-6, and soluble triggering receptor expressed on myeloid cells-1 in blood were constantly higher during zero end-expiratory pressure; EBC cytokines appeared mostly related to soluble IL-8 and inversely related to soluble triggering receptor expressed on myeloid cells-1. CONCLUSIONS: In brain-injured, mechanically ventilated patients with neither acute lung injury nor sepsis, EBC markers appear to indicate the presence of subtle pulmonary inflammation that is mostly unaffected by PEEP. There is evidence for a systemic inflammatory response, especially in patients during zero end-expiratory pressure.

Medical Research Council dyspnea scale does not relate to fibroblast foci profusion in IPF.

BACKGROUND: In Idiopathic pulmonary fibrosis (IPF) irreversibly progressive fibrosing parenchymal damage, leads to defects in mechanics and gas exchange, manifesting with disabling exertional dyspnea. Previous studies have shown a relationship between fibroblast foci (FF) profusion and severity and survival and a relationship between dyspnea grade and severity and outcome. We hypothesized a relationship between Medical Research Council (MRC) dyspnea scale with FF, and a relationship between FF and functional parameters and survival. METHODS: We retrospectively reviewed 24 histologically documented IPF patients. Profusion of FF was semiquantitatively evaluated by two scores, Brompton and Michigan. Survival analysis was performed by fitting Cox regression models to examine the relationship of the two scores with survival and the non-parametric Spearman correlation coefficient was calculated to describe the relationships of FF scores with dyspnea scores and functional parameters. RESULTS: No statistically significant correlation between FF scores and the MRC scores was observed (p = 0.96 and p = 0.508 respectively). No significant correlation between FF scores and survival (p = 0.438 and p = 0.861 respectively) or any functional parameter was observed. CONCLUSIONS: The lack of relationship between the MRC dyspnea scale and the FF might relate to the fact that dyspnea in IPF better reflects the overall of lung damage and its related consequences on mechanics and gas exchange whereas FF, one of its histological hallmarks, may not reflect its entire histology derangement also constrained by the geographically limited sampled tissue. This might be also valid for the observed lack of association between FF and survival or functional parameters.

Epidemiology, risk factors for and outcome of candidaemia among non-neutropenic patients in a Greek intensive care unit.

To determine the epidemiology, risk factors for and outcome of candidaemia in critically ill patients, a matched case-control study was performed in a 25-bed intensive care unit (ICU) from August 2004 to January 2006. Candidaemia occurred in 33 patients; each patient was matched to four controls according to admission illness severity, diagnostic category and length of ICU stay. Candida non-albicans species predominated (67.7%). The presence of acute respiratory distress syndrome (ARDS) was the only independent risk factor for candidaemia development (OR, 2.93; 95% CI 1.09-7.81, P = 0.032). Mortality was 60.6% among patients with candidaemia and 22% among controls (P < 0.001). The presence of candidaemia (OR, 9.37; 95% CI 3.48-25.26, P < 0.001) and the illness severity on admission (acute physiologic and chronic health evaluation II score, OR, 1.17; 95% CI 1.12-1.24, P < 0.001) were independently associated with mortality. Among candidaemic patients, risk factors for mortality were the severity of organ dysfunction (sequential organ failure assessment score, OR, 1.57; 95% CI 1.00-2.46, P = 0.05) and a low serum albumin level (OR, 0.74; 95% CI 0.59-0.94, P = 0.012) both of them occurred on candidaemia onset. We conclude that in critically ill patients matched for illness severity and length of ICU stay, the only independent risk factor for candidaemia was the presence of ARDS. Mortality was independently associated with acquisition of candidaemia and with the illness severity at candidaemia onset.

MRC chronic Dyspnea Scale: Relationships with cardiopulmonary exercise testing and 6-minute walk test in idiopathic pulmonary fibrosis patients: a prospective study.

BACKGROUND: Exertional dyspnea is the most prominent and disabling feature in idiopathic pulmonary fibrosis (IPF). The Medical Research Chronic (MRC) chronic dyspnea score as well as physiological measurements obtained during cardiopulmonary exercise testing (CPET) and the 6-minute walk test (6MWT) are shown to provide information on the severity and survival of disease. METHODS: We prospectively recruited IPF patients and examined the relationship between the MRC score and either CPET or 6MWT parameters known to reflect physiologic derangements limiting exercise capacity in IPF patients RESULTS: Twenty-five patients with IPF were included in the study. Significant correlations were found between the MRC score and the distance (r = -.781, p < 0.001), the SPO2 at the initiation and the end (r = -.542, p = 0.005 and r = -.713, p < 0.001 respectively) and the desaturation index (r = .634, p = 0.001) for the 6MWT; the MRC score and VO2 peak/kg (r = -.731, p < 0.001), SPO2 at peak exercise (r = -. 682, p < 0.001), VE/VCO2 slope (r = .731, p < 0.001), VE/VCO2 at AT (r = .630, p = 0.002) and the Borg scale at peak exercise (r = .50, p = 0.01) for the CPET. In multiple logistic regression analysis, the only variable independently related to the MRC is the distance walked at the 6MWT. CONCLUSION: In this population of IPF patients a good correlation was found between the MRC chronic dyspnoea score and physiological parameters obtained during maximal and submaximal exercise testing known to reflect ventilatory impairment and exercise limitation as well as disease severity and survival. This finding is described for the first time in the literature in this group of patients as far as we know and could explain why a simple chronic dyspnea score provides reliable prognostic information on IPF.

Predictors of positive sputum cultures in exacerbations of chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Although sputum culture in patients with an acute exacerbation of COPD is of uncertain value, it is routinely done. The ability to clinically identify patients likely or unlikely to yield bacterial sputum isolates would potentially reduce unnecessary tests. The objective of this study was to identify the clinical predictors of positive sputum cultures in this patient population. METHODS: Consecutive patients with a COPD exacerbation requiring an emergency visit were prospectively enrolled. Quantitative sputum culture was performed on-site. Data on current smoking, sputum purulence, FEV(1), Medical Research Council chronic dyspnoea scale, BMI, severe exacerbations in the preceding year requiring hospitalization, PaO(2), PaCO(2), Acute Physiology and Chronic Health Evaluation (APACHE) II score, and oral and inhaled steroid use were recorded. RESULTS: Of the 94 patients enrolled, sputum from 36 yielded bacterial pathogens. These patients were characterized by a higher frequency of purulent sputum, lower FEV(1), BMI and PaO(2,) higher APACHE II score and more frequent use of inhaled steroids (P < 0.05). On multivariate regression, purulent sputum, FEV(1) and BMI were independent determinants of a positive sputum culture. Using receiver-operator-optimized thresholds for these variables (purulent sputum, FEV(1) < 35% predicted and BMI < or = 22 kg/m(2)), we proposed a regression coefficient-weighted prediction model that accurately determined the likelihood of sputum bacterial isolation. CONCLUSIONS: A prediction model based on the variables of purulent sputum, FEV(1) and BMI predicted sputum culture result with about 90% accuracy. Pending further validation, this model may save valuable healthcare resources.

History of mechanical ventilation may affect respiratory mechanics evolution in acute respiratory distress syndrome.

PURPOSE: The aim of this study was to investigate the effect of mechanical ventilation (MV) before acute respiratory distress syndrome (ARDS) on subsequent evolution of respiratory mechanics and blood gases in protectively ventilated patients with ARDS. METHODS: Nineteen patients with ARDS were stratified into 2 groups according to ARDS onset relative to the onset of MV: In group A (n = 11), MV was applied at the onset of ARDS; in group B (n = 8), MV had been initiated before ARDS. Respiratory mechanics and arterial blood gas were assessed in early (

Plasma pro- and anti-inflammatory cytokine levels and outcome prediction in unselected critically ill patients.

PURPOSE: To determine the inter-relationships between cytokine levels and physiological scores in predicting outcome in unselected, critically ill patients. METHODS: To this end, 127 patients (96 men), having a mean+/-SD age of 45+/-20 years, with a wide range in admission diagnoses (medical, surgical, and multiple trauma patients) were prospectively investigated. Severity of critical illness and organ dysfunction were graded by acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores, respectively. Blood samples were drawn on admission in the ICU to determine pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, and IL-10. The main outcome measure was 28-day mortality. RESULTS: Overall, 88 patients survived and 39 patients died. Univariate logistic regression analysis showed that SOFA, APACHE II, IL-8, IL-6, and IL-10 on admission in the ICU were related to mortality. Multiple logistic regression analysis in the entire cohort of critically ill patients revealed that SOFA (OR=1.341, p<0.001) and IL-6 (OR=1.075, p=0.01) constituted independent outcome predictors. receiver operator characteristics curve analysis showed that SOFA, APACHE II, and IL-6 had the highest area under the curve values. IL-6 correlated with APACHE II (r(s)=0.44, p<0.0001) and SOFA (r(s)=0.40, p<0.0001) scores. CONCLUSIONS: In mixed ICU patients cytokine concentrations on admission in the ICU represent independent outcome predictors in the presence of disease severity scores.

The Medical Research Council chronic dyspnea score predicts the survival of patients with idiopathic pulmonary fibrosis.

BACKGROUND: The Medical Research Council (MRC) chronic dyspnea scale (6-point) is used in different clinical conditions to grade breathlessness on daily activities. We have previously shown that in patients with histologically documented usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF), the MRC dyspnea scale is useful in estimating disease severity. The aim of this study was to further investigate the usefulness of the MRC scale in IPF as a marker of survival. METHODS: The records of 25 patients with histologically documented UIP/IPF were retrospectively reviewed. Clinical parameters, pulmonary function tests, and arterial blood gases at the time of diagnosis, as well as survival time were retrieved and recorded for each patient. The impact of the different variables determined at diagnosis on survival was examined using the Kaplan-Meier and uni- and multi-variate Cox-regression analyses. RESULTS: Among the baseline clinical and physiologic parameters determined at the time of IPF diagnosis, the MRC score, the Tiffeneau index, and the total lung capacity were the only significant and independent predictors of survival. In specific, a high MRC score, a high Tiffeneau index, and a low total lung capacity at presentation were associated with shorter survival. CONCLUSION: In accordance with the previous work, our results indicate that the Tiffeneau index and total lung capacity (TLC) are the important determinants of survival in patients with IPF. In addition, we show that the simple MRC chronic dyspnea score estimated at the time of diagnosis is equally predictive of survival and may aid clinicians in assessing the prognosis of new cases of IPF.

CD8+ T lymphocytes in bronchoalveolar lavage in idiopathic pulmonary fibrosis.

BACKGROUND: Recently it was shown that in Idiopathic Pulmonary Fibrosis (IPF) tissue infiltrating CD8+ T lymphocytes (TLs) are associated with breathlessness and physiological indices of disease severity, as well as that CD8+ TLs recovered by bronchoalveolar lavage (BAL) relate to those infiltrating lung tissue. Since BAL is a far less invasive technique than tissue biopsy to study mechanisms in IPF we further investigated the usefulness offered by this means by studying the relationship between BAL macrophages, neutrophils, eosinophils, CD3+, CD4+, CD8+, CD8+/38+ TLs and CD4+/CD8+ ratio with breathlessness and physiological indices. PATIENTS AND METHODS: 27 IPF patients, 63 +/- 9 years of age were examined. Cell counts were expressed as percentages of total cells and TLs were evaluated by flow cytometry. FEV1, FVC, TLC, RV, DLCO, PaO2, and PaCO2 were measured in all. Breathlessness was assessed by the Medical Research Council (MRC) chronic dyspnoea scale. RESULTS: CD8+ TLs correlated positively (rs = 0.46, p = 0.02), while CD4+/CD8+ ratio negatively (rs = -0.54, p = 0.006) with the MRC grade. CD8+ TLs correlated negatively with RV (rs = -0.50, p = 0.017). CD8+/38+ TLs were negatively related to the FEV1 and FVC (rs = -0.53, p = 0.03 and rs = -0.59, p = 0.02, respectively). Neutrophils correlated positively with the MRC grade (rs = 0.42, p = 0.03), and negatively with the DLCO (rs = -0.54, p = 0.005), PaO2 (rs = -0.44, p = 0.03), and PaCO2 (rs = -0.52, p = 0.01). CONCLUSION: BAL CD8+ TLs associations with physiological and clinical indices seem to indicate their implication in IPF pathogenesis, confirming our previous tissue study.

Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators.

OBJECTIVE: Angiopoietin (Ang)-2 is an endothelium-specific growth factor, regulated by proinflammatory stimuli, that destabilizes vascular endothelium and increases vascular leakage; consequently, Ang-2 may contribute to sepsis pathophysiology. We have studied 1) serum Ang-2 levels in critically-ill patients and investigated potential relationships with inflammatory mediators and indices of disease severity and 2) the effect of sepsis-related inflammatory mediators on Ang-2 production by lung endothelium in vitro. DESIGN: Prospective clinical study followed by cell culture studies. SETTING: General intensive care unit and research laboratory of a university hospital. SUBJECTS: Human and bovine lung microvascular endothelial cells and 61 patients (32 men). Patients were grouped according to their septic stage as having: no systemic inflammatory response syndrome (n = 6), systemic inflammatory response syndrome (n = 8), sepsis (n = 16), severe sepsis (n = 18), and septic shock (n = 13). INTERVENTIONS: Cells were exposed to lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-6. MEASUREMENTS AND MAIN RESULTS: Patients' serum Ang-2 levels were significantly increased in severe sepsis as compared with patients with no systemic inflammatory response syndrome or sepsis (p < .05 by analysis of variance). Positive linear relationships were observed with: serum tumor necrosis factor-alpha (rs = 0.654, p < .001), serum interleukin-6 (rs = 0.464, p < .001), Acute Physiology and Chronic Health Evaluation II score (rs = 0.387, p < .001), and Sequential Organ Failure Assessment score (rs = 0.428, p < .001). Multiple regression analysis revealed that serum Ang-2 is mostly related to serum tumor necrosis factor-alpha and severe sepsis. Treatment of human lung microvascular endothelial cells with all mediators resulted in a concentration-dependent Ang-2 reduction. Treatment of bovine lung microvascular endothelial cells with lipopolysaccharide and tumor necrosis factor-alpha increased Ang-2 release, and interleukin-6 reduced basal Ang-2 levels. CONCLUSIONS: First, patients' serum Ang-2 levels are increased during severe sepsis and associated with disease severity. The strong relationship of serum Ang-2 with serum tumor necrosis factor-alpha suggests that the latter may participate in the regulation of Ang-2 production in sepsis. Second, inflammatory mediators reduce Ang-2 release from human lung microvascular endothelial cells, implying that this vascular bed may not be the source of increased Ang-2 in human sepsis.

Respiratory mechanics in brain-damaged patients.

OBJECTIVE: To assess respiratory mechanics on the 1st and 5th days of mechanical ventilation in a cohort of brain-damaged patients on positive end-expiratory pressure (PEEP) of 8 cmH(2)O or zero PEEP (ZEEP). DESIGN AND SETTING: Physiological study with randomized control trial design in a multidisciplinary intensive care unit of a university hospital. PATIENTS AND MEASUREMENTS: Twenty-one consecutive mechanically ventilated patients with severe brain damage and no acute lung injury were randomly assigned to be ventilated with ZEEP (n = 10) or with 8 cmH(2)O of PEEP (n = 11). Respiratory mechanics and arterial blood gases were assessed on days 1 and day 5 of mechanical ventilation. RESULTS: In the ZEEP group on day 1 static elastance and minimal resistance were above normal limits (18.9 +/- 3.8 cmH(2)O/l and 5.6 +/- 2.2 cmH(2)O/l per second, respectively); on day 5 static elastance and iso-CO(2) minimal resistance values were higher than on day 1 (21.2 +/- 4.1 cmH(2)O/l; 7.0 +/- 1.9 cmH(2)O/l per second, respectively). In the PEEP group these parameters did not change significantly. One of the ten patients on ZEEP developed acute lung injury. On day 5 there was a significant decrease in PaO(2)/FIO(2) in both groups. CONCLUSIONS: On day 1 of mechanical ventilation patients with brain damage exhibit abnormal respiratory mechanics. After 5 days of mechanical ventilation on ZEEP static elastance and minimal resistance increased significantly, perhaps reflecting "low lung volume" injury. Both could be prevented by administration of moderate levels of PEEP.

The combination of the load/force balance and the frequency/tidal volume can predict weaning outcome.

OBJECTIVE: To examine whether an appropriately designed combination of an index of ventilatory endurance and the frequency divided by tidal volume ratio (f/VT) provides prognostic information for weaning outcome not offered by any index alone. DESIGN AND SETTING: Prospective study in a multidisciplinary intensive care unit, university hospital. PATIENTS: 124 consecutive mechanically ventilated patients. INTERVENTIONS: We designed an index of ventilatory endurance (load/force balance) calculated as the mean inspiratory airway pressure (PI) during controlled mechanical ventilation/maximum inspiratory pressure (MIP) [PI equals the triplicate of mean airway pressure (Paw) displayed by the ventilator] and tested its capacity in predicting weaning outcome at 48 h along with f/VT and many other indices in 75 consecutive mechanically ventilated patients ready to wean. A stepwise discriminant function analysis was used to test the performance of appropriately designed index combination. Threshold values of indices and their combination were prospectively validated in another group of 45 consecutive patients. RESULTS: Stepwise discriminant analysis showed that PI/MIP and f/VT were the only indices that remained in the model with the function D=7.628xmean Paw/MIP+0.0158xf/VT-2.374. The cutoff point of D=0.5 had 94% sensitivity, 67% specificity, and 87% correct classifications. Prospective validation demonstrated similar results. The simplified discriminant function D=15xmean Paw/MIP+0.003xf/VT-5 and the cut-off point of D=1.0 had 89% sensitivity, 67% specificity, and 85% correct classifications. CONCLUSIONS: The combination of mean Paw/MIP and f/VT in a simplified discriminant function is useful in predicting weaning outcome.

Neutrophil CD64 expression and serum IL-8: sensitive early markers of severity and outcome in sepsis.

The aim of the present study was to investigate which biomarker/s reliably assess severity and mortality early in the sepsis process. In 47 critically-ill patients within the 24h of septic onset, Interleukins (IL)-8, -1beta, -6, -10, and -12p70, tumor necrosis factor-alpha (TNF-alpha), procalcitonin (PCT) and C-reactive protein (CRP) were measured in serum. Additionally, CD64 expression was measured in neutrophils. In early sepsis, neutrophil CD64 expression and IL-8 levels are the only biomarkers that increased with sepsis severity, differentiating disease stages: sepsis, severe sepsis and septic shock (p<0.001). The biomarkers that best evaluate the severity of sepsis (via APACHE II) were CD64, IL-8 and IL-6 (p<0.01), and the severity of organ failure (via SOFA) were CD64 and IL-8 (p<0.01). CD64 expression and IL-8 levels were associated with mortality within 28-days (OR=1.3, p=0.01 for CD64 and OR=1.26, p=0.024 for IL-8 by logistic regression analysis) and ROC curve analysis showed high sensitivity and specificity for predicting sepsis stages and the 28 day mortality. We conclude that there is an early increase of neutrophil CD64 expression and IL-8 levels during sepsis. Based on this single measurement it is possible to reliably assess the stage, detect the severity and predict the 28-day mortality of sepsis.

The Medical Research Council dyspnea scale in the estimation of disease severity in idiopathic pulmonary fibrosis.

BACKGROUND: Medical Research Council (MRC) chronic dyspnea scale, used for the estimation of disability due to dyspnea, may serve as a simple index of disease severity and extent in patients with idiopathic pulmonary fibrosis (IPF). However, its relationship with other commonly used measures has not been evaluated. METHODS: The association of MRC chronic dyspnea scale with lung function indices and high-resolution computerized tomography (HRCT) scores such as the total interstitial disease score (TIDs) and the fibrosis score (Fs) was examined in 26 untreated patients with IPF sequentially recruited over a period of 3 years. The aim of this observational study was to explore the relationship between dyspnea, impairment of lung function and CT estimation of disease severity in patients with IPF. RESULTS: The MRC dyspnea score was significantly associated with FVC, FEV1, TLC, DLCO, PaO2, and PaCO2 and with both HRCT scores. In multiple regression analysis only the FVC (OR = 0.85, 95% CI = 0.75-0.95, P = 0.004) and PaCO2 (OR = 0.69, 95% CI = 0.50-0.95, P = 0.02) correlated with dyspnea. Furthermore, both TIDs and Fs were negatively associated with FVC, FEV1, TLC and PaO2. In multiple regression analysis only the FVC correlated with both TIDs (r2 = 0.57, P = 0.0001) and Fs (r2 = 0.46, P = 0.0005). CONCLUSIONS: These observations suggest that the MRC dyspnea scale could offer useful information about the estimation of severity in patients with IPF. Furthermore among functional indices the FVC seems to be the best estimator of disease severity and extent.

Posttraumatic stress and depressive reactions among children and adolescents after the 1999 earthquake in Ano Liosia, Greece.

OBJECTIVE: This study evaluated the severity of posttraumatic stress and depressive reactions among children and adolescents 3 months after the 1999 earthquake in Ano Liosia, Greece, and additionally assessed the relationship of these reactions to objective and subjective features of earthquake exposure, sex, school level, postearthquake difficulties, death of a family member, and thoughts of revenge. METHOD: This school-based study of 1,937 students was conducted in two differentially exposed cities (Ano Liosia, at the epicenter, and Dafni, 10 kilometers from the epicenter) with an earthquake exposure questionnaire, the UCLA Posttraumatic Stress Disorder (PTSD) Reaction Index, and the Depression Self-Rating Scale. RESULTS: Endorsement of earthquake-related exposure items between the two cities was congruent with the extent of earthquake impact in each city. Median PTSD Reaction Index scores were significantly higher in Ano Liosia. The estimated rates of PTSD and clinical depression for both cities combined were 4.5% and 13.9%, respectively. Depression, subjective and objective earthquake-related experiences, and difficulties at home accounted for 41% of the variance in severity of PTSD reactions. PTSD score was the single most powerful variable predicting depression (36% of the variance), with only sex making a small but significant additional contribution. CONCLUSIONS: This study demonstrated the feasibility of conducting large-scale school-based postdisaster mental health screening for planning intervention strategies. The present findings regarding PTSD and depression indicate the need to provide targeted specialized postdisaster mental health services to subgroups with significant levels of posttraumatic stress and depressive reactions after an earthquake of moderate intensity.