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Biomedical subjects

Rafael Fernandez

Publications and source records attributed to Rafael Fernandez.

11 recordsLinked to original sources
PubMed2006

Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands.

We report structure-activity relationships for organometallic RuII complexes of the type [(eta6-arene)Ru(XY)Cl]Z, where XY is an N,N- (diamine), N,O- (e.g., amino acidate), or O,O- (e.g., beta-diketonate) chelating ligand, the arene ranges from benzene derivatives to fused polycyclic hydrocarbons, and Z is usually PF6. The X-ray structures of 13 complexes are reported. All have the characteristic "piano-stool" geometry. The complexes most active toward A2780 human ovarian cancer cells contained XY=ethylenediamine (en) and extended polycyclic arenes. Complexes with polar substituents on the arene or XY=bipyridyl derivatives exhibited reduced activity. The activity of the O,O-chelated complexes depended strongly on the substituents and on the arene. For arene=p-cymene, XY=amino acidate complexes were inactive. Complexes were not cross-resistant with cisplatin, and cross-resistance to Adriamycin was circumvented by replacing XY=en with 1,2-phenylenediamine. Some complexes were also active against colon, pancreatic, and lung cancer cells.

2,2'-Dipyridyl↗
PubMed2006

Noninvasive ventilation in patients with "do-not-intubate" orders: medium-term efficacy depends critically on patient selection.

OBJECTIVE: Randomized clinical trials demonstrating benefits of noninvasive ventilation (NIV) systematically exclude patients with "do-not-intubate" (DNI) orders, but in daily clinical practice these patients are frequently treated with NIV. A recent North American study found a 43% hospital survival rate in patients with DNI orders. Our hypothesis was that, due to the very different social and cultural setting, written DNI orders in a southern European country would be restricted to a population with a poor outcome, independently of whether they receive NIV, and we analyzed hospital survival in patients receiving NIV and the impact of DNI orders on survival. DESIGN AND SETTING: Retrospective cohort study in a general ICU in a university-affiliated hospital. PATIENTS AND METHODS: All 233 patients treated with NIV during 2002-2004. We recorded clinical characteristics on admission, mortality risk by APACHE II and ICU and hospital outcome, and 6-month outcome. RESULTS: Hospital survival was 66%. Survival was better in the 199 patients without DNI orders than in the 36 with DNI orders both during hospitalization (74% vs. 26%, OR 7.9) and after 6 months (64% vs. 15%, OR 10.2). In both groups the presence of COPD was associated with better prognosis during hospitalization, but not in the medium-term. CONCLUSION: Our study suggests that NIV offers low expectations for medium-term survival in DNI patients.

APACHE↗
PubMed2006

Bisabolanes from the red alga Laurencia scoparia.

Three novel halogenated beta-bisabolene sesquiterpenoids (1-3), together with two know triquinane alcohol sesquiterpenes (6 and 7), were isolated from the red alga Laurencia scoparia and their structures elucidated by spectroscopic methods. Single-crystal X-ray crystallography allowed us to confirm the structure of 1 as well as to determine the absolute configuration of all stereocenters. To the best of our knowledge, the isolation of beta-bisabolenes from the genus Laurencia has no precedent in the literature. Compound 1 showed weak in vitro anthelmintic activity against parasitant stage (L4) Nippostrongilus brasiliensis.

Animals↗
PubMed2006

A modified McCabe score for stratification of patients after intensive care unit discharge: the Sabadell score.

INTRODUCTION: Mortality in the ward after an intensive care unit (ICU) stay is considered a quality parameter, and is described as a source of avoidable mortality. Additionally, the attending intensivist frequently anticipates fatal outcome after ICU discharge. Our objective was to test the ability of a new score to stratify patients according to ward mortality after ICU discharge. METHODS: A prospective cohort study was performed in the general ICU of a university-affiliated hospital. In 2003 and 2004 we prospectively recorded the attending intensivist's subjective prognosis at ICU discharge about the hospital outcome for each patient admitted to the ICU (the Sabadell score), which was later compared with the real hospital outcome. RESULTS: We studied 1,521 patients with a mean age of 60.2 +/- 17.8 years. The median (25-75% percentile) ICU stay was five (three to nine) days. The ICU mortality was 23.8%, with 1,156 patients being discharged to the ward. Post-ICU ward mortality was 9.6%, mainly observed in patients with a Sabadell score of 3 (81.3%) or a score of 2 (41.1%), whereas lower mortality was observed in patients scoring 1 (17.2%) and scoring 0 (1.7%). Multivariate analysis selected age and the Sabadell score as the only variables associated with ward mortality, with an area under the receiver operating curve of 0.88 (95% CI 0.84-0.93) for the Sabadell score. CONCLUSION: The Sabadell score at ICU discharge works effectively to stratify patients according to hospital outcome.

Adult↗
PubMed2005

Use of synthetic peptides to locate novel integrin alpha2beta1-binding motifs in human collagen III.

A set of 57 synthetic peptides encompassing the entire triplehelical domain of human collagen III was used to locate binding sites for the collagen-binding integrin alpha(2)beta(1). The capacity of the peptides to support Mg(2+)-dependent binding of several integrin preparations was examined. Wild-type integrins (recombinant alpha(2) I-domain, alpha(2)beta(1) purified from platelet membranes, and recombinant soluble alpha(2)beta(1) expressed as an alpha(2)-Fos/beta(1)-Jun heterodimer) bound well to only three peptides, two containing GXX'GER motifs (GROGER and GMOGER, where O is hydroxyproline) and one containing two adjacent GXX'GEN motifs (GLKGEN and GLOGEN). Two mutant alpha(2) I-domains were tested: the inactive T221A mutant, which recognized no peptides, and the constitutively active E318W mutant, which bound a larger subset of peptides. Adhesion of activated human platelets to GER-containing peptides was greater than that of resting platelets, and HT1080 cells bound well to more of the peptides compared with platelets. Binding of cells and recombinant proteins was abolished by anti-alpha(2) monoclonal antibody 6F1 and by chelation of Mg(2+). We describe two novel high affinity integrin-binding motifs in human collagen III (GROGER and GLOGEN) and a third motif (GLKGEN) that displays intermediate activity. Each motif was verified using shorter synthetic peptides.

Amino Acid Motifs↗
PubMed2005

Mfge8 is critical for mammary gland remodeling during involution.

Apoptosis is a critical process in normal mammary gland development and the rapid clearance of apoptotic cells prevents tissue injury associated with the release of intracellular antigens from dying cells. Milk fat globule-EGF-factor 8 (Mfge8) is a milk glycoprotein that is abundantly expressed in the mammary gland epithelium and has been shown to facilitate the clearance of apoptotic lymphocytes by splenic macrophages. We report that mice with disruption of Mfge8 had normal mammary gland development until involution. However, abnormal mammary gland remodeling was observed postlactation in Mfge8 mutant mice. During early involution, Mfge8 mutant mice had increased numbers of apoptotic cells within the mammary gland associated with a delay in alveolar collapse and fat cell repopulation. As involution progressed, Mfge8 mutants developed inflammation as assessed by CD45 and CD11b staining of mammary gland tissue sections. With additional pregnancies, Mfge8 mutant mice developed progressive dilatation of the mammary gland ductal network. These data demonstrate that Mfge8 regulates the clearance of apoptotic epithelial cells during mammary gland involution and that the absence of Mfge8 leads to inflammation and abnormal mammary gland remodeling.

Animals↗
PubMed2005

Statin therapy prior to ICU admission: protection against infection or a severity marker?

OBJECTIVE: Examine the impact of previous statin therapy on hospital mortality and whether it is due to a protective effect against ICU-acquired infections. DESIGN AND SETTING: Cohort comparison study by retrospective chart-based analysis in a 26-bed, university-affiliated, medical-surgical ICU. PATIENTS: We analyzed data from 438 patients at high risk of ICU-acquired infections, i.e., those receiving mechanical ventilation for more than 96 h, 38 (8.7%) of whom had been treated with statins prior to and during ICU admission. MEASUREMENTS AND RESULTS: We recorded clinical characteristics, number and type of ICU-acquired infections, and ICU and hospital mortality. Statin-treated patients were older (71.7+/-8.3 vs. 61.5+/-18.3 years), but differences in predicted mortality risk by APACHE II (39.5+/-24.7 vs. 35.8+/-24.3%) did not reach statistical significance. The ICU-acquired infection rate in statin-treated patients was nonsignificantly lower (29% vs. 38%) and delayed (median 12 vs.10 days), without differences regarding the source of infections. Nevertheless, hospital mortality was significantly higher in statin-treated patients (61% vs. 42%), even after adjustment for APACHE II predicted risk (observed/expected ratio 1.53 vs. 1.17). CONCLUSIONS: Statin therapy is associated with worse outcome, probably because underlying clinical conditions are insufficiently considered in mortality predictors. Its presumed protective effect against ICU infections remains unconfirmed.

APACHE↗
PubMed2005

Susi, a negative regulator of Drosophila PI3-kinase.

The Phosphatidylinositol-3 kinase/Protein Kinase B (PI3K/PKB) signaling pathway controls growth, metabolism, and lifespan in animals, and deregulation of its activity is associated with diabetes and cancer in humans. Here, we describe Susi, a coiled-coil domain protein that acts as a negative regulator of insulin signaling in Drosophila. Whereas loss of Susi function increases body size, overexpression of Susi reduces growth. We provide genetic evidence that Susi negatively regulates dPI3K activity. Susi directly binds to dP60, the regulatory subunit of dPI3K. Since Susi has no overt similarity to known inhibitors of PI3K/PKB signaling, it defines a novel mechanism by which this signaling cascade is kept in check. The fact that Susi is expressed in a circadian rhythm, with highest levels during the night, suggests that Susi attenuates insulin signaling during the fasting period.

Animals↗
PubMed2003

Extubation failure: diagnostic value of occlusion pressure (P0.1) and P0.1-derived parameters.

OBJECTIVE: To evaluate the ability of the new, built-in occlusion pressure (P0.1) measurement to predict extubation failure. DESIGN AND SETTING: Prospective observational multicentre study in the ICU of five general hospitals. PATIENTS: Hundred thirty patients on mechanical ventilation longer than 48 h when considered ready for weaning. MEASUREMENTS AND RESULTS: Patients underwent a 30-min spontaneous breathing trial with simultaneous monitoring of occlusion pressure (P0.1) and breathing pattern (f/Vt). Sixteen patients (12%) failed the weaning trial and full ventilatory support was resumed, while 114 tolerated the trial and were extubated. Twenty-one (18%) required reintubation within 48 h. The area under the ROC curve for diagnosing extubation failure was 0.53 for f/Vt, 0.59 for P0.1 and 0.61 for P0.1*f/Vt (p=NS). Accordingly, P0.1*f/Vt more than 100 detected extubation failure with a sensitivity of 0.89, specificity of 0.35, positive predictive value of 0.21 and negative predictive value of 0.94. CONCLUSION: During a first trial of spontaneous breathing on pressure support ventilation (PSV), bedside P0.1 and P0.1*f/Vt are of little help, if any, for predicting extubation failure.

Adult↗
PubMed2002

Recruitment maneuvers in acute lung injury.

Maintaining optimal lung recruitment has a marked effect on the outcome of patients who suffer from ARDS. RMs superimposed on mechanical ventilation have the potential to recruit atelectatic lungs in the course of general anesthesia; however, the physiologic benefits are less evident in ARDS patients who are ventilated at low VT values and high PEEP levels. Currently, the following technical aspects warrant further investigation: optimal time (the first hours after intubation or the first days of ARDS), duration (from 15 seconds to 2 minutes), mode (continuous positive end-expiratory pressure or pressure controlled ventilation with high PEEP), and type of patients (pulmonary versus extrapulmonary ARDS). Before the routine implementation of RMs to recruit the lungs fully in ARDS patients, clinicians also need more information on side effects and contraindications. Although RMs are transient, they may be associated with complications such as hypotension, bradycardia, and barotrauma. Moreover, further studies are needed to compare the efficacy of periodic high-pressure RMs that are superimposed on mechanical ventilation with ventilation using high PEEP levels and low VT values without RMs in patients who have early ARDS after initial hemodynamic stabilization.

Acute Disease↗