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C Consales

Publications and source records attributed to C Consales.

6 recordsLinked to original sources

Sepsis and organ dysfunction: an ongoing challenge.

In recent years the problem of infection has become increasingly significant, especially in intensive care hospital wards such as Intensive Care Units (ICU), emergency medicine, surgery and critically ill patient care departments. Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as severe sepsis or septic shock. In these conditions the triggering event may coincide with the functional impairment of one or more vital organs or systems, thus leading to poorer prognosis in patients with overt signs of sepsis or systemic inflammation syndromes. The available data are quite alarming, as most prevention and treatment is performed empirically and requires considerable human and technological resources. Clinical signs are often misleading and, in some circumstances, it may be difficult or even impossible to identify the source of the infection which might otherwise be removed relatively simply, using proper antimicrobial treatment or a less invasive surgical removal of the area from which the infection originates based on needle-guided radiology. In addition, the complex pathophysiological mechanisms involved can be an obstacle to gaining a full understanding of the various biohumoral interactions or mediators action mechanisms. It may not be easy to enroll patients belonging to homogeneous groups in terms of age, underlining disease, immune profile or genetic predisposition, although the use of specific severity indexes has proved helpful also to establish the prognosis. Although the interpretation of generalised inflammation as a warning sign also in the absence of clear signs of infection or a state of overt inflammation has to rely largely on simple intuition, it has helped to drive experimental and clinical research work towards the investigation of interaction between different factors such as infection and sepsis, or inflammation and coagulation. An additional useful tool is the possibility of modulating the endothelial response which may support the process of disseminated thrombosis typical of sepsis evolution. In this context the improvement of standards of care can shed light on the efficacy of different treatments.

Blood Coagulation↗

Systemic and organ dysfunction response during infusion of recombinant human activated protein C (rhAPC) in severe sepsis and septic shock.

AIM: The aim of this study was the assessment of the efficacy of recombinant human activated protein C (rhAPC) in septic patients. METHODS: A continuous observational prospective study on ICU patients with severe sepsis and septic shock was carried out. Applying the inclusion criteria of a national trial on the use of rhAPC, 15 patients (12 males and 3 females) were enrolled, mean age was 65.9 (SD 9.6), APACHE II score was > or =25. The following variables were assessed on 7 time-points (T1-T7): overall SOFA score; organ-specific SOFA score; APACHE II score; PCR, APTT, INR, fibrinogen, platelet count. Wilcoxon's statistical test and Spearman's correlation test (rho coefficient) between the SOFA and APACHE II scores were used. Test results with a P value below 0.05 were deemed significant. RESULTS: A significant correlation was identified between the APACHE II and SOFA scores. No significant change was found in Friedman's test and the respiratory, haematological and hepatic SOFA score, whereas cardiovascular, renal and neurological SOFA scores showed a significant trend between the ranks at the 7 time-points (chi2=14; df=6; P=0.029). During rhAPC treatment Friedman's test showed significant changes of PCR values over the 7 time-points (chi2=19.2; df=6; P=0.02). Wilcoxon's test indicated a significant decrease in the values recorded during the T2-T6 period. On day 28, 12 of the 15 patients originally enrolled were still alive. Mortality rate was therefore 20% (CI 95%). CONCLUSIONS: RhAPC is the first biological agent approved for the treatment of severe sepsis and septic shock. Our experience is confined to patients with severe sepsis and septic shock, and some severity indexes showed a modulation of the inflammatory processes and haemostatic balance, 2 factors which play a key role in the evolution of sepsis and organ dysfunction.

APACHE↗

Evidence for a mesodermal embryonic regulator of the sea urchin CyIIa gene.

The CyIIa gene of the sea urchin embryo is a model for study of cis-regulation downstream of cell-type specification, as CyIIa transcription follows the specification and initial differentiation of the embryonic domains in which it is expressed. These are the skeletogenic and secondary mesenchyme and gut. We carried out a detailed structural and functional analysis of a cis-regulatory region of this gene, extending 780 bp upstream and 125 bp downstream of the transcription start site, that had been shown earlier to reproduce faithfully the complex and dynamic CyIIa pattern of expression. This analysis revealed that the overall pattern of expression of the CyIIa gene appears to be governed mainly by two independent sets of DNA elements, which are target sites for specific proteins present in blastula-stage nuclear extract. One type of element, which controls a dynamic program of expression in both skeletogenic and secondary mesenchyme cells, contains the consensus-binding site for a member of the ets transcription factor family. The other, which is responsible for the terminal or permanent phase of CyIIa expression in the gut, shares homologies with the late module of the endoderm-specific Endo16 gene (endo16 Module B). Oligonucleotides containing replicas of these two target sites fused upstream of a sea urchin basal promoter are sufficient to confer accurate mesenchyme and late gut expression of an injected GFP construct. The finding of a single protein target site that recapitulates CyIIa expression in both primary and secondary mesenchyme cells suggests the existence of a pan-mesodermal gene expression program in the sea urchin embryo.

Actins↗

Analysis of cadherin/catenin complexes in transformed thyroid epithelial cells: modulation by beta 1 integrin subunit.

We have analysed the expression of cadherin/catenin complex molecules in PC C13 rat thyroid cells transformed in vitro with different oncogenes. No significant downregulation of either E-cadherin, alpha-, beta- and gamma-catenin was detected following the introduction of activated forms of myc, adenovirus E1A, ras, raf, myc + ras, E1A + raf. However, ras- and raf-transformed PC C13 cells showed altered adherens junctions. An altered distribution of cadherin/catenin complexes characterized by radially oriented membrane spikes perpendicular to cell edges was the most prominent feature evidenced by immunofluorescence. No beta1 integrin localization was observed in areas where this altered pattern of E-cadherin expression was detected. However, beta1 integrin subunit expression was detected at areas of cell-cell contact where E-cadherin showed a normal pattern of expression. Furthermore, ras- and raf-transformed PC C13 cells showed the ability to migrate in collagen gels, in contrast to their normal untransformed counterpart. Overexpression of beta1 integrin was found to restore normal E-cadherin localization at cell-cell contacts and to partially inhibit the ability to migrate in collagen gels. Finally, two cell lines obtained by ras transformation in vivo, and derived from a rat primary thyroid carcinoma (TK6) and its lung metastasis (MPTK6), were found to have lost gamma-catenin expression. TK6 lost also E-cadherin expression and membrane localization of alpha-catenin. These results suggest that: i) in vitro thyroid cell transformation is associated to a change in cadherin/catenin complexes distribution rather than to a decrease in expression; ii) in vivo transformation is associated to the loss of expression of some of these molecules likely due to tumor progression; iii) alterations in beta1 integrin subunit expression can result in changes in cadherin/catenin function thus implying that an integrin-cadherin synergy may exist in thyroid cells.

Adenovirus E1A Proteins↗

Are most ICU infections really nosocomial? A prospective observational cohort study in mechanically ventilated patients.

A prospective cohort study was undertaken with two end points: (i) to compare the 48 h time cut-off with the carrier state criterion for classifying infections, and (ii) to determine a time cut-off more in line with the carrier state concept. All patients admitted to the intensive care unit and expected to require mechanical ventilation for a period > or = 3 days were enrolled. Surveillance cultures of throat and rectum were obtained on admission and thereafter twice weekly to distinguish micro-organisms that were imported into the intensive care unit from those acquired during the stay in the unit. A total of 117 patients with median age of 61 years and median Simplified Acute Physiology Score II of 42, were included in the study. Of these patients, 48 (41%) developed a total of 74 infection episodes. Using the 48 h cut-off point, 80% of all infections were classified as ICU-acquired. According to the carrier state criterion, 44 infections (60%) were of primary endogenous development caused by micro-organisms imported into the intensive care unit. Seventeen secondary endogenous (23%) and 13 exogenous (17%) infections were caused by bacteria acquired in the unit. The carrier state classification allowed the transfer of 49% of infections from the ICU-acquired group into the import group. A time cut-off of nine days was found to identify ICU-acquired infections better than two days. These data suggest that monitoring of carriage of micro-organisms may be a more realistic approach to classify infections developing in the intensive care unit.

Adult↗

Expression of the RET receptor tyrosine kinase and GDNFR-alpha in normal and leukemic human hematopoietic cells and stromal cells of the bone marrow microenvironment.

The RET proto-oncogene product is a receptor tyrosine kinase representing the signal-transducing molecule of a multisubunit surface receptor complex for the glial cell line-derived neurotrophic factor (GDNF), in which a novel glycosyl-phosphatidylinositol (PI)-linked protein (termed GDNFR-alpha) acts as the ligand-binding component. We have analyzed expression of RET and GDNFR-alpha in purified normal hematolymphopoietic cells, leukemia/lymphoma cell lines, and 154 primary samples from patients with hematopoietic malignancies encompassing different lineages and differentiation stages. Relatively low amounts of RET mRNA were found in early CD34+ hematopoietic progenitors, but RET transcripts appeared to increase after myelomonocytic maturation. No expression of RET was found in peripheral blood and tissue B and T lymphocytes. Analysis of human myelomonocytic cell lines was overall consistent with results obtained on purified normal cells. Accordingly, RET expression was mainly confined to acute myeloid leukemias (AMLs) displaying either monocytic (French-American-British M4 and M5) or intermediate-mature myeloid (M2 and M3) phenotypes, being less frequently detected in early myeloid (M0 and M1) AMLs. In contrast, RET mRNA was sporadically detected in B-cell tumors, whereas, among T-cell malignancies, RET transcripts were mainly detected in cells of postthymic and mature T-cell phenotype. RET broad detection in primary tumors was not paralleled by the mutual expression of GDNFR-alpha, which was detected only in 2 isolated primary samples and in 3 leukemia/lymphoma cell lines. However, GDNFR-alpha transcripts, in the absence of RET mRNA, were found in normal bone marrow stromal cells (BMSC), in BM fibroblasts, and in two osteoblast cell lines previously described to support normal hematopoiesis. In the presence of GDNF-receptors derived from BMSC by PI-specific phospholipase C cleavage, GDNF efficiently bound RET-expressing AML blasts and was functionally active by reducing their clonogenic growth and triggering the monocytic maturation of leukemic cells.

Adipose Tissue↗