Determining personalized treatment by gene expression profiling in metastatic breast carcinoma patients: a pilot study.

PURPOSE: The present study evaluates the massive study of gene expression in metastatic breast carcinoma (MBC) patients using microarray gene expression profiling (MAGE) complemented with conventional sequencing, immunohistochemistry (IHC) and fluorescent "in situ" hybridization (FISH), seeking to optimize the treatment in a subset of heavily pretreated patients and with limited life expectancy. PATIENTS, MATERIAL AND METHODS: MBC patients in hormone therapy progression with survival expectancy of at least 3 months (m) have been included. The MAGE contains gene probes representing genes known to potentially interact with available drugs as cited in the literature. RESULTS: Thirty-nine procedures were performed from October 2010 to April 2016. Within the 30 evaluable procedures, considering all hormonal manipulations as a single line, the patients had received a median of 4 treatment lines prior to MAGE (range 1-7). Progression was observed in 6 cases, stable disease (SD) in 7 cases and partial response (PR) in 16 cases, which implies a clinical benefit rate (SD + PR) of 76%. Actuarial median progression-free survival (PFS) was 6 m (95% CI 2.5-9.5) in patients with clinical benefit. The median overall survival (OS) for the entire series was 11 m (95% CI 2.2-19.8). CONCLUSION: Data presented here indicate that the use of MAGE provides relevant information to establish personalized treatment in frail patients with limited life expectancy in which therapeutic futility is a particularly difficult burden to assume.

The determination of copeptin levels helps management decisions among transient ischaemic attack patients.

BACKGROUND: Most approaches to transient ischaemic attack (TIA) triage use clinical scores and vascular imaging; however, some biomarkers have been suggested to improve the prognosis of TIA patients. METHODS: Serum levels of copeptin, adiponectin, neopterin, neuron-specific enolase, high-sensitivity C-reactive protein, IL-6, N-terminal pro-B-type natriuretic peptide, S100ß, tumour necrosis factor-alpha and IL-1α as well as clinical characteristics were assessed on consecutive TIA patients during the first 24 h of the onset of symptoms. RESULTS: Among 237 consecutive TIA patients, 12 patients (5%) had a stroke within 7 days and 15 (6%) within 90 days. Among all candidate biomarkers analysed, only copeptin was significantly increased in patients with stroke recurrence (SR) within 7 days (P = 0.026) but not within 90 days. A cut-off point of 13.8 pmol/l was established with a great predictive negative value (97.4%). Large artery atherosclerosis (LAA) [hazard ratio (HR) 12.7, 95% CI 3.2-50.1, P < 0.001] and copeptin levels ≥13.8 pmol/l (HR 3.9, 95% CI 1.01-14.4, P = 0.039) were independent predictors of SR at the 7-day follow-up. LAA was the only predictor of 90-day SR (HR 7.4, 95% CI 2.5-21.6, P < 0.001). ABCD3I was associated with 7- and 90-day SRs (P = 0.025 and P = 0.034, respectively). The association between copeptin levels and LAA had a diagnostic accuracy of 90.3%. CONCLUSIONS: Serum copeptin could be an important prognostic biomarker to guide management decisions among TIA patients. Therefore, TIA patients with copeptin levels below 13.8 pmol/l and without LAA have an insignificant risk of 7-day SR and could be managed on an outpatient basis.

The use of the acute Pd/Pa drop after intracoronary nitroglycerin infusion to rule out significant FFR: CANICA (Can intracoronary nitroglycerin predict fractional flow reserve without adenosine?) multicenter study.

OBJECTIVE: Functional assessment of coronary artery stenosis is performed by measuring the fractional flow reserve (FFR) under hyperemic conditions (Adenosine). However, the use of adenosine portends limitations. OBJECTIVE: We sought to investigate the relationship and correlation between FFR and the Pd/Pa value obtained just after the intracoronary infusion (acute drop) of nitroglycerin (Pd/Pa-NTG) and if this parameter enhances diagnostic accuracy for FFR prediction compared to the resting baseline Pd/Pa. METHODS: We conducted a multicenter study including prospectively patients presenting intermediate coronary artery stenosis (30-70%) evaluated with pressure wire. Resting baseline Pd/Pa, Pd/Pa-NTG and FFR were measured. RESULTS: 283 patients (335 lesions) were included. Resting baseline Pd/Pa value was 0.72 to 1.0 (0.93 ± 0.04), Pd/Pa-NTG was 0.60 to 1.0 (0.87 ± 0.07) and FFR 0.55 to 1.0 (0.83 ± 0.08). The ROC curves for resting baseline Pd/Pa and for Pd/Pa-NTG, using a FFR ≤ 0.80 showed an AUC of 0.88 (95% CI: 0.84-0.92, P < 0.001) and 0.94 (95% CI: 0.92-0.96, P < 0.001) respectively. The optimal cutoff values of resting baseline Pd/Pa and Pd/Pa-NTG for an FFR > 0.80, were >0.96 and >0.88, respectively. These values were present in a 29.8% (n = 100) and a 47.1% (n = 158), of the total lesions. Scatter plots showed a better correlation and agreement points with Pd/Pa-NTG than resting baseline Pd/Pa. The cutoff value of Pd/Pa-NTG > 0.88 showed an excellent NPV (96.2% for FFR > 0.8 and 100% for FFR > 0.75) and sensitivity (95% for FFR > 0.8 and 100% for FFR > 0.75) which were consistently high across all the subgroups analysis. CONCLUSION: The cutoff value of acute Pd/Pa-NTG > 0.88 has a high NPV meaning adenosine-FFR can be avoided in almost half of lesions.

N-terminal pro-brain natriuretic peptide level determined at different times identifies transient ischaemic attack patients with atrial fibrillation.

BACKGROUND AND PURPOSE: The etiological classification of patients with transient ischaemic attack (TIA) is a difficult endeavor and the use of serum biomarkers could improve the diagnostic accuracy. The aim of this study was to correlate atrial fibrillation, the main cardioembolic etiology (CE), with different serum biomarkers measured in consecutive TIA patients. METHODS: The concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha, neuron-specific enolase, high-sensitivity C-reactive protein, IL-1-α and the N-terminal pro-B type natriuretic peptide (NT-proBNP) were quantified in the serum of 140 patients with TIA and 44 non-stroke subjects. Measurements were performed at different times throughout evolution: within 24 h of symptoms onset and at days 7 and 90. RESULTS: With the exception of IL-6, all biomarkers were higher in TIA patients than in controls. NT-proBNP was significantly related to the presence or new diagnosis of AF at all time points analyzed. Furthermore, the baseline NT-proBNP level was significantly higher than values at the 7-day and 90-day follow-up. For this reason, different cut-off values were obtained at different times: 313 pg/ml at baseline [odds ratio (OR) = 18.99, P < 0.001], 181 pg/ml at 7 days (OR = 11.4, P = 0.001) and 174 pg/ml (OR = 8.46, P < 0.001) at 90 days. CONCLUSION: High levels of NT-proBNP determined during the first 3 months after a TIA were associated with AF. Consequently, this biomarker may be useful to reclassify undetermined TIA patients as having disease of CE.

Nephrotic syndrome as paraneoplastic manifestation of a primary pulmonary lymphoepithelioma-like carcinoma.

We present a case of nephrotic syndrome secondary to a membranous glomerulonephritis (MG), in a nonsmoking female with a solitary pulmonary nodule, which did not show growth during 2 years of followup. A biopsy by videothoracoscopy showed a granulomatous non-neoplastic process with giant multinucleated cells. The appearance of a nephrotic syndrome and its interpretation as paraneoplastic revealed the existence of a primary pulmonary lymphoepithelioma-like carcinoma (LELC), a very rare pulmonary tumor. After resection of tumor there was a complete recovery from the nephrotic syndrome. This case highlights how the investigation of paraneoplastic syndromes can help in the early diagnosis of some malignancies.

Hemosiderin deposits confounds tracking of iron-oxide-labeled stem cells: an experimental study.

BACKGROUND: The aim of the present research was to study the possible interference of hemosiderin deposits with the histological detection of dextran-coated, iron-labeled, mesenchymal stem cells after intracoronary administration in a porcine model of myocardial infarction. MATERIALS AND METHODS: A myocardial infarction was induced in six animals that received intracoronary iron-labeled autologous mesenchymal stem cells (group 1; n = 2) or placebo (group 2; n = 4). Six control animals without myocardial infarction underwent direct intramyocardial injections of iron-labeled autologous mesenchymal stem cells (group 3; n = 2) or placebo (group 4; n = 4). Histological sections from explanted hearts were stained with Prussian blue to identify dextran-coated, iron-labeled, mesenchymal stem cells. RESULTS: After Prussian blue staining, granular blue labeling in the tissue was observed in both groups of animals with infarcts. Similar granular blue labeling was detected in hearts from control animals without infarction that had received iron-labeled mesenchymal stem cells. However, hearts from control animals without infarction that received placebo did not have any granular blue labeling in the tissue. CONCLUSIONS: Hemosiderin from infarction hemorrhage interferes with detection of dextran-coated iron-labeled mesenchymal stem cells after intracoronary administration, suggesting that this marker is not useful to detect mesenchymal stem cells in a porcine model of myocardial infarction.

A novel EGFR nonsense mutation in a non-small-cell lung cancer (NSCLC) patient who did not derive any clinical benefit with combination chemotherapy and erlotinib.

Most of the somatic epidermal growth factor receptor (EGFR) mutations described to date in non-smallcell lung cancer (NSCLC) patients are located in the kinase domain and are considered activating mutations. Some of these mutations are associated with response to specific EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib. Here we report a case of a previously undescribed EGFR nonsense mutation in a lung adenocarcinoma patient who did not derive any clinical benefit with combination chemotherapy and erlotinib. To the best of our knowledge this is the second report in the literature describing an EGFR nonsense mutation in lung cancer patients.

Treatment of peritoneal carcinomatosis from ovarian cancer. Present, future directions and proposals.

Peritoneal carcinomatosis, considered years ago as a final stage of unresectable cancer, can now be managed with curative intention by means of a radical cytoreductive surgical procedure with associated peritonectomy and intraperitoneal chemotherapy, as described by Sugarbaker. Malignant neoplasms such as mesothelioma and pseudomyxoma peritonei, ovarian and colon cancer nowadays are experiencing some new therapeutical approaches. Higher survival rates can be reached in ovarian cancer, which is commonly diagnosed in the presence of peritoneal carcinomatosis, using an optimal cytoreductive radical surgery with intraperitoneal chemotherapy. An actualised review of the treatment of advanced ovarian cancer and a proposal of a national multicentre protocol for the treatment of peritoneal carcinomatosis from ovarian cancer has been performed by a group of Spanish surgeons and oncologists dedicated to a therapeutical approach to this pathology.

Umbilical cord blood-derived stem cells spontaneously express cardiomyogenic traits.

BACKGROUND: Umbilical cord blood (UCB) has been widely used for hematopoietic stem cell transplantation. The UCB-derived stem cells (UCBSCs) have been proposed as an alternative to bone marrow (BM)-derived mesenchymal stem cells (MSCs) for cardiac cell-based therapy. Herein we studied whether UCBSCs spontaneously exhibit cardiac-specific markers in vitro. METHODS: Human UCBSCs were isolated, expanded, and phenotyped by flow cytometry, quantitative RT-PCR, and immunofluorescence. Cell pluripotency and proliferation were also assessed by adipogenic and osteogenic media and in growth assays. RESULTS: Among 25 analyzed UCB, 16% of cases afforded primary culture satisfactory generation of UCBSCs. Duplication time (Td) of cultures was 2.16 +/- 0.06 days. The cells were strongly positive for CD105 (18.5 +/- 0.14), CD44 (27 +/- 2.8), CD166 (13 +/- 9), CD29 (59 +/- 9.4), CD90 (60 +/- 11) and consistently negative for CD117 (1.2 +/- 0.1), CD106 (1.1 +/- 0), CD34 (1.2 +/- 0.2), CD14 (1 +/- 0), and CD45 (1 +/- 0), consistent with a mesenchymal lineage. Adipogenesis and osteogenesis of cells resulted in low accumulation of intracellular lipid droplets and high deposition of calcium. The UCBSCs showed gene transcripts for alpha-actinin, connexin (Cx)-43, SERCA-2, and stromal cell-derived factor (SDF)-1alpha. At the protein level, the cells abundantly expressed alpha-actinin, Cx-43, SERCA-2 and SDF-1alpha. In contrast, these cells did not express the cardiac transcription factors GATA-4, Tbx5, and Nkx2.5, nor the sarcomeric proteins beta-myosin heavy chain (beta-MyHC) or cardiac troponin I (cTnI). CONCLUSIONS: Human UCBSCs may represent an alternative source of stem cells for myocardial-cell replacement. These cells can be highly expanded. They spontaneously express proteins of paramount importance for cardiovascular regeneration, such as Cx-43, SERCA-2, and SDF-1alpha.

[Pneumonia by Corynebacterium pseudodiphteriticum: an infection to consider]. / Neumonía por Corynebacterium pseudodiphteriticum: una patología a considerar.

Corynebacterium pseudodiphteriticum has been considered a very infrequent respiratory pathogen. We report three cases of pneumonia due to C. pseudodiphteriticum, describing their clinical and microbiological features. There were two patients with pre-existing chronic respiratory disease, one of their with steroidal therapy, and other associated with endotracheal intubation. The diagnostic was made by Gram stain and quantitative cultures from respiratory tract specimens. All patients were cured after treatment with amoxicillin-clavulanate, ceftriaxone and vancomycin respectively. C. pseudodiphteriticum must be consider as a possible causal agent of pneumonia in patients with underlying respiratory disease or endotracheal intubation. Antimicrobial susceptibility testing of C. pseudodiphteriticum may be useful for correct treatment of infected patients, but beta-lactam antibiotics are an appropriate therapeutic option against this bacteria.

Infections of implantable cardioverter-defibrillators: frequency, predisposing factors and clinical significance.

The prognosis for patients with ventricular arrhythmias has improved dramatically with the aid of implantable cardioverter-defibrillators (ICDs). Although infection is a serious complication that frequently causes dysfunction and loss of ICDs, the frequency, predisposing risk-factors, and clinical and microbiological features are only partially understood. This study describes a retrospective review of 423 procedures in 278 patients with ICD primary implants and replacements performed at a tertiary-care hospital. Generators were placed in either a pectoral (68%) or abdominal (32%) site, and electrodes were placed transvenously in 97% of the patients. Most (95%) interventions were performed in a one-stage procedure. Infection developed with ten (2.4%) implanted devices. Four cases occurred within 30 days of surgery ('early infections') and six occurred > 1 month after surgery ('late infections'). In univariate analysis, factors associated with the development of an early infection were: two-stage surgery, a sub-costal approach, and abdominal generator placement. In patients with late infections, a significant association was found with trauma or decubitus ulcer in the generator area. Infection presented with local signs without systemic complications. Seven of the ten patients required complete removal of the system.

Identification of cardiomyogenic lineage markers in untreated human bone marrow-derived mesenchymal stem cells.

BACKGROUND: Recent reports refute the classic paradigm by which human heart is unable to repair itself following disease or injury. Cardiac and noncardiac stem cells with cardiac regeneration potential have been documented. We studied whether untreated mesenchymal stem cells express markers of cardiomyogenic lineage in vitro. METHODS: Mesenchymal stem cells were obtained from human iliac crest marrow aspirates. Cells were isolated and characterized using flow cytometry by surface expression of CD105, CD166, CD29, CD44, CD14, and CD34. To evaluate their cardiomyogenic potential, presence of cardiac proteins (cardiac troponin I, sarcomeric alpha-actinin, beta myosin heavy chain (beta-MyHC), connexin-43, and SERCA-2), and transcription factors (GATA-4) were assessed. RESULTS: Mesenchymal stem cells expressed CD105 (4.25 +/- 0.35), CD166 (27.83 +/- 1.89), and CD29 (9.4 +/- 0.57) and were negative for CD34, CD14, and CD45. In absence of additional stimuli in the culture media, these cells expressed connexin-43, alpha-actinin, and GATA-4, and were negative for SERCA-2, cardiac troponin I, and beta-MyHC. CONCLUSIONS: Human adult mesenchymal stem cells spontaneously exhibit markers of cardiac phenotype in vitro. In the appropiate myocardial environment, these cells may transdifferentiate into mature cardiomyocytes.

Prior aspirin use in unstable angina patients with modified plasma inflammatory markers and endothelial nitric oxide synthase in neutrophils.

BACKGROUND: Prior use of aspirin in patients with acute coronary syndrome has been associated with a lower incidence of acute myocardial infarction. The aim of this study was to explore if prior aspirin therapy in unstable angina (UA) patients could modify systemic inflammatory markers such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) and the expression of endothelial nitric oxide synthase (eNOS) in neutrophils. MATERIALS AND METHODS: Unstable angina was defined as transient S-T segment changes without significant increases in CK and CK-MB. We studied 50 consecutive patients admitted to hospital within 24 h after the onset of chest pain. The number of patients with prior aspirin was significantly higher (n = 32) than those not taking aspirin (n = 18) on admission. RESULTS: Plasma levels of IL-6 and ICAM-1 were significantly increased in the UA patients when compared with the healthy control volunteers (n = 20) used as a reference for normal values. Plasma levels of both IL-6 and ICAM-1 were reduced in patients taking aspirin. There were no differences in the plasma levels of TNF-alpha between the UA patients and the control volunteers. The eNOS protein expression was also higher in neutrophils from the UA patients taking aspirin than in those not taking aspirin. CONCLUSION: Patients taking aspirin before UA showed a lower systemic inflammatory response and higher eNOS protein expression in their neutrophils

Expression of an endothelial-type nitric oxide synthase isoform in human neutrophils: modification by tumor necrosis factor-alpha and during acute myocardial infarction.

OBJECTIVES: The purpose of this study was to determine whether human neutrophils express an endothelial-type nitric oxide synthase (eNOS), and to study the effect of tumor necrosis factor-alpha (TNF-alpha) on its expression. BACKGROUND: Several studies have demonstrated the presence of a constitutively expressed nitric oxide svnthase (NOS) in neutrophils. Cardiovascular disease is characterized by increased levels of plasma TNF-alpha, a cytokine that has demonstrated eNOS messenger ribonucleic acid (mRNA) destabilization in cultured endothelial cells. METHODS: Neutrophils were obtained from healthy volunteers and from patients with acute myocardial infarction (AMI). RESULTS: Human neutrophils express eNOS mRNA and eNOS protein. Stimulation of neutrophils with TNF-alpha decreased eNOS protein expression by reducing eNOS mRNA stabilization. In the present study, we also show that the cytosol of human neutrophils contains proteins that bind to a specific region within the 3'-untranslated region (3'-UTR) of eNOS mRNA. Tumor necrosis factor-alpha increased the binding of the cytosolic proteins to the 3'-UTR of eNOS mRNA. Simvastatin reduced the TNF-alpha-related binding activity of neutrophil cytosolic proteins to eNOS mRNA, which was associated with its protective effect on eNOS protein expression. The in vivo reproduction of the in vitro findings was performed in neutrophils obtained from patients with AMI and showed a diminished expression of eNOS protein, which was associated with increased binding of the cytosolic proteins. CONCLUSIONS: These observations demonstrate that human neutrophils express eNOS, which is downregulated by TNF-alpha and during AMI. This effect is associated with increased binding of neutrophil cytosolic proteins to the 3'-UTR of eNOS mRNA.

[Survey on the preoperative evaluation in Catalonian surgical centers. II. What is the attitude and opinion of the professionals involved?]. / Encuesta sobre la valoración preoperatoria en los centros quirúrgicos catalanes (II). Cuál es la actitud y la opinión de los profesionales implicados?

OBJECTIVE: Previous studies have provided evidence of the existence of differences in preoperative assessment practices and have questioned the usefulness of generalized testing for all patients. The objective of this study was to determine the attitudes and opinions of anesthesiologists and surgeons about their application of preoperative assessment procedures and their knowledge of the scientific principles underlying their practice. SUBJECTS AND METHODS: A questionnaire was mailed to 227 specialists in anesthesiology and postoperative intensive care, general and gastrointestinal surgery, orthopedic surgery and traumatology of all hospitals in Catalonia (Spain) with active operating theaters. RESULTS: The overall response rate was 61% of the surveyed population, with 86% of the Catalan hospitals represented. The medical literature supports the routine performance of a chest x-ray and an ECG in the opinion of 17 and 26% of the respondents, respectively. Those two procedures are always ordered by 43 and 37%, respectively, even if they believe that the medical literature does not support generalized application. Legal protection was given as the reason for routine ordering of preoperative tests in asymptomatic patients, and 89% believed that a protocol for selective preoperative assessment procedures would improve efficiency. CONCLUSIONS: This study reveals a discrepancy between the opinions of professionals involved in preoperative assessment and their real practice in Catalan hospitals, probably influenced by perceived need for legal protection.

[Survey on the preoperative evaluation in Catalonian surgical centers. I. What is the preoperative routine?]. / Encuesta sobre la valoración preoperatoria en los centros quirúrgicos catalanes (I). Cuál es la práctica preoperatoria?

OBJECTIVE: To describe the preoperative assessment procedures currently used in hospitals in Catalonia (Spain). SUBJECTS AND METHODS: The study population consisted of all heads of departments of anesthesiology, general and gastrointestinal surgery, orthopedic surgery and traumatology of hospitals and clinics in Catalonia with active operating theaters. Information was obtained by self-administered questionnaire prepared by an interdisciplinary team. RESULTS: Of the 227 questionnaires sent, 139 (61%) were answered and returned. A preoperative assessment visit was programmed according to 112 (81%) of the respondents and 123 (89.8%) reported following a protocol that included ordering preoperative tests. The same tests were ordered for all patients by 25% of the respondents. A chest film and an ECG were always ordered according to 61 and 65%, respectively, and always when the patient was over a certain age according to 36 and 32%, respectively. Coagulation and blood sugar tests and a complete blood workup were always ordered according to 94%, 95% and 89%, respectively. Tests were considered valid for less than six months by most. CONCLUSIONS: This survey provides evidence of widespread use of preoperative assessment, although application falls short of including all scheduled patients. According to these results, selective protocols for ordering complementary preoperative tests are rarely applied.

Cerivastatin prevents tumor necrosis factor-alpha-induced downregulation of endothelial nitric oxide synthase: role of endothelial cytosolic proteins.

Cardiovascular disease is accompanied by an impaired endothelium-dependent vasodilatory response. Loss of endothelial nitric oxide synthase (eNOS) expression may contribute to endothelial dysfunction. The aim of the present study was to analyze the effect of cerivastatin, a novel HMG CoA reductase inhibitor, on tumor necrosis factor-alpha (TNF-alpha)-induced downregulation of eNOS protein expression in bovine aortic endothelial cells (BAEC). TNF-alpha (10 ng/ml)- incubated BAEC showed a reduced expression of eNOS protein and decreased eNOS mRNA stabilization. This effect was associated with an increased binding activity of BAEC cytosolic proteins to the 3'-untranslated region (3'UTR) of eNOS mRNA. Cerivastatin prevented TNF-alpha-induced downregulation of eNOS protein expression in a concentration-dependent manner (10(-8) to 10(-5) M). Cerivastatin also prevented the binding of the cytosolic proteins to 3'-UTR of eNOS mRNA and was associated with eNOS mRNA stabilization. The reduced expression of eNOS protein by TNF-alpha was also prevented by coincubation with cycloheximide. In addition cycloheximide inhibited the binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA, suggesting the inducible character of the mentioned-cytosolic proteins. TNF-alpha stimulated the translocation of nuclear factor-kappaB (NF-kappaB), an effect that was not modified by cerivastatin. Furthermore, an inhibitor of NF-kappaB translocation, pyrrolidine dithiocarbamate failed to modify both the downregulation of eNOS expression and the increased binding activity of the cytosolic proteins to 3'-UTR of eNOS mRNA by TNF-alpha. The effect of cerivastatin on eNOS expression and the binding activity of the cytosolic proteins were reversed by coincubation with L-mevalonate. In conclusion, cerivastatin stabilized eNOS mRNA and upregulated eNOS expression in the endothelium, and this was associated with a decreased binding activity of cytosolic proteins to 3'-UTR of eNOS mRNA. The effect of cerivastatin on the regulation of eNOS expression was independent of NF-kappaB mobilization by TNF-alpha. These findings suggest that cerivastatin may have beneficial effects on the endothelial dysfunction associated with cardiovascular diseases beyond its effect on lowering cholesterol.

Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation.

A recent study has shown that losartan, an AT-1-receptor antagonist, interacts with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors in human platelets. The aim of this study was to analyze the ability of different angiotensin II (Ang II) AT-1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers. Platelets were stimulated with the TxA2 analogue, U46619 (10(-6) M). U46619-stimulated platelet activation was significantly reduced by both losartan and irbesartan in a dose-dependent manner. Only maximal doses of valsartan (5 x 10(-6) M) and the main metabolite of losartan, EXP3174 (5 x 10(-6) M), reduced U46619-induced platelet activation. Whereas the active form of candesartan cilexetil (candesartan, CV-11974) failed to modify platelet activation involved by TxA2, telmisartan showed a higher effect than valsartan and EXP3174 but lower than either losartan and irbesartan. Losartan or irbesartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed with lower ability with the other AT-1 antagonists. Although platelets expressed AT-1-type receptors, exogenous Ang II did not modify platelet activation. This effect was not modified by blocking the AT-2 receptor with PD123319. These results suggest that some AT-1-receptor antagonists reduce TxA2-dependent activation independent of Ang II involvement.

Doxazosin modifies Bcl-2 and Bax protein expression in the left ventricle of spontaneously hypertensive rats.

BACKGROUND: Increased apoptosis has recently been reported in the heart of spontaneously hypertensive rats (SHRs). OBJECTIVE: To investigate the molecular basis of apoptosis in the left ventricle of SHRs in terms of the expression of Bcl-2 protein (which protects from apoptosis) and Bax protein (which acts as an apoptotic promoter). In addition, we analysed the involvement of alpha -adrenergic receptors in the left ventricular apoptosis of SHRs. METHODS: The study was performed in untreated SHRs (n=16) and SHRs that were orally treated with doxazosin (10 mg/kg body weight per day, for 15 days), a selective alpha1-receptor blocker (n=16). A group of Wistar-Kyoto (WKY) rats (n=16) was used as the control. RESULTS: The left ventricles of untreated SHRs showed a significant increase in Bcl-2 protein expression and a reduced presence of Bax protein. The ratio of Bcl-2:Bax in SHRs was higher than in WKY rats, suggesting an anti-apoptotic state. Paradoxically, both the number of apoptotic cardiac cells and the cleavage of an 85-kDa fragment of the poly (ADP-ribose) polymerase (PARP), a marker of caspase-3 activity, were higher in the left ventricle of SHRs than in WKY rats, suggesting an apoptotic situation. Bax promotes cell apoptosis when it is bound to Bcl-2. We then determined the abundance of Bax-Bcl-2 complexes in the left ventricle of the two groups of animals. Bax-Bcl-2 complexes were more abundant in SHRs than WKY rats. In a second set of experiments, we analysed the role of alpha1-adrenergic blockade by doxazosin in the above-described mechanisms. Doxazosin treatment reduced the formation of Bax-Bcl-2 complexes in the left ventricle of SHRs, and this was accompanied by a decrease in the levels of 85kDa PARP and a reduction in apoptotic left ventricular cells. CONCLUSIONS: The present work suggests that the presence of Bax-Bcl-2 complexes in the left ventricle could be a more reliable marker of the apoptotic state than the determination of the absolute expression of Bcl-2 and Bax proteins. Moreover, the inhibition of alpha1 -adrenergic receptors by doxazosin decreased the abundance of BaxBcl-2 complexes and promoted a reduction of apoptosis in the left ventricle of SHRs.

[Multinational European project and multicenter Spanish study of quality improvement of assistance on consultation-liaison psychiatry in general hospital: clinical profile in Spain]. / El proyecto multinacional europeo y multicéntrico español de mejora de calidad asistencial en psiquiatría de enlace en el hospital general: el perfil clínico en España.

BACKGROUND: In the frame of the European study on quality assurance in consultation liaison psychiatry and psychosomatics (supported by the BIOMED 1 program), the clinical <> of consultation-liaison psychiatry units pertaining to six Spanish general hospitals is analyzed. PATIENTS AND METHOD: A sample of 3. 608 consecutive patients referred to the consultation-liaison psychiatry units of five public general hospitals (Clínico of Zaragoza, Clínico of Barcelona, General of Alicante, Ramón y Cajal of Madrid, Princesa of Madrid) and one private gynecological hospital (Dexeus of Barcelona) was studied. The data were recorded with a standardized instrument (CL-BDoK-P), validated in a previous study. RESULTS: Consult request took place 10.6 days (on average) after the patients admission (<>), half the requests were urgent, and psychiatric consultants examined the patients 1.9 days (on average) after the request (<>). The most frequent reasons for referral were current psychiatric symptoms (50.3%), unexplained physical symptoms (15.2%), substance abuse (9.2%), psychiatric history (8.5%), suicide risk (6%) and coping with illness (5.8%). The main referral services were internal medicine (17.5%), traumatology (7.5%) and general surgery (7.3%). An important clinical activity is documented in patients frequently considered to be <>, with broad spectrum diagnostic and interventions processes and both in-hospital and out-patient follow-up. However, some problems were also detected in the clinical <>. CONCLUSIONS: The results outline the clinical importance of Spanish consultation-liaison psychiatry in the general hospital, but the possibility of improving its efficiency through the implementation of integrative models, organizational changes and modern models of <> is also emphasized.