Begoña Campos

Expression of transforming growth factor-b1 and hypoxia-inducible factor-1a in an experimental model of kidney transplantation.

Background. Ischemia-reperfusion syndrome has been recognized as an important pathogenic factor in renal transplantation, not only in the development of delayed graft function but also in the development of acute and chronic rejection. Hypoxia-inducible factor (HIF)-1 activates transcription of several genes implicated in cell survival, such as vascular endothelial growth factor (VEGF), and in tissue repair transforming growth factor (TGF)-&bgr;. The purpose of this study was to characterize TGF-&bgr;1, VEGF, and HIF-1&agr; expression profiles during renal transplantation with heart-beating donors (HBD) and non-heart-beating donors (NHBD). Methods. An experimental model of renal transplantation using 40 pairs of large, white, Landrace pigs and including HBD and NHBD was used. Cold-ischemia time was the same in all groups (6 hr), and three groups of NHBD (30, 45, and 90 min) were studied. Immunosuppressive therapy consisted of cyclosporine, except in one HBD group, which was treated with azathioprine. TGF-&bgr;1, VEGF, and HIF-1&agr; expression profiles were performed in renal biopsies obtained at different times: after anesthetic induction (basal); 30, 45, and 90 min after warm ischemia; after cold ischemia; 1 hr after reperfusion; and 5 days after transplantation. Results. TGF-&bgr;1 expression increased after cold ischemia in HBD and remained unaltered during the surgical process in all NHBD groups. HIF-1&agr; and VEGF expression were not greatly modified during surgery in the HBD or NHBD groups. All groups showed a significant increase in TGF-&bgr;1 and HIF-1&agr; expression as well as down-regulation of VEGF 5 days after transplantation, and these effects were independent of immunosuppressive treatment. There were no statistically significant differences among the groups at 5 days after transplantation, although the increase in TGF-&bgr;1 was more pronounced in the HBD groups, especially in azathioprine-treated animals. Conclusions. The initial up-regulation of TGF-&bgr;1 observed in HBD immediately after cold ischemia could have a positive effect on epithelial-tubular regeneration. Warm ischemia has a detrimental effect on TGF-&bgr;1 expression during the early phases of renal transplantation and has no effect on VEGF and HIF-1&agr; expression. The up-regulation of TGF-&bgr;1 and HIF-1&agr; observed after transplantation could have a positive effect on tubular repair. TGF-&bgr;1 expression was lower in animals treated with cyclosporine, probably because of cellular toxicity.

AXL receptor tyrosine kinase is increased in patients with heart failure

BACKGROUND AXL is a membrane receptor tyrosine kinase highly expressed in the heart and has a conspicuous role in cardiovascular physiology. The role of AXL in heart failure (HF) has not been previously addressed. METHODS AND RESULTS AXL protein was enhanced 6-fold in myocardial biopsies of end-stage HF patients undergoing heart transplantation compared to controls from heart donors (P<0.0001). Next, we performed a transversal study of patients with chronic HF (n=192) and a group of controls with no HF (n=67). sAXL and BNP circulating levels were quantified and clinical and demographic data were collected. sAXL levels in serum were higher in HF (86.3 ± 2.0 ng/mL) than in controls (67.8 ± 2.0 ng/mL; P<0.0001). Also, sAXL correlated with several parameters associated with worse prognosis in HF. Linear regression analysis indicated that serum creatinine, systolic blood pressure and atrial fibrillation, but not BNP levels, were predictive of sAXL levels. Cox regression analysis indicated that high sAXL values at enrollment time were related to the major HF events (all-cause mortality, heart transplantation and HF hospitalizations) at one year follow-up (P<0.001), adding predictive value to high BNP levels. CONCLUSIONS Myocardial expression and serum concentration of AXL is elevated in HF patients compared to controls. Furthermore, peripheral sAXL correlates with parameters associated with the progression of HF and with HF events at short term follow-up. All together these results suggest that sAXL could belong to a new molecular pathway involved in myocardial damage in HF, independent from BNP.

Mammalian target of rapamycin inhibition prevents glomerular hypertrophy in a model of renal mass reduction.

Background. Sirolimus (SRL) is a potent and specific immunosuppressive drug used in organ transplantation, as basic therapy or in combination with calcineurin inhibitors. Although SRL is a nonnephrotoxic drug, many reports have related its use with the development of proteinuria, especially after conversion. Therefore, the aim of this study was to elucidate the interrelation between early and late SRL administration on the development of glomerular hypertrophy and proteinuria in a model of renal mass reduction (RMR). Methods. Rats underwent 2/3 cryoablation of the left kidney and subsequent right nephrectomy (n=42) or sham operations (n=29). Two weeks before (early study) or 12 weeks after (late study) surgery, SRL or vehicle was administered three times weekly. Creatinine clearance and proteinuria were determined throughout the study, and a complete histologic analysis was performed at the end of the study. Results. Treatment with SRL had no effect on creatinine clearance, independently of the administration time. Four weeks after RMR, a significant increase in proteinuria was observed. Proteinuria was stabilized after early and late SRL administration, whereas vehicle-treated animals showed a further increase in proteinuria. Glomerular hypertrophy was strongly associated with proteinuria, and early SRL introduction prevented glomerular enlargement. The histologic analysis showed less structural damage in the two groups of animals treated with SRL than in the control group. Conclusion. Although early SRL introduction blocked glomerular hypertrophy, SRL treatment revealed the potential to halt progression of proteinuria and histologic damage at any time of administration in a model of RMR.

Analysis of the arrhythmogenic substrate in human heart failure

BACKGROUND The mechanism of sudden cardiac death in patients with heart failure (HF) is uncertain. Both electrical instability and structural remodelling could be factors that lead to fatal arrhythmias. We sought to analyse the expression of the sodium (SCN5A) and potassium (KCND3) channels as well as the fibrosis content in the ventricles of human HF and of non-diseased hearts under different post-mortem intervals. METHODS AND RESULTS We analysed normal human hearts as controls [n=20 for the right ventricle (RV) and n=13 for the left ventricle (LV)] and human hearts from HF patients, which were obtained at the time of cardiac transplantation, as cases (n=48 for RV and n=34 for LV). Transcription of the SCN5A (probes SCN5A E4-5, E11-12, and E28) and KCND3 channels and of COLLAGEN I and III were assayed by real-time polymerase chain reaction. In addition, paraffin sections were used to analyse the percentage of collagen deposition in both cases and controls. KCND3 mRNA expression in the LV was lower in the cases than in controls (P<.001). Higher levels of SCN5A mRNA were found in the HF samples when analysed with probe SCN5A E4-5 (P<.05). SCN5A expression was lower in the controls with longer post-mortem interval (n=4) than in the controls with a shorter post- mortem interval (n=16, P<.01). KCND3 mRNA levels were also different between the two control groups (P<.05). Collagen deposition was higher in the LV tissues of the cases when compared to controls (P<.001), and it was higher in the LV from HF patients than in the RV (P<.05). Furthermore, collagen deposition was higher in the LV samples from patients with implanted cardiac defibrillator (ICD) therapy than in the LV of patients with no ICD therapy (P<.05). CONCLUSIONS These data indicate that ionic and structural remodelling could be pathophysiological mechanisms of cardiac arrhythmias in HF patients.

Influence of renal replacement therapy on immune response after one and two doses of the A(H1N1) pdm09 vaccine

Please cite this paper as: Quintana et al. (2012) Influence of renal replacement therapy on immune response after one and two doses of the A(H1N1) pdm09 vaccine. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12024.

Use of serum levels of high sensitivity troponin T, galectin-3 and C-terminal propeptide of type I procollagen at long term follow-up in heart failure patients with reduced ejection fraction: Comparison with soluble AXL and BNP

BACKGROUND Prognostic biomarkers are needed to improve the management of the heart failure (HF) epidemic, being the brain natriuretic peptides the most valuable. Here we evaluate 3 biomarkers, high sensitivity troponin T (hs-TnT), galectin-3 (Gal-3) and C-terminal propeptide of type I procollagen (CICP), compare them with a recently described new candidate (sAXL), and analyze their relationship with BNP. METHODS HF patients with reduced ejection fraction (n=192) were included in this prospective observational study, with measurements of candidate biomarkers, functional, clinical and echocardiographic variables. A Cox regression model was used to determine predictors for clinical events, i.e. all-cause mortality and heart transplantation. RESULTS Hs-TnT circulating values were correlated to clinical characteristics indicative of more advanced HF. When analyzing the event-free survival at a mean follow-up of 3.6years, patients in the higher quartile of either BNP, hs-TnT, CICP and sAXL had increased risk of suffering a clinical event, but not Gal-3. Combination of high sAXL and BNP values had greater predictive value (HR 6.8) than high BNP alone (HR 4.9). In a multivariate Cox regression analysis, BNP, sAXL and NYHA class were independent risk factors for clinical events. CONCLUSIONS In this HF cohort, hs-TnT is a good HF marker and has a very significant prognostic value. The prognostic value of CICP and sAXL was of less significance. However, hs-TnT did not add predictive value to BNP, while sAXL did. This suggests that elevated troponin has a common origin with BNP, while sAXL could represent an independent pathological mechanism.

ACE2 and ACE in acute and chronic rejection after human heart transplantation

OBJECTIVES The authors sought to evaluate cardiac activity of angiotensin-converting enzyme (ACE) and ACE2 after heart transplantation (HT) and its relation with acute rejection (AR) and chronic allograft vasculopathy (CAV). BACKGROUND The renin-angiotensin system is altered in heart failure and HT. However, ACE and ACE2 activities in post-HT acute and chronic rejection have not been previously studied. METHODS HT patients (n = 45) were included when appropriate serial endomyocardial biopsies (EMB) and coronary angiography were available for analysis. In 21 patients, three post-HT time points were selected for CAV study in EMB tissue: basal (0-3 wks), second (2-3 months) and third (4-5 months). At 10 years post-HT, CAV was evaluated by coronary angiography (CA) and patients were grouped by degree of CAV: 0-1, non-CAV (n = 15) and 2-3, CAV (n = 6). For the AR study, 28 HT patients with evidence of one EMB rejection at grade 3 and two EMB grade 1A and/or 1B rejections were selected. RESULTS Post-HT, ACE2 activity was increased in the CAV group, compared to non-CAV. Patients with AR showed increased ACE, but not ACE2, activity. CONCLUSIONS Our results suggest that early post-HT cardiac ACE2 activity may have an important role in CAV development. In contrast, ACE activity was increased in AR. The renin-angiotensin system seems to be altered after HT and strategies to balance the system may be useful.

Rendimiento académico e inserción laboral de los titulados en medicina por la Universitat de Barcelona. Un estudio longitudinal

Introduction. The Bologna process has brought about changes in the structure of the Spanish University giving prominence to the concepts of competence and quality. This posed the challenge of showing the contribution of the University of Barcelona (UB) in the training of doctors to Catalan society, and the distribution of these graduates in relation to the entire group of professional associations in the province of Barcelona. Subjects and methods. Longitudinal study of four classes of freshman students of the Faculty of Medicine, UB, who were admitted between 1994 and 2001. For each cohort academic performance, specialized training and licensing statistics were obtained after looking up different databases and using the R software. Results. Between 85% and 96% of students who entered medical school obtained a degree in Medicine in a period shorter than seven years. Of all graduates comprised 83% recorded in medical professional association of the province (COMB). In comparison with the total professional members, these classes highlighted by a greater proportion of women (3 out of 4) and virtually no immigration rates. Conclusions. Graduates in Medicine from the UB demonstrated high performance of their studies and inserted into the profession in its geographical area.