Ana Pinto Borges

Apoptosis of peripheral CD4(+) T-lymphocytes in end-stage renal disease patients under hemodialysis and rhEPO therapies.

End-stage renal disease (ESRD) under hemodialyses (HD) is related with a higher propensity to infections, essentially due to T-cell lymphopenia. We postulated that HD procedure affects CD4+ T cells, especially by inducing apoptotic death and that recombinant human erythropoietin (rhEPO) therapy may also play an important role in the modulation of the immune system in these patients. T-cell phenotype and apoptosis of HD patients and healthy controls were evaluated by flow cytometry using anticoagulated whole-blood samples. In 12 HD patients, these parameters were also analyzed before and immediately after HD procedure. HD patients showed a decrease in total circulating CD3+ lymphocytes, especially in CD4+ T cells (0.747 ± 0.410 vs. 0.941 ± 0.216 × 109/L, p < 0.05), which could be a consequence of the higher proportion of CD3+ and CD4+ lymphocytes in the latest stage of apoptosis (or death) and of the higher proportion of apoptotic CD4+ T cells observed in the patients immediately after HD procedure (2.91 ± 0.780 vs. 3.90 ± 1.96, p < 0.05). A positive and statistically significant correlation between CD3+ and CD4+ lymphocytes in latest stage of apoptosis (or death) with HD time was found (CD3+: r = 0.592, p < 0.01; CD4+: r = 0.501, p < 0.01). We also found a negative and significant correlation between weekly rhEPO doses and the number of CD4+ T cells (r = –0.358, p < 0.05). In conclusion, HD procedure still contributes to the development of T-cell lymphopenia, at least in part, by apoptosis induction. It was also shown that rhEPO therapy is associated with the CD4+ T-cell decline, possibly by immune modulation, eliminating atypical cells and helping to restore the CD4+ T-cell subset.

Multidimensional screening with complementary activities: Regulating a monopolist with unknown cost and unknown preference for empire building

We study the optimal regulation of a monopolist when intrinsic efficiency (intrinsic cost) and empire building tendency (marginal utility of output) are private information, but actual cost (the difference between intrinsic cost and effort level) is observable. This is a problem of multidimensional screening with complementary activities. Results are not only driven by the prior probabilities of the four possible types, but also by the relative magnitude of the uncertainty along the two dimensions of private information. If the marginal utility of output varies much more (less) across managers than the intrinsic marginal cost, there is empire building (efficiency) dominance. In that case, an inefficient empire builder produces more (less) and at lower (higher) marginal cost than an efficient money-seeker. It is only when variabilities are similar that there may be the natural ranking of activities (empire builders produce more, while efficient managers produce at a lower cost).

USING COST OBSERVATION TO REGULATE A MANAGER WHO HAS A PREFERENCE FOR EMPIRE-BUILDING ?

We study regulation of a manager who has a preference for empire-building (high output), in the presence of moral hazard (unobservable effort) and adverse selection (unobservable productivity). We find that the optimal contract is linear in cost, being composed by a fixed payment plus a partial cost reimbursement. The preference for higher output reduces the managers tendency to announce that his or her productivity is low, allowing a more powered incentive scheme (a lower fraction of the cost is reimbursed), which alleviates the problem of moral hazard.

Elastase release during the hemodialysis procedure seems to induce changes in red blood cell membrane proteins

To the Editor: Elastase is a serine proteinase, expressed mainly by neutrophils, and also by monocytes and mast cells. It is a component of the primary azurophil granules of the neutrophils. Within the cell, it is involved in the degradation of microorganisms that are phagocytosed, and, outside the cell, it may degrade local extracellular matrix proteins, favoring neutrophil migration into or through tissues. 1,2 Recently, we showed that the red blood cell (RBC) membrane protein composition is altered in hemodialysis (HD) patients, particularly in nonresponders to recombinant human erythropoietin (rhEPO) therapy. 3,4 We also showed that the HD procedure induces neutrophil activation. 5,6 Therefore, we hypothesized that the RBC changes could be due to the release of elastase by neutrophils during HD. Our aim was to study the effect of elastase in RBC membrane protein composition from healthy controls and from HD patients under rhEPO therapy (responders and non-responders) to strengthen this hypothesis. We performed in vitro assays using RBC from 18 HD patients (10 responders and 8 nonresponders) and of 8 healthy controls. Classification of the patients, as responders or non-responders, was performed in accordance with the European Best Practice Guidelines, which defines resistance to rhEPO as a failure to achieve target Hb levels (between 11 and 12g/dL) with maintained doses of rhEPO higher than 300IU/kg/wk of epoietin or 1.5mg/kg/wk of darbopoietin-a. The two groups of patients were matched for age, gender, weight, body mass index, mean time under HD, urea reduction ratio, urea Ktv, and parathyroid hormone serum levels. Hemodialysis patients (10 males, 8 females; mean age 62.1 15.7 years) were under therapeutic HD 3 times per week, for 3‐5 hours, for a median period of time of 35 months. All patients used the highflux polysulfone FX-class dialysers of Fresenius (Fresenius Medical Care, Bad Homburg, Germany). The causes of renal failure in patient’s population were as follows: diabetic nephropathy (n=5), chronic glomerulonephritis (n=3), polycystic kidney disease (n=2), hypertensive nephrosclerosis (n=2), obstructive nephropathy (n=1), and chronic renal failure of uncertain etiology (n=5). Patients with autoimmune disease, malignancy, hematological disorders, and acute or chronic infection were excluded. All patients gave their informed consent to participate in this study. In HD patients, this assay used RBCs collected before and immediately after the HD procedure. Red blood cell suspensions (5 10 8 cell/mL; 10mL PBS, pH 7.4) were incubated for 3 hours at 371C, under the following assay conditions: without elastase and with 0.03, 0.1, and 0.5mg/mL of elastase. After incubation, the relative amount of each major RBC membrane protein was evaluated by densitometry. 3 We found no significant differences in the membrane protein composition of the RBCs from healthy controls and from responders and nonresponders after the HD procedure, when incubated without and with different elastase concentrations. However, the RBCs from responders and nonresponders HD patients, collected before the HD procedure, showed some susceptibility to elastase; the RBCs from responders incubated with 0.5mg/mL of elastase showed a significant decrease in ankyrin [7.0 (6.5‐7.5%) vs. 6.0 (5.9‐6.5%), P=0.024] and trends toward a decrease in spectrin [25.6 (25.1‐ 26.9%) vs. 24.7 (24.4‐25.6%), P=0.073) and an increase in band 3 [36.6 (34.8‐37.6%) vs. 39.1 (36.9‐39.4%), P=0.077) as compared with RBCs incubated without elastase. Similar changes were found for the RBCs incubated with 0.1mg/mL of elastase. In nonresponder patients, the RBCs incubated with 0.1 and 0.5mg/mL of elastase showed a significant decrease in spectrin [25.5 (24.9‐25.9%) and 25.3 (24.8‐26.2%), respectively, vs.

Comparison of Bio-Plex measurements with standard techniques.

Sandra Ribeiro 1,2 , Henrique Nascimento 1,2 , Ana Borges 1,2 , Maria do Sameiro Faria 3,4 , Petronila Rocha-Pereira 2,5 , El í sio Costa 2,6 , Lu í s Belo 1,2,* and Alice Santos-Silva 1,2, * 1 Faculdade Farm á cia , Departamento de Ci ê ncias Biol ó gicas, Servi ç o de Bioqu í mica, Universidade do Porto, Porto , Portugal 2 Instituto Biologia Molecular e Celular (IBMC) , Universidade do Porto, Porto , Portugal 3 FMC , Dinefro – Di á lises e Nefrologia, SA , Portugal 4 Instituto de Ci ê ncias Biom é dicas Abel Salazar (ICBAS) , Universidade do Porto, Porto , Portugal 5 Centro Investiga ç ã o Ci ê ncias Sa ú de (CICS) , Universidade Beira Interior, Covilh ã , Portugal 6 Instituto de Ci ê ncias da Sa ú de da Universidade Cat ó lica Portuguesa , Porto , Portugal