Effects of long-term estrogen replacement therapy versus combined hormone replacement therapy on nitric oxide-dependent vasomotor function

Postmenopausal hormone replacement therapy (HRT) with estrogen may increase production of the predominant endothelium-derived vasodilator nitric oxide (NO) and consequently improve vascular reactivity. In contrast, concurrent progestin therapy may oppose this beneficial effect. We studied the effect of long-term estrogen HRT and combined HRT on vasomotor function and on plasma nitrate, which reflects the amount of NO in the circulation. As lipid peroxidation affects NO production and impairs endothelial function, we also measured the amount of the in vivo lipid peroxidation marker urinary 8-iso-prostaglandin F(2 alpha). The study group comprised 15 women receiving estradiol valerate HRT (mean age, 56 yr; treatment duration, 10.5 yr) and 15 women receiving combined HRT with estradiol valerate and levonorgestrel (mean age, 58 yr; treatment duration, 11.3 yr). The peak flow velocity (PFV) and pulsatility index of the common carotid and internal carotid artery and the abdominal aorta were measured by ultrasonography after long-term HRT (baseline), after a 4-wk pause and again 3 wk after reintroducing HRT. A statistically significant interaction between the groups and time points was observed in the PFV of the internal carotid artery (P = 0.011). In women taking estradiol valerate, the PFV values decreased significantly after withdrawal of HRT (P = 0.007) and increased again to the baseline level after reintroduction of therapy (P < 0.001). In women receiving combined HRT, the PFV remained stable over all study periods. At baseline, the PFV of women taking estradiol valerate correlated with the plasma nitrate concentration in the common carotid artery (r = 0.646; P = 0.009) and in the abdominal aorta (r = 0.579; P = 0.024). For pulsatility index and urinary 8-iso-prostaglandin F(2 alpha) excretion, there were no significant differences between the groups. Our results suggest that the favorable effects of long-term estrogen treatment on blood flow are at least partly mediated through NO. The addition of levonorgestrel to the treatment regimen appears to abolish this effect.     

Treatment with Low Doses of Polyclonal Immunoglobulin Improves B Cell Function During Immune Reconstitution in a Murine Model

Propose

After autologous stem cell transplantation (ASCT) the immunological B cell compartment recovers slowly. Delays on the recovery of B cell function after autologous stem cell transplantation are due to the low lymphocytes count and to their intrinsic dysfunction.

Methods

We studied the in vivo B cell reconstitution after ASCT examining the independent effect of polyclonal IgG (PolyIg), Fab or Fc fragments infusions in a murine animal model during a period of 12 weeks. These molecules were used in low doses, mimicking the recommended use of IVIg in the case of hypogammaglobulinemia in humans. Flow cytometry analysis and ELISA tests were conducted to monitor the reconstitution of B cells and serum immunoglobulin production. Panama blot and PCA factor 1 analysis were used to study the kinetics of immunoglobulin repertoires reconstitution. Mechanistic studies were also performed using in vitro cell culture.

Results

During follow-up after ASCT, peripheral B cells expand independently of treatment, correcting the immediate increase in sBAFF (soluble B cell activating factor) induced by previous intense myeloablation. Treatments with Fab and Fc fragments infusions promote significant IgM and IgG production comparing to control. Although the complete recovery of antibody repertoire is only achieved at the end of follow-up after ASCT, there is an earlier and significantly stronger recovery in the treated mice, which is evident at 9 weeks after ASCT. At 30 weeks after ASCT, normal values of antibody repertoire were detected in all individuals. Mechanistic studies show that Fab and Fc fragments promote IgG1 production by indirect pathways.

Conclusions

The results presented here demonstrate that polyclonal immunoglobulin indirectly improves the function of the reconstituted B cells and their IgG production by means of Fc-mediated effects on bystander cells. These results further stimulate the discussion about the advantages of IVIg therapy during immune reconstitution after human ASCT.     

Natural infection of cortelezzii complex (Diptera: Psychodidae: Phlebotominae) with Leishmania braziliensis in Chaco, Argentina

In Argentina, American Cutaneous Leishmaniasis (ACL) extends up to 29°S in the phytogeographic regions of the Yungas (west), Chaco (center) and Paranaense (east). Since the Phlebotominae vectors of this disease in the western Chaco (dry Chaco) are unknown, in the present work, we studied the natural infection in Phlebotominae by PCR-ERFLP and Dot blot in order to incriminate these organisms as potential vectors. Captures with CDC-type traps were performed monthly in the domicile, the peridomicile and the forest in the Municipio Misión Nueva Pompeya, Chaco, Argentina, in two sites with human cases of ACL: Los Pozos (24°54'S, 61°22'W) and Fortín Arenales (24°58'S, 61°21'W), from November 2006 to December 2007. A total of 1702 Phlebotominae were captured: Mygonemyia migonei (83.8%), cortelezzii complex (11.1%), Mycropigomyia peresi (3.3%), Mycropygomy quinquefer (1.2%), Pintomyia torresi (0.2%) and Nyssomyia neivai (0.2%). Although no significant differences were found in species diversity, there were significant differences in abundance between both sites studied. A total of 80 phlebotomine females were analyzed: 50 of the cortelezzii complex and 30 My. migonei. No intestinal flagellates were observed by light microscopy. Two pools of 10 individuals of the cortelezzii complex of the peridomicile and forest of Fortín Arenales were reactive by PCR and Dot blot for Leishmania (Viannia) braziliensis. In Argentina, Evandromyia cortelezzii has been incriminated as a likely vector of ACL because of its abundance in areas of sporadic outbreaks. In the present work, Ev. cortelezzii females were found naturally infected, thus reinforcing the hypothesis that the members of the cortelezzii complex act as vectors of the disease.     

Implementation of a pre-hospital network favoring primary angioplasty in STEMI to reduce mortality: the Algarve Project

ObjectiveTo analyze the impact of reperfusion by either primary percutaneous coronary intervention (PPCI) or fibrinolysis, and mortality rates of a pre-hospital fast-track network for treating patients with ST-elevation myocardial infarction (STEMI).Methods and ResultsA pre-hospital network for STEMI patients, designated the Green Lane for Acute Myocardial Infarction (GL-AMI), has been implemented in the southern region of Portugal – the Algarve Project. We performed an observational study based on a prospective registry of 1338 patients admitted to Faro Hospital between 2004 and 2009, classified in two groups according to the method of admission: emergency department group (EDG) and GL-AMI group (GLG). More patients from GLG were reperfused (p < 0.0001). PPCI was the preferred method of reperfusion, 73.1% in GLG and 45.3% in EDG. Time delays were significantly shorter in GLG, except for pre-hospital delay: pre-hospital delay (p = 0.11); door-to-needle (p < 0.0001); door-to-balloon (p < 0.0001); and delay between symptoms and reperfusion (p < 0.0001). In-hospital mortality (4.3% vs 9.2%, p = 0.0007) and 6-month mortality (6.3% vs 13.8%, p < 0.0001) were significantly lower in GLG.ConclusionsThe Algarve Project significantly reduced the time delay between onset of symptoms and reperfusion, significantly increased the rate of reperfusion, and significantly reduced in-hospital and six-month mortality.