Effect of losartan on human platelet activation

OBJECTIVE: Previous studies have demonstrated that losartan can block the thromboxane A2 receptor on the vascular wall. The aim of the present study was to assess the effect of losartan on human platelet activation. METHODS: Platelets were obtained from 15 healthy men, aged 26-40 years. Platelet activation was measured by changes in the light transmission of platelet-rich plasma stimulated by the thromboxane A2 analog U46619 (5 x 10(-6) mol/l) or ADP (10(-5) mol/l). RESULTS: U46619-stimulated platelet aggregation was significantly inhibited by losartan in a dose-dependent manner. Only a high dose of EXP 3174 (5 x 10(-5) mol/l), the in vivo active metabolite of losartan, was able to attenuate U46619-induced platelet activation. Captopril, an angiotensin I converting inhibitor, failed to modify U46619-induced platelet aggregation. Furthermore, the binding of [3H]-U46619 to platelets was competitively inhibited by losartan, whereas only a high dose of EXP 3174 reduced the binding of [3H]-U46619. Captopril failed to modify the binding of [3H]-U46619 to platelets. Losartan also reduced the platelet activation induced by ADP (10(-5) mol/l), a platelet agonist partially dependent on thromboxane A2. In addition, when thromboxane A2 generation was blocked by aspirin, ADP-induced platelet aggregation was inhibited to a similar degree to the inhibition induced by losartan. Exogenous angiotensin II did not elicit any modification of either U46619- or ADP-stimulated platelet aggregation. CONCLUSIONS: Losartan decreased platelet aggregation by a thromboxane A2-dependent mechanism. EXP 3174 was less potent than losartan in reducing thromboxane A2-dependent platelet activation. Captopril and exogenous angiotensin II had no effect on human platelet activation. These results suggest that losartan reduced thromboxane A2-dependent platelet activation independently of its effect on angiotensin II.     

Clinical-Echocardiographic Correlation of Myocardial Infarction with Extension to Right Chambers

In order to determine the transesophageal echocardiographic characteristics in patients with acute myocardial infarction of right ventricle and establish the relationship between these findings, the clinical condition, and their prognostic value, 38 patients consecutively admitted to the Instituto Nacional de Cardiología with a diagnosis of acute left ventricular myocardial infarction with extension to right ventricle and/or atrium were retrospectively studied. Of the left ventricular infarctions, 37 were posteroinferior and one anterior. Significant elevations of CPK and DHL were found in 35. In 30 patients (78%) electrocardiographic evidence of extension of infarction to the right ventricle was found, and in 3, evidence of right atrial infarction. Twenty-one patients presented clinical data compatible with right ventricular infarction. In 19, cardiac rhythm and atrioventricular conduction disturbances were documented. Coronary angiograms practiced on 34 patients demonstrated single-vessel (right coronary) disease in 12, affection of two vessels in 14, and lesions in three or more in 6. Coronary arteries presented no significant lesions in two cases. With TEE, alterations of right ventricular segmental mobility were demonstrated in all patients, and in 6, alterations of right atrial mobility as well. As respects the ventricular wall movement index, 68.5% had total scores (RV + LV) of <5. The other 31.5% had scores >/= 5. In 26%, the right ventricular wall movement index was >/=4. The RVDD/LVDD ratio was 1 or less in 30 patients (78%) and >1 in only 8 (22%). The conclusions from these findings are that: (1) TEE is an excellent diagnostic means of identifying right ventricular and/or atrial infarction; and (2) a relationship exists between the magnitude of right ventricular damage and a wall movement index of 5 or more or an RV/LV diastolic diameter ratio > 1:postinfarction hemodynamic deterioration is significantly greater and the incidence of intrahospitalary complications higher.     

A strategy to improve treatment‐related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays

Background

Treatment‐related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world.

Procedure

A collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper‐middle income country, and Dana‐Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced‐intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact.

Results

The Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995–2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P = 0.005), abandonment (32% to 9%; P &amp;lt; 0.001), and event‐free survival with abandonment considered an event (47% to 65% at 2 years; P = 0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy ≥4 weeks delayed predicted markedly inferior disease‐free survival (P = 0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high‐income countries.

Conclusions

Implementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. Pediatr Blood Cancer 2015;62:1395–1402. © 2015 Wiley Periodicals, Inc.     

Clinical profile of eprosartan

Angiotensin II (AII) receptor blockers offer an alternative means of blocking the renin-angiotensin-aldosterone system (RAAS) to angiotensin converting enzyme (ACE) inhibitors. Being highly selective for the AII receptor subtype AT₁, AII receptor blockers may avoid side-effects associated with ACE inhibitor treatment, such as cough. Eprosartan is a non-biphenyl, non-tetrazole competitive blocker that is chemically distinct from other AII receptor blockers, which may account for differences in its pharmacological properties. It induces dual blockade of AT₁ receptors both presynaptically and postsynaptically, reducing sympathetic nerve activity to a significantly greater degree than other AT₁ receptor blockers.At the recommended dose of 600 mg once daily, eprosartan effectively lowers blood pressure (BP) in hypertensive patients to a similar degree as seen with other AII receptor blockers and ACE inhibitors. However, a greater proportion of patients achieved adequate BP control compared with enalapril. When eprosartan is given in combination with hydrochlorothiazide (HCTZ), it provides a significantly greater BP reduction compared with eprosartan alone.Eprosartan has a side-effect profile that is similar to placebo and to other AII receptor blockers, but is better than that of enalapril because it lacks the propensity to cause dry cough. Eprosartan is not metabolized by the cytochrome P450 enzyme system, and so has no interaction with drugs that affect this system. Eprosartan completely reverses renal vasoconstriction induced by AII and may, therefore, have further applications in situations where stimulation of the RAAS is a problem. In summary, eprosartan, alone or in combination with HCTZ, provides an effective and well-tolerated approach to lowering BP in patients with all grades of hypertension. Further development of eprosartan may offer therapeutic opportunities that go far beyond the current recommendations.     

The utility of cervical elastosonography in prediction of cervical insufficiency: cervical elastosonography and cervical insufficiency

Objective: To evaluate the utility of cervical elastosonography (ES) in prediction of cervical insufficiency (CI).

asis="http://docs.oasis-open.org/ns/oasis-exchange/table">Methods: A total of 40 women, of which 20 who had previously received the diagnosis of CI and 20 healty women were included in the study. None of the women were pregnant. All subjects underwent sonographic evaluation including cervical length measurement and ES of uterine cervix. Adjacent muscular tissue was the reference point for elastosonography evaluation. Tissue strain ratio values were obtained from all the patients.

asis="http://docs.oasis-open.org/ns/oasis-exchange/table">Results: The area around the internal cervical os of the group with CI was found to be significantly softer as compared to the control group (higher SR rate, p?&amp;lt;?0.05). Furthermore, the outer parts of the cervix (sites A and D) were also found harder in the group that had CI (lower SR rate, p?&amp;lt;?0.05).

asis="http://docs.oasis-open.org/ns/oasis-exchange/table">Conclusions: According to our knowledge, this is preliminary study to evaluate the predictive value of cervical ES in CI and we concluded that ES can be used as reliable method to determine CI but it is necessary to be studied in different cohort groups.     

Maternal and umbilical cord copeptin levels in pregnancies complicated by fetal growth restriction

Objective: The aim of this study was to compare maternal and fetal serum copeptin concentrations in pregnancies complicated by isolated fetal growth restriction (FGR), and uncomplicated pregnancies, and to investigate relationships between copeptin levels and clinical parameters.

asis="http://docs.oasis-open.org/ns/oasis-exchange/table">Methods: Maternal and fetal serum copeptin levels were measured in 21 women with pregnancies complicated by isolated FGR and 20 women with normal pregnancies (control group). Doppler assessment of the uterine and umbilical arteries was performed in each patient.

asis="http://docs.oasis-open.org/ns/oasis-exchange/table">Results: Maternal serum copeptin levels were significantly higher in women with isolated FGR compared to controls (p?=?0.042). In addition, maternal copeptin levels were inversely correlated with the uterine artery pulsatility and resistance indices and positively correlated with neonatal birth weight. Umbilical vein copeptin levels were significantly increased in neonates with adverse outcomes (p?=?0.001).

asis="http://docs.oasis-open.org/ns/oasis-exchange/table">Conclusions: Increased maternal copeptin concentration may reflect a response to stress, thus serving as a compensatory mechanism in pregnancies complicated by FGR.     

Intramolecular radical cyclization approach to access highly substituted indolines and 2,3-dihydrobenzofurans under visible-light

The combination of visible-light and tris(trimethylsilyl)silane promoting intramolecular reductive cyclization protocol for the synthesis of functionalized indolines and 2,3-dihydrobenzofurans has been developed. The transformations occur in the absence of transition metal and additional photocatalyst. In addition, quantum yield (&amp;#x003a6;) was determined and electron paramagnetic resonance spectroscopy was performed to better understand the reaction pathway.

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The combination of visible-light and tris(trimethylsilyl)silane promoting intramolecular reductive cyclization protocol for the synthesis of functionalized indolines and 2,3-dihydrobenzofurans has been developed.<a class="inline_block ts_canvas" href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&amp;amp;p=PMC3&amp;amp;id=9079632_c8ra01787e-ga.jpg" target="tileshopwindow" rel="noopener">a>     

In situ X-ray absorption spectroscopy study of CuO–NiO/CeO2–ZrO2 oxides: redox characterization and its effect in catalytic performance for partial oxidation of methane

In this work we analyze the effect of adding CuO to a NiO/Ce_0.9Zr_0.1O₂ oxide by in situ X-ray absorption near-edge structure XANES technique in Ce L3, Ni K and Cu K absorption edges in terms of sample reducibility and catalytic activity. The oxidation states of Ce, Ni and Cu cations are followed up during temperature programmed reduction (TPR) experiments in diluted hydrogen and during catalytic tests for partial oxidation of methane (POM) reaction. Redox behavior was correlated to conventional fixed bed reactor results. The effect of firing temperature, crystallite size, CeO₂&amp;#x02013;ZrO₂ support and the presence of Cu and/or Ni as an active phase is also analyzed. Results showed a beneficial effect of CuO addition in terms of Ce and Ni reduction. A stronger interaction of NiO species with the support was revealed upon analysis of XANES reduction profiles in sample NiO/ZDC in contrast to bimetallic CuO&amp;#x02013;NiO/ZDC sample. Reduction onset temperature was found to depend on Ni crystallite size, being markedly promoted when samples exhibited low values of crystallite size both in supported and non-supported CuO&amp;#x02013;NiO species. In situ catalytic experiments for partial oxidation of methane showed a clear interplay between the redox behavior from the Ce in the CeO₂&amp;#x02013;ZrO₂ support and the Ni from the active phase. Sample NiO/ZDC exhibited a continuous reduction of Ce cations in CH₄&amp;#x02009;:&amp;#x02009;O₂ feed flow, carbon formation was detected in X-ray Powder Diffraction (XPD) patterns and Ni re-oxidation was found to take place, clear indications of catalyst deactivation. In contrast, sample CuO&amp;#x02013;NiO/Ce_0.9Zr_0.1O₂ displayed a slight re-oxidation of Ce and no re-oxidation of Ni altogether with the suppression of carbon formation.

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In situ X-Ray Absorption (XAS) experiments in reducing atmospheres (H₂ and CH₄&amp;#x02009;:&amp;#x02009;O₂) uncovered Ce, Ni and Cu redox interplay during catalytic experiments.<a class="inline_block ts_canvas" href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&amp;amp;p=PMC3&amp;amp;id=9079307_c8ra01528g-ga.jpg" target="tileshopwindow" rel="noopener">a>     

Cadmium specific proteomic responses of a highly resistant Pseudomonas aeruginosa san ai

Pseudomonas aeruginosa san ai is a promising candidate for bioremediation of cadmium pollution, as it resists a high concentration of up to 7.2 mM of cadmium. Leaving biomass of P. aeruginosa san ai exposed to cadmium has a large biosorption potential, implying its capacity to extract heavy metal from contaminated medium. In the present study, we investigated tolerance and accumulation of cadmium on protein level by shotgun proteomics approach based on liquid chromatography and tandem mass spectrometry coupled with bioinformatics to identify proteins. Size exclusion chromatography was used for protein prefractionation to preserve native forms of metalloproteins and protein complexes. Using this approach a total of 60 proteins were observed as up-regulated in cadmium-amended culture. Almost a third of the total numbers of up-regulated were metalloproteins. Particularly interesting are denitrification proteins which are over expressed but not active, suggesting their protective role in conditions of heavy metal exposure. P. aeruginosa san ai developed a complex mechanism to adapt to cadmium, based on: extracellular biosorption, bioaccumulation, the formation of biofilm, controlled siderophore production, enhanced respiration and modified protein profile. An increased abundance of proteins involved in: cell energy metabolism, including denitrification proteins; amino acid metabolism; cell motility and posttranslational modifications, primarily based on thiol-disulfide exchange, were observed. Enhanced oxygen consumption of biomass in cadmium-amended culture versus control was found. Our results signify that P. aeruginosa san ai is naturally well equipped to overcome and survive high doses of cadmium and, as such, has a great potential for application in bioremediation of cadmium polluted sites.

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When exposed to cadmium a highly resistant strain P. aeruginosa san ai responds by an increased metalloprotein expression (particularly denitrification proteins), an enhanced respiration, and a pronounced thiol-disulfide protein modifications.<a class="inline_block ts_canvas" href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&amp;amp;p=PMC3&amp;amp;id=9078880_c8ra00371h-ga.jpg" target="tileshopwindow" rel="noopener">a>