Impairment of the Plasmodium falciparum Erythrocytic Cycle Induced by Angiotensin Peptides

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1–7). Parasite infection decreased Ang-(1–7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1–7) decreased the level of infection in an A779 (specific antagonist of Ang-(1–7) receptor, MAS)-sensitive manner. 10−7 M PD123319, an AT2 receptor antagonist, partially reversed the effects of Ang-(1–7) and Ang II. However, 10−6 M losartan, an antagonist of the AT1 receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10−8 M Ang II or 10−8 M Ang-(1–7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10−7 M A779. 10−6 M dibutyryl-cAMP increased the level of infection and 10−7 M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1–7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1–7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus

Impairment of the Plasmodium falciparum Erythrocytic Cycle Induced by Angiotensin Peptides

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1–7). Parasite infection decreased Ang-(1–7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1–7) decreased the level of infection in an A779 (specific antagonist of Ang-(1–7) receptor, MAS)-sensitive manner. 10−7 M PD123319, an AT2 receptor antagonist, partially reversed the effects of Ang-(1–7) and Ang II. However, 10−6 M losartan, an antagonist of the AT1 receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10−8 M Ang II or 10−8 M Ang-(1–7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10−7 M A779. 10−6 M dibutyryl-cAMP increased the level of infection and 10−7 M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1–7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1–7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Biópsias endometriais seriadas em vacas Nelore (Bos taurus indicus) durante o ciclo estra

Endometrial histologycal alterations were evaluated from repeated collection of uterine samples in Nelore (Bos taurus indicus) during the estrous cycle. Sixteen adult cows with a synchronized estrous cycle were used. The endometrial samples were collected in DO (day zero; ovulation day), D5 (day five), D9 (day nine) and D13 (day thirteen) of the estous cycle. Before the samples collections, we evaluated the ovary and the uterus by transrectal ultrasonography in all the animals. The mononuclear infiltrate was predominant, however their intensity wasn’t ranged throughout the estrous cycle, isn’t representing a direct consequence of the biopsies (P > 0.05). Intensity of polymorphonuclear infiltrate varied between harvests, being absent in the first and last sample (P 0,05). A intensidade de infiltrado polimorfonuclear variou entre as colheitas, sendo ausente na primeira e na última amostra (P < 0,05). Assim, pôde-se concluir que a biópsia endometrial em vacas é uma técnica adequada para a avaliação da higidez uterina

Paracrine signaling of human mesenchymal stem cell modulates retinal microglia population number and phenotype in vitro

Cellular therapy with mesenchymal stem cells (MSC) is emerging as an effective option to treat optic neuropathies. In models of retinal degeneration, MSC injected in the vitreous body protects injured retinal ganglion cells and stimulate their regeneration, however the mechanism is still unknown. Considering the immunomodulating proprieties of MSC and the controversial role of microglial contribution on retinal regeneration, we developed an in vitro co-culture model to analyze the effect of MSC on retinal microglia population.Fil: Teixeira Pinheiro, Leandro C.. Universidade Federal do Rio de Janeiro; Brasil. Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa; BrasilFil: Toledo, Maria Fernanda. Universidade Federal do Rio de Janeiro; Brasil. Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Nascimento dos Santos, Gabriel. Universidade Federal do Rio de Janeiro; BrasilFil: Mendez Otero, Rosalia. Universidade Federal do Rio de Janeiro; Brasil. Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa; BrasilFil: Mesentier Louro, Louise A.. University of Stanford; Estados Unidos. Universidade Federal do Rio de Janeiro; BrasilFil: Santiago, Marcelo F.. Universidade Federal do Rio de Janeiro; Brasil. Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa; Brasi

Treatment delays among women with breast cancer in a low socio-economic status region in Brazil

Abstract Background Considering the inequalities and the areas of low socioeconomic status in Brazil, access to health services is a challenge and the delay between diagnosis and treatment represents an important factor of worse prognosis in patients with breast cancer. Herein, we describe the clinical and epidemiological profiles of women with breast cancer and evaluate their access to health services, as well as treatment delays, at a reference centre of the Cariri region, Ceará, Brazil. Methods This is a retrospective study that included 473 women treated with breast cancer between 2009 and 2011 at the Oncology Centre of the Cariri. Results The majority of these patients were aged between 40 and 69 years old (65.7%), without a completed high school degree (89.2%). They were married (62.9%) and were already diagnosed but had not yet been subjected to any previous treatment (77.8%). It was observed that 91.8% were referred from the public health service, and treatment was paid for by the public health service in 92.9% of the cases. The patients whose source of referral was the public system waited longer between diagnosis and the treatment initiation (p = 0.031; Mann–Whitney’s test), with a median waiting time of 71.5 days versus 39 days for those receiving referrals from private services. In addition, those with public referrals prior to diagnosis also experienced a longer waiting time between the first medical visit and treatment initiation (77 days vs. 37 days; p = 0.036; Mann–Whitney’s test), with the waiting time for the biopsy being an important factor in this delay. Conclusions Late diagnosis was often the result of inefficiency of the prevention policies coupled with difficulty accessing the public health network. It was commonly observed that, even after diagnosis, the patients needed to wait too long before entering the Oncology Service because of long waiting queues in the public health system

Long-term neuronal survival, regeneration, and transient target reconnection after optic nerve crush and mesenchymal stem cell transplantation

Abstract Background Retina and/or optic nerve injury may cause irreversible blindness, due to degeneration of retinal ganglion cells. We and others have previously shown that the intravitreal injection of mesenchymal stem cells (MSCs) protects injured retinal ganglion cells and stimulates their regeneration after optic nerve injury, but the long-term effects of this therapy are still unknown. Methods We injected rat MSC (rMSC) intravitreally in adult (3–5 months) Lister Hooded rats of either sex after optic nerve crush. Retinal ganglion cell survival, axonal regeneration, and reconnection were analyzed 60 and 240 days after crush by immunohistochemistry for Tuj1, anterograde labeling with cholera-toxin B and by immunohistochemistry for nerve growth factor-induced gene A (NGFI-A, driven by light stimulation) in the superior colliculus after a cycle of light deprivation-stimulation. Visual behaviors (optokinetic reflex, looming response, and preference for dark) were analyzed 70 days after crush. Results rMSC treatment doubled the number of surviving retinal ganglion cells, preferentially of a larger subtype, and of axons regenerating up to 0.5 mm. Some axons regenerated to the lateral geniculate nucleus and superior colliculus. NGFI-A+ cells were doubled in rMSC-treated animals 60 days after crush, but equivalent to vehicle-injected animals 240 days after crush, suggesting that newly formed synapses degenerated. Animals did not recover visual behaviors. Conclusions We conclude that rMSC-induced neuroprotection is sustained at longer time points. Although rMSCs promoted long-term neuroprotection and long-distance axon regeneration, the reconnection of retinal ganglion cells with their targets was transitory, indicating that they need additional stimuli to make stable reconnections