Luciana Cristina dos Santos Silva

Characterization of a new angiotensin antagonist selective for angiotensin-(1–7): Evidence that the actions of angiotensin-(1–7) are mediated by specific angiotensin receptors

In this study we describe a new angiotensin antagonist [Asp1-Arg2-Val3-Tyr4-Ile5-His6-D-Ala7, (A-779)] selective for the heptapeptide angiotensin-(1-7) [Ang-(1-7)]. A-779 blocked the antidiuretic effect of Ang-(1-7) in water-loaded rats and the changes in blood pressure produced by Ang-(1-7) microinjection into the dorsal-medial and ventrolateral medulla. In contrast, A-779 did not change the dipsogenic, pressor, or myotropic effects of angiotensin II (Ang II). Also, A-779 did not affect the antidiuretic effect of vasopressin or the contractile effects of angiotensin III, bradykinin, or substance P on the rat ileum. In the rostral ventrolateral medulla, the pressor effect produced by Ang-(1-7) microinjection was completely blocked by A-779 but not by AT1 or AT2 receptor antagonists (DUP 753 and CGP 42112A, respectively). Conversely, the pressor effect produced by Ang II was not changed by A-779 but was completely blocked by DUP 753. Binding studies substantiated these observations: A-779 did not compete significantly for 125I-Ang II binding to adrenocortical membranes at up to a 1 microM concentration. Low affinity binding was also observed in adrenomedullary membranes with an IC50 greater than 10 microM. Our results show that A-779 is a potent and selective antagonist for Ang-(1-7). More importantly, our data indicate that specific angiotensin receptors mediate the central and peripheral actions of Ang-(1-7).

Evidence that angiotensin-(1-7) plays a role in the central control of blood pressure at the ventro-lateral medulla acting through specific receptors.

In this study we determined which angiotensin receptors may mediate the cardiovascular effects elicited by angiotensin-(1-7) [Ang-(1-7)] in the rostral ventrolateral medulla (RVLM) and caudal pressor area (CPA) of the ventrolateral medulla (VLM) of anesthetized rats. Furthermore the role of endogenous angiotensins in these areas was also investigated. The pressor effect produced by unilateral microinjection of Ang-(1-7) into the RVLM or CPA was not modified by either the AT1 receptor antagonist, DuP 753 or by the AT2 receptor antagonist, CGP 42112A, but was completely blocked by the Ang-(1-7) selective antagonist, A-779. In contrast, the pressor effect produced by microinjection of angiotensin II (Ang II) was completely blocked by DuP 753 but was not changed by CGP 42112A or A-779. Bilateral microinjection of A-779 into the RVLM or CPA produced a significant fall in mean arterial pressure and heart rate. Microinjection of DuP 753 produced a pressor effect comparable to bilateral injection of vehicle. These results indicate that, although Ang II acts in the VLM through an AT1 receptor subtype, the cardiovascular effects produced by microinjection of Ang-(1-7) into the RVLM and CPA are mediated by a specific angiotensin receptor (AT5?). Furthermore, our data provide evidence that endogenous Ang-(1-7) participates at the VLM in the neural control of arterial blood pressure.

Cardiovascular effects produced by micro-injection of angiotensin-(1–7) on vasopressor and vasodepressor sites of the ventrolateral medulla

In this study, we determined the cardiovascular effects produced by micro-injection of the heptapeptide Angiotensin-(1-7) [Ang-(1-7)] into the rat ventrolateral medulla (VLM). Micro-injection of Ang-(1-7) into the rostral VLM and the caudal pressor area of the VLM produced significant increases in arterial pressure, comparable to that observed with micro-injection of Ang II. The changes in arterial pressure were associated with more variable changes in heart rate (HR) (usually tachycardia). On the other hand, micro-injection of Ang-(1-7) into the caudal depressor area induced decreases in arterial pressure and HR. The results suggest that, besides Ang II, Ang-(1-7) is involved in the mediation of the cardiovascular actions of the renin-angiotensin system in the VLM.

Guidelines for the diagnosis and treatment of schistosomal myeloradiculopathy

Schistosomal myeloradiculopathy is the most severe and disabling ectopic form of Schistosoma mansoni infection. The prevalence of SMR in centres in Brazil and Africa that specialise in attending patients with non traumatic myelopathy is around 5%. The initial signs and symptoms of the disease include lumbar and/or lower limb pain, paraparesis, urinary and intestinal dysfunctions, and impotence in men. The cerebrospinal fluid of SMR patients shows an increase in protein concentration and in the number of mononuclear cells in 90% of cases; eosinophils have been reported in 40%. The use of magnetic resonance imaging is particularly valuable in the diagnosis of Schistosomal myeloradiculopathy. The exclusion of other myelopathies and systemic diseases remains mandatory. Early diagnosis and treatment with steroids and schistosomicides provide a cure for most patients, whilst delayed treatment can result in irreversible physical disabilities or death. To improve awareness concerning Schistosomal myeloradiculopathy amongst public health professionals, and to facilitate the control of the disease, the Brazilian Ministry of Health has launched a program of education and control of this ectopic form of schistosomiasis. The present paper reviews current methods for the diagnosis of SMR and outlines protocols for treatment of the disease.

Treatment of Schistosomal Myeloradiculopathy with Praziquantel and Corticosteroids and Evaluation by Magnetic Resonance Imaging: A Longitudinal Study

BACKGROUND The best treatment for schistosomal myeloradiculopathy (SMR) remains undefined. There is also no longitudinal study to estimate the value of magnetic resonance imaging (MRI) in the diagnosis and follow-up of this disease. METHODS Patients with the following presentation were considered for study: lumbar and/or lower limb pain; lower limb weakness; anesthesia, hypoesthesia, or paresthesia; bladder and/or intestinal dysfunction; and sexual impotence. Sixteen patients with SMR were treated with oral praziquantel (50 mg/kg in a single dose) and methylprednisolone (15 mg/kg/day intravenously for 5 days) followed by prednisone (1 mg/kg/day orally for 6 months). Clinical outcome was prospectively evaluated in months 2 and 6 of treatment. RESULTS Image alterations were detected by MRI at diagnosis for all patients, and normalization or improvement was reported at the end of treatment. There was statistically significant clinical melioration at both the second and sixth months of therapy for most neurological alterations. However, the best clinical outcome was achieved when the steroid was given for >2 months. CONCLUSIONS Treatment with praziquantel associated with corticosteroids was successful in all cases. MRI proved to be a good method for the diagnosis of SMR and helpful in the evaluation of response to treatment.

Morbidity of schistosomiasis mansoni in the state of Minas Gerais, Brazil

From 2002 to 2005, a program of active search for patients with hepatosplenic schistosomiasis and schistosomal myeloradiculopathy has been implemented in the state of Minas Gerais by the local Health Department. The state was divided in 28 regional health centers and the local representatives have been trained to identify and direct patients with hepatosplenic schistosomiasis and neuroschistosomiasis to a reference center in Belo Horizonte, the capital of the state of Minas Gerais. Seventy five patients with hepatosplenic schistosomiasis and 54 with schistosomal myeloradiculopathy have been referred and examined in the reference center in a period of time of 3 years. Schistosomal myeloradiculopathy should be emphasized because the number of cases reported is increasing rapidly and when timely diagnosed and treated, they respond promptly to treatment. Left untreated, they die or become invalid for life. In our view, the time has come for more active investigation of the different aspects of morbidity caused by schistosomiasis mansoni in Brazil.

Serum and cerebral spinal fluid levels of chemokines and Th2 cytokines in Schistosoma mansoni myeloradiculopathy

Schistosomal myeloradiculopathy (SMR) is the most common neurological form of Schistosoma mansoni infection. In this study we investigated the expression of chemokines and Th2 cytokines in serum and cerebral spinal fluid (CSF) of SMR patients. SMR patients presented increased serum levels of CCL11/eotaxin and CCL24/eotaxin‐2 when compared to controls. SMR patients also had higher levels of IL‐13 in CSF. Thus, SMR patients present enhancement of both IL‐13 and CCR3 acting chemokines, both of which may facilitate the expression of a Th2 response and Th2‐dependent damage to the spinal cord. As this cytokine is responsible for promoting Th2 responses, this finding is in accordance to the view that Th2 cells are important in the immunological process against the S. mansoni.

Ultrasound in schistosomiasis mansoni

We reviewed ultrasound features in patients with schistosomiasis mansoni. The alterations that we observed in acute and hepatosplenic schistosomiasis are described. The advantages and disadvantages of using ultrasound patterns in the evaluation of liver fibrosis are discussed. Other diseases that are important in the differential diagnosis of schistosomal liver fibrosis are presented. Ultrasound is an effective and flexible diagnostic tool in the evaluation of a variety of diseases. It presents no harmful effects to patients, allowing non-invasive studies in hospitalized patients and in other facilities.

Schistosomiasis control program in the state of Minas Gerais in Brazil

The Schistosomiasis Control Program (PCE) was implemented in Minas Gerais (MG) in 1984. In 1999, the state started the investigation and control of schistosomiasis in 470 municipalities. The aim of the present paper is to report the evolution of this Program from 1984-2007. The program included a coproscopic survey carried out in the municipalities of known endemic areas using a quantitative method. Positives were treated with praziquantel and given a program of health education. The information for this study was obtained from data collected and stored by the Health State Department. From 2003-2007, 2,643,564 stool examinations resulted in 141,284 positive tests for Schistosoma mansoni (5.3%). In the first evaluation after treatment, a decrease in the number of municipalities with prevalence over 10% was documented. In one village, selected for a more detailed evaluation, the percentage of positive tests decreased from 14.9% in the baseline survey to 5.3% after treatment. A reference centre for patients with severe schistosomiasis was created in Belo Horizonte, MG. Based on our findings, we believe that the implementation of PCE in MG is on the right path and in due time these new initiatives will provide desirable results.

Aspartate aminotransferase to platelet ratio index and blood platelet count are good markers for fibrosis evaluation in schistosomiasis mansoni

The assessment of periportal fibrosis is of major importance in determining strategies, prognosis and risk for complications in schistosomiasis mansoni . For the last 2 decades, abdominal ultrasound has been used as the gold standard for the evaluation of liver fibrosis in schistosomiasis mansoni , because hepatic biopsy has been shown to have low sensitivity in diagnosing advanced schistosomiasis. However, ultrasound has disadvantages: 1. it is expensive; 2. it takes several months of training for the examiner to learn and apply WHO’s protocol for ultrasound in schistosomiasis; 3. it is a subjective procedure and, thence, examiner-dependent. It would be of interest to find a non-invasive, simpler routine laboratory test, to accurately evaluate liver fibrosis in schistosomiasis mansoni. In the last 5 years several non-invasive indexes have been proposed for predicting the degree of fibrosis in viral hepatitis. The aspartate aminotransferase to platelet ratio index (APRI) was found to exhibit a high degree of accuracy in identifying presence of significant fibrosis and cirrhosis in patients with chronic hepatitis C. APRI is obtained using the following formula: