Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts

Albaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease, using dogs as hosts. The T. cruzi strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with T. cruzi strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas' disease.     

Effects of specific treatment on parasitological and histopathological parameters in mice infected with different Trypanosoma cruzi clonal genotypes

The goal of this study was to verify the effect of specific treatment on parasitological and histopathological parameters in mice experimentally infected with different Trypanosoma cruzi clonal genotypes. Twenty cloned stocks were selected, representative of the whole phylogenetic diversity of the protozoan and belonging to the clonal genotypes 19 and 20 (T. cruzi I) and 39 and 32 (T. cruzi II). The stocks were inoculated in 40 BALB/c mice divided into four groups: (i) treated with benznidazole, (ii) treated with itraconazole and (iii and iv) untreated control groups (NT) for each drug, respectively. Seven parameters related to parasitaemia curves and histopathological lesions were analysed. Four during the acute phase (AP) and three during both the AP and chronic phase (CP) of infection. Statistical comparison between benznidazole-treated and NT groups for the biological parameters showed significant differences for all genotypes. Benznidazole treatment led to lower patent period, maximum of parasitaemia, day of maximum parasitaemia and area under the parasitaemia curve for all genotypes analysed. Percentage of positive haemoculture during AP and CP was lower for genotypes 19 and 32. Tissue parasitism (TP) and inflammatory process (IP) during AP were lower for genotypes 19 and 32, respectively. In general, itraconazole treatment induced a smaller reduction in these same parameters between treated and NT animals in relation to benznidazole treatment. Our results indicate that phylogenetic divergence among T. cruzi clonal genotypes must be taken in account in chemotherapy and studies dealing with all aspects of the parasite and the disease.     

Features of primary vesicoureteral reflux and renal damage in children at a single institution in Brazil from 1969 to 1999

OBJECTIVES: The purpose of the study was to evaluate the clinical/radiological features of patients with primary vesicoureteral reflux (VUR) admitted to a single institution from 1969 to 1999. METHODS: The patients' records were retrospectively reviewed and the following clinical data obtained at admission were analyzed: age, gender, race, date of entry, previous symptoms, weight, height, blood pressure, and serum renal function. The renal imaging tests at baseline were also retrospectively analyzed including voiding cystourethrography, excretory urography, DMSA scan, and ultrasonography. For statistical analysis, reflux was classified into two categories: (1) mild/moderate (grade I/II/III) and (2) severe (grade IV/IV). Renal damage was categorized according to the following classification: (I) mild, focal damage; (II) moderate, more extensive scars, and (III) severe, generalized damage or shrunken kidney. The odds ratio (OR) and the respective confidence interval (95%CI) were calculated to compare the difference in risk between groups. RESULTS: A total of 461 patients were enrolled in the protocol. There was a predominance of female gender (71%) and white race (73%). Mean age at VUR diagnosis was 2.8 y and 93% of the patients had urinary infection before admission. Bilateral reflux was diagnosed in 249 (54%) children, for a total of 710 renal units for study. The distribution of reflux grade was as follows: grade I (7%); II (36%); III (26%); IV (23%), and V (8%). Of the 450 children investigated, 180 (40%) presented with renal damage, for a total of 234 (26%) units with renal scars. Renal damage was associated with the following factors: Diagnosis after 2 y of age (OR = 1.5, 95%CI = 1.08-2.1, p = 0.01), severe degree of reflux (OR = 6, 95%CI = 4-9, p < 0.001). There was a significant risk of severe renal damage for male gender (OR = 1.9, IC95% = 1.3-2.1, p = 0.001). CONCLUSION: There was a predominance of renal damage in children diagnosed above 2 y and with a high degree of reflux. Severe renal damage was associated with male gender.     

Primary progressive aphasia: analisys of 16 cases

Primary progressive aphasia (PPA) is an intriguing syndrome, showing some peculiar aspects that differentiate it from classical aphasic pictures caused by focal cerebral lesions or dementia. The slow and progressive deterioration of language occurring in these cases provides an interesting model to better understand the mechanisms involved in the linguistic process. We describe clinical and neuroimaging aspects found in 16 cases of PPA. Our patients underwent language and neuropsychological evaluation, magnetic resonance imaging (MRI) and single photon emission computerized tomography (SPECT). We observed a clear distinction in oral expression patterns; patients were classified as fluent and nonfluent. Anomia was the earliest and most evident symptom in both groups. Neuroimaging pointed to SPECT as a valuable instrument in guiding the differential diagnosis, as well as in making useful clinical and anatomical correlations. This report and a comparison to literature are an attempt to contribute to a better understanding of PPA.     

Control of the efficiency of agonist-induced information transfer and stability of the ternary complex containing the delta opioid receptor and the alpha subunit of G(i1) by mutation of a receptor/G protein contact interface

Fusion proteins were constructed between the delta opioid receptor and forms of the alpha subunit of G(i1) in which cysteine(351) was mutated to a range of amino acids. GDP reduced the binding of the agonist [(3)H]DADLE but not the antagonist [(3)H]naltrindole to both the receptor alone and all the delta opioid receptor-Cys(351)XaaG(i1)alpha fusion proteins. For the fusion proteins the pEC(50) for GDP was strongly correlated with the n-octanol/H(2)O partition co-efficient of G protein residue(351). Fusion proteins in which this residue was either isoleucine or glycine had similar observed binding kinetics for [(3)H]DADLE. However, the rate of dissociation of [(3)H]DADLE was substantially greater for the glycine-containing fusion protein than that containing isoleucine, indicating that more hydrophobic residues imbued greater stability to the agonist-receptor-G protein ternary complex. This resulted in a higher affinity of binding of [(3)H]DADLE to the fusion protein containing isoleucine(351). In expectation with the binding data, maximal DADLE-stimulated GTP hydrolysis by the isoleucine(351)-containing fusion protein was two-fold greater and the potency of DADLE seven-fold higher than for the version containing glycine.These results demonstrate that the stability of the ternary complex between delta opioid receptor, G(i1)alpha and an agonist (but not antagonist) ligand is dependent upon the nature of residue(351) of the G protein and that this determines the effectiveness of information flow from the receptor to the G protein.     

The barrel field of the adult mouse SmI cortex as revealed by NADPH-diaphorase histochemistry

The main goal of the present work was to investigate the pattern of NADPH-diaphorase activity in the somatosensory cortex of the adult mouse. Our results show that this enzyme, which is responsible for the production of the neuronal messenger nitric oxide, is abundant within the neuropil of SmI cortex, revealing the complete pattern of barrel fields. A previous study, however, had reported that NADPH-diaphorase reactivity within the barrels was transient, disappearing after the second postnatal week. We hypothesize that the massive occurrence of NADPH-diaphorase in the barrel fields of the adult mouse brain is related to the potential for plastic changes in the somatosensory cortex that is maintained throughout maturity.     

Prevalence of celiac disease in Brazilian children with type 1 diabetes mellitus

OBJECTIVE: Although the relationship between celiac disease and diabetes mellitus type 1 is well recognized, there are no studies of this association in Brazil. This study aims to identify the prevalence of celiac disease in a group of children with diabetes mellitus type 1 undergoing treatment in the pediatric endocrinology division of a university hospital in Minas Gerais, Brazil. METHODS: Immunoglobulin (Ig)A and IgG antigliadin antibodies (enzyme-linked immunoadsorbent assay) were measured in blood collected from 236 children and adolescents with diabetes mellitus type 1. Patients with antigliadin antibodies then had jejunal biopsy and determination of antiendomysial antibodies by indirect immunofluorescence. RESULTS: Twenty-one patients had IgA or IgG antigliadin antibodies. Nineteen underwent jejunal biopsy. Six had mucosal alterations compatible with celiac disease; four had nonspecific histologic changes; nine had normal biopsies. Thirteen antigliadin antibody-positive patients were antiendomysial antibody-negative; one antiendomysial antibody-negative patient had celiac disease. The prevalence of celiac disease was 2.6% among 234 patients. CONCLUSIONS: Measurement of antigliadin antibodies in patients with diabetes mellitus type 1 helped in the selection of patients to undergo jejunal biopsy. Antiendomysial antibodies were highly specific and moderately sensitive in predicting celiac disease. The prevalence of celiac disease was higher in diabetics than in the general population, suggesting the need for regular screening assessment of diabetic children.