Prodrugs for the treatment of neglected diseases

Recently, World Health Organization ( WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people, mainly in developing countries, die each year from infectious diseases. From 1975 to 1999, 1393 new drugs were approved yet only 1% were for the treatment of neglected diseases [ 3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas' disease ( American trypanosomiasis), sleeping sickness ( African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis.

Experimental and theoretical studies on the enhanced photoluminescence activity of zinc sulfide with a capping agent

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A Study of the Effect of Nitrogen and Air Plasma Immersion Ion Implantation Treatments on the Properties of Carbon Fiber

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Mecanismos de alojamento de magmas granitóides :exemplo do plúton de Japi(RN)

This dissertation describes the igneous suites of the Japi granitoid pluton, intrusive in the Paleoproterozoic gneiss-migmatite complex of the eastern domain of the Seridó Belt, northeastern Brazil. Field relations show that the pluton is affected by strong deformation associated to the Brasiliano orogeny (known as the D3 phase) , with a NW-trending extensionalleft-hand senestral shear zone (the Japi Shear Zone, JSZ) bordering the intrusive body to the west. Four plutonic suites are found in the main pluton and as satellyte intrusions, besides Iate pegmatite and pink leucogranites. An alkaline granitoid suite, dominated by syenogranites bearing sodic augite (and subordinate hornblende), define a main elliptical intrusion. In its northern part, this intrusion is made up by concentric sheets, contrasting with a smaller rounded stock to the south. These granites display a pervasive solid-state S>L fabric developed under high T conditions, characterized by plastic deformation of quartz and feldspar. It is especially, developed along the border of the pluton, with inward dips. A regular magmatic layering is present sometimes, parallel to the tectonic foliation. The syntectonic emplacement as regards to the Brasiliano (D3) event is indicated by the common occurrence of dykes and sheets along transtensional or extensional sites of the major structure. Field relations attest to the early emplacement of the alkaline granites as regards to the other suites. A basic-to-intermediate suite occurs as a western satellyte body and occupying the southern tail of the main alkaline pluton. It comprises a wide variety of compositional terms, including primitive gabbros and gabbro-norites, differentiated to monzonitic intermediate facies containing amphibole and biotite as their main mafic phases. These rocks display transitional high-K calc-alkaline to shoshonitic affinities. Porphyritic monzogranite suítes commonly occur as dykes and minor intrusives, isolated or associated with the basic-tointermediate rocks. In the latter case, magma mingling and mixing features attest that these are contemporaneous igneous suites. These granites show K-feldspar phenocrysts and a hornblende+biotite+titanite assemblage, displaying subalkaline/monzonitic geochemical affinities. Both suites exhibit SL magmatic fabrics overprinting or transitional to solid-state D3 deformation related to the JSI. Chemical data clearly show that they are related to different parental magmas. Finally, a microgranite suite occurs along a few topographic ridges paralell to the JSI. It comprises dominantly granodiorites with a mineralogy similar to the one of the porphyritic granitoids. However, discriminant diagrams show their distinct calc-alkaline affinity. The granodiorites display an essencially magmatic fabric, even though an incipient D3 solid-state structure may be developed along the JSI. Intrusion relationships with the previous suites, as well as regards to the D3 structures, point to their Iate emplacement. All these suites are intrusive in a Paleoproterozoic, high-grade gneiss-migmatite complex affected by two previous deformation phases (D1, D2). The fabrics associated with these earlier events are folded and overprinted by the younger D3 structures along the JSZ. The younger deformation is characterized by NE-dipping foliations and N/NE-plunging stretching lineations. In the JSZ northern termination the foliation acquires an ENE orientation, containing a stretching lineation plunging to the south. Symmetric kinematic cri teria developed at this site confirms the transpressional termination of the JSZ, as also shown by orthorrombic quartz c-axis patterns. E-W-trending d extra I shear zones developed in the central part of the JSZ are interpreted as antithetic structures associated to the transtensional deformation along the JSZ. This is consistent with its extensional-transcurrent kinematics and a flat-and-ramp geometry at depth, as shown by gravimetric data. The lateral displacement of the negative residual Bouguer anomalies, as regards to the main outcropping alkaline pluton, may be modelized by other deeper-seated granite bodies. Based on numerical modelling it was possible to infer two distinct intrusion styles for the alkaline pluton. The calculated model values are consistent with an emplacement by sheeting for the northern body, as already suggested by satellyte imagery and field mapping. On the other hand, the results point to a transition towards a diapir-related style associated to the smaller. southern stock. This difference in intrusion styles may relate to intensity variations and transtensional sites of the shear deformation along the JSZ. Trace element and Sr and Nd isotopes of the alkaline granites are compatible with their derivation trom a more basic crustal source, as compared to the presently outcropping highgrade gneisses, with participation (or alternatively dominated by) of an enriched lithospheric mantle component. Like other igneous suites in the Seridó Belt, the high LlL contents and fractionated REE patterns of the basic rocks also point to an enriched mantle as the source for this kind of magmatism. Geochemical and isotope data are compatible with a lower crustal origin for the porphyritic granites. On the basis of the strong control of the JSZ on the emplacement of lower crustal (porphyritic and alkaline granites) or lithospheric mantle (basic rocks, alkaline granites or a component of them) magmas, one may infer a deep root for this structure, bearing an important role in magma extraction, transport and emplacement in the Japi region, eastern domain of the Seridó Belt

The effects of male age on sperm analysis by motile sperm organelle morphology examination (MSOME)

Background: This study aimed to investigate the influence of age on sperm quality, as analysed by motile sperm organelle morphology examination (MSOME).Methods: Semen samples were collected from 975 men undergoing evaluation or treatment for infertility. Sperm cells were evaluated at 8400x magnification using an inverted microscope equipped with Nomarski (differential interference contrast) optics. Two forms of spermatozoa were considered: normal spermatozoa and spermatozoa with large nuclear vacuoles (LNV, defined as vacuoles occupying > 50% of the sperm nuclear area). At least 200 spermatozoa per sample were evaluated, and the percentages of normal and LNV spermatozoa were determined. The subjects were divided into three groups according to age: Group I, less than or equal to 35 years; Group II, 36-40 years; and Group III, greater than or equal to 41 years.Results: There was no difference in the percentages of normal sperm between the two younger (I and II) groups (P > 0.05). The percentage of normal sperm in the older group (III) was significantly lower than that in the younger (I and II) groups (P < 0.05). There was no difference in the percentage of LNV spermatozoa between the younger (I and II) groups (P > 0.05). The percentage of LNV spermatozoa was significantly higher in the older group (III) than in the younger (I and II) groups (P < 0.05). Regression analysis demonstrated a significant decrease in the incidence of normal sperm with increasing age (P < 0.05; r = -0.10). However, there was a significant positive correlation between the percentage of spermatozoa with LNV and male age (P < 0.05, r = 0.10).Conclusion: The results demonstrated a consistent decline in semen quality, as reflected by morphological evaluation by MSOME, with increased age. Considering the relationship between nuclear vacuoles and DNA damage, these age-related changes predict that increased paternal age should be associated with unsuccessful or abnormal pregnancy as a consequence of fertilisation with damaged spermatozoa. Given that sperm nuclear vacuoles can be evaluated more precisely at high magnification, these results support the routine use of MSOME for ICSI as a criterion for semen analysis.

The Effect of Power Bleaching Actived by Several Light Sources on Enamel Microhardness

The purpose of this study was to evaluate the influence of different light sources for in-office bleaching on surface microhardness of human enamel. One hundred and five blocks of third molars were distributed among seven groups. The facial enamel surface of each block was polished and baseline Knoop microhardness of enamel was assessed with a load of 25 g for 5 s. Subsequently, the enamel was treated with 35% hydrogen peroxide bleaching agent and photo-activated with halogen light (group A) during 38 s, LED (group B) during 360 s, and high intensity diode laser (group C) during 4 s. The groups D (38 s), E (360 s), and F (4 s) were treated with the bleaching agent without photo-activated. The control (group G) was only kept in saliva without any treatment. Microhardness was reassessed after 1 day of the bleaching treatment, and after 7 and 21 days storage in artificial saliva. The mean percentage and standard deviation of microhardness in Knoop Hardness Number were: A 97.8 +/- 13.1 KHN; B 95.5 +/- 12.7 KHN; C 84.2 +/- 13.6 KHN; D 128.6 +/- 20.5 KHN; E 133.9 +/- 14.2 KHN; F 123.9 +/- 14.2 KHN; G 129.8 +/- 18.8 KHN. Statistical analysis (p < 0.05; Tukey test) showed that microhardness percentage values were significantly lower in the groups irradiated with light when compared with the non-irradiated groups. Furthermore, the non-irradiated groups showed that saliva was able to enhance the microhardness during the measurement times. The enamel microhardness was decreased when light sources were used during the bleaching process and the artificial saliva was able to increase microhardness when no light was used.

Insights into the role of oligomeric state on the biological activities of crotoxin: crystal structure of a tetrameric phospholipase A(2) formed by two isoforms of crotoxin B from Cratalus durissus terrificus venom

Crotoxin B (CB or Cdt PLA(2)) is a basic Asp49-PLA(2) found in the venom of Crotalus durissus terrificus and it is one of the subunits that constitute the crotoxin (Cro). This heterodimeric toxin, main component of the C. d. terrificus venom, is completed by an acidic, nontoxic, and nonenzymatic component (crotoxin A, CA or crotapotin), and it is related to important envenomation effects such as neurological disorders, myotoxicity, and renal failure. Although Cro has been crystallized since 1938, no crystal structure of this toxin or its subunits is currently available. In this work, the authors present the crystal structure of novel tetrameric complex formed by two dimers of crotoxin B isoforms (CB1 and CB2). The results suggest that these assemblies are stable in solution and show that Ser1 and Glu92 of CB1 and CB2, respectively, play an important role in the oligomerization. The tetrameric and dimeric conformations resulting from the association of the isoforms may increase the neurotoxicity of the toxin CB by the creation of new binding sites, which could improve the affinity of the molecular complexes to the presynaptic membrane.

Genetic differentiation among ten populations of the genus Neoplecostomus (Teleostei: Loricariidae) from the upper Parana River basin

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Monitoring the positioning of short polycationic peptides in model lipid bilayers by combining hydrogen/deuterium exchange and electrospray ionization mass spectrometry

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Colony defense behavior of the primitively eusocial wasp, Mischocyttarus cerberus is related to age

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

HB D Los Angeles in a Brazilian family

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação eletroforética, cromatográfica e molecular da Hb D Los Angeles no Brasil

A variante de hemoglobina (Hb) D mais comum, Hb D Los Angeles ou D Punjab, é originada de uma transversão GAA->CAA no códon 121 da globina beta; essa mutação resulta na substituição do ácido glutâmico por glutamina na proteína. É a terceira variante de hemoglobina mais freqüente da população brasileira. Como as hemoglobinas D apresentam migração similar à hemoglobina S em pH alcalino, e com a hemoglobina A em pH ácido, são necessários vários testes para o correto diagnóstico. No presente estudo objetivou-se relacionar os diferentes procedimentos laboratoriais de rotina diagnóstica, além da análise molecular, para estabelecer o perfil de Hb D Los Angeles no Brasil. Foram analisados 47 indivíduos da população brasileira com provável Hb D Los Angeles, por vários procedimentos eletroforéticos em diferentes condições de pH, além da cromatografia líquida de alta pressão, e testes moleculares para confirmação da mutação. Foram encontrados quatro tipos de combinações de hemoglobinas: 42 indivíduos portadores de hemoglobina AD Los Angeles, dois indivíduos com doença de Hb S/D Los Angeles, dois indivíduos com Hb D Los Angeles e talassemia beta e um indivíduo com Hb D Los Angeles e Hb Lepore. Os indivíduos heterozigotos para D Los Angeles são assintomáticos, entretanto, em associação com outras variantes e talassemias podem apresentar graus variáveis de manifestações clínicas. Os resultados apresentados enfatizaram a necessidade da associação de várias metodologias para a identificação da Hb D Los Angeles, além de auxiliar na elucidação de combinações raras.

Androgen receptor in the Mongolian gerbil ventral prostate: Evaluation during different phases of postnatal development and following androgen blockage

The normal growth, differentiation and maintenance of the morphofunctional integrity of the prostate gland are dependent on the interaction of constant levels of androgens with their receptors. The need to study the responses to hormones under several conditions and the effect of their blockage is due to the fact that the human prostate is the site of a great number of age-related diseases, and the ones with a major medical importance are prostate cancer (Cap) and benign prostatic hyperplasia (BPH), which can both be treated with androgen suppression. Seventy-five male gerbils were divided, randomly, into 3 groups of 25 animals each, where each group corresponded to one phase of postnatal development. In each phase, it was possible to morphologically and stereologically analyze the compartments of prostatic ventral lobe, as well as to immunohistochemically analyze the degree of expression of androgen receptors (ARs) after the androgen blockage therapies. In addition, it was possible to establish the hormonal dosage of serum testosterone levels given the comparative approach of the expression of androgen receptors. There is a pattern of AR distribution in the prostatic ventral lobe throughout postnatal development, in which the younger the animal is the higher, the interaction of circulating androgens that stimulate the AR expression in both the epithelial and stromal compartments. The androgen blockage therapies decreased AR expression in the prostatic compartments, but the androgen reposition after these blockages was not sufficient to recover the glandular structure or stimulate the AR expression up to normal physiological conditions. Both the regulation and distribution of androgen receptors along the gerbil prostatic tissues are complex mechanisms that are likely to be genetically regulated by androgens prenatally or by other factors that are still unknown. This rodent species seems to be a valuable model in the attempt to improve the understanding of the morphophysiological and pathological behavior of this important gland in humans throughout aging and to stimulate new therapeutic ideas to fight prostate cancer. (C) 2008 Elsevier Ltd. All rights reserved.

DNA barcode discovers two cryptic species and two geographical radiations in the invasive drosophilid Zaprionus indianus

Comparing introduced to ancestral populations within a phylogeographical context is crucial in any study aiming to understand the ecological genetics of an invasive species. Zaprionus indianus is a cosmopolitan drosophilid that has recently succeeded to expand its geographical range upon three continents (Africa, Asia and the Americas). We studied the distribution of mitochondrial DNA (mtDNA) haplotypes for two genes (CO-I and CO-II) among 23 geographical populations. mtDNA revealed the presence of two well-supported phylogenetic lineages (phylads), with bootstrap value of 100%. Phylad I included three African populations, reinforcing the African-origin hypothesis of the species. Within phylad II, a distinct phylogeographical pattern was discovered: Atlantic populations (from the Americas and Madeira) were closer to the ancestral African populations than to Eastern ones (from Madagascar, Middle East and India). This means that during its passage from endemism to cosmopolitanism, Z. indianus exhibited two independent radiations, the older (the Eastern) to the East, and the younger (the Atlantic) to the West. Discriminant function analysis using 13 morphometrical characters was also able to discriminate between the two molecular phylads (93.34 +/- 1.67%), although detailed morphological analysis of male genitalia using scanning electron microscopy showed no significant differences. Finally, crossing experiments revealed the presence of reproductive barrier between populations from the two phylads, and further between populations within phylad I. Hence, a bona species status was assigned to two new, cryptic species: Zaprionus africanus and Zaprionus gabonicus, and both were encompassed along with Z. indianus and Zaprionus megalorchis into the indianus complex. The ecology of these two species reveals that they are forest dwellers, which explains their restricted endemic distribution, in contrast to their relative cosmopolitan Z. indianus, known to be a human-commensal. Our results reconfirm the great utility of mtDNA at both inter- and intraspecific analyses within the frame of an integrated taxonomical project.

New occurrence of the rare genus Doliocatella (Stigonematales, Cyanophyceae)

A new occurrence of the genus Doliocatella (Cyanophyceae, Cyanobacteria) is reported. The type species of the genus, D. formosa, is described from a stream of the tropical Amazonian rainforest (Manaus, Amazonas State, Brazil). A detailed taxonomic description with photomicrographs and ecological characteristics are provided based on the three worldwide species records. D. formosa is characterized by the presence of uniseriate main filaments, cylindrical branches, and mostly cylindrical cells; heterocytes are absent. D. formosa occurs under limited and special conditions, i.e. habitats with low pH and relatively high temperatures. The species has a restricted ecological distribution, limited to tropical lotic ecosystems, but it is found over a relatively wide geographical range.