Leishmaniasis treatment—a challenge that remains: a review

Leishmaniasis is a disease caused by flagellate protozoan Leishmania spp. and represents an emergent illness with high morbidity and mortality in the tropics and subtropics. Since the discovery of the first drugs for Leishmaniasis treatment (i.e., pentavalent antimonials), until the current days, the search for substances with antileishmanial activity, without toxic effects, and able to overcome the emergence of drug resistant strains still remains as the current goal. This article reports the development of new chemotherapies through the rational design of new drugs, the use of products derived from microorganisms and plants, and treatments related to immunity as new alternatives for the chemotherapy of leishmaniasis.     

Malarial anaemia: a crossroad?

Despite the apparent frailty of a complex cycle, Plasmodium falciparum seems remarkably fit in its ability to escape human interventions. The red blood cell is central in a number of aspects of the cycle. Hence, hematocrit reduction is of paramount importance in vector survival and reproduction, gametocyte induction and infectiousness, and host pathology. Here, in the light of recent observations, the importance of anemia for P. falciparum is emphasized, suggesting that among populations at risk for malaria, the subgroup of anemic patients may be preferential amplifiers of the plasmodial cycle.     

Rag-1: a topoisomerase?

Recombination activating genes Rag-1 and Rag-2 were isolatedon the basis of their ability to confer V(D)J recombinationactivity when co-expressed in fibroblasts. The mode of actionof the products of these genes is not known. Based on sequencecomparison data, it was suggested that Rag-1 protein could actlike a topoisomerase and that tyroslne in position 998 couldbe the active site tyrosine. We tested this hypothesis by introducinga point mutation on the Rag-1 cDNA, transforming the tyrosinecodon into a phenylalanine codon. We show that the mutationhas no effect on site specific recombination implying that Tyr-998is not essential for the recombination reaction.     

SIDS: a pathophysiologic solution?

Recent massive reductions in SIDS cases, world-wide, since the introduction of parental advice to sleep infants in the supine position, has the epidemiologic value of eliminating some hypotheses and strengthening others. A pathophysiologic cause of death now seems likely rather than a pathologic one. Without the characteristic morbidity consistent in disease, epidemiologically identified risk factors may assume primary importance. However, this hypothesis suggests that in addition to such risks, there may be an unrecognised pathologic condition in some infants which potentiates susceptibility.     

Thymocytes self-renewal: a major hope or a major threat?

Thymus transplants were never used to correct T-cell intrinsic deficiencies, as it is generally believed that thymocytes have short intrinsic lifespans. This notion is based on multiple thymus transplantation experiments, where it was shown that thymus-resident cells were rapidly replaced by progenitors migrating from the bone marrow (BM). This substitution occurs even when bone marrow precursors are unable to generate T cells, as in Rag1/2⁻ or severe combined immunodeficiency (SCID)-deficient mice. In contrast, two groups reported that neonatal thymi transplanted into mice that cannot respond to IL-7 harbor populations with extensive capacity to self-renew, which maintain continuous thymocyte generation for several months after surgery. The consequences of this self-renewal capacity differed in these two laboratories. We found that these thymus transplants rapidly reconstitute the full diversity of peripheral T-cell repertoires 1 month after surgery, the earliest time point studied. Moreover, transplantation experiments performed across major histocompatibility barriers show that allogeneic-transplanted thymi are not rejected, and allogeneic cells do not induce graft-versus-host disease, both syngeneic and allogeneic transplants inducing rapid protection from infection. These results indicate a potential use of neonatal thymus transplants to correct T-cell intrinsic deficiencies. The other group observed that continuous thymocyte renewal from BM precursors was fundamental to prevent tumor development. In the absence of this input, thymocytes from the transplanted thymus generated tumors with all the characteristics of T-cell acute lymphoblastic leukemia (T-ALL). Moreover, they suggested that the absence of BM competition was responsible for the T-ALLs developing in X-linked severe combined immunodeficiency (SCID)-X1 patients, deficient in the expression of IL2-Rγ_c. These patients were treated with autologous CD34⁺ cells transfected with virus vectors expressing γ_c in the absence of myeloablation. We here review the potential therapeutic impact of thymus transplantation and compare the results of these two laboratories aiming to find an answer to the ‘Dr Jekill versus Mr. Hyde’ status of thymus transplantation experiments.     

Polycystic ovary syndrome: a hypothalamic or a gonadal anomaly?

Evidence obtained from the study of polycystic ovarian disease in the female is reviewed. The etiology of this problem remains unknown, in spite of advances achieved by means of biochemical and morphologic studies. No correlation has been observed between histological findings and the pituitary or gonadal hormone production. However, an abnormal hypothalamic-pituitary-gonadal interaction prevails, characterized by a increased LH-FSH ratio associated with high level of androgens, mainly androstenedione. The pituitary reserve test performed with potent GnRH agonists have confirmed the hyper-response of LH along with that of androstenedione, as well as augmentation of 17-hydroxyprogesterone. Since the pattern of gonadotropins and steroid hormone secretion in women with polycystic ovarian disease resembles that seen in normal men, the basic alteration may well consist in a functionally "masculinized" hypothalamus.     

Galactose-1-phosphate is a regulator of inositol monophosphatase: a fact or a fiction?

Classic galactosemia is due to the deficiency of galactose-1-phosphate uridyl transferase and is transmitted as an autosomal recessive disorder. Patients suffering from classic galactosemia display acute symptoms such as poor growth, feeding difficulties, jaundice, hepatomegaly etc., which disappear when the individual is on galactose free diet. However, these patients continue to suffer from defects such as neurological disturbances and ovarian dysfunction, due to the accumulation of galactose-1-phosphate, which is a normal intermediate of galactose metabolism. The biochemical mechanism of galactose-1-phosphate mediated toxicity is still an enigma. Recent experiments strongly suggest that galactose-1-phosphate is also a substrate for inositol monophosphatase (IMPase). Phosphatidylinositol bisphosphate [PI(P)2] dependent signaling serves as a second messenger for several neurotransmitters in the brain. Therefore, the brain is critically dependent on IMPase for the supply of free inositol in order to sustain [PI(P)2] signaling. Circumstantial evidence strongly supports the possibility that being a substrate, galactose-1-phosphate could modulate IMPase function in vivo. The implication of this idea is discussed in relation to classic galactosemia as well as bipolar disorder, which has been thought to be due to the hyper-activation of [PI(P)2] mediated second messenger pathways(s).     

Hydrogel biomaterials: a smart future?

Hydrogels were the first biomaterials developed for human use. The state-of-the-art and potential for the future are discussed. Recently, new designs have produced mechanically strong synthetic hydrogels. Protein-based hydrogels and hybrid hydrogels containing protein domains present a novel advance; such biomaterials may self-assemble from block or graft copolymers containing biorecognition domains. One of the domains, the coiled coil, ubiquitously found in nature, has been used as an example to demonstrate the developments in the design of smart hydrogels. The application potential of synthetic, protein based, DNA based, and hybrid hydrogels bodes well for the future of this class of biomaterials.