The importance of a shared vision in emergency preparedness: engaging partners in a home-rule state

This article discusses the importance of having a strong vision and culture within the context of emergency preparedness in a home-base state. It proposes a broader vision of public health, one that places public health emergency preparedness and response squarely at the center of the public health mission as a core function. It also lays out work currently underway and the future direction for maximizing the value of response-oriented partnerships at the state and local levels in the Evergreen State. The role of health care professionals and dental providers is specified in more detail. Broadening the public health vision requires recognition of the importance of multisectorial partnerships and their response potential, including the potential roles of all health-related professions and the development of systems to use that potential effectively.     

Arylimidamide DB766, a Potential Chemotherapeutic Candidate for Chagas' Disease Treatment

Chagas'' disease, a neglected tropical illness for which current therapy is unsatisfactory, is caused by the intracellular parasite Trypanosoma cruzi. The goal of this work is to investigate the in vitro and in vivo effects of the arylimidamide (AIA) DB766 against T. cruzi. This arylimidamide exhibits strong trypanocidal activity and excellent selectivity for bloodstream trypomastigotes and intracellular amastigotes (Y strain), giving IC₅₀s (drug concentrations that reduce 50% of the number of the treated parasites) of 60 and 25 nM, respectively. DB766 also exerts striking effects upon different parasite stocks, including those naturally resistant to benznidazole, and displays higher activity in vitro than the reference drugs. By fluorescent and transmission electron microscopy analyses, we found that this AIA localizes in DNA-enriched compartments and induces considerable damage to the mitochondria. DB766 effectively reduces the parasite load in the blood and cardiac tissue and presents efficacy similar to that of benznidazole in mouse models of T. cruzi infection employing the Y and Colombian strains, using oral and intraperitoneal doses of up to 100 mg/kg/day that were given after the establishment of parasite infection. This AIA ameliorates electrocardiographic alterations, reduces hepatic and heart lesions induced by the infection, and provides 90 to 100% protection against mortality, which is similar to that provided by benznidazole. Our data clearly show the trypanocidal efficacy of DB766, suggesting that this AIA may represent a new lead compound candidate to Chagas'' disease treatment.Chagas'' disease (CD) is a neglected tropical illness that affects at least 12 million people in areas of disease endemicity in Latin America, where 50 million people are at risk of infection (22-24). In addition, many reports show that the occurrence of CD in areas where the disease is not endemic, such as the United States and Europe, is attributed mainly to the migration of infected people (30, 31, 50). The etiological agent is the intracellular obligatory parasite Trypanosoma cruzi, a hemoflagellate protozoan that presents a complex life cycle with distinct morphological stages in its obligatory passage through vertebrate and invertebrate hosts (63). CD can be transmitted by Triatominae insect feces, blood transfusion, organ transplantation, laboratory accidents, and oral and congenital routes (42, 66). It has the following two successive phases: a short acute phase characterized by a patent parasitemia, followed by a long progressive chronic phase that included mainly cardiac and/or digestive alterations (7, 61). The current therapy for CD comprised of nifurtimox (Nif) (5-nitrofurane, Bayer 2502; Bayer, Germany) and benznidazole (Bz) (2-nitroimidazole; Laboratório Farmacêutico do Estado de Pernambuco [LAFEPE], Brazil) has limitations, including long treatment periods, occurrence of side effects, variable results, and low efficacy during the chronic phase, which justify the search for new drugs (60, 69). Although Bz is not an ideal drug, it arrests electrocardiographic alterations, reduces progression of the disease, and protects the patients against deterioration of the clinical condition (70).Aromatic diamidines (AD) and analogues target the minor groove of DNA and represent a promising class of antiparasitic agents (58, 65, 72). AD and their congeners present broad-spectrum activity against pathogenic microorganisms, and some of them have veterinary and human clinical uses {e.g., pentamidine isethionate [1,5-bis(4-amidino-phenoxy)pentane] (Pentacarinat; Rhodia)} (45, 57, 72). However, these compounds often cause considerable side effects and require parenteral routes of administration, which stimulates the synthesis and screening of new analogs and prodrugs to overcome these limitations (19, 34, 56, 59). The effect of several AD analogues was demonstrated against T. cruzi, and among them, significant in vitro activity was found for arylimidamides (AIAs), including DB889, DB786, and DB702 (46, 54, 55). Also, diamidines protect against mortality in mouse experimental models of acute T. cruzi infection (15, 19).In the present work, our goal was to evaluate in vitro and in vivo the activity of a new synthesized AIA, DB766, against T. cruzi. Our data showed the excellent trypanocidal effect of DB766 upon different forms and strains of the parasite, displaying efficacy similar to that of benznidazole in mouse experimental models of acute infection. Our results suggest that this AIA as well as other compounds of this class represent very promising candidates for Chagas'' disease treatment.     

Spinal cord microglia in experimental allergic neuritis. Evidence for fast and remote activation.

We have studied the response and the spatial distribution pattern of microglial cells during experimental allergic neuritis induced in the Lewis rat by the transfer of varying doses of activated T cells specific either for the P2 or P0 protein. The microglial reaction was studied immunocytochemically at the light and electron microscopic level using a panel of monoclonal antibodies which included two recently produced antibodies against rat microglial cells, Murine Clone 101 and 102. Activation of microglial cells became apparent through changes in their immunophenotype and morphology within 48 hours of T cell transfer and therefore preceded the onset of clinical disease. Activated microglial cells showed an increased expression of the complement type three receptor, the murine clone 101 and 102 determinants and major histocompatibility complex antigens. The microglial reaction in experimental allergic neuritis occurs at a site remote from the inflammatory changes in the peripheral nerve, the microglial reaction being most prominent in the dorsal and ventral grey matter of the lumbar and the thoracic spinal cord. Similar changes were also observed at this time in the terminal projection fields of the primary, afferent, sensory fibers, such as the nucleus gracilis. Subsequently, after 7 days, motoneurons, particularly in the ventral grey matter of the lumbar spinal cord, were ensheathed by perineuronal microglial cells. These perineuronal microglial cells were in close contact with the neuronal plasma membrane and occasionally appeared to detach afferent synaptic terminals from the surface. Microglial responses were not detected in animals injected with nonpathogenic T cells specific either for the purified protein derivative or ovalbumin. This early activation of microglial cells observed in experimental allergic neuritis suggests that a rapid and remote signaling might be operating in the microglial responses during T cell-mediated autoimmune diseases.     

Trypanosoma cruzi-triggered meningoencephalitis is a CCR1/CCR5-independent inflammatory process

Encephalitis rarely occurs during acute Trypanosoma cruzi infection. However, the central nervous system (CNS) is the major site of infection reactivation in immunocompromised patients. We show that the acute T. cruzi-triggered CD8-enriched meningoencephalitis paralleled the in situ expression of CCL3/MIP-1alpha and CCL5/RANTES mRNA. The frequency of CCR5-bearing cells was increased among peripheral blood mononuclear cells (PBMC) of infected mice. Further, CCL5/RANTES-driven in vitro PBMC migration was partially abrogated by the CCR1/CCR5 antagonist Met-RANTES. However, Met-RANTES treatment of infected mice altered neither parasitism nor intensity and nature of the CNS inflammation, indicating that T. cruzi-elicited meningoencephalitis is a CCR1/CCR5 independent process.     

Trypanosoma cruzi-induced depressive-like behavior is independent of meningoencephalitis but responsive to parasiticide and TNF-targeted therapeutic interventions

Inflammatory cytokines and microbe-borne immunostimulators have emerged as triggers of depressive behavior. Behavioral alterations affect patients chronically infected by the parasite Trypanosoma cruzi. We have previously shown that C3H/He mice present acute phase-restricted meningoencephalitis with persistent central nervous system (CNS) parasitism, whereas C57BL/6 mice are resistant to T. cruzi-induced CNS inflammation. In the present study, we investigated whether depression is a long-term consequence of acute CNS inflammation and a contribution of the parasite strain that infects the host. C3H/He and C57BL/6 mice were infected with the Colombian (type I) and Y (type II) T. cruzi strains. Forced-swim and tail-suspension tests were used to assess depressive-like behavior. Independent of the mouse lineage, the Colombian-infected mice showed significant increases in immobility times during the acute and chronic phases of infection. Therefore, T. cruzi-induced depression is independent of active or prior CNS inflammation. Furthermore, chronic depressive-like behavior was triggered only by the type I Colombian T. cruzi strain. Acute and chronic T. cruzi infection increased indoleamine 2,3-dioxygenase (IDO) expression in the CNS. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine abrogated the T. cruzi-induced depressive-like behavior. Moreover, treatment with the parasiticide drug benznidazole abrogated depression. Chronic T. cruzi infection of C57BL/6 mice increased tumor necrosis factor (TNF) expression systemically but not in the CNS. Importantly, TNF modulators (anti-TNF and pentoxifylline) reduced immobility. Therefore, direct or indirect parasite-induced immune dysregulation may contribute to chronic depressive disorder in T. cruzi infection, which opens a new therapeutic pathway to be explored.     

Comparison of IgG reactivities to Plasmodium vivax merozoite invasion antigens in a Brazilian Amazon population

Naturally acquired antibody reactivity to two major Plasmodium vivax vaccine candidates was investigated in 294 donors from three malaria-endemic communities of Rond?nia state, Brazil. Antibody recognition of recombinantly expressed antigens covering five different regions of P. vivax reticulocyte binding protein 1 (PvRBP1) and region II of P. vivax Duffy binding protein (PvDBP-RII) were compared. Positive IgG responses to these antigens were significantly related to the level of malaria exposure in terms of past infections and years of residence in the endemic area when corrected for age. The highest prevalence of anti-PvRBP1 total IgG antibodies corresponded to the amino acid regions denoted PvRBP1(431-748) (41%) and PvRBP1(733-1407) (47%). Approximately one-fifth of positively responding sera had titers of at least 1:1,600. Total IgG responses to PvDBP-RII were more prevalent (67%), of greater magnitude, and acquired more rapidly than those to individual PvRBP1 antigens. Responses to both PvRBP1 and PvDBP-RII were biased toward the cytophilic subclasses IgG1 and IgG3. These data provide the first insights on acquired antibody responses to PvRBP1 and a comparative view with PvDBP-RII that may prove valuable for understanding protective immune responses to these two vaccine candidates as they are evaluated as components of multitarget blood-stage vaccines.     

Infection with Toxoplasma gondii increases atherosclerotic lesion in ApoE-deficient mice

Toxoplasma gondii is an intracellular protozoan that elicits a potent inflammatory response during the acute phase of infection. Herein, we evaluate whether T. gondii infection alters the natural course of aortic lesions. ApoE knockout mice were infected with T. gondii, and at 5 weeks of infection, serum, feces, and liver cholesterol; aortic lesion size, cellularity, and inflammatory cytokines; and levels of serum nitrite and gamma interferon (IFN-gamma) were analyzed. Our results showed that serum cholesterol and atherogenic lipoproteins were reduced after T. gondii infection. The reduction of serum levels of total cholesterol and atherogenic lipoproteins was associated with increases in the aortic lesion area, numbers of inflammatory cells, and expression of monocyte chemoattractant protein 1 and inducible nitric oxide synthase mRNA in the site of lesions as well as elevated concentrations of IFN-gamma and nitrite in sera of T. gondii-infected animals. These results suggest that infection with T. gondii accelerates atherosclerotic development by stimulating the proinflammatory response and oxidative stress, thereby increasing the area of aortic lesion.     

Essential role of VLA-4/VCAM-1 pathway in the establishment of CD8+ T-cell-mediated Trypanosoma cruzi-elicited meningoencephalitis

Central nervous system (CNS) damage can occur during Trypanosoma cruzi infection, especially in immunosuppressed patients. The enhanced susceptibility of C3H/He mice to CD8-mediated acute meningoencephalitis is associated with higher up-regulation of vascular cell adhesion molecule-1 (VCAM-1) on CNS vascular endothelia than in the less susceptible C57BL/6. Further, in vitro adhesion of activated peripheral blood cells to CNS blood vessels was abrogated by anti-VLA-4 antibodies that also inhibited cell migration into the CNS of T. cruzi-infected mice. Lastly, the reactivation of meningoencephalitis in immunosuppressed chronically infected mice was associated with VCAM-1 up-regulation. Therefore, we hypothesize that VLA-4/VCAM-1 pathway plays a pivotal role in the establishment of T. cruzi-elicited encephalitis.     

In vivo glioblastoma growth is reduced by apyrase activity in a rat glioma model

Background  

ATP is an important signalling molecule in the peripheral and central nervous system. Both glioma growth and tumor resection induces cell death, thus liberating nucleotides to the extracellular medium. Nucleotides are hydrolyzed very slowly by gliomas when compared with astrocytes and induce neuronal cell death and glioma proliferation. The objective of the present study was to test the involvement of extracellular ATP in glioblastoma growth in a rat glioma model.