Serological Cross-Reactivity in Zoonotic Flaviviral Infections of Medical Importance

Flaviviruses are enveloped RNA viruses from the family Flaviviridae that comprise many important human pathogenic arboviruses such as Yellow Fever, Dengue, and Zika viruses. Because they belong to the same genus, these viruses show sequence and structural homology among them, which results in serological cross-reactivity. Upon infection, the immune system produces both species-specific and cross-reactive antibodies, and depending on the virus, in a successive flavivirus infection, cross-reactive antibodies either enhance protection or exacerbate the disease-the latter usually due to antibody-dependent enhancement. These antigenic relationships between different flaviviruses that lead to serological cross-reactivity make them difficult to be identified through serological methods, especially when it comes to successive flavivirus infections. We present here an overview of the main structural, epidemiological, and immunological aspects of flaviviruses, highlighting the role of neutralizing antibodies in fighting viral infections and in the original antigenic sin problem. Finally, we draw attention to the importance of developing a rapid serological diagnostic test for flaviviruses with high sensitivity and specificity, especially when considering that cross-reactive immunity can influence the outcome of these infections

In Vitro and In Vivo Investigation of the Efficacy of Arylimidamide DB1831 and Its Mesylated Salt Form - DB1965 - against Trypanosoma cruzi Infection

Chagas disease is caused by infection with the intracellular protozoan parasite Trypanosoma cruzi. At present, nifurtimox and benznidazole, both compounds developed empirically over four decades ago, represent the chemotherapeutic arsenal for treating this highly neglected disease. However, both drugs present variable efficacy depending on the geographical area and the occurrence of natural resistance, and are poorly effective against the later chronic stage. As a part of a search for new therapeutic opportunities to treat chagasic patients, pre-clinical studies were performed to characterize the activity of a novel arylimidamide (AIA - DB1831 (hydrochloride salt) and DB1965 (mesylate salt)) against T.cruzi. These AIAs displayed a high trypanocidal effect in vitro against both relevant forms in mammalian hosts, exhibiting a high selectivity index and a very high efficacy (IC50 value/48 h of 5–40 nM) against intracellular parasites. DB1965 shows high activity in vivo in acute experimental models (mouse) of T.cruzi, showing a similar effect to benznidazole (Bz) when compared under a scheme of 10 daily consecutive doses with 12.5 mg/kg. Although no parasitological cure was observed after treating with 20 daily consecutive doses, a combined dosage of DB1965 (5 mg/kg) with Bz (50 mg/kg) resulted in parasitaemia clearance and 100% animal survival. In summary, our present data confirmed that aryimidamides represent promising new chemical entities against T.cruzi in therapeutic schemes using the AIA alone or in combination with other drugs, like benznidazole

Loss of 5'-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness.

The 5'-methylthioadenosine phosphorylase (MTAP) gene is located in the chromosomal region 9p21. MTAP deletion is a frequent event in a wide variety of human cancers; however, its biological role in tumorigenesis remains unclear. The purpose of this study was to characterize the MTAP expression profile in a series of gliomas and to associate it with patients' clinicopathological features. Moreover, we sought to evaluate, through glioma gene-edited cell lines, the biological impact of MTAP in gliomas. MTAP expression was evaluated in 507 glioma patients by immunohistochemistry (IHC), and the expression levels were associated with patients' clinicopathological features. Furthermore, an in silico study was undertaken using genomic databases totalizing 350 samples. In glioma cell lines, MTAP was edited, and following MTAP overexpression and knockout (KO), a transcriptome analysis was performed by NanoString Pan-Cancer Pathways panel. Moreover, MTAP's role in glioma cell proliferation, migration, and invasion was evaluated. Homozygous deletion of 9p21 locus was associated with a reduction of MTAP mRNA expression in the TCGA (The Cancer Genome Atlas) - glioblastoma dataset (p < 0.01). In addition, the loss of MTAP expression was markedly high in high-grade gliomas (46.6% of cases) determined by IHC and Western blotting (40% of evaluated cell lines). Reduced MTAP expression was associated with a better prognostic in the adult glioblastoma dataset (p < 0.001). Nine genes associated with five pathways were differentially expressed in MTAP-knockout (KO) cells, with six upregulated and three downregulated in MTAP. Analysis of cell proliferation, migration, and invasion did not show any significant differences between MTAP gene-edited and control cells. Our results integrating data from patients as well as in silico and in vitro models provide evidence towards the lack of strong biological importance of MTAP in gliomas. Despite the frequent loss of MTAP, it seems not to have a clinical impact in survival and does not act as a canonic tumor suppressor gene in gliomas

The biological in vitro effect and selectivity of aromatic dicationic compounds on Trypanosoma cruzi

Trypanosoma cruzi is a parasite that causes Chagas disease, which affects millions of individuals in endemic areas of Latin America. One hundred years after the discovery of Chagas disease, it is still considered a neglected illness because the available drugs are unsatisfactory. Aromatic compounds represent an important class of DNA minor groove-binding ligands that exhibit potent antimicrobial activity. This study focused on the in vitro activity of 10 aromatic dicationic compounds against bloodstream trypomastigotes and intracellular forms of T. cruzi. Our data demonstrated that these compounds display trypanocidal effects against both forms of the parasite and that seven out of the 10 compounds presented higher anti-parasitic activity against intracellular parasites compared with the bloodstream forms. Additional assays to determine the potential toxicity to mammalian cells showed that the majority of the dicationic compounds did not considerably decrease cellular viability. Fluorescent microscopy analysis demonstrated that although all compounds were localised to a greater extent within the kinetoplast than the nucleus, no correlation could be found between compound activity and kDNA accumulation. The present results stimulate further investigations of this class of compounds for the rational design of new chemotherapeutic agents for Chagas disease

LEVANTAMENTO RETROSPECTIVO DOS ATENDIMENTOS DO AMBULATÓRIO DE FISIOTERAPIA DERMATO-FUNCIONAL DA UNIVERSIDADE POTIGUAR

A fisioterapia dermato-funcional é uma área do conhecimento em plena expansão, caracterizada por fornecer serviço nos três níveis de atenção à saúde, tratando diferentes patologiasde âmbito estético e reparador. A Universidade Potiguar (UNP) é uma instituição pioneira no estado do Rio Grande do Norte no serviço de fisioterapia dermato-funcional e oportuniza àpopulação carente o acesso a tratamentos de alto custo, com a utilização de recursos avançados neste segmento. O objetivo deste estudo foi verificar as características da população atendida na Clínica Escola de Fisioterapia Dermato-Funcional da UnP. Trata-se de um estudo descritivo, retrospectivo, no qual, foram analisados os prontuários de 863 pacientes que freqüentaram o serviço de fisioterapia dermato-funcional, de 2000 a 2009. Observou-se uma variação no públicode pacientes que frequentou o serviço, constatando-se que, no ano de 2001, o percentual de homens que procurou o serviço foi de, no máximo, 4,4%, aumentado para 30,27% em 2009.Foram atendidos quase 100 pacientes anualmente, tratando diferentes patologias, em destaque a adiposidade. Os pacientes realizaram, na maioria dos casos, de 01 a 05 sessões, com importante índice de abandono. Esse abandono pode estar relacionado a frequentes interrupções dosatendimentos devido ao período de férias ou mudanças na estrutura curricular semestralmente e isso pode ser considerado uma das limitações dessa assistência.Retrospective survey of the attendances outpatient physical therapy dermato-functional University PotiguarPhysical therapy is a dermato-functional knowledge area in full expansion, characterized by providing three levels of service in health care, treating different pathologies within aestheticand restorative. The University Potiguar – UNP is a pioneer institution in the state of Rio Grande 42 do Norte in the physiotherapy service dermato-functional and takes advantage of the poor access to high-cost treatments with the use of advanced features in this segment. The aim of this studywas to determine the characteristics of the population served in Clinical Dermatology, School of Physiotherapy Functional UNP. It is a descriptive, retrospective study, which analyzed the medicalrecords of 863 patients who attended physiotherapy service dermato-functional, from 2000 to 2009. There was a change in public patients attending the physiotherapy service dermato-functional, noting that in 2001 the percentage of men attending the service was up to 4.4% increased to 30.27% in 2009. We served almost 100 patients annually, treating different diseases, highlighted adiposity. Patients were, in most cases, 01 to 05 sessions, with significant dropout rate. This dropmay be related to frequent interruptions of attendance due to vacation or changes in curriculum structure every six months and may be considered one of the limitations of this assistance.Key words: Public Health. Aesthetics. Dermatology. Physical Therapy

Cancer and thrombosis: Managing the risks and approaches to thromboprophylaxis

Patients with cancer are at increased risk of venous thromboembolism (VTE) compared with patients without cancer. This results from both the prothrombotic effects of the cancer itself and iatrogenic factors, such as chemotherapy, radiotherapy, indwelling central venous devices and surgery, that further increase the risk of VTE. Although cancer-associated thrombosis remains an important cause of morbidity and mortality, it is often underdiagnosed and undertreated. However, evidence is accumulating to support the use of low-molecular-weight heparins (LMWHs) in the secondary prevention of VTE in patients with cancer. Not only have LMWHs been shown to be at least as effective as coumarin derivatives in this setting, but they have a lower incidence of complications, including bleeding, and are not associated with the practical problems of warfarin therapy. Furthermore, a growing number of studies indicate that LMWHs may improve survival among patients with cancer due to a possible antitumor effect. Current evidence suggests that LMWHs should increasingly be considered for the long-term management of VTE in patients with cancer

Ecosystem heterogeneity and diversity mitigate Amazon forest resilience to frequent extreme droughts

© 2018 The Authors. New Phytologist © 2018 New Phytologist Trust The impact of increases in drought frequency on the Amazon forest's composition, structure and functioning remain uncertain. We used a process- and individual-based ecosystem model (ED2) to quantify the forest's vulnerability to increased drought recurrence. We generated meteorologically realistic, drier-than-observed rainfall scenarios for two Amazon forest sites, Paracou (wetter) and Tapajós (drier), to evaluate the impacts of more frequent droughts on forest biomass, structure and composition. The wet site was insensitive to the tested scenarios, whereas at the dry site biomass declined when average rainfall reduction exceeded 15%, due to high mortality of large-sized evergreen trees. Biomass losses persisted when year-long drought recurrence was shorter than 2–7 yr, depending upon soil texture and leaf phenology. From the site-level scenario results, we developed regionally applicable metrics to quantify the Amazon forest's climatological proximity to rainfall regimes likely to cause biomass loss > 20% in 50 yr according to ED2 predictions. Nearly 25% (1.8 million km2) of the Amazon forests could experience frequent droughts and biomass loss if mean annual rainfall or interannual variability changed by 2σ. At least 10% of the high-emission climate projections (CMIP5/RCP8.5 models) predict critically dry regimes over 25% of the Amazon forest area by 2100

Tuberculosis of the breast with erythema nodosum: a case report

<p>Abstract</p> <p>Introduction</p> <p>There has been an increasing number of tuberculosis cases worldwide, but tuberculosis of the breast remains rare. In rare cases this is seen with a cutaneous manifestation of erythema nodosum.</p> <p>Case presentation</p> <p>We report the case of a 33-year-old Chinese woman with tuberculosis of the left breast accompanied by erythema nodosum on the anterior aspect of both lower legs. Due to her poor clinical response to conventional therapy, and the histopathological findings of fine needle aspiration cytology, there were strong indications of tuberculosis. Her clinical diagnosis was confirmed by molecular detection of <it>Mycobacterium tuberculosis </it>complex by polymerase chain reaction. The diagnosis was further confirmed by a second polymerase chain reaction test of erythema nodosum which tested positive for <it>Mycobacterium tuberculosis</it> complex. She received anti-tuberculous therapy for 18 months, and finally underwent residual lumpectomy. During her follow-up examination after 12 months, no evidence of either residual or recurrent disease was present.</p> <p>Conclusion</p> <p>Histopathological features and a high index of clinical suspicion are necessary to confirm a diagnosis of tuberculosis of the breast. Anti-tuberculous therapy with or without simple surgical intervention is the core treatment.</p

Selective and Efficient Mitochondrial Staining with Designed 2,1,3-Benzothiadiazole Derivatives as Live Cell Fluorescence Imaging Probes

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Novel designed 2,1,3-benzothiadiazole fluorescent probes were synthesized, characterized and applied as live cell fluorescence imaging probe staining only mitochondria in mammalian cancer cell lines (MCF-7). The efficiency of these new probes was found to be much superior to that of the commercially available MitoTracker (R) Red. Cellular and in vitro experiments allowed better understanding of the relationship between the planned molecular architecture of the new dyes and the observed cellular selectivity.234770781Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundacao de Apoio a Pesquisa do Distrito Federal (FAPDF)INCT-CatalysisBrasilia Fundacao de Empreendimentos Cientificos e Tecnologicos (Finatec)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)PetrobrasDPP-UnBQuiCSI TeamLMC (IQ-UnB)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP