Syndromic approach to arboviral diagnostics for global travelers as a basis for infectious disease surveillance

Background Arboviruses have overlapping geographical distributions and can cause symptoms that coincide with more common infections. Therefore, arbovirus infections are often neglected by travel diagnostics. Here, we assessed the potential of syndrome-based approaches for diagnosis and surveillance of neglected arboviral diseases in returning travelers. Method To map the patients high at risk of missed clinical arboviral infections we compared the quantity of all arboviral diagnostic requests by physicians in the Netherlands, from 2009 through 2013, with a literature-based assessment of the travelers’ likely exposure to an arbovirus. Results 2153 patients, with travel and clinical history were evaluated. The diagnostic assay for dengue virus (DENV) was the most commonly requested (86%). Of travelers returning from Southeast Asia with symptoms compatible with chikungunya virus (CHIKV), only 55% were tested. For travelers in Europe, arbovirus diagnostics were rarely requested. Over all, diagnostics for most arboviruses were requested only on severe clinical presentation. Conclusion Travel destination and syndrome were used inconsistently for triage of diagnostics, likely resulting in vast under-diagnosis of arboviral infections of public health significance. This study shows the need for more awareness among physicians and standardization of syndromic diagnostic algorithms

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 models of autoimmune inflammatory ocular diseases

A inflamação ocular é uma das principais causas de perda visual e cegueira. As uveítes constituem um grupo complexo e heterogêneo de doenças caracterizadas por inflamação dos tecidos intraoculares. O olho pode ser o único órgão envolvido ou a uveíte pode ser parte de uma doença sistêmica. A etiologia é desconhecida em um número significativo de casos, que são considerados idiopáticos. Modelos animais têm sido desenvolvidos para estudar a fisiopatogênese da uveíte autoimune devido às dificuldades na obtenção de tecidos de olhos humanos inflamados para experimentos. Na maioria desses modelos, que simulam as uveítes autoimunes em humanos, a uveíte é induzida com proteínas específicas de fotorreceptores (antígeno-S, proteína ligadora de retinoide do interfotoreceptor, rodopsina, recoverina e fosducina). Antígenos não retinianos, como proteínas associadas à melanina e proteína básica de mielina, são também bons indutores de uveíte em animais. Entender os mecanismos básicos e a patogênese dessas doenças oculares é essencial para o desenvolvimento de novas formas de tratamento das uveítes autoimunes e de novos agentes terapêuticos. Nesta revisão serão abordados os principais modelos experimentais utilizados para o estudo de doenças inflamatórias oculares autoimunes.

Prevalence and causes of visual impairment in a Brazilian population: The Botucatu Eye Study

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

Synergism between plant extract and antimicrobial drugs used on Staphylococcus aureus diseases

Searches for substances with antimicrobial activity are frequent, and medicinal plants have been considered interesting by some researchers since they are frequently used in popular medicine as remedies for many infectious diseases. The aim of this study was to verify the synergism between 13 antimicrobial drugs and 8 plant extracts - guaco (Mikania glomerata), guava (Psidium guajava), clove (Syzygium aromaticum), garlic (Allium sativum), lemongrass (Cymbopogon citratus), ginger (Zingiber officinale), carqueja (Baccharis trimera), and mint (Mentha piperita) - against Staphylococcus aureus strains, and for this purpose, the disk method was the antimicrobial susceptibility test performed. Petri dishes were prepared with or without dilution of plant extracts at sub-inhibitory concentrations in Mueller-Hinton Agar (MHA), and the inhibitory zones were recorded in millimeters. In vitro anti-Staphylococcus aureus activities of the extracts were confirmed, and synergism was verified for all the extracts; clove, guava, and lemongrass presented the highest synergism rate with antimicrobial drugs, while ginger and garlic showed limited synergistic capacity.

B-mode ultrasonography biometry of the Amazon Parrot (Amazona aestiva) eye

PurposeUltrasonographic evaluation of the eye is a relatively recent addition to routine ophthalmic diagnostics in small animal ophthalmology. Some parameters for ophthalmic biometry have been established. There are few studies in clinical avian ophthalmology that describe ultrasound images of eye in some nocturnal avian species and in other birds that do not belong to the Brazilian fauna, but the psittacine family is not represented. The purpose of this study was to describe the following measurements: the distances between cornea and anterior lens capsule (D1) between the anterior and posterior lens capsule (D2), between posterior lens capsule and optic papilla (D3) and the axial length.MethodSixty four transpalpebral ocular ultrasound examinations were performed on 32 Blue fronted Amazon parrots (Amazona aestiva) with no history of previous ophthalmic disease.Result and DiscussionThe measurements were taken in sagital planes using a 10 MHz linear probe without a standoff pad. The mean values for the left eye were; D1 0.17 +/- 0.03 cm, D2 0.35 +/- 0.02 cm, D3 0.73 +/- 0.04 cm and the axial length 1.26 +/- 0.06 cm. In the right eye D1 0.17 +/- 0.02 cm, D2 0.34 +/- 0.02 cm, D3 0.74 +/- 0.03 cm and the axial length 1.25 +/- 0.05 cm. No significant statistical difference was observed among the birds or between the left and right eye. The description of these parameters will allow the veterinary practitioner to evaluate the structural changes that specific diseases may cause in these animals.

Chorismate synthase: An attractive target for drug development against orphan diseases

The increase in incidence of infectious diseases worldwide, particularly in developing countries, is worrying. Each year, 14 million people are killed by infectious diseases, mainly HIV/AIDS, respiratory infections, malaria and tuberculosis. Despite the great burden in the poor countries, drug discovery to treat tropical diseases has come to a standstill. There is no interest by the pharmaceutical industry in drug development against the major diseases of the poor countries, since the financial return cannot be guaranteed. This has created an urgent need for new therapeutics to neglected diseases. A possible approach has been the exploitation of the inhibition of unique targets, vital to the pathogen such as the shikimate pathway enzymes, which are present in bacteria, fungi and apicomplexan parasites but are absent in mammals. The chorismate synthase (CS) catalyses the seventh step in this pathway, the conversion of 5-enolpyruvylshikimate-3-phosphate to chorismate. The strict requirement for a reduced flavin mononucleotide and the anti 1,4 elimination are both unusual aspects which make CS reaction unique among flavin-dependent enzymes, representing an important target for the chemotherapeutic agents development. In this review we present the main biochemical features of CS from bacterial and fungal sources and their difference from the apicomplexan CS. The CS mechanisms proposed are discussed and compared with structural data. The CS structures of some organisms are compared and their distinct features analyzed. Some known CS inhibitors are presented and the main characteristics are discussed. The structural and kinetics data reviewed here can be useful for the design of inhibitors. © 2007 Bentham Science Publishers Ltd.

Signaling Pathways Activation by Primary Endodontic Infectious Contents and Production of Inflammatory Mediators

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

Use of Guanidine Compounds in the Treatment of Neglected Tropical Diseases

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

Speech-language therapy for treatment of dysphagia and dysphonia in systemic granulomatous diseases: granulomatous diseases: dysphagia and dysphonia treatments

The granulomatous lesions are frequently founded in infectious diseases and can involve the larynx and pharynx and can cause varying degrees of dysphonia and dysphagia. There is still no systematic review that analyzes effectiveness of speech therapy in systemic granulomatous diseases. Research strategy: A systematic review was performed according to Cochrane guideline considering the inclusion of RCTs and quasi-RCTs about the effectiveness of speech-language therapy to treat dysphagia and dysphonia symptoms in systemic granulomatous diseases of the larynx and pharynx. Selection criteria: The outcome planned to be measured in this review were: swallowing impairment, frequency of chest infections and voice and swallowing symptoms. Data analysis: We identified 1,140 citations from all electronic databases. After an initial shift we only selected 9 titles to be retrieved in full-text. After full reading, there was no RCT found in this review and therefore, we only described the existing 2 case series studies. Results: There were no randomized controlled trials found in the literature. Therefore, two studies were selected to be included only for narratively analysis as they were case series. Conclusion: There is no evidence from high quality studies about the effectiveness of speech-language therapy in patients with granulomatous diseases of the larynx and pharynx. The investigators could rely in the outcomes suggested in this review to design their own clinical trials.

Emergence of Diseases From Wildlife Reservoirs

Interest in the epidemiology of emerging diseases of humans and livestock as they relate to wildlife has increased greatly over the past several decades. Many factors, most anthropogenic, have facilitated the emergence of diseases from wildlife. Some livestock diseases have ‘‘spilled over’’ to wildlife and then ‘‘spilled back’’ to livestock. When a population is exposed to an infectious agent, depending on an interaction of factors involving the host, agent, and environment, the population may be resistant to infection or may become a dead-end host, a spillover host, or a maintenance host. Each exposure is unique; the same species of host and agent may respond differently in different situations. Management actions that affect the environment and behavior of a potential host animal may allow the emergence of a new or as yet undetected disease. There are many barriers in preventing, detecting, monitoring and managing wildlife diseases. These may include political and legal hurdles, lack of knowledge about many diseases of wildlife, the absence of basic data on wildlife populations, difficulties with surveillance, and logistical constraints. Increasing interaction between wildlife and humans or domestic animals may lead to disease emergence and require innovative methods and strategies for disease surveillance and management in wildlife.

Phosphene Thresholds Elicited by Transcorneal Electrical Stimulation in Healthy Subjects and Patients with Retinal Diseases

PURPOSE. To evaluate electrically evoked phosphene thresholds (EPTs) in healthy subjects and in patients with retinal disease and to assess repeatability and possible correlations with common ophthalmologic tests. METHODS. In all, 117 individuals participated: healthy subjects (n = 20) and patients with retinitis pigmentosa (RP, n = 30), Stargardt's disease (STG, n = 14), retinal artery occlusion (RAO, n = 20), nonarteritic anterior ischemic optic neuropathy (NAION, n = 16), and primary open-angle glaucoma (POAG, n = 17). EPTs were determined at 3, 6, 9, 20, 40, 60, and 80 Hz with 5+5-ms biphasic current pulses using DTL electrodes. Subjects were examined twice (test-retest range: 1-6 weeks). An empirical model was developed to describe the current-frequency relationship of EPTs. Visual acuity, visual field (kinetic + static), electrophysiology (RP, RAO, STG: Ganzfeld-electroretinography [ERG]/multifocal-ERG; POAG: pattern-ERG; NAION: VEP), slit-lamp biomicroscopy, fundus examination, and tonometry were assessed. RESULTS. EPTs varied between disease groups (20 Hz: healthy subjects: 0.062 +/- 0.038 mA; STG: 0.102 +/- 0.097 mA; POAG: 0.127 +/- 0.09 mA; NAION: 0.244 +/- 0.126 mA; RP: 0.371 +/- 0.223 mA; RAO: 0.988 +/- 1.142 mA). In all groups EPTs were lowest at 20 Hz. In patients with retinal diseases and across all frequencies EPTs were significantly higher than those in healthy subjects, except in STG at 20 Hz (P = 0.09) and 40 Hz (P = 0.17). Test-retest difference at 20 Hz was 0.006 mA in the healthy group and 0.003-0.04 mA in disease groups. CONCLUSIONS. Considering the fast, safe, and reliable practicability of EPT testing, this test might be used more often under clinical circumstances. Determination of EPTs could be potentially useful in elucidation of the progress of ophthalmologic diseases, either in addition to standard clinical assessment or under conditions in which these standard tests cannot be used meaningfully. (ClinicalTrials.gov number, NCT00804102.) (Invest Ophthalmol Vis Sci. 2012; 53: 7440-7448) DOI:10.1167/iovs.12-9612

Prior history of sexually transmitted diseases in women living with AIDS in Sao Paulo, Brazil

Objectives: To describe the epidemiological profile, risk behaviors, and the prior history of sexually transmitted diseases (STDs) in women living with acquired immunodeficiency syndrome (AIDS). Methods: Cross-sectional study, performed at the Centro de Referencia e Treinamento em DST/AIDS of Sao Paulo. The social, demographic, behavioral, and clinical data such as age, schooling, marital status, age at first sexual intercourse, number of sexual partners, parity, use of drugs, time of HIV diagnosis, CD4 count, and viral load determination were abstracted from the medical records of women living with AIDS who had gynecological consultation scheduled in the period from June 2008 to May 2009. Results: Out of 710 women who were scheduled to a gynecological consultation during the period of the study, 598 were included. Previous STD was documented for 364 (60.9%; 95% CI: 56.9%-64.8%) women. The associated factors with previous STDs and their respective risks were: human development index (HDI) <0.50 (ORaj = 5.5; 95% CI: 2.8-11.0); non-white race (ORaj = 5.2; 95% CI: 2.5-11.0); first sexual intercourse at or before 15 years of age (ORaj = 4.4; 95% CI: 2.3-8.3); HIV infection follow-up time of nine years or more (ORaj = 4.2; 95% CI: 2.3-7.8)]; number of sexual partners during the entire life between three and five partners (ORaj = 2.2; 95% CI: 1.1-4.6), and six or more sexual partners (ORaj = 3.9; 95% CI: 1.9-8.0%); being a sex worker (ORaj = 1.9; 95% CI: 1.1-3.1). Conclusions: A high prevalence of a prior history of STDs in the studied population was found. It is essential to find better ways to access HIV infection prevention, so that effective interventions can be more widely implemented. (C) 2012 Elsevier Editora Ltda. All rights reserved.

JC virus-associated central nervous system diseases in HIV-infected patients in Brazil: clinical presentations, associated factors with mortality and outcome

Introduction: Several presentations of neurologic complications caused by JC virus (JCV) in human immunodeficiency virus (HIV)-infected patients have been described and need to be distinguished from the "classic" form of progressive multifocal leukoencephalopathy (PML). The objectives of this study were: 1) to describe the spectrum and frequency of presentations of JCV-associated central nervous system (CNS) diseases; 2) identify factors associated with in-hospital mortality of patients with JCV-associated CNS disease; and 3) to estimate the overall mortality of this population. Material and methods: This was a retrospective study of HIV-infected patients admitted consecutively for JCV-associated CNS diseases in a referral teaching center in Sao Paulo, Brazil, from 2002 to 2007. All patients with laboratory confirmed JCV-associated CNS diseases were included using the following criteria: compatible clinical and radiological features associated with the presence of JCV DNA in the cerebrospinal fluid. JCV-associated CNS diseases were classified as follows: 1) classic PML; 2) inflammatory PML; and 3) JC virus granule cell neuronopathy (GCN). Results: We included 47 cases. JCV-associated CNS diseases were classified as follows: 1) classic PML: 42 (89%); 2) inflammatory PML: three (6%); and 3) JC virus GCN: four (9%). Nosocomial pneumonia (p = 0.003), previous diagnosis of HIV infection (p = 0.03), and imaging showing cerebellar and/or brainstem involvement (p = 0.02) were associated with in-hospital mortality. Overall mortality during hospitalization was 34%. Conclusions: Novel presentations of JCV-associated CNS diseases were observed in our setting; nosocomial pneumonia, previous diagnosis of HIV infection, and cerebellar and/or brainstem involvement were associated with in-hospital mortality; and overall mortality was high. (C) 2012 Elsevier Editora Ltda. All rights reserved.

Vesicles as carriers of virulence factors in parasitic protozoan diseases

Different types of shed vesicles as, for example, exosomes, plasma-membrane-derived vesicles or microparticles, are the focus of intense research in view of their potential role in cell cell communication and under the perspective that they might be good tools for immunotherapy, vaccination or diagnostic purposes. This review discusses ways employed by pathogenic trypanosomatids to interact with the host by shedding vesicles that contain molecules important for the establishment of infection, as opposed to previous beliefs considering them as a waste of cellular metabolism. Trypanosomatids are compared with Apicomplexa, which circulate parasite antigens bound to vesicles shed by host cells. The knowledge of the origin and chemical composition of these different vesicles might lead to the understanding of the mechanisms that determine their biological function. (C) 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.