Risk of chronic arthralgia and impact of pain on daily activities in a cohort of patients with chikungunya virus infection from Brazil

Objectives: To investigate risk factors for persistent arthralgia in patients with chikungunya, and describe its impact on daily activities. Methods: From September 2014 to July 2016, a surveillance study enrolled patients with acute febrile illness in Salvador, Brazil, and detected those with chikungunya virus infection using IgM enzyme-linked immunosorbent assay or reverse transcriptase polymerase chain reaction. Telephone follow-ups were performed to ascertain the progression of disease. Results: Of 153 followed cases, 65 (42.5%) reported chronic arthralgia that lasted >3 months, and 47 (30.7%) were still symptomatic at the time of the interview (approximately 1.5 years after symptom onset). Limitations in daily activities and mental distress were reported by 93.8% and 61.5% of those with chronic arthralgia, respectively. Female sex [risk ratio (RR) 1.79, 95% confidence interval (CI) 1.95–2.69] and age (RR 1.02 for each 1-year increase, 95% CI 1.01–1.03) were independent risk factors for chronic arthralgia. Chronic arthralgia was not associated with co-infection with dengue virus (RR 0.97, 95% CI 0.48–1.94) or chikungunya viral load at diagnosis (median chikungunya virus RNA of 5.60 and 5.52 log10 copies/μL for those with and without chronic arthralgia, respectively; P = 0.75). Conclusions: These findings reinforce the high frequency of chronic chikungunya arthralgia, and highlight the substantial disability associated with the persistence of pain. Development of novel strategies to mitigate the transmission of chikungunya virus and to provide long-term medical assistance for patients with chikungunya are needed urgently.Fil: Silva, Monaíse M. O.. Fundación Oswaldo Cruz; BrasilFil: Kikuti, Mariana. Universidade Federal da Bahia; Brasil. Fundación Oswaldo Cruz; BrasilFil: Anjos, Rosângela O.. Fundación Oswaldo Cruz; BrasilFil: Portilho, Moyra M.. Fundación Oswaldo Cruz; BrasilFil: Santos, Viviane C.. Fundación Oswaldo Cruz; BrasilFil: Gonçalves, Thaiza S.F.. Fundación Oswaldo Cruz; BrasilFil: Tauro, Laura Beatriz. Fundación Oswaldo Cruz; Brasil. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Puerto Iguazú; ArgentinaFil: Moreira, Patrícia S. S.. Fundación Oswaldo Cruz; BrasilFil: Jacob Nascimento, Leile C.. Fundación Oswaldo Cruz; BrasilFil: Santana, Perla M.. Fundación Oswaldo Cruz; BrasilFil: Campos, Gúbio S.. Universidade Federal da Bahia; BrasilFil: Siqueira, André M.. Fundación Oswaldo Cruz; BrasilFil: Kitron, Uriel D.. University of Emory; Estados Unidos. Fundación Oswaldo Cruz; BrasilFil: Reis, Mitermayer G.. University of Yale; Estados Unidos. Fundación Oswaldo Cruz; Brasil. Universidade Federal da Bahia; BrasilFil: Ribeiro, Guilherme S.. Fundación Oswaldo Cruz; Brasil. Universidade Federal da Bahia; Brasi

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Metabolic Investigation of the Mycoplasmas from the Swine Respiratory Tract

International audienceBackgroundThe respiratory tract of swine is colonized by several bacteria among which are three Mycoplasma species: Mycoplasma flocculare, Mycoplasma hyopneumoniae and Mycoplasma hyorhinis. While colonization by M. flocculare is virtually asymptomatic, M. hyopneumoniae is the causative agent of enzootic pneumonia and M. hyorhinis is present in cases of pneumonia, polyserositis and arthritis. The genomic resemblance among these three Mycoplasma species combined with their different levels of pathogenicity is an indication that they have unknown mechanisms of virulence and differential expression, as for most mycoplasmas.MethodsIn this work, we performed whole-genome metabolic network reconstructions for these three mycoplasmas. Cultivation tests and metabolomic experiments through nuclear magnetic resonance spectroscopy (NMR) were also performed to acquire experimental data and further refine the models reconstructed in silico.ResultsEven though the refined models have similar metabolic capabilities, interesting differences include a wider range of carbohydrate uptake in M. hyorhinis, which in turn may also explain why this species is a widely contaminant in cell cultures. In addition, the myo-inositol catabolism is exclusive to M. hyopneumoniae and may be an important trait for virulence. However, the most important difference seems to be related to glycerol conversion to dihydroxyacetone-phosphate, which produces toxic hydrogen peroxide. This activity, missing only in M. flocculare, may be directly involved in cytotoxicity, as already described for two lung pathogenic mycoplasmas, namely Mycoplasma pneumoniae in human and Mycoplasma mycoides subsp. mycoides in ruminants. Metabolomic data suggest that even though these mycoplasmas are extremely similar in terms of genome and metabolism, distinct products and reaction rates may be the result of differential expression throughout the species.ConclusionsWe were able to infer from the reconstructed networks that the lack of pathogenicity of M. flocculare if compared to the highly pathogenic M. hyopneumoniae may be related to its incapacity to produce cytotoxic hydrogen peroxide. Moreover, the ability of M. hyorhinis to grow in diverse sites and even in different hosts may be a reflection of its enhanced and wider carbohydrate uptake. Altogether, the metabolic differences highlighted in silico and in vitro provide important insights to the different levels of pathogenicity observed in each of the studied species

Fetal deaths in Brazil: a systematic review

OBJECTIVE To review the frequency of and factors associated with fetal death in the Brazilian scientific literature. METHODS A systematic review of Brazilian studies on fetal deaths published between 2003 and 2013 was conducted. In total, 27 studies were analyzed; of these, 4 studies addressed the quality of data, 12 were descriptive studies, and 11 studies evaluated the factors associated with fetal death. The databases searched were PubMed and Lilacs, and data extraction and synthesis were independently performed by two or more examiners. RESULTS The level of completeness of fetal death certificates was deficient, both in the completion of variables, particularly sociodemographic variables, and in defining the underlying causes of death. Fetal deaths have decreased in Brazil; however, inequalities persist. Analysis of the causes of death indicated maternal morbidities that could be prevented and treated. The main factors associated with fetal deaths were absent or inadequate prenatal care, low education level, maternal morbidity, and adverse reproductive history. CONCLUSIONS Prenatal care should prioritize women that are most vulnerable (considering their social environment or their reproductive history and morbidities) with the aim of decreasing the fetal mortality rate in Brazil. Adequate completion of death certificates and investment in the committees that investigate fetal and infant deaths are necessary

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.</p

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism

Cathepsin K induces platelet dysfunction and affects cell signaling in breast cancer - molecularly distinct behavior of cathepsin K in breast cancer

BACKGROUND: Breast cancer comprises clinically and molecularly distinct tumor subgroups that differ in cell histology and biology and show divergent clinical phenotypes that impede phase III trials, such as those utilizing cathepsin K inhibitors. Here we correlate the epithelial-mesenchymal-like transition breast cancer cells and cathepsin K secretion with activation and aggregation of platelets. Cathepsin K is up-regulated in cancer cells that proteolyze extracellular matrix and contributes to invasiveness. Although proteolytically activated receptors (PARs) are activated by proteases, the direct interaction of cysteine cathepsins with PARs is poorly understood. In human platelets, PAR-1 and −4 are highly expressed, but PAR-3 shows low expression and unclear functions. METHODS: Platelet aggregation was monitored by measuring changes in turbidity. Platelets were immunoblotted with anti-phospho and total p38, Src-Tyr-416, FAK-Tyr-397, and TGFβ monoclonal antibody. Activation was measured in a flow cytometer and calcium mobilization in a confocal microscope. Mammary epithelial cells were prepared from the primary breast cancer samples of 15 women with Luminal-B subtype to produce primary cells. RESULTS: We demonstrate that platelets are aggregated by cathepsin K in a dose-dependent manner, but not by other cysteine cathepsins. PARs-3 and −4 were confirmed as the cathepsin K target by immunodetection and specific antagonists using a fibroblast cell line derived from PARs deficient mice. Moreover, through co-culture experiments, we show that platelets activated by cathepsin K mediated the up-regulation of SHH, PTHrP, OPN, and TGFβ in epithelial-mesenchymal-like cells from patients with Luminal B breast cancer. CONCLUSIONS: Cathepsin K induces platelet dysfunction and affects signaling in breast cancer cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2203-7) contains supplementary material, which is available to authorized users