First report of autochthonous transmission of Zika virus in Brazil

In the early 2015, several cases of patients presenting symptoms of mild fever, rash, conjunctivitis and arthralgia were reported in the northeastern Brazil. Although all patients lived in a dengue endemic area, molecular and serological diagnosis for dengue resulted negative. Chikungunya virus infection was also discarded. Subsequently, Zika virus (ZIKV) was detected by reverse transcription-polymerase chain reaction from the sera of eight patients and the result was confirmed by DNA sequencing. Phylogenetic analysis suggests that the ZIKV identified belongs to the Asian clade. This is the first report of ZIKV infection in Brazil.

Cell entry of Lassa virus induces tyrosine phosphorylation of dystroglycan.

The extracellular matrix (ECM) receptor dystroglycan (DG) serves as a cellular receptor for the highly pathogenic arenavirus Lassa virus (LASV) that causes a haemorrhagic fever with high mortality in human. In the host cell, DG provides a molecular link between the ECM and the actin cytoskeleton via the adapter proteins utrophin or dystrophin. Here we investigated post-translational modifications of DG in the context of LASV cell entry. Using the tyrosine kinase inhibitor genistein, we found that tyrosine kinases are required for efficient internalization of virus particles, but not virus-receptor binding. Engagement of cellular DG by LASV envelope glycoprotein (LASV GP) in human epithelial cells induced tyrosine phosphorylation of the cytoplasmic domain of DG. LASV GP binding to DG further resulted in dissociation of the adapter protein utrophin from virus-bound DG. This virus-induced dissociation of utrophin was affected by genistein treatment, suggesting a role of receptor tyrosine phosphorylation in the process.

Antiviral activity of a small-molecule inhibitor of arenavirus glycoprotein processing by the cellular site 1 protease.

Arenaviruses merit interest as clinically important human pathogens and include several causative agents, chiefly Lassa virus (LASV), of hemorrhagic fever disease in humans. There are no licensed LASV vaccines, and current antiarenavirus therapy is limited to the use of ribavirin, which is only partially effective and is associated with significant side effects. The arenavirus glycoprotein (GP) precursor GPC is processed by the cellular site 1 protease (S1P) to generate the peripheral virion attachment protein GP1 and the fusion-active transmembrane protein GP2, which is critical for production of infectious progeny and virus propagation. Therefore, S1P-mediated processing of arenavirus GPC is a promising target for therapeutic intervention. To this end, we have evaluated the antiarenaviral activity of PF-429242, a recently described small-molecule inhibitor of S1P. PF-429242 efficiently prevented the processing of GPC from the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) and LASV, which correlated with the compound's potent antiviral activity against LCMV and LASV in cultured cells. In contrast, a recombinant LCMV expressing a GPC whose processing into GP1 and GP2 was mediated by furin, instead of S1P, was highly resistant to PF-429242 treatment. PF-429242 did not affect virus RNA replication or budding but had a modest effect on virus cell entry, indicating that the antiarenaviral activity of PF-429242 was mostly related to its ability to inhibit S1P-mediated processing of arenavirus GPC. Our findings support the feasibility of using small-molecule inhibitors of S1P-mediated processing of arenavirus GPC as a novel antiviral strategy.

Primary dengue virus infections induce differential cytokine production in Mexican patients

Severe dengue pathogenesis is not fully understood, but high levels of proinflammatory cytokines have been associated with dengue disease severity. In this study, the cytokine levels in 171 sera from Mexican patients with primary dengue fever (DF) and dengue haemorrhagic fever (DHF) from dengue virus (DENV) 1 (n = 116) or 2 (n = 55) were compared. DF and DHF were defined according to the patient’s clinical condition, the primary infections as indicated by IgG enzymatic immunoassay negative results, and the infecting serotype as assessed by real-time reverse transcription-polymerase chain reaction. Samples were analysed for circulating levels of interleukin (IL)-12p70, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, IL-6, and IL-8 using a commercial cytometric bead array. Significantly higher IFN-γ levels were found in patients with DHF than those with DF. However, significantly higher IL-12p70, TNF-α, and IL-6 levels were associated with DHF only in patients who were infected with DENV2 but not with DENV1. Moreover, patients with DF who were infected with DENV1 showed higher levels of IL-12p70, TNF-α, and IL-6 than patients with DHF early after-fever onset. The IL-8 levels were similar in all cases regardless of the clinical condition or infection serotype. These results suggest that the association between high proinflammatory cytokine levels and dengue disease severity does not always stand, and it once again highlights the complex nature of DHF pathogenesis.

Spatial and temporal country-wide survey of temephos resistance in Brazilian populations of Aedes aegypti

The organophosphate temephos has been the main insecticide used against larvae of the dengue and yellow fever mosquito (Aedes aegypti) in Brazil since the mid-1980s. Reports of resistance date back to 1995; however, no systematic reports of widespread temephos resistance have occurred to date. As resistance investigation is paramount for strategic decision-making by health officials, our objective here was to investigate the spatial and temporal spread of temephos resistance in Ae. aegypti in Brazil for the last 12 years using discriminating temephos concentrations and the bioassay protocols of the World Health Organization. The mortality results obtained were subjected to spatial analysis for distance interpolation using semi-variance models to generate maps that depict the spread of temephos resistance in Brazil since 1999. The problem has been expanding. Since 2002-2003, approximately half the country has exhibited mosquito populations resistant to temephos. The frequency of temephos resistance and, likely, control failures, which start when the insecticide mortality level drops below 80%, has increased even further since 2004. Few parts of Brazil are able to achieve the target 80% efficacy threshold by 2010/2011, resulting in a significant risk of control failure by temephos in most of the country. The widespread resistance to temephos in Brazilian Ae. aegypti populations greatly compromise effective mosquito control efforts using this insecticide and indicates the urgent need to identify alternative insecticides aided by the preventive elimination of potential mosquito breeding sites.

A non-enteric adenovirus A12 gastroenteritis outbreak in Rio de Janeiro, Brazil

A gastroenteritis outbreak that occurred in 2013 in a low-income community in Rio de Janeiro was investigated for the presence of enteric viruses, including species A rotavirus (RVA), norovirus (NoV), astrovirus (HAstV), bocavirus (HBoV), aichivirus (AiV), and adenovirus (HAdV). Five of nine stool samples (83%) from patients were positive for HAdV, and no other enteric viruses were detected. Polymerase chain reaction products were sequenced and subjected to phylogenetic analysis, which revealed four strains and one strain of non-enteric HAdV-A12 and HAdV-F41, respectively. The HAdV-A12 nucleotide sequences shared 100% nucleotide similarity. Viral load was assessed using a TaqMan real-time PCR assay. Stool samples that were positive for HAdV-A12 had high viral loads (mean 1.9 X 107 DNA copies/g stool). All four patients with HAdV-A12 were < 25 months of age and had symptoms of fever and diarrhoea. Evaluation of enteric virus outbreaks allows the characterisation of novel or unique diarrhoea-associated viruses in regions where RVA vaccination is routinely performed.

Rapid diagnosis of human brucellosis by peripheral-blood PCR assay.

A single-step PCR assay with genus-specific primers for the amplification of a 223-bp region of the sequence encoding a 31-kDa immunogenetic Brucella abortus protein (BCSP31) was used for the rapid diagnosis of human brucellosis. We examined peripheral blood from 47 patients, with a total of 50 cases of brucellosis, and a group of 60 control subjects, composed of patients with febrile syndromes of several etiologies other than brucellosis, asymptomatic subjects seropositive for Brucella antibodies, and healthy subjects. Diagnosis of brucellosis was established in 35 cases (70%) by isolation of Brucella in blood culture and in the other 15 cases (30%) by clinical and serological means. The sensitivity of our PCR assay was 100%, since it correctly identified all 50 cases of brucellosis, regardless of the duration of the disease, the positivity of the blood culture, or the presence of focal forms. The specificity of the test was 98.3%, and the only false-positive result was for a patient who had had brucellosis 2 months before and possibly had a self-limited relapse. In those patients who relapsed, the results of our PCR assay were positive for both the initial infection and the relapse, becoming negative once the relapse treatment was completed and remaining negative in the follow-up tests at 2, 4, and 6 months. In conclusion, these results suggest that the PCR assay is rapid and easy to perform and highly sensitive and specific, and it may therefore be considered a useful tool for diagnosis of human brucellosis.

Daptomycin-associated eosinophilic pneumonia in two patients with prosthetic joint infection.

Background: Daptomycin is used increasingly to treat prosthetic joint infection (PJI). A possible side effect of this drug is eosinophilic pneumonia. We describe two patients with PJI treated with daptomycin who had this side effect with different clinical presentations. METHODS: Case reports and review of the literature. RESULTS: The first case was a 64-year-old male who received daptomycin as a part of the treatment for PJI caused by methicillin-resistant Staphylococcus epidermidis (MRSE). He developed fever without other symptoms; bronchoalveolar lavage (BAL) revealed eosinophils. The second was a 61-year-old male who also used daptomycin as part of the treatment of PJI caused by MRSE and developed severe lung symptoms. Bronchoalveolar lavage and pleural fluid showed an increased number of eosinophils. CONCLUSION: Daptomycin-induced pneumonia can present with a wide range of symptoms, from fever alone to severe lung symptoms. Surgeons should be aware of this possible side effect when prescribing daptomycin.

Combined modality treatment with full-dose chemotherapy and concomitant boost radiotherapy for advanced head and neck carcinoma

Résumé Le but de cette étude est d'évaluer la faisabilité et l'efficacité d'un traitement des carcinomes pharyngo-laryngés avancés par combinaison de chimiothérapie intensive associé à une radiothérapie accélérée. Vingt-trois patients ont été inclus (age médian 54 ans, entre 35 et 70 ans). Les localisations tumorales étaient l'hypopharynx (n=7), base de langue (n=10), nasopharynx (n=2) ou l'oesophage proximal (n.1), ou sans porte d'entrée (n=3). Le traitement comprend trois cycles de chimiothérapie (cisplatin 100mg/m2 à J1 ; 5-FU 1000mg/m2 par jour pendant 5 jours en perfusion continue, précédé par de l'amifostine 910mg/m2 ; répété toutes les trois semaines). La radiothérapie concomitante, accélérée (dose totale de 70Gy en 6 semaines) a été débuté au premier jour du deuxième cycle de chimiothérapie. Vingt et un patients ont pu achever la radiothérapie. Dix-huit patients étaient en rémission complète à la fin du traitement. Avec un suivi médian de 45 mois, le taux de survie globale atteint 56% (95% Cl, 32-79%). Le contrôle loco-régional était de 71% (95% CI, 52-91%). La toxicité associée au traitement consistait en une insuffisance rénale réversible (≥grade II) chez 9 patients (43%) et une agranulocytose fébrile chez 9 patients (43%). Tous les patients ont présenté une mucite modérée à sévère (grade II/III) et 19 patients ont montré une toxicité cutanée de grade III. En conclusion, le traitement combiné de radiothérapie accélérée avec une chimiothérapie concomitante à base de Cisplatin/5-FU full-dose avec amifostine est faisable. La toxicité est importante mais reste maîtrisable dans le cadre d'un centre multidisciplinaire. Le taux de survie globale à 4 ans est prometteur, la recherche en vue de traitements moins toxiques doit se poursuivre. Abstract The purpose of this study was to evaluate the feasibility and efficacy of a treatment concept combining three cycles of full-dose chemotherapy (CT) with concomitant accelerated uninterrupted radiotherapy (RI). Twenty- three patients (median age: 54 years, range: 35-70) with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were included. The primary tumor involved the hypopharynx (n=7), base of the tongue (n=10), nasopharynx (n=2) or upper esophagus (n=1) or its location was unknown (n=3). Treatment consisted of three cycles of chemotherapy (cisplatin 100 mg/m2 on day 1; 5-FU 1,000 mg/m2 per day for 5 days as a continuous infusion, preceded by amifostine 910 mg/m2). repeated every 3 weeks. Uninterrupted concomitant boost-accelerated RI (total dose of 70 Gy in 6 weeks) started together on day 1 of the second cycle. All but two patients received the full course of RT. Eighteen patients achieved complete remission (78%). At a median follow-up of 45 months the overall survival was 56% (95% c.i. 32-79%) and the loco-regional control 71% (95% c.i. 52-91%). Toxicity involved reversible renal insufficiency of grade II in 9 patients (39%) and neutropenic fever in 9 patients (39%). All patients suffered from moderate to severe mucositis (grade HMI), and 19 patients presented cutaneous toxicity grade III. Concomitant boost-accelerated RI combined with concurrent full-dose cisplatin/5-FU chemotherapy and amifostine is feasible with manageable, although substantial, toxicity. The overall survival of 4 years is promising. Newer regimens causing less acute mucosal and skin toxicity are needed.

Crises as a disease of the body politick: a metaphor in the history of nineteenth century economics

This paper examines the use of the medical metaphor in the early theories of crises. It first considers the borrowing of medical terminology and generic references to disease which, notwithstanding their relatively trivial character, illustrate how crises were originally conceived as disturbances (often of a political nature) to a naturally healthy system. Then it shows how a more specific metaphor, the fever of speculation, shifted the emphasis by treating prosperity as the diseased phase, to which crises are a remedy. The metaphor of the epidemic spreading of the disease introduced the theme of the cumulative character of both upswing and downswing, while the similitude with intermittent fevers accounted for the recurring nature of crises. Finally, the paper examines how the medical reflections on the causality of diseases contributed to the epistemology of crises theory, and reflects on the metaphisical shift accompanying the transition from the theories of crises to the theories of cycles.

The role of the vascular endothelium in arenavirus haemorrhagic fevers.

Viral haemorrhagic fevers (VHF) caused by arenaviruses are among the most devastating emerging human diseases. The most important pathogen among the arenaviruses is Lassa virus (LASV), the causative agent of Lassa fever that is endemic to West Africa. On the South American continent, the New World arenavirus Junin virus (JUNV), Machupo (MACV), Guanarito (GTOV), and Sabia virus (SABV) have emerged as causative agents of severe VHFs. Clinical and experimental studies on arenavirus VHF have revealed a crucial role of the endothelium in their pathogenesis. However, in contrast to other VHFs, haemorrhages are not a salient feature of Lassa fever and fatal cases do not show overt destruction of vascular tissue. The functional alteration of the vascular endothelium that precede shock and death in fatal Lassa fever may be due to more subtle direct or indirect effects of the virus on endothelial cells. Haemorrhagic disease manifestations and vascular involvement are more pronounced in the VHF caused by the South American haemorrhagic fever viruses. Recent studies on JUNV revealed perturbation of specific endothelial cell function, including expression of cell adhesion molecules, coagulation factors, and vasoactive mediators as a consequence of productive viral infection. These studies provided first possible links to some of the vascular abnormalities observed in patients, however, their relevance in vivo remains to be investigated.

Safety of falciparum malaria diagnostic strategy based on rapid diagnostic tests in returning travellers and migrants: a retrospective study.

BACKGROUND: Rapid diagnostic tests for malaria (RDTs) allow accurate diagnosis and prompt treatment. Validation of their usefulness in travellers with fever was needed. The safety of a strategy to diagnose falciparum malaria based on RDT followed by immediate or delayed microscopy reading at first attendance was evaluated in one referral hospital in Switzerland. METHODS: A retrospective study was conducted in the outpatient clinic and emergency ward of University Hospital, covering a period of eight years (1999-2007). The study was conducted in the outpatient clinic and emergency ward of University Hospital. All adults suspected of malaria with a diagnostic test performed were included. RDT and microscopy as immediate tests were performed during working hours, and RDT as immediate test and delayed microscopy reading out of laboratory working hours. The main outcome measure was occurrence of specific complications in RDT negative and RDT positive adults. RESULTS: 2,139 patients were recruited. 1987 had both initial RDT and blood smear (BS) result negative. Among those, 2/1987 (0.1%) developed uncomplicated malaria with both RDT and BS positive on day 1 and day 6 respectively. Among the 152 patients initially malaria positive, 137 had both RDT and BS positive, four only BS positive and five only RDT positive (PCR confirmed) (six had only one test performed). None of the four initially RDT negative/BS positive and none of the five initially BS negative/RDT positive developed severe malaria while 6/137 of both RDT and BS positive did so. The use of RDT allowed a reduction of a median of 2.1 hours to get a first malaria test result. CONCLUSIONS: A malaria diagnostic strategy based on RDTs and a delayed BS is safe in non-immune populations, and shortens the time to first malaria test result.

Secretory IgA in human serum.

Secretory component (SC) was detected by the radioactive single radial diffusion technique in nearly all sera examined. The SC was shown to be associated with polymeric serum IgA. The mean level of secretory IgA (SIgA) in normal sera from India, Africa and Europe was about 0.03 to 0.04 mg/ml. The mean level was elevated in patients with a variety of disorders involving secretory surfaces (e.g., acute bacterial enterocolitis or respiratory tract carcinoma), but also in disorders with no known involvement of secretory surfaces. The highest levels were seen in lactating women, with a mean level five times higher than that in the general population. SIgA was also found at lower levels in cord serum, serum from breast-fed newborns and serum from children 3 to 10 years old.

Three years of haemovigilance in a general university hospital.

The aim of this study is to describe a newly implemented haemovigilance system in a general university hospital. We present a series of short cases, highlighting particular aspects of the reports, and an overview of all reported incidents between 1999 and 2001. Incidents related to transfusion of blood products were reported by the clinicians using a standard preformatted form, giving a synopsis of the incident. After analysis, we distinguished, on the one hand, transfusion reactions, that are transfusions which engendered signs or symptoms, and, on the other hand, the incidents where management errors and/or dysfunctions took place. Over 3 years, 233 incidents were reported, corresponding to 4.2 events for 1000 blood products delivered. Of the 233, 198 (85%) were acute transfusion reactions and 35 (15%) were management errors and/or dysfunctions. Platelet units gave rise to statistically (P < 0.001) more transfusion reactions (10.7 per thousand ) than red blood cells (3.5 per thousand ) and fresh frozen plasma (0.8 per thousand ), particularly febrile nonhaemolytic transfusion reactions and allergic reactions. A detailed analysis of some of the transfusion incident reports revealed complex deviations and/or failures of the procedures in place in the hospital, allowing the implementation of corrective and preventive measures. Thus, the haemovigilance system in place in the 'Centre Hospitalier Universitaire Vaudois, CHUV' appears to constitute an excellent instrument for monitoring the security of blood transfusion.

Acute inflammatory reaction associated with endoluminal bypass grafts.

PURPOSE: Nonspecific inflammatory reactions characterized by local tenderness, fever, and flu-like discomfort have been seen in patients undergoing endoluminal graft placement in the abdominal aorta or the femoral arteries. We undertook a study to assess the clinical and laboratory parameters of this inflammation. METHODS: Ten patients with femoropopliteal artery (n = 9) or aortic (n = 1) lesions were treated with EndoPro System 1 stent-grafts made of nitinol alloy and covered with a polyester (Dacron) fabric. Eleven patients implanted with a bare nitinol stent served as the control group. RESULTS: In the stent-graft group, four patients showed clinical signs of acute inflammation manifested by fever and local tenderness. Three of these patients suffered thrombosis of the stent-grafts during the first month of follow-up. Plasma levels of interleukin-1 beta and interleukin-6 in all stent-graft patients were markedly increased 1 day after intervention (7.3 +/- 2.8 versus 90.2 +/- 34.1 pg/mL and 15.6 +/- 5.8 versus 175.5 +/- 66.3 pg/mL, respectively; p < 0.01). This was followed by an increase in fibrinogen (3.0 +/- 0.2 versus 5.0 +/- 0.2 g/L; p < 0.05) and C-reactive protein (14.6 +/- 3.3 versus 77.5 +/- 15.0 mg/L; p < 0.01) at 1 week. No direct correlation between the inflammatory markers and symptoms could be found. In vitro analysis showed that individual components of the stent-graft did not activate human neutrophils, whereas the intact stent-graft itself induced a marked neutrophil activation. CONCLUSIONS: The component of the self-expanding stent-graft responsible for the nonspecific inflammatory reaction was not identified in this study. It is likely that the stent-graft itself or some as yet unrecognized element of the device other than the Dacron fabric or metal alloy may be a potent in vivo inducer of cytokine reaction by neutrophils.