Detection of a New Yellow Fever Virus Lineage Within the South American Genotype I in Brazil

Nucleotide sequences of two regions of the genomes of 11 yellow fever virus (YFV) samples isolated from monkeys or humans with symptomatic yellow fever (YF) in Brazil in 2000,2004, and 2008 were determined with the objective of establishing the genotypes and studying the genetic variation. Results of the Bayesian phylogenetic analysis showed that sequences generated from strains from 2004 and 2008 formed a new subclade within the clade 1 of the South American genotype I. The new subgroup is here designated as 1E. Sequences of YFV strains recovered in 2000 belong to the subclade 1D, which comprises previously characterized YFV strains from Brazil. Molecular dating analyses suggested that the new subclade 1E started diversifying from 1D about 1975 and that the most recent 2004-2008 isolates arose about 1985. J. Med. Virol. 82:175-185, 2010. (C) 2009 Wiley-Liss, Inc.

Alboserpin, a Factor Xa Inhibitor from the Mosquito Vector of Yellow Fever, Binds Heparin and Membrane Phospholipids and Exhibits Antithrombotic Activity

The molecular mechanism of factor Xa (FXa) inhibition by Alboserpin, the major salivary gland anticoagulant from the mosquito and yellow fever vector Aedes albopictus, has been characterized. cDNA of Alboserpin predicts a 45-kDa protein that belongs to the serpin family of protease inhibitors. Recombinant Alboserpin displays stoichiometric, competitive, reversible and tight binding to FXa (picomolar range). Binding is highly specific and is not detectable for FX, catalytic site-blocked FXa, thrombin, and 12 other enzymes. Alboserpin displays high affinity binding to heparin (K(D) similar to 20 nM), but no change in FXa inhibition was observed in the presence of the cofactor, implying that bridging mechanisms did not take place. Notably, Alboserpin was also found to interact with phosphatidylcholine and phosphatidylethanolamine but not with phosphatidylserine. Further, annexin V (in the absence of Ca(2+)) or heparin outcompetes Alboserpin for binding to phospholipid vesicles, suggesting a common binding site. Consistent with its activity, Alboserpin blocks prothrombinase activity and increases both prothrombin time and activated partial thromboplastin time in vitro or ex vivo. Furthermore, Alboserpin prevents thrombus formation provoked by ferric chloride injury of the carotid artery and increases bleeding in a dose-dependent manner. Alboserpin emerges as an atypical serpin that targets FXa and displays unique phospholipid specificity. It conceivably uses heparin and phosphatidylcholine/phosphatidylethanolamine as anchors to increase protein localization and effective concentration at sites of injury, cell activation, or inflammation.

The three-dimensional structure of bothropasin, the main hemorrhagic factor from Bothrops jararaca venom: Insights for a new classification of snake venom metalloprotease subgroups

Bothropasin is a 48 kDa hemorrhagic PIII snake venom metalloprotease (SVMP) isolated from Bothrops jararaca, containing disintegrin/cysteine-rich adhesive domains. Here we present the crystal structure of bothropasin complexed with the inhibitor POL647. The catalytic domain consists of a scaffold of two subdomains organized similarly to those described for other SVMPs, including the zinc and calcium-binding sites. The free cysteine residue Cys(189) is located within a hydrophobic core and it is not available for disulfide bonding or other interactions. There is no identifiable secondary structure for the disintegrin domain, but instead it is composed mostly of loops stabilized by seven disulfide bonds and by two calcium ions. The ECD region is in a loop and is structurally related to the RGD region of RGD disintegrins, which are derived from I`ll SVMPs. The ECD motif is stabilized by the Cys(117)_Cys(310) disulfide bond (between the disintegrin and cysteine-rich domains) and by one calcium ion. The side chain of Glu(276) of the ECD motif is exposed to solvent and free to make interactions. In bothropasin, the HVR (hyper-variable region) described for other Pill SVMPs in the cysteine-rich domain, presents a well-conserved sequence with respect to several other Pill members from different species. We propose that this subset be referred to as PIII-HCR (highly conserved region) SVMPs. The differences in the disintegrin-like, cysteine-rich or disintegrin-like cysteine-rich domains may be involved in selecting target binding, which in turn could generate substrate diversity or specificity for the catalytic domain. (C) 2008 Elsevier Ltd. All rights reserved.

The small nuclear ribonucleoprotein U1A interacts with NS5 from yellow fever virus

The flavivirus NS5 protein is one of the most important proteins of the replication complex, and cellular proteins can interact with it. This study shows for the first time that the yellow fever virus (YFV) NS5 protein is able to interact with U1A, a protein involved in splicing and polyadenylation. We confirmed this interaction by GST-pulldown assay and by co-immunoprecipitation in YFV-infected cells. A region between amino acids 368 and 448 was identified as the site of interaction of the NS5 protein with U1A. This region was conserved among some flaviviruses of medical importance. The implications of this interaction for flavivirus replication are discussed.

Yellow fever vaccination coverage among children in Brazilian capitals

Brazil recommends universal yellow fever (YF) vaccination for children who reside in or travel to endemic areas. We conducted a household survey to calculate YF vaccine coverage among children 18-30 months of age in 27 capital cities. A total of 9285 children were surveyed in the 15 cities with YF fever universal vaccination; 7290(79%) had documented evidence of YF vaccination by 12 months of age, 7996 (86%) by 18 months of age, and 8479 (91%) prior to the survey. In 12 cities with selective YF vaccination coverage was only 1% by 18 months of age. YF fever vaccination can be improved to reach all children where vaccine is recommended. (C) 2010 Elsevier Ltd. All rights reserved.

Economic recovery from the Argentine great depression : institutions, expectations, and the change of macroeconomic regime

This work explores how Argentina overcame the Great Depression and asks whether active macroeconomic interventions made any contribution to the recovery. In particular, we study Argentine macroeconomic policy as it deviated from gold-standard orthodoxy after the final suspension of convertibility in 1929. As elsewhere, fiscal policy in Argentina was conservative, and had little power to smooth output. Monetary policy became heterodox after 1929. The first and most important stage of institutional change took place with the switch from a metallic monetary regime to a fiduciary regime in 1931; the Caja de Conversión (Conversion Office, a currency board) began rediscounting as a means to sterilize gold outflows and avoid deflationary pressures, thus breaking from orthodox "mIes of the game." However, the actual injections of liquidity were small' and were not enough to fully offset the incipient monetary contractions: the "Keynes" effect was weak or negative. Rather, recovery derived from changes in beliefs and expectations surrounding the shift in the monetary and exchange-rate regime,and the delinking of gold flows and the money base. Agents perceivod a new regime, as shown by the path of consumption, investment, and estimated ex ante real interest rates: the "Mundell" effect was dominant. Notably, this change of regime predated a later, and supposedly more significant, stage of institutional reform, namely the creation of the central bank in 1935. Still, the extent of intervention was weak, and insufficient to fully offset externaI shocks to prices and money. Argentine macropolicy was heterodox in terms of the change of regime, but still conservative in terms of the tentative scope of the measures taken .

Trends in rheumatic fever: clinical aspects and perspectives in prophylactic treatments

Introduction: Rheumatic fever (RF), a systemic illness that may occur following Group A beta-hemolytic streptococcal (GABHS) pharyngitis in children, is a major problem in countries with limited resources. Because of its long track record and low cost, an injection of benzathine penicillin G (BPG) suspension every 3 or 4 weeks has been used as secondary prophylaxis. Despite its excellent in vitro efficacy, the inability of BPG to eradicate GABHS has been frequently reported.Areas covered: This work reviews the possible causes of failure, as well as the inconvenience of the current prophylactic treatment of acute RF and suggests a new pharmacotherapeutic system that could replace the current one.Expert opinion: RF is a major problem concerning only countries with limited resources and could be considered as a neglected disease. The dose regimen using BPG suspension results in failures, which could be avoided by the use of nanocarrier-based systems. To meet this ultimate goal, the research should be transposed from the laboratory scale to an industrial and clinical application level. This research should be conducted to produce a pharmaceutical dosage form that will be commercially available, consumed by and affordable for patients. However, health, environmental and socioeconomic hazards should be considered.

The early systemic and gastrointestinal oxygenation effects of hemorrhagic shock resuscitation with hypertonic saline and hypertonic saline 6% dextran-70: A comparative study in dogs

The smaller volemic state from hypertonic (7.5%) saline (HS) solution administration in hemorrhagic shock can determine lesser systemic oxygen delivery and tissue oxygenation than conventional plasma expanders. In a model of hemorrhagic shock in dogs, we studied the systemic and gastrointestinal oxygenation effects of HS and hyperoncotic (6%) dextran-70 in combination with HS (HSD) solutions in comparison with lactated Ringer's (LR) and (6%) hydroxyethyl starch (HES) solutions. Forty-eight mongrel dogs were anesthetized, mechanically ventilated, and subjected to splenectomy. A gastric air tonometer was placed. in the stomach for intramucosal gastric CO2 (Pgco(2)) determination and for the calculation of intramucosal. pH (pHi):[pHi = pHa - log(Pgco(2)/Paco(2))].The dogs were hemorrhaged (42% of blood volume) to hold mean arterial blood pressure at 40-50 mm Hg over 30 min and were then resuscitated with LR (n = 12) in a 3:1 relation to removed blood volume; HS (n = 12), 6 mL / kg; HSD (n = 12), 6 mL / kg; and HES (mean molecular weight, 200 kDa; degree of substitution, 0.5) (n = 12) in a 1:1 relation to the removed blood volume. Hemodynamic, systemic, and gastric oxygenation variables were measured at baseline, after 30 min of hemorrhage, and 5, 60, and 120 min after intravascular fluid resuscitation. After fluid resuscitation, HS showed significantly lower arterial pH and mixed venous Po-2 and higher systemic oxygen uptake index and systemic oxygenation extraction than LR and HES (P < 0.05), whereas HSD showed significantly lower arterial pH than LR and HES (P < 0.05). Only HS and HSD did not return arterial pH and pHi to control levels (P < 0.05). In conclusion, all solutions improved systemic and gastrointestinal oxygenation after hemorrhagic shock in dogs. However, the HS solution showed the worst response in comparison to LR and HES solutions in relation to systemic oxygenation, whereas HSD showed intermediate values. HS and HSD solutions did not return regional oxygenation to control values.

Early hemodynamic and renal effects of hemorrhagic shock resuscitation with lactated Ringer's solution, hydroxyethyl starch, and hypertonic saline with or without 6% dextran-70

Background. Considering the renal effects of fluid resuscitation in hemorrhaged patients, the choice of fluid has been a source of controversy. In a model of hemorrhagic shock, we studied the early hemodynamic and renal effects of fluid resuscitation with lactated Ringer's (LR), 6% hydroxyethyl starch (HES), and 7.5% hypertonic saline (HS) with or without 6% dextran-70 (HSD).Materials and methods. Forty-eight dogs were anesthetized and submitted to splenectomy. An estimated 40% blood volume was removed to maintain mean arterial pressure (MAP) at 40 mm Hg for 30 min. The dogs were divided into four groups: LR, in a 3:1 ratio to removed blood volume; HS, 6 mL kg(-1); HSD, 6 mL kg(-1); and HES in a 1:1 ratio to removed blood volume. Hemodynamics and renal function were studied during shock and 5, 60, and 120 min after fluid replacement.Results. Shock treatment increased MAP similarly in all groups. At 5 min, cardiac filling pressures and cardiac performance indexes were higher for LR and HES but, after 120 min, there were no differences among groups. Renal blood flow and glomerular filtration rate (GFR) were higher in LR at 60 min but GFR returned to baseline values in all groups at 120 min. Diuresis was higher for LR at 5 min and for LR and HES at 60 min. There were no differences among groups in renal variables 120 min after treatment.Conclusions. Despite the immediate differences in hemodynamic responses, the low-volume resuscitation fluids, HS and HSD, are equally effective to LR and HES in restoring renal performance 120 min after hemorrhagic shock treatment. (c) 2006 Elsevier B.V. All rights reserved.

The Effects of 6% Hydroxyethyl Starch-Hypertonic Saline in Resuscitation of Dogs with Hemorrhagic Shock

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Does the Choice of the Halogenated Anesthetic Influence Renal Function during Hemorrhagic Shock and Resuscitation?

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Higher prevalence of obsessive-compulsive spectrum disorders in rheumatic fever

Objective: This study aims to compare the prevalence of obsessive-compulsive spectrum disorders (OCSD) in psychiatric outpatients with and without a history of rheumatic fever (RF).Methods: An analytical cross-sectional study assessing a large sample of consecutive psychiatric outpatients at a Brazilian private practice was conducted during a 10-year period. Psychiatric diagnoses were made by a senior psychiatrist based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Best-estimate diagnosis procedure was also performed.Results: The total sample comprised 678 subjects, 13 of whom (1.92%) presented with a previous history of RF. This group showed a higher prevalence of subclinical obsessive-compulsive disorder (P=.025) and OCSD (P=.007) when compared to individuals with no such history.Conclusions: A previous history of RF was associated with OCSD. These results suggest that clinicians should be encouraged to actively investigate obsessive-compulsive symptoms and related disorders in patients with a positive history of RF. (C) 2009 Published by Elsevier B.V.