Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF

Background In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA). Methods In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2-0-3.0). Patients and investigators were masked to treatment allocation. Between Dec 18,2006, and June 17,2009,14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767. Findings 7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2.79% rivaroxaban vs 2.96% warfarin; hazard ratio [HR] 0-94,95% CI 0.77-1.16) and those without (1.44% vs 1.88%; 0.77, 0.58-1-01; interaction p=0.23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13.31% rivaroxaban vs 13.87% warfarin; HR 0.96,95% CI 0.87-1-07) and those without (16.69% vs 15.19%; 1.10, 0.99-1.21; interaction p=0.08). Interpretation There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.

Clinical trial design in non-invasive brain stimulation psychiatric research

Major depressive disorder (MDD) trials - investigating either non-pharmacological or pharmacological interventions - have shown mixed results. Many reasons explain this heterogeneity, but one that stands out is the trial design due to specific challenges in the field. We aimed therefore to review the methodology of non-invasive brain stimulation (NIBS) trials and provide a framework to improve clinical trial design. We performed a systematic review for randomized, controlled MDD trials whose intervention was transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in MEDLINE and other databases from April 2002 to April 2008. We created an unstructured checklist based on CONSORT guidelines to extract items such as power analysis, sham method, blinding assessment, allocation concealment, operational criteria used for MDD, definition of refractory depression and primary study hypotheses. Thirty-one studies were included. We found that the main methodological issues can be divided in to three groups: (1) issues related to phase II/small trials, (2) issues related to MDD trials and, (3) specific issues of NIBS studies. Taken together, they can threaten study validity and lead to inconclusive results. Feasible solutions include: estimating the sample size a priori; measuring the degree of refractoriness of the subjects; specifying the primary hypothesis and statistical tests; controlling predictor variables through stratification randomization methods or using strict eligibility criteria; adjusting the study design to the target population; using adaptive designs and exploring NIBS efficacy employing biological markers. In conclusion, our study summarizes the main methodological issues of NIBS trials and proposes a number of alternatives to manage them. Copyright (C) 2011 John Wiley & Sons, Ltd.

ABCB1 haplotype is associated with major molecular response in chronic myeloid leukemia patients treated with standard-dose of imatinib

Background: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor used for treating chronic myeloid leukemia (CML). IM has high efficacy, however some individuals develop a resistance due to impaired bio-availability. Polymorphisms in genes encoding membrane transporters such as ABCB1 have been associated with differences in protein expression and function that influence the response to several drugs. Aim: To investigate the relationship of ABCB1 polymorphisms with markers of response to IM in patients with CML Methods: One hundred eighteen CML patients initially treated with a standard dose of IM (400 mg/day) for 18 months were selected at two health centers in Sao Paulo City, Brazil. The response criteria were based on the European LeukemiaNet recommendations. ABCB1 polymorphisms c.1236C>T (rs1128503), c.3435C>T (rs1045642) and c.2677G>T/A (rs2032582) were evaluated by PCR-RFLP. Results: ABCB1 polymorphisms were not related with a risk for CML in this sample population (p<0.05). In the CML group, frequencies of ABCB1 SNPs were similar between responder and non-responder patients (p>0.05). In the responder group, the frequency of ABCB11236CT/2677GT/3435CT haplotype was higher in patients with major molecular response (MMR) (51.7%) than in patients without MMR (8.3%, p = 0.010). Furthermore, carriers of this haplotype had increased the probability of reaching the MMR compared with the non-carriers (OR: 11.8; 95% CI: 1.43-97.3, p = 0.022). Conclusions: The ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients. (C) 2011 Elsevier Inc. All rights reserved.

Non-classical HLA-E gene variability in Brazilians: a nearly invariable locus surrounded by the most variable genes in the human genome

The non-classical human leukocyte antigen (HLA) class I genes present a very low rate of variation. So far, only 10 HLA-E alleles encoding three proteins have been described, but only two are frequently found in worldwide populations. Because of its historical background, Brazilians are very suitable for population genetic studies. Therefore, 104 bone marrow donors from Brazil were evaluated for HLA-E exons 14. Seven variation sites were found, including two known single nucleotide polymorphisms (SNPs) at positions +424 and +756 and five new SNPs at positions +170 (intron 1), +1294 (intron 3), +1625, +1645 and +1857 (exon 4). Haplotyping analysis did show eight haplotypes, three of them known as E*01:01:01, E*01:03:01 and E*01:03:02:01 and five HLA-E new alleles that carry the new variation sites. The HLA-E*01:01:01 allele was the predominant haplotype (62.50%), followed by E*01:03:02:01 (24.52%). Selective neutrality tests have disclosed an interesting pattern of selective pressures in which balancing selection is probably shaping allele frequency distributions at an SNP at exon 3 (codon 107), sequence diversity at exon 4 and the non-coding regions is facing significant purifying pressure. Even in an admixed population such as the Brazilian one, the HLA-E locus is very conserved, presenting few polymorphic SNPs in the coding region.

Rhodolith Beds Are Major CaCO3 Bio-Factories in the Tropical South West Atlantic

Rhodoliths are nodules of non-geniculate coralline algae that occur in shallow waters (<150 m depth) subjected to episodic disturbance. Rhodolith beds stand with kelp beds, seagrass meadows, and coralline algal reefs as one of the world's four largest macrophyte-dominated benthic communities. Geographic distribution of rhodolith beds is discontinuous, with large concentrations off Japan, Australia and the Gulf of California, as well as in the Mediterranean, North Atlantic, eastern Caribbean and Brazil. Although there are major gaps in terms of seabed habitat mapping, the largest rhodolith beds are purported to occur off Brazil, where these communities are recorded across a wide latitudinal range (2 degrees N - 27 degrees S). To quantify their extent, we carried out an inter-reefal seabed habitat survey on the Abrolhos Shelf (16 degrees 50' - 19 degrees 45'S) off eastern Brazil, and confirmed the most expansive and contiguous rhodolith bed in the world, covering about 20,900 km(2). Distribution, extent, composition and structure of this bed were assessed with side scan sonar, remotely operated vehicles, and SCUBA. The mean rate of CaCO3 production was estimated from in situ growth assays at 1.07 kg m(-2) yr(-1), with a total production rate of 0.025 Gt yr(-1), comparable to those of the world's largest biogenic CaCO3 deposits. These gigantic rhodolith beds, of areal extent equivalent to the Great Barrier Reef, Australia, are a critical, yet poorly understood component of the tropical South Atlantic Ocean. Based on the relatively high vulnerability of coralline algae to ocean acidification, these beds are likely to experience a profound restructuring in the coming decades.

Chaos-based communication systems in non-ideal channels

Recently, many chaos-based communication systems have been proposed. They can present the many interesting properties of spread spectrum modulations. Besides, they can represent a low-cost increase in security. However, their major drawback is to have a Bit Error Rate (BER) general performance worse than their conventional counterparts. In this paper, we review some innovative techniques that can be used to make chaos-based communication systems attain lower levels of BER in non-ideal environments. In particular, we succinctly describe techniques to counter the effects of finite bandwidth, additive noise and delay in the communication channel. Although much research is necessary for chaos-based communication competing with conventional techniques, the presented results are auspicious. (C) 2011 Elsevier B. V. All rights reserved.

Glucocorticoid: Major Factor for Reduced Immunogenicity of 2009 Influenza A (H1N1) Vaccine in Patients with Juvenile Autoimmune Rheumatic Disease

Objective. To assess the immunogenicity and safety of non-adjuvanted influenza A H1N1/2009 vaccine in patients with juvenile autoimmune rheumatic disease (ARD) and healthy controls, because data are limited to the adult rheumatologic population. Method's. A total of 237 patients with juvenile ARD [juvenile systemic lupus erythematosus (JSLE), juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM), juvenile scleroderma, and vasculitis] and 91 healthy controls were vaccinated. Serology for anti-H1N1 was performed by hemagglutination inhibition assay. Seroprotection rate, seroconversion rate, and factor-increase in geometric mean titer (GMT) were calculated. Adverse events were evaluated. Results. Age was comparable in patients and controls (14.8 +/- 3.0 vs 14.6 +/- 3.7 years, respectively; p = 0.47). Three weeks after immunization, seroprotection rate (81.4% vs 95.6%; p = 0.0007), seroconversion rate (74.3 vs 95.6%; p < 0.0001), and the factor-increase in GMT (12.9 vs 20.3; p = 0.012) were significantly lower in patients with juvenile ARD versus controls. Subgroup analysis revealed reduced seroconversion rates in JSLE (p < 0.0001), JIA (p = 0.008), JDM (p = 0.025), and vasculitis (p = 0.017). Seroprotection (p < 0.0001) and GMT (p < 0.0001) were decreased only in JSLE. Glucocorticoid use and lymphopenia were associated with lower seroconversion rates (60.4 vs 82.9%; p = 0.0001; and 55.6 vs 77.2%; p = 0.012). Multivariate logistic regression including diseases, lymphopenia, glucocorticoid, and immunosuppressants demonstrated that only glucocorticoid use (p = 0.012) remained significant. Conclusion. This is the largest study to demonstrate a reduced but adequate immune response to H1N1 vaccine in patients with juvenile ARD. It identified current glucocorticoid use as the major factor for decreased antibody production. The short-term safety results support its routine recommendation for patients with juvenile ARD. ClinicalTrials.gov; NCT01151644. (First Release Nov 15 2011; J Rheumatol 2012;39:167-73; doi:10.3899/jrheum.110721)

Galaxy interactions I. Major and minor mergers

Aims. We study galaxy pair samples selected from the Sloan Digital Sky Survey (SDSS-DR7) and we perform an analysis of minor and major mergers with the aim of investigating the dependence of galaxy properties on interactions. Methods. We build a galaxy pair catalog requiring r(p) < 25 kpc h(-1) and Delta V < 350 km s(-1) within redshift z < 0.1. By visual inspection of SDSS images we remove false identifications and we classify the interactions into three categories: pairs undergoing merging, M; pairs with evident tidal features, T; and non disturbed, N. We also divide the pair sample into minor and major interactions according to the luminosity ratio of the galaxy members. We study star formation activity through colors, the 4000 angstrom break, and star formation rates. Results. We find that similar to 10% of the pairs are classified as M. These systems show an excess of young stellar populations as inferred from the D-n(4000) spectral index, colors, and star formation rates of the member galaxies, an effect which we argue is directly related to the ongoing merging process. We find similar to 30% of the pairs exhibiting tidal features (T pairs) with member galaxies showing evidence of old stellar populations. This can be associated either to the disruptive effect of some tidal interactions, or to the longer time-scale of morphological disturbance with respect to the bursts of the tidal induced star formation. Regardless of the color distribution, we find a prominent blue peak in the strongest mergers, while pairs with tidal signs under a minor merger show a strong red peak. Therefore, our results show that galaxy interactions are important in driving the evolution of galaxy bimodality. By adding stellar masses and star formation rates of the two members of the pairs, we explore the global efficiency of star formation of the pairs as a whole. We find that, at a given total stellar mass, major mergers are significantly more efficient (a factor approximate to 2) in forming new stars, with respect to both minor mergers or a control sample of non-interacting galaxies. We conclude that the characteristics of the interactions and the ratio of luminosity galaxy pair members involved in a merger are important parameters in setting galaxy properties.

Severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors

Abstract Background Lower respiratory tract infection (LRTI) is a major cause of pediatric morbidity and mortality, especially among non-affluent communities. In this study we determine the impact of respiratory viruses and how viral co-detections/infections can affect clinical LRTI severity in children in a hospital setting. Methods Patients younger than 3 years of age admitted to a tertiary hospital in Brazil during the months of high prevalence of respiratory viruses had samples collected from nasopharyngeal aspiration. These samples were tested for 13 different respiratory viruses through real-time PCR (rt-PCR). Patients were followed during hospitalization, and clinical data and population characteristics were collected during that period and at discharge to evaluate severity markers, especially length of hospital stay and oxygen use. Univariate regression analyses identified potential risk factors and multivariate logistic regressions were used to determine the impact of specific viral detections as well as viral co-detections in relation to clinical outcomes. Results We analyzed 260 episodes of LRTI with a viral detection rate of 85% (n = 222). Co-detection was observed in 65% of all virus-positive episodes. The most prevalent virus was Respiratory Syncytial Virus (RSV) (54%), followed by Human Metapneumovirus (hMPV) (32%) and Human Rhinovirus (HRV) (21%). In the multivariate models, infants with co-detection of HRV + RSV stayed 4.5 extra days (p = 0.004), when compared to infants without the co-detection. The same trends were observed for the outcome of days of supplemental oxygen use. Conclusions Although RSV remains as the main cause of LRTI in infants our study indicates an increase in the length of hospital stay and oxygen use in infants with HRV detected by RT-PCR compared to those without HRV. Moreover, one can speculate that when HRV is detected simultaneously with RSV there is an additive effect that may be reflected in more severe clinical outcome. Also, our study identified a significant number of children infected by recently identified viruses, such as hMPV and Human Bocavirus (HBov), and this is a novel finding for poor communities from developing countries.

Antioxidant activity and chemical composition of the non polar fraction of Gracilaria domingensis (Kützing) Sonder ex Dickie and Gracilaria birdiae (Plastino & Oliveira)

Gracilaria domingensis (Kützing) Sonder ex Dickie and Gracilaria birdiae (Plastino & Oliveira) (Gracilariales, Rhodophyta) are seaweeds that occur on the Brazilian coast. Based on their economic and pharmaceutical importance, we investigated the antioxidant activity of the methanolic, ethyl acetate and hexane extracts of both species. The hexane extracts display a high antioxidant activity and comparative analyses indicated G. birdiae as the most active species. Chemical investigation of these fractions showed several carotenoids and fatty acids, as well as cholesterol and sitosterol derivatives. HPLC-DAD analysis of G. birdiae showed violaxanthin (0.04 μg.mg-1 of dry material), antheraxanthin (5.31 μg.mg-1), aloxanthin (0.09 μg.mg-1), zeaxanthin (0.45 μg.mg-1) and β-carotene (0.37 μg.mg-1) as the major carotenoids. G. domingensis showed a similar carotenoid profile, however, with much lower concentration than G. birdiae. Gas chromatography coupled to mass spectrometry was used to determine other nonpolar compounds of these seaweeds. The main compounds detected in both studied species were the fatty acids 16:0; 18:1 Δ9; 20:3 Δ6,9,12, 20:4 Δ5,8,11,14. We found no specificity of compounds in either species. However, G. birdiae, presented higher contents of carotenoids and arachidonic acid than G. domingensis.

Rainwater major and trace element contents in Southeastern Brazil: an assessment of a sugar cane region in dry and wet period

The purpose of this study was to assess the composition of the rainwater in Araraquara City, Brazil, a region strongly influenced by pre-harvest burning of sugar cane crops. Chemical and mineralogical variables were measured in rainwater collected during the harvest, dry period of 2009 and the non-harvest, wet period of 2010. Ca2+ and NH4+ were responsible for 55% of cations and NO3- for 45% of anions in rainwater. Al and Fe along with K were the most abundant among trace elements in both soluble and insoluble fractions. High volume weighted mean concentration (VWM) for most of the analyzed species were observed in the harvest, dry period, mainly due to agricultural activities and meteorological conditions. The chemistry of the Araraquara rainwater and principal component analysis (PCA) quantification clearly indicate the concurrence of a diversity of sources from natural to anthropogenic especially related to agricultural activities.

Cell therapy prevents structural, functional and molecular remodeling of remote non-infarcted myocardium

Background/objectives: Therapy using bone marrow (BM) cells has been tested experimentally and clinically due to the potential ability to restore cardiac function by regenerating lost myocytes or increasing the survival of tissues at risk after myocardial infarction (MI). In this study we aimed to evaluate whether BM-derived mononuclear cell (MNC) implantation can positively influence the post-MI structural remodeling, contractility and Ca(2 +)-handling proteins of the remote non-infarcted tissue in rats. Methods and results: After 48 h of MI induction, saline or BM-MNC were injected. Six weeks later, MI scars were slightly smaller and thicker, and cardiac dilatation was just partially prevented by cell therapy. However, the cardiac performance under hemodynamic stress was totally preserved in the BM-MNC treated group if compared to the untreated group, associated with normal contractility of remote myocardium as analyzed in vitro. The impaired post-rest potentiation of contractile force, associated with decreased protein expression of the sarcoplasmic reticulum Ca2 +-ATPase and phosphorylated-phospholamban and overexpression of Na(+)/Ca(2 +) exchanger, were prevented by BM-MNC, indicating preservation of the Ca(2 +) handling. Finally, pathological changes on remodeled remote tissue such as myocyte hypertrophy, interstitial fibrosis and capillary rarefaction were also mitigated by cell therapy. Conclusions: BM-MNC therapy was able to prevent cardiac structural and molecular remodeling after MI, avoiding pathological changes on Ca(2 +)-handling proteins and preserving contractile behavior of the viable myocardium, which could be the major contributor to the improvements of global cardiac performance after cell transplantation despite that scar tissue still exists.

The dengue virus non-structural 1 protein: risks and benefits

The dengue virus (DENV) non-structural 1 (NS1) protein plays a critical role in viral RNA replication and has a central position in DENV pathogenesis. DENV NS1 is a glycoprotein expressed in infected mammalian cells as soluble monomers that dimerize in the lumen of the endoplasmic reticulum; NS1 is subsequently transported to the cell surface, where it remains membrane associated or is secreted into the extracellular milieu as a hexameric complex. During the last three decades, the DENV NS1 protein has also been intensively investigated as a potential target for vaccines and antiviral drugs. In addition, NS1 is the major diagnostic marker for dengue infection. This review highlights some important issues regarding the role of NS1 in DENV pathogenesis and its biotechnological applications, both as a target for the development of safe and effective vaccines and antiviral drugs and as a tool for the generation of accurate diagnostic methods