Ebastine in the light of CONGA recommendations for the development of third-generation antihistamines

In 2003 a consensus group on new-generation antihistamines (CONGA) defined the characteristics required for a third-generation H1 antihistamine as there had been much controversy about this issue since the early 1990s. One of the antihistamines that had been claimed to belong to such a group is the second-generation antihistamine, ebastine. The objective of this review is to analyze the pharmacology of ebastine, in light of the CONGA recommendations for the development of new-generation antihistamines: (1) anti-inflammatory properties, (2) potency, efficacy and effectiveness, (3) lack of cardiotoxicity, (4) lack of drug interactions, (5) lack of CNS effects, and (6) pharmacological approach. Ebastine seems to have anti-inflammatory properties that help to ameliorate nasal congestion, though this has not yet been conclusively demonstrated. Its pharmacological–therapeutic profile does not differ greatly from that of other second-generation antihistamines. Its cardiac safety has been widely assessed and no cardiac toxicity has been found at therapeutic doses despite initial concerns. The risk of potentially relevant drug interactions has been investigated and ruled out. Ebastine does not produce sedation at therapeutic doses and drug interaction studies with classical CNS depressants have not demonstrated a synergistic effect. Pharmacologically, ebastine is an H1 inverse agonist. Perhaps the answer to the quest for new-generation antihistamines lies not only in H1 but in a combined approach with other histamine receptors

Specific Plasma MicroRNA Signatures Underlying the Clinical Outcomes of Hepatitis E Virus Infection

The pathogenic mechanisms determining the diverse clinical outcomes of HEV infection (e.g., self-limiting vs chronic or symptomatic vs asymptomatic) are not yet understood. Because specific microRNA signatures during viral infection inform the cellular processes involved in virus replication and pathogenesis, we investigated plasma microRNA profiles in 44 subjects, including patients with symptomatic acute (AHE, n = 7) and chronic (CHE, n = 6) hepatitis E, blood donors with asymptomatic infection (HEV BDs, n = 9), and anti-HEV IgG+IgM- (exposed BDs, n = 10) and anti-HEV IgG-IgM- (naïve BDs, n = 12) healthy blood donors. By measuring the abundance of 179 microRNAs in AHE and naïve BDs by RT-qPCR, we identified 51 potencial HEV-regulated microRNAs (PBH < 0.05). Further analysis showed that HEV genotype 3 infection is associated with miR-122, miR-194, miR-885, and miR-30a upregulation and miR-221, miR-223, and miR-27a downregulation. AHE showed significantly higher levels of miR-122 and miR-194, and lower levels of miR-221, miR-27a, and miR-335 compared to HEV BDs. This specific microRNA signature in AHE could promote virus replication and reduce antiviral immune responses, contributing to the development of clinical symptoms. We found that mir-194, miR-335, and miR-221 can discriminate between asymptomatic HEV infections and those developing acute symptoms, whereas miR-335 correctly classify AHE and CHE. Conclusions: Our data suggest that diverse outcomes of HEV infection result from different HEV-induced microRNA dysregulations. The specific microRNA signatures described offer novel information that may serve to develop biomarkers of HEV infection outcomes and improve our understanding of HEV pathogenesis, which may facilitate the identification of antiviral targets

The stealth episome: suppression of gene expression on the excised genomic island PPHGI-1 from Pseudomonas syringae pv. phaseolicola

Pseudomonas syringae pv. phaseolicola is the causative agent of halo blight in the common bean, Phaseolus vulgaris. P. syringae pv. phaseolicola race 4 strain 1302A contains the avirulence gene avrPphB (syn. hopAR1), which resides on PPHGI-1, a 106 kb genomic island. Loss of PPHGI-1 from P. syringae pv. phaseolicola 1302A following exposure to the hypersensitive resistance response (HR) leads to the evolution of strains with altered virulence. Here we have used fluorescent protein reporter systems to gain insight into the mobility of PPHGI-1. Confocal imaging of dual-labelled P. syringae pv. phaseolicola 1302A strain, F532 (dsRFP in chromosome and eGFP in PPHGI-1), revealed loss of PPHGI-1::eGFP encoded fluorescence during plant infection and when grown in vitro on extracted leaf apoplastic fluids. Fluorescence-activated cell sorting (FACS) of fluorescent and non-fluorescent PPHGI-1::eGFP F532 populations showed that cells lost fluorescence not only when the GI was deleted, but also when it had excised and was present as a circular episome. In addition to reduced expression of eGFP, quantitative PCR on sub-populations separated by FACS showed that transcription of other genes on PPHGI-1 (avrPphB and xerC) was also greatly reduced in F532 cells harbouring the excised PPHGI-1::eGFP episome. Our results show how virulence determinants located on mobile pathogenicity islands may be hidden from detection by host surveillance systems through the suppression of gene expression in the episomal state

Design and validation of a three-instrument toolkit for the assessment of competence in electrocardiogram rhythm recognition

Background: Rapid and accurate interpretation of cardiac arrhythmias by nurses has been linked with safe practice and positive patient outcomes. Although training in electrocardiogram (ECG) rhythm recognition is part of most undergraduate nursing programmes, research continues to suggest that nurses and nursing students lack competence in recognising cardiac rhythms. In order to promote patient safety, nursing educators must develop valid and reliable assessment tools that allow the rigorous assessment of this competence before nursing students are allowed to practise without supervision. Aim: To develop and psychometrically evaluate a toolkit to holistically assess competence in ECG rhythm recognition. Methods: Following a convenience sampling technique, 293 nursing students from a nursing faculty in a Spanish university were recruited for the study. The following three instruments were developed and psychometrically tested: a knowledge assessment tool (ECG-KAT), a skills assessment tool (ECG-SAT) and a self-efficacy assessment tool (ECG-SES). Reliability and validity (content, criterion and construct) of these tools were meticulously examined. Results: A high Cronbach’s alpha coefficient demonstrated the excellent reliability of the instruments (ECG-KAT=0.89; ECG-SAT=0.93; ECG-SES=0.98). An excellent context validity index (S-CVI/Ave>0.94) and very good criterion validity were evidenced for all the tools. Regarding construct validity, principal component analysis revealed that all items comprising the instruments contributed to measure knowledge, skills or self-efficacy in ECG rhythm recognition. Moreover, known-groups analysis showed the tools’ ability to detect expected differences in competence between groups with different training experiences. Conclusion: The three-instrument toolkit developed showed excellent psychometric properties for measuring competence in ECG rhythm recognition

Phylogenetic history demonstrates two different lineages of dengue type 1 virus in Colombia

Background: Dengue Fever is one of the most important viral re-emergent diseases affecting about 50 million people around the world especially in tropical and sub-tropical countries. In Colombia, the virus was first detected in the earliest 70′s when the disease became a major public health concern. Since then, all four serotypes of the virus have been reported. Although most of the huge outbreaks reported in this country have involved dengue virus serotype 1 (DENV-1), there are not studies about its origin, genetic diversity and distribution. Results: We used 224 bp corresponding to the carboxyl terminus of envelope (E) gene from 74 Colombian isolates in order to reconstruct phylogenetic relationships and to estimate time divergences. Analyzed DENV-1 Colombian isolates belonged to the formerly defined genotype V. Only one virus isolate was clasified in the genotype I, likely representing a sole introduction that did not spread. The oldest strains were closely related to those detected for the first time in America in 1977 from the Caribbean and were detected for two years until their disappearance about six years later. Around 1987, a split up generated 2 lineages that have been evolving separately, although not major aminoacid changes in the analyzed region were found. Conclusion: DENV-1 has been circulating since 1978 in Colombia. Yet, the phylogenetic relationships between strains isolated along the covered period of time suggests that viral strains detected in some years, although belonging to the same genotype V, have different recent origins corresponding to multiple re-introduction events of viral strains that were circulating in neighbor countries. Viral strains used in the present study did not form a monophyletic group, which is evidence of a polyphyletic origin. We report the rapid spread patterns and high evolution rate of the different DENV-1 lineages

Discovery of VHE Gamma Radiation from IC443 with the MAGIC Telescope

We report the detection of a new source of very high energy (VHE, E_gamma >= 100GeV) gamma-ray emission located close to the Galactic Plane, MAGIC J0616+225, which is spatially coincident with SNR IC443. The observations were carried out with the MAGIC telescope in the periods December 2005 - January 2006 and December 2006 - January 2007. Here we present results from this source, leading to a VHE gamma-ray signal with a statistical significance of 5.7 sigma in the 2006/7 data and a measured differential gamma-ray flux consistent with a power law, described as dN_gamma/(dA dt dE) = (1.0 +/- 0.2)*10^(-11)(E/0.4 TeV)^(-3.1 +/- 0.3) cm^(-2)s^(-1)TeV^(-1). We briefly discuss the observational technique used and the procedure implemented for the data analysis. The results are put in the perspective of the multiwavelength emission and the molecular environment found in the region of IC443.Comment: Accepted by ApJ Letter

Circulation of Different Lineages of Dengue Virus 2, Genotype American/Asian in Brazil: Dynamics and Molecular and Phylogenetic Characterization

The American/Asian genotype of Dengue virus type 2 (DENV-2) was introduced into the Americas in the 80′s. Although there is no data showing when this genotype was first introduced into Brazil, it was first detected in Brazil in 1990. After which the virus spread throughout the country and major epidemics occurred in 1998, 2007/08 and 2010. In this study we sequenced 12 DENV-2 genomes obtained from serum samples of patients with dengue fever residing in São José do Rio Preto, São Paulo (SJRP/SP), Brazil, in 2008. The whole open reading frame or envelope sequences were used to perform phylogenetic, phylogeographic and evolutionary analyses. Isolates from SJRP/SP were grouped within one lineage (BR3) close to isolates from Rio de Janeiro, Brazil. Isolates from SJRP were probably introduced there at least in 2007, prior to its detection in the 2008 outbreak. DENV-2 circulation in Brazil is characterized by the introduction, displacement and circulation of three well-defined lineages in different times, most probably from the Caribbean. Thirty-seven unique amino acid substitutions were observed among the lineages, including seven amino acid differences in domains I to III of the envelope protein. Moreover, we dated here, for the first time, the introduction of American/Asian genotype into Brazil (lineage BR1) to 1988/89, followed by the introduction of lineages BR2 (1998–2000) and BR3 (2003–05). Our results show a delay between the introduction and detection of DENV-2 lineages in Brazil, reinforcing the importance and need for surveillance programs to detect and trace the evolution of these viruses. Additionally, Brazilian DENV-2 differed in genetic diversity, date of introduction and geographic origin and distribution in Brazil, and these are important factors for the evolution, dynamics and control of dengue.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq Grant )Fundação de Amparo à Pesquisa do Estado de São PauloFundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG grant

Phylogenetic reconstruction of dengue virus type 2 in Colombia

Background: Dengue fever is perhaps the most important viral re-emergent disease especially in tropical and subtropical countries, affecting about 50 million people around the world yearly. In Colombia, dengue virus was first detected in 1971 and still remains as a major public health issue. Although four viral serotypes have been recurrently identified, dengue virus type 2 (DENV-2) has been involved in the most important outbreaks during the last 20 years, including 2010 when the fatality rate highly increased. As there are no major studies reviewing virus origin and genotype distribution in this country, the present study attempts to reconstruct the phylogenetic history of DENV-2 using a sequence analysis from a 224 bp PCR-amplified product corresponding to the carboxyl terminus of the envelope (E) gene from 48 Colombian isolates. Results: As expected, the oldest isolates belonged to the American genotype (subtype V), but the strains collected since 1990 represent the American/Asian genotype (subtype IIIb) as previously reported in different American countries. Interestingly, the introduction of this genotype coincides with the first report of dengue hemorrhagic fever in Colombia at the end of 1989 and the increase of cases during the next years. Conclusion: After replacement of the American genotype, several lineages of American/Asian subtype have rapidly spread all over the country evolving in new clades. Nevertheless, the direct association of these new variants in the raise of lethality rate observed during the last outbreak has to be demonstrated

Genome Sequence Analysis of Dengue Virus 1 Isolated in Key West, Florida

Dengue virus (DENV) is transmitted to humans through the bite of mosquitoes. In November 2010, a dengue outbreak was reported in Monroe County in southern Florida (FL), including greater than 20 confirmed human cases. The virus collected from the human cases was verified as DENV serotype 1 (DENV-1) and one isolate was provided for sequence analysis. RNA was extracted from the DENV-1 isolate and was used in reverse transcription polymerase chain reaction (RT-PCR) to amplify PCR fragments to sequence. Nucleic acid primers were designed to generate overlapping PCR fragments that covered the entire genome. The DENV-1 isolate found in Key West (KW), FL was sequenced for whole genome characterization. Sequence assembly, Genbank searches, and recombination analyses were performed to verify the identity of the genome sequences and to determine percent similarity to known DENV-1 sequences. We show that the KW DENV-1 strain is 99% identical to Nicaraguan and Mexican DENV-1 strains. Phylogenetic and recombination analyses suggest that the DENV-1 isolated in KW originated from Nicaragua (NI) and the KW strain may circulate in KW. Also, recombination analysis results detected recombination events in the KW strain compared to DENV-1 strains from Puerto Rico. We evaluate the relative growth of KW strain of DENV-1 compared to other dengue viruses to determine whether the underlying genetics of the strain is associated with a replicative advantage, an important consideration since local transmission of DENV may result because domestic tourism can spread DENVs

Trazodone plus pregabalin combination in the treatment of fibromyalgia: a two-phase, 24-week, open-label uncontrolled study

<p>Abstract</p> <p>Background</p> <p>Although trazodone is frequently used by fibromyalgia patients, its efficacy on this disease has not been adequately studied. If effective, pregabalin, whose beneficial effects on pain and sleep quality in fibromyalgia have been demonstrated, could complement the antidepressant and anxiolytic effects of trazodone. The aim of the present study was to assess the effectiveness of trazodone alone and in combination with pregabalin in the treatment of fibromyalgia.</p> <p>Methods</p> <p>This was an open-label uncontrolled study. Trazodone, flexibly dosed (50-300 mg/day), was administered to 66 fibromyalgia patients during 12 weeks; 41 patients who completed the treatment accepted to receive pregabalin, also flexibly dosed (75-450 mg/day), added to trazodone treatment for an additional 12-week period. Outcome measures included the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI), the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), the Brief Pain Inventory (BPI), the Short-Form Health Survey (SF-36), and the Patients' Global Improvement scale (PGI). Emergent adverse reactions were recorded. Data were analyzed with repeated measures one-way ANOVA and paired Student's t test.</p> <p>Results</p> <p>Treatment with trazodone significantly improved global fibromyalgia severity, sleep quality, and depression, as well as pain interference with daily activities although without showing a direct effect on bodily pain. After pregabalin combination additional and significant improvements were seen on fibromyalgia severity, depression and pain interference with daily activities, and a decrease in bodily pain was also apparent. During the second phase of the study, only two patients dropped out due to side effects.</p> <p>Conclusions</p> <p>Trazodone significantly improved fibromyalgia severity and associated symptomatology. Its combination with pregabalin potentiated this improvement and the tolerability of the drugs in association was good.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00791739">NCT00791739</a></p