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Adenovirus infections [keywords]
- Discovery and structure-based optimization of adenain inhibitors. [Journal Article]
- ACS Med Chem Lett 2014 Aug 14; 5(8):937-41.
The cysteine protease adenain is the essential protease of adenovirus and, as such, represents a promising target for the treatment of ocular and other adenoviral infections. Through a concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition. These hits enabled the first high-resolution X-ray cocrystal structures of adenain with inhibitors bound and revealed the binding mode of 1 and 2. The screening hits were optimized by a structure-guided medicinal chemistry strategy into low nanomolar drug-like inhibitors of adenain.
- Respiratory viruses are continuously detected in children with chronic tonsillitis throughout the year. [JOURNAL ARTICLE]
- Int J Pediatr Otorhinolaryngol 2014 Jul 21.
To evaluate the oscillations on the viral detection in adenotonsillar tissues from patients with chronic adenotonsillar diseases as an indicia of the presence of persistent viral infections or acute subclinical infections.Cross-sectional prospective study.Tertiary hospital.The fluctuations of respiratory virus detection were compared to the major climatic variables during a two-year period using adenoids and palatine tonsils from 172 children with adenotonsillar hypertrophy and clinical evidence of obstructive sleep apnoea syndrome or recurrent adenotonsillitis, without symptoms of acute respiratory infection (ARI), by TaqMan real-time PCR.The rate of detection of at least one respiratory virus in adenotonsillar tissue was 87%. The most frequently detected viruses were human adenovirus in 52.8%, human enterovirus in 47.2%, human rhinovirus in 33.8%, human bocavirus in 31.1%, human metapneumovirus in 18.3% and human respiratory syncytial virus in 17.2%. Although increased detection of human enterovirus occurred in summer/autumn months, and there were summer nadirs of human respiratory syncytial virus in both years of the study, there was no obvious viral seasonality in contrast to reports with ARI patients in many regions of the world.Respiratory viruses are continuously highly detected during whole year, and without any clinical symptomatology, indicating that viral genome of some virus can persist in lymphoepithelial tissues of the upper respiratory tract.
- Respiratory infections in children up to two years of age on prophylaxis with palivizumab. [Journal Article]
- Rev Paul Pediatr 2014 Jun; 32(2):152-8.
To identify the viruses involved in acute respiratory tract infections and to analyze the rates of hospitalization and death in children on palivizumab prophylaxis.Prospective cohort of 198 infants up to one year old who were born before 29 weeks of gestational age and infants under two years old with hemodynamically unstable cardiopathy or chronic pulmonary disease who received prophylactic palivizumab against severe respiratory syncytial virus infections in 2008. During the study period, in each episode of acute respiratory tract infection, nasopharyngeal aspirate was collected to identify respiratory syncytial virus, adenovirus, parainfluenza 1, 2 and 3, influenza A and B by direct immunofluorescence, rhinovirus and metapneumovirus by polymerase chain reaction preceded by reverse transcription. Data regarding hospitalization and deaths were monitored.Among the 198 studied infants, 117 (59.1%) presented acute respiratory tract infections, with a total of 175 episodes. Of the 76 nasopharyngeal aspirates collected during respiratory tract infections, 37 were positive, as follow: rhinovirus (75.7%), respiratory syncytial virus (18.9%), parainfluenza (8.1%), adenovirus 2 (2.7%), metapneumovirus (2.7%) and three samples presented multiple agents. Of the 198 children, 48 (24.4%) were hospitalized: 30 (15.2%) for non-infectious etiology and 18 (9.1%) for respiratory causes. Among these 18 children, one case of respiratory syncytial virus was identified. Two deaths were reported, but respiratory syncytial virus was not identified.During the prophylaxis period, low frequency of respiratory syncytial virus infections and low rates of hospitalization were observed, suggesting the benefit of palivizumab prophylaxis.
- Comparison of severe pneumonia caused by Human metapneumovirus and respiratory syncytial virus in hospitalized children. [Journal Article]
- Indian J Pathol Microbiol 2014 Jul-Sep; 57(3):413-7.
The objective of this study is to compare the incidence and clinical characteristics of severe pneumonia caused by Human metapneumovirus (hMPV) to respiratory syncytial virus (RSV) infection in children.A total of 151 children hospitalized with severe pneumonia, were tested for hMPV using reverse-transcription polymerase chain reaction. At the same time, samples were tested for RSV and other common respiratory viruses. Medical records, including clinical, laboratory data, and chest radiography findings, were reviewed for all children.Of the 151 samples, 88 (58.3%) were positive for respiratory viruses. Of the 88 positive, there were 6 (4.0%) with hMPV, 66 (43.7%) with RSV, 13 (8.6%) with influenza A, 2 (1.3%) with parainfluenza virus III, 1 (0.7%) with parainfluenza virus I, 1 (0.7%) with adenovirus and 1 (0.7%) with influenza B. hMPV-infected patients were significantly older than RSV-infected patients (P < 0.001). Children with hMPV pneumonia had fever more frequently (P = 0.03). Two hMPV-positive patients (33.3%) required admission to an intensive care unit, and two patients (33.3%) required mechanical ventilation. The duration of illness was 18.33 ± 7.09 days. These characteristics of hMPV infections were similar to patients with RSV infections.Human metapneumovirus is an infrequent viral pathogen causing severe pneumonia in children. Children with hMPV were older than those with RSV. The disease caused by hMPV was similar in presentation and severity to RSV, with a minority of children requiring additional respiratory support.
- Influenza-like illness sentinel surveillance in one hospital in Medellin, Colombia. 2007-2012. [JOURNAL ARTICLE]
- Influenza Other Respir Viruses 2014 Aug 6.
The city of Medellin in Colombia has almost no documentation of the causes of acute respiratory infections (ARIs). As part of an ongoing collaboration, we conducted an epidemiologic surveillance for influenza and other respiratory viruses. It described the influenza strains that were circulating in the region along with their distribution over time, and performing molecular characterization to some of those strains. This will contribute to the knowledge of local and national epidemiology.To analyze viral etiologic agents associated with influenza like illness (ILI) in participants reporting to one General hospital in Medelllin, Colombia.From January 2007 to December 2012, a total of 2039 participants were enrolled. Among them, 1120 (54·9%) were male and 1364 (69%) were under the age of five. Only 124 (6%) were older than the age of 15. From all 2039 participants, 1040 samples were diagnosed by either isolation or RT-PCR. One or more respiratory viruses were found in 737 (36%) participants. Of those, 426 (57·8%) got influenza A or B. Adenoviral and parainfluenza infections represented 19·1% and 14·9% of viral infections, respectively. Influenza A was detected almost throughout the whole year except for the first quarter of 2010, right after the 2009 influenza A pandemic. Influenza B was detected in 2008, 2010, and 2012 with no pattern detected. During 2008 and 2010, both types circulated in about the same proportion. Unusually, in many months of 2012, the proportion of influenza B infections was higher than influenza A (ranging between 30% and 42%). The higher proportion of adenovirus was mainly detected in the last quarter of years 2007 and 2010. Adenoviral cases are more frequent in participants under the age of four.The phylogenetic analysis of influenza viruses shows that only in the case of influenza A/H1N1, the circulating strains totally coincide with the vaccine strains each year.
- Evaluation of the Temporal Association between Kawasaki Disease and Viral Infections in South Korea. [Journal Article]
- Korean Circ J 2014 Jul; 44(4):250-4.
This study is aimed at elucidating potential temporal associations between the occurrence of Kawasaki disease (KD) and various viral infections.We obtained monthly patterns of KD from the seventh nationwide survey and viral detection data from the Korea Centers for Disease Control and Prevention from 2009 to 2011 and evaluated temporal correlations between them for each month. The respiratory viruses detected using a multiplex real-time-polymerase chain reaction kit were influenza virus (A/H1N1, A/H3N2, A/H5N1, and B), adenovirus, parainfluenza virus (type 1, 2, 3), respiratory syncytial virus (type A, B), human rhinovirus, human coronavirus (OC43/229E, NL63), human bocavirus, and enterovirus.We obtained data from a total of 13031 patients who were treated for acute KD from 87 hospitals with pediatric residence programs. During this survey, KD showed highest overall incidence in summer and winter seasons and lowest incidence in February and October. We received viral detection data for a total of 14267 patients. Viral detection was highest during winter and spring seasons. The most commonly detected virus was human rhinovirus (32.6%), followed by influenza virus (26.8%). The monthly incidence of KD showed significant correlation with the monthly overall viral detection (p=0.022, r=0.382). In particular, human bocavirus and enterovirus have significant correlations with monthly patterns of KD occurrence (p=0.032 and p=0.007, respectively) and influenza virus correlated with KD occurrence with borderline significance (p=0.063).The temporal association between monthly occurrence of KD and viral detection suggests the etiologic importance of precedent infection in the development of KD.
- Acute gastroenteritis and enteric viruses in hospitalised children in southern Brazil: aetiology, seasonality and clinical outcomes. [JOURNAL ARTICLE]
- Mem Inst Oswaldo Cruz 2014 Jul; 109(4):428-435.
Viral acute gastroenteritis (AG) is a significant cause of hospitalisation in children younger than five years. Group A rotavirus (RVA) is responsible for 30% of these cases. Following the introduction of RVA immunisation in Brazil in 2006, a decreased circulation of this virus has been observed. However, AG remains an important cause of hospitalisation of paediatric patients and only limited data are available regarding the role of other enteric viruses in these cases. We conducted a prospective study of paediatric patients hospitalised for AG. Stool samples were collected to investigate human adenovirus (HAdV), RVA, norovirus (NoV) and astrovirus (AstV). NoV typing was performed by nucleotide sequencing and phylogenetic analysis. From the 225 samples tested, 60 (26%) were positive for at least one viral agent. HAdV, NoV, RVA and AstV were detected in 16%, 8%, 6% and 0% of the samples, respectively. Mixed infections were found in nine patients: HAdV/RVA (5), HAdV/NoV (3) and HAdV/NoV/RVA (1). The frequency of fever and lymphocytosis was significantly higher in virus-infected patients. Phylogenetic analysis of NoV indicated that all of these viruses belonged to genotype GII.4. The significant frequency of these pathogens in patients with AG highlights the need to routinely implement laboratory investigations.
- Marmosets as a preclinical model for testing "off-label" use of doxycycline to turn on Flt3L expression from high-capacity adenovirus vectors. [JOURNAL ARTICLE]
- Mol Ther Methods Clin Dev 2014 Feb 5.
We developed a combined conditional cytotoxic, i.e., herpes simplex type 1-thymidine kinase (TK), plus immune-stimulatory, i.e., fms-like tyrosine kinase ligand-3-mediated gene therapy for glioblastoma multiforme (GBM). Therapeutic transgenes were encoded within high-capacity adenoviral vectors (HC-Ad); TK was expressed constitutively, while Flt3L was under the control of the TetOn regulatable promoter. We previously assessed efficacy and safety in intracranial GBM rodent models. But, since this approach involves expression of a cytokine within the brain, we chose the nonhuman primate, i.e., Callithrix jaccus (marmoset) as it has been established that its immune response shares similarities with man. We characterized the safety, cell-type specific expression, and doxycycline (DOX)-inducibility of HC-Ad-TetOn-Flt3L delivered within the striatum. We used allometrically scaled DOX doses delivered orally, twice daily for one month, mimicking the route and duration of DOX administration planned for the GBM trial. Flt3L was effectively expressed within astrocytes, microglia, oligodendrocytes, and neurons. No evidence of brain or systemic toxicities due to the treatment was encountered. Our data indicate that DOX doses equivalent to those used in humans to treat infections can be safely used "off-label" to turn "on" therapeutic gene expression from HC-Ad-TetOn-Flt3L; providing evidence for the safety of this approach in the clinic.
- The relevance of respiratory viral infections in the exacerbations of chronic obstructive pulmonary disease-A systematic review. [REVIEW]
- J Clin Virol 2014 Jul 4.
Despite the increasing knowledge on the role of viruses in exacerbations of COPD (AECOPD), it is less clear which viruses are involved and to what extent they contribute to exacerbations. This review aims to systematically combine and evaluate the available literature of the prevalence of respiratory viruses in patients with AECOPD, detected by PCR.An electronic search strategy was performed on PubMed and Embase and reference lists were screened for eligible studies. Cross-sectional, prospective studies and case-control studies were included. The primary outcome measure was the prevalence of respiratory viruses (adenovirus, bocavirus, coronavirus, EBV, hMPV, influenza, parainfluenza, rhino-/enterovirus, RSV) in respiratory secretions of patients during an AECOPD. Secondary outcomes were the odds of the presence of the viruses in different respiratory secretions and the odds of the presence of viruses in upper and lower respiratory tract (URT/LRT) samples.Nineteen studies with 1728 patients were included. Rhino-/enteroviruses (16.39%), RSV (9.90%) and influenza (7.83%) were the most prevalent viruses detected with lower detection rates of coronaviruses (4.08%) and parainfluenza (3.35%). Adenovirus (2.07%), hMPV (2.78%) and bocaviruses (0.56%) appear to be rare causative agents of AECOPD. Definitive conclusions regarding the role of EBV cannot be made. Seven of the eight analyzed viruses had a higher prevalence in LRT samples. Coronaviruses were detected more frequently in the URT.Respiratory viruses are frequently detected in both URT and LRT samples in AECOPD with rhino-/enteroviruses, RSV and influenza viruses the most prevalent viruses. Detection rates vary between the two sites for different viruses.
- Genetic Vaccination against Experimental Infection with Myotropic Parasite Strains of Trypanosoma cruzi. [Journal Article]
- Mediators Inflamm 2014.:605023.
In earlier studies, we reported that a heterologous prime-boost regimen using recombinant plasmid DNA followed by replication-defective adenovirus vector, both containing Trypanosoma cruzi genes encoding trans-sialidase (TS) and amastigote surface protein (ASP) 2, provided protective immunity against experimental infection with a reticulotropic strain of this human protozoan parasite. Herein, we tested the outcome of genetic vaccination of F1 (CB10XBALB/c) mice challenged with myotropic parasite strains (Brazil and Colombian). Initially, we determined that the coadministration during priming of a DNA plasmid containing the murine IL-12 gene improved the immune response and was essential for protective immunity elicited by the heterologous prime-boost regimen in susceptible male mice against acute lethal infections with these parasites. The prophylactic or therapeutic vaccination of resistant female mice led to a drastic reduction in the number of inflammatory infiltrates in cardiac and skeletal muscles during the chronic phase of infection with either strain. Analysis of the electrocardiographic parameters showed that prophylactic vaccination reduced the frequencies of sinus arrhythmia and atrioventricular block. Our results confirmed that prophylactic vaccination using the TS and ASP-2 genes benefits the host against acute and chronic pathologies caused by T. cruzi and should be further evaluated for the development of a veterinary or human vaccine against Chagas disease.