There is solid evidence indicating that hyperphosphorylated tau protein, the main component of intracellular neurofibrillary tangles present in the brain of Alzheimer disease patients, plays a key ...role in progression of this disease. However, it has been recently reported that extracellular unmodified tau protein may also induce a neurotoxic effect on hippocampal neurons by activation of M1 and M3 muscarinic receptors. In the present work we show an essential component that links both effects, which is tissue-nonspecific alkaline phosphatase (TNAP). This enzyme is abundant in the central nervous system and is mainly required to keep control of extracellular levels of phosphorylated compounds. TNAP dephosphorylates the hyperphosphorylated tau protein once it is released upon neuronal death. Only the dephosphorylated tau protein behaves as an agonist of muscarinic M1 and M3 receptors, provoking a robust and sustained intracellular calcium increase finally triggering neuronal death. Interestingly, activation of muscarinic receptors by dephosphorylated tau increases the expression of TNAP in SH-SY5Y neuroblastoma cells. An increase in TNAP activity together with increases in protein and transcript levels were detected in Alzheimer disease patients when they were compared with healthy controls.
Cervical cancer (CC) and genital warts (GW) are a significant public health issue in Venezuela. Our objective was to assess the cost-effectiveness of the two available vaccines, bivalent and ...quadrivalent, against Human Papillomavirus (HPV) in Venezuelan girls in order to inform decision-makers.
A previously published Markov cohort model, informed by the best available evidence, was adapted to the Venezuelan context to evaluate the effects of vaccination on health and healthcare costs from the perspective of the healthcare payer in an 11-year-old girls cohort of 264,489. Costs and quality-adjusted life years (QALYs) were discounted at 5%. Eight scenarios were analyzed to depict the cost-effectiveness under alternative vaccine prices, exchange rates and dosing schemes. Deterministic and probabilistic sensitivity analyses were performed.
Compared to screening only, the bivalent and quadrivalent vaccines were cost-saving in all scenarios, avoiding 2,310 and 2,143 deaths, 4,781 and 4,431 CCs up to 18,459 GW for the quadrivalent vaccine and gaining 4,486 and 4,395 discounted QALYs respectively. For both vaccines, the main determinants of variations in the incremental costs-effectiveness ratio after running deterministic and probabilistic sensitivity analyses were transition probabilities, vaccine and cancer-treatment costs and HPV 16 and 18 distribution in CC cases. When comparing vaccines, none of them was consistently more cost-effective than the other. In sensitivity analyses, for these comparisons, the main determinants were GW incidence, the level of cross-protection and, for some scenarios, vaccines costs.
Immunization with the bivalent or quadrivalent HPV vaccines showed to be cost-saving or cost-effective in Venezuela, falling below the threshold of one Gross Domestic Product (GDP) per capita (104,404 VEF) per QALY gained. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results.
Respiratory syncytial virus (RSV) is an important cause of serious lower respiratory tract disease in infants. Several studies have shown evidence pointing to the genome of the host as an important ...factor determining susceptibility to respiratory disease caused by RSV. We sequenced the complete exomes of 54 patients infected by RSV that needed hospitalization due to development of severe bronchiolitis. The Iberian sample (IBS) from The 1000 Genomes Project (1000G) was used as control group; all the association results were pseudo-replicated using other 1000G-European controls and Spanish controls. The study points to SNP rs199665292 in the olfactory receptor (OR) gene OR13C5 as the best candidate variant (P-value = 1.16 × 10
; OR = 5.56). Genetic variants at HLA genes (HLA-DQA1, HLA-DPB1), and in the mucin 4 gene (MUC4) also emerge as susceptibility candidates. By collapsing rare variants in genes and weighing by pathogenicity, we obtained confirmatory signals of association in the OR gene OR8U1/OR8U8, the taste receptor TAS2R19, and another mucin gene (MUC6). Overall, we identified new predisposition variants and genes related to RSV infection. Of special interest is the association of RSV to olfactory and taste receptors; this finding is in line with recent evidence pointing to their role in viral infectious diseases.
Cuando se somete a cirugía a los pacientes con enfermedades reumáticas, una decisión difícil es si se suspende o no la medicación antirreumática durante el período perioperatorio. La mayor dificultad ...reside en lograr un equilibrio entre mantener el control de la enfermedad y optimizar la cicatrización de la herida quirúrgica, así como reducir al mínimo el riesgo de infección postoperatoria y el de otros tipos de morbilidad. En el presente manuscrito revisamos los datos disponibles sobre el uso de los glucocorticoides (GC), los medicamentos antirreumáticos modificadores de la enfermedad (DMARD) y los productos biológicos en el período perioperatorio de pacientes con enfermedades reumáticas.
Molecular techniques can often reveal a broader range of pathogens in respiratory infections. We aim to investigate the prevalence and age pattern of viral co-infection in children hospitalized with ...lower tract acute respiratory infection (LT-ARI), using molecular techniques.
A nested polymerase chain reaction approach was used to detect Influenza (A, B), metapneumovirus, respiratory syncytial virus (RSV), parainfluenza (1-4), rhinovirus, adenovirus (A-F), bocavirus and coronaviruses (NL63, 229E, OC43) in respiratory samples of children with acute respiratory infection prospectively admitted to any of the GENDRES network hospitals between 2011-2013. The results were corroborated in an independent cohort collected in the UK.
A total of 204 and 97 nasopharyngeal samples were collected in the GENDRES and UK cohorts, respectively. In both cohorts, RSV was the most frequent pathogen (52.9% and 36.1% of the cohorts, respectively). Co-infection with multiple viruses was found in 92 samples (45.1%) and 29 samples (29.9%), respectively; this was most frequent in the 12-24 months age group. The most frequently observed co-infection patterns were RSV-Rhinovirus (23 patients, 11.3%, GENDRES cohort) and RSV-bocavirus / bocavirus-influenza (5 patients, 5.2%, UK cohort).
The presence of more than one virus in pediatric patients admitted to hospital with LT-ARI is very frequent and seems to peak at 12-24 months of age. The clinical significance of these findings is unclear but should warrant further analysis.
To assess the effectiveness of a Hib vaccination program against X-ray defined bacterial pneumonia in children <2 years in Colombia.
389 cases of radiologically confirmed pneumonia were recruited ...from hospitals in Bogotá and Medellin, Colombia. Two controls per case, matched on age, sex, and socio-economic level, were selected from children attending child health services at the hospitals where pneumonia cases were admitted.
The risk of having X-ray confirmed pneumonia decreased with each Hib dose received; the vaccine effectiveness was 47% (2–72%) among those receiving one dose; 52% for two doses received, and 55% for three doses. These effectiveness levels remained after adjusting for other factors associated with risk of pneumonia.
This study indicates that trials may have underestimated the proportion of radiological pneumonia in the under 2s that is due to Hib. This suggests that the impact of the vaccination will be greater than expected if it can be extended to reach the poorest children, who are at the greatest risk.
Cuando se somete a cirugía a los pacientes con enfermedades reumáticas, una decisión difícil es si se suspende o no la medicación antirreumática durante el período perioperatorio. La mayor dificultad ...reside en lograr un equilibrio entre mantener el control de la enfermedad y optimizar la cicatrización de la herida quirúrgica, así como reducir al mínimo el riesgo de infección postoperatoria y el de otros tipos de morbilidad. En el presente manuscrito revisamos los datos disponibles sobre el uso de los glucocorticoides (GC), los medicamentos antirreumáticos modificadores de la enfermedad (DMARD) y los productos biológicos en el período perioperatorio de pacientes con enfermedades reumáticas.
Cuando se somete a cirugía a los pacientes con enfermedades reumáticas, una decisión difícil es si se suspende o no la medicación antirreumática durante el período perioperatorio. La mayor dificultad ...reside en lograr un equilibrio entre mantener el control de la enfermedad y optimizar la cicatrización de la herida quirúrgica, así como reducir al mínimo el riesgo de infección postoperatoria y el de otros tipos de morbilidad. En el presente manuscrito revisamos los datos disponibles sobre el uso de los glucocorticoides (GC), los medicamentos antirreumáticos modificadores de la enfermedad (DMARD) y los productos biológicos en el período perioperatorio de pacientes con enfermedades reumáticas.
Aims: To assess the effectiveness of a Hib vaccination program against X-ray defined bacterial pneumonia in children <2 years in Colombia. Methods: 389 cases of radiologically confirmed pneumonia ...were recruited from hospitals in Bogotá and Medellin, Colombia. Two controls per case, matched on age, sex, and socio-economic level, were selected from children attending child health services at the hospitals where pneumonia cases were admitted. Results: The risk of having X-ray confirmed pneumonia decreased with each Hib dose received; the vaccine effectiveness was 47% (2-72%) among those receiving one dose; 52% for two doses received, and 55% for three doses. These effectiveness levels remained after adjusting for other factors associated with risk of pneumonia. Conclusions: This study indicates that trials may have underestimated the proportion of radiological pneumonia in the under 2s that is due to Hib. This suggests that the impact of the vaccination will be greater than expected if it can be extended to reach the poorest children, who are at the greatest risk.
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