Epidemiología de la enfermedad neumocócica invasiva en la región de Tarragona, 2012-2015: incidencia, letalidad y cobertura de serotipos para las distintas formulaciones vacunales antineumocócicas

ABSTRACT Background: Nowadays, after licensure of the second generation new pneumococcal conjugate vaccines (PCV10/PCV13). The epidemiology of the pneumococcal disease must be re-evaluated. The present study described incidence, lethality and serotype distribution of invasive pneumococcal disease (IPD) in the general population of Tarragona’s region (Spain) after licensure of these vaccines. Methods: Retrospective study that included all cases of IPD (pneumococcus isolated in sterile sites) diagnosed among all-age individuals in the Spanish region of Tarragona (Tarragonés, Alt Camp and Baix Penedés counties) from 01/01/2012 to 31/12/2015. Incidence and lethality rates were estimated by age strata and globally. Similarly, it was determined the prevalence of IPD cases caused by serotypes included in the distinct formulations of multivalent conjugate vaccines (pcv7), PCV10 and PCV13) or 23-valent polysaccharide vaccine (PPV23). Results: A total of 171 IPD cases were observed, which means a global incidence (per 100,000 persons-year) of 10.82 (7.86 in ≤14 years, 5.94 in 15-64 years and 36.46 in ≥65 years; p<0.001). Overall lethality rate was 6.8% (none in children, 9,3% in people 15-64 years and 6.9% in people ≥65 years). A serotype was identified in 132 (77.2%) of the 171 studied samples. Serotype-vaccine coverages (cases due to vaccine-type serotypes) were 14.4%, 26.5%, 42.4% and 78.8% for the PCV7, PCV10, PCV13 and PPV23, respectively (p<0.001). Conclusion: Incidence and lethality of IPD were intermediate-low in the region of Tarragona throughout 2012-2015. During this period, Serotype-vaccine coverage was almost double for the 23-valent than for the 13-valent vaccine.RESUMEN Fundamentos: En la actualidad, tras la comercialización de las nuevas vacunas neumocócicas conjugadas de segunda generación (VNC10/VNC13), la epidemiología de la enfermedad neumocócica debe ser reevaluada. El presente estudio tuvo como objetivo describir la incidencia, letalidad y distribución serotípica de la enfermedad neumocócica invasiva (ENI) en la población general del área de Tarragona durante el cuatrienio posterior a la introducción de estas vacunas. Métodos: Estudio observacional retrospectivo que incluyó todos los casos de ENI (Streptococcus pneumoniae aislado en sangre, líquido cefalorraquídeo, líquido pleural/articular/peritoneal o muestras de tejidos profundos obtenidas de forma estéril mediante punción-aspiración o biopsia) diagnosticados en el área de Tarragona (comarcas del Tarragonés, Alt Camp y Baix Penedés) entre 01/01/2012 y 31/12/2015. Se estimaron tasas de incidencia y letalidad (globalmente y por estratos etarios) y se determinó la prevalencia de casos causados por serotipos incluidos en las distintas formulaciones de vacunas antineumocócicas conjugadas heptavalente (VNC7), decavalente (VNC10), tridecavalente (VNC13) y polisacárida tricosavalente (VNP23). Resultados: Se observaron 171 casos de ENI, lo que representó una incidencia (por 100.000 personas-año) de 10,82 (7,86 en ≤14 años, 5,94 en 15-64 años y 36,46 en ≥65 años; p<0,001). La letalidad fue del 6,8% (ninguna en niños, 9,3% en 15-64 años y 6,9% en personas ≥65 años; p<0,001). El serotipo responsable fue identificado en 132 (77,2%) de las 171 muestras estudiadas. La cobertura serotípica (casos causados por serotipos vacunales) fue del 14,4%, 26,5%, 42,4% y 78,8% para la VNC7, VNC10, VNC13 y VNP23, respectivamente (p<0,001). Conclusiones: Durante el periodo 2012-2015 la incidencia y letalidad por ENI fue intermedia-baja en el área de Tarragona, destacando que la cobertura serotípica fue casi doble para la vacuna 23-valente que para la 13-valente

Amyloid beta-peptide increases BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2 α

Alzheimer's disease (AD) is tightly linked to oxidative stress since amyloid beta-peptide (Aβ) aggregates generate free radicals. Moreover, the aggregation of Aβ is increased by oxidative stress, and the neurotoxicity induced by the oligomers and fibrils is in part mediated by free radicals. Interestingly, it has been reported that oxidative stress can also induce BACE1 transcription and expression. BACE1 is the key enzyme in the cleavage of the amyloid precursor protein to produce Aβ, and the expression of this enzyme has been previously shown to be enhanced in the brains of Alzheimer's patients. Here, we have found that BACE1 expression is increased in the hippocampi from AD patients at both the early (Braak stage II) and late (Braak stage VI) stages of the disease as studied by immunohistochemistry and western blot. To address the role of Aβ and oxidative stress in the regulation of BACE1 expression, we have analyzed the effect of subtoxic concentrations of Aβ oligomers (0.25 μM) and H2O2 (10 mM) on a human neuroblastoma cell line. Firstly, our results show that Aβ oligomers and H2O2 induce an increase of BACE1 mRNA as we studied by qPCR. Regarding BACE1 translation, it is dependent on the phosphorylation of the eukaryotic initiation factor 2α (eIF2α), since BACE1 mRNA bears a 5'UTR that avoids its translation under basal conditions. BACE1 5'UTR contains four upstream initiating codons (uAUGs), and its translation is activated when eIF2α is phosphorylated. Consistently, we have obtained that Aβ oligomers and H2O2 increase the levels of BACE1 and p-eIF2α assayed by western blot and confocal microscopy. Our results suggest that Aβ oligomers increase BACE1 translation by phosphorylating eIF2α in a process that involves oxidative stress and conforms a pathophysiological loop, where the Aβ once aggregated favors its own production continuously by the increase in BACE1 expression as observed in AD patients.This research was funded by the Spanish Ministry of Economy and Business through the grant Plan Estatal SAF2017-83372-R and SAF2014-52228-R (FEDER funds/UE) to FJM and RV, Chilean Government through Fondecyt 11611065 and AFB170005 to AA and REDES 180084 to AA and FJM, and MDM-2014-0370 through the María de Maeztu Programme for Units of Excellence in R&D to Departament de Ciències Experimentals i de la Salut. Silvia Menéndez is supported by the Health Deparment of the Generalitat de Catalunya, Spain (PERIS SLT006/17/00040). This work was also supported by the Advanced Microscopy Facility UC