The Proof-of-Concept of MBA121, a Tacrine-Ferulic Acid Hybrid, for Alzheimer's Disease Therapy.

Great effort has been devoted to the synthesis of novel multi-target directed tacrine derivatives in the search of new treatments for Alzheimer's disease (AD). Herein we describe the proof of concept of MBA121, a compound designed as a tacrine-ferulic acid hybrid, and its potential use in the therapy of AD. MBA121 shows good ß-amyloid (Aß) anti-aggregation properties, selective inhibition of human butyrylcholinesterase, good neuroprotection against toxic insults, such as Aß1-40, Aß1-42, and H2O2, and promising ADMET properties that support translational developments. A passive avoidance task in mice with experimentally induced amnesia was carried out, MBA121 being able to significantly decrease scopolamine-induced learning deficits. In addition, MBA121 reduced the Aß plaque burden in the cerebral cortex and hippocampus in APPswe/PS1ΔE9 transgenic male mice. Our in vivo results relate its bioavailability with the therapeutic response, demonstrating that MBA121 is a promising agent to treat the cognitive decline and neurodegeneration underlying AD.

Individual and collective protective responses during the early phase of the COVID-19 pandemic in 10 different countries: Results from the EUCLID online survey.

BACKGROUND: In times of unprecedented infectious disease threats, it is essential to understand how to increase individual protective behaviors and support for collective measures. The present study therefore examines factors associated with individual and collective pathways. METHODS: Data was collected through an online survey from 4483 participants (70.8% female, M = 41.2 years) across 10 countries from April 15, 2020 to June 2, 2020 as part of the "EUCLID" project (https://euclid.dbvis.de). Structural equation modeling was used to examine individual and collective pathways across and within countries. RESULTS: Overall, the adoption of individual protective behaviors and support for collective measures were high. Risk perception on the individual level and perceived effectiveness at the collective level were positively associated with both individual protective behaviors and support for collective measures. Furthermore, the model explained considerable variance in individual (40.7%) and collective protective behaviors (40.8%) and was largely replicated across countries. CONCLUSIONS: The study extends previous research by demonstrating that individual risk perception and perceived effectiveness of collective measures jointly affect individual protective health behaviors and support for collective measures. These findings highlight the need to jointly consider a variety of behavioral actions against infectious disease threats, acknowledging interactions between individual and collective pathways.

Factores asociados al nivel de ansiedad y de conocimientos sobre puericultura y lactancia de embarazadas primerizas / Factors associated with the anxiety level and knowledge about childcare and lactation in first-time pregnant women

Objetivo: Conocer el nivel de ansiedad y conocimientos de puericultura y lactancia de las embarazadas primerizas actuales, y las variables clínico-demográficas con las que se relacionan. Diseño: Estudio transversal. Emplazamiento: Siete centros de salud del Área V (Asturias). Participantes: Embarazadas primerizas que completaron cursos preparto del 01.06.2015 al 31.10.2015, excluyendo gestación múltiple, embarazo de riesgo, lactancia materna (LM) contraindicada y problemas lingüísticos. Intervenciones: Cuestionario de variables sociodemográficas, cuestionario ansiedad STAI y 23 preguntas sobre puericultura y lactancia. Mediciones principales: Realizamos análisis descriptivo y coeficientes de regresión lineal múltiple (programa R). Resultados; Captamos 104 embarazadas, con una edad media de 34,2(DE: 4,5) años; el 94,2% eran españolas, el 61,5% universitarias, el 17,3% fumadoras en el embarazo, y el 23,1% tenía antecedentes psicopatológicos. El 88,4% planeaba dar LM. El STAI estado (STAI-E) medio fue de 18,1(DE: 7,4) y puntuaron 4,5(DE: 2,3) errores de media. Las preguntas más falladas versaban sobre causas de fiebre (56,7%), medición de fiebre (54,8%) y deposiciones fisiológicas (55,7%). El análisis multivariante entre conocimientos y perfil mostró asociaciones estadísticamente significativas con ser extranjera, universitaria, con planificación del embarazo y con la matrona. En relación con el STAI-E, este fue significativo para ser fumadora, haber recibido LM, antecedentes psicopatológicos y matrona. Conclusiones: Las embarazadas actuales que completan cursos preparto son principalmente maduras, universitarias y españolas. Poseen buenos conceptos sobre lactancia pero muchas desconocen conceptos básicos de fiebre y deposiciones del lactante. Las madres extranjeras, con embarazo no deseado y estudios primarios parecen tener conceptos más confusos. Las madres fumadoras, con antecedentes psicopatológicos y que no han recibido LM presentan más ansiedad. La matrona influye significativamente sobre la ansiedad y los conceptos adquiridos

Objective: To know the level of anxiety and knowledge of childcare and lactation of the current pregnant women, and the clinical-demographic variables with which they are related. Design: Cross-sectional study. Setting:Seven health centers of Area V (Asturias). Participants: First-time pregnant women who completed preparatory courses from 01.06.2015 to 31.10.2015, excluding multiple gestation, risk pregnancy, contraindicated breastfeeding and language problems. Interventions: Sociodemographic variables questionnaire, STAI state anxiety questionnaire and 23 questions about childcare and lactation. Main measurements: We performed descriptive and multivariate analysis (program R) of the variables of the questionnaire. Results: We captured 104 pregnant women; average age 34.2(SD: 4.5), 94.2% Spanish, 61.5% university, 17.3% smokers in pregnancy, 23.1% with psychopathological antecedents; 88.4% planned to give breastfeeding. The mean STAI-S was 18.1(SD: 7.4) and scored 4.5(SD: 2.3) mean errors. The most faulty ones were on causes of fever (56.7%), fever measurement (54.8%) and physiological stools (55.7%). The multivariate analysis between knowledge and profile showed statistically significant associations with: being foreign, university, pregnancy planning and matron. In relation to the STAI-S was significant for being a smoker, receiving breastfeeding, psychopathological antecedents and matron. Conclusions: The current pregnant women who complete preparatory courses are mainly mature, university and Spanish. They have good concepts about breastfeeding but many are unaware of basic concepts of fever and stool of the infant. Foreign mothers with unwanted pregnancy and primary education seem to have more confusing concepts. Smoking mothers with psychopathological antecedents and who have not received breastfeeding present more anxiety. The matron significantly influences anxiety and acquired concepts

[Factors associated with the anxiety level and knowledge about childcare and lactation in first-time pregnant women]. / Factores asociados al nivel de ansiedad y de conocimientos sobre puericultura y lactancia de embarazadas primerizas.

OBJECTIVE: To know the level of anxiety and knowledge of childcare and lactation of the current pregnant women, and the clinical-demographic variables with which they are related. DESIGN: Cross-sectional study. SETTING: Seven health centers of Area V (Asturias). PARTICIPANTS: First-time pregnant women who completed preparatory courses from 01.06.2015 to 31.10.2015, excluding multiple gestation, risk pregnancy, contraindicated breastfeeding and language problems. INTERVENTIONS: Sociodemographic variables questionnaire, STAI state anxiety questionnaire and 23 questions about childcare and lactation. MAIN MEASUREMENTS: We performed descriptive and multivariate analysis (program R) of the variables of the questionnaire. RESULTS: We captured 104 pregnant women; average age 34.2(SD: 4.5), 94.2% Spanish, 61.5% university, 17.3% smokers in pregnancy, 23.1% with psychopathological antecedents; 88.4% planned to give breastfeeding. The mean STAI-S was 18.1(SD: 7.4) and scored 4.5(SD: 2.3) mean errors. The most faulty ones were on causes of fever (56.7%), fever measurement (54.8%) and physiological stools (55.7%). The multivariate analysis between knowledge and profile showed statistically significant associations with: being foreign, university, pregnancy planning and matron. In relation to the STAI-S was significant for being a smoker, receiving breastfeeding, psychopathological antecedents and matron. CONCLUSIONS: The current pregnant women who complete preparatory courses are mainly mature, university and Spanish. They have good concepts about breastfeeding but many are unaware of basic concepts of fever and stool of the infant. Foreign mothers with unwanted pregnancy and primary education seem to have more confusing concepts. Smoking mothers with psychopathological antecedents and who have not received breastfeeding present more anxiety. The matron significantly influences anxiety and acquired concepts.

Multiple sclerosis and mixed microbial infections. Direct identification of fungi and bacteria in nervous tissue.

Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS), leading to multifocal demyelination and neurodegeneration. The etiology of this incurable disease is unknown and remains a matter of intensive research. The possibility that microbial infections, such as viruses or bacteria, can trigger an autoimmune reaction in CNS tissue has been suggested. However, the recent demonstration that bacteria are present in CNS tissue points to a direct involvement of microbial infections in the etiology of MS. In the present study, we provide the first evidence of fungal infection in CNS tissue of MS patients, and demonstrate that fungal DNA from different species can be detected in the CNS. We used, nested PCR assays together with next-generation sequencing to identify the fungal species in the nervous tissue of 10 patients with MS. Strikingly, Trichosporon mucoides was found in the majority of MS patients, and particularly high levels of this fungus were found in two patients. Importantly, T. mucoides was not detected in the CNS of control subjects. We were also able to visualize fungal structures in CNS tissue sections by immunohistochemistry using specific antifungal antibodies, which also revealed the accumulation of a number of microbial cells in microfoci. Again, microbial structures were not observed in CNS sections from controls. In addition to fungi, neural tissue from MS patients was also positive for bacteria. In conclusion, our present observations point to the novel concept that MS could be caused by polymicrobial infections. Thus, mycosis of the CNS may be accompanied by opportunistic bacterial infection, promoting neuroinflammation and directly causing focal lesions, followed by demyelination and axonal injury.

Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia in elderly people. The etiology of this disease remains a matter of intensive research in many laboratories. We have advanced the idea that disseminated fungal infection contributes to the etiology of AD. Thus, we have demonstrated that fungal proteins and DNA are present in nervous tissue from AD patients. More recently, we have reported that bacterial infections can accompany these mycoses, suggesting that polymicrobial infections exist in AD brains. In the present study, we have examined fungal and bacterial infection in brain tissue from AD patients and control subjects by immunohistochemistry. In addition, we have documented the fungal and bacterial species in brain regions from AD patients and control subjects by next-generation sequencing (NGS). Our results from the analysis of ten AD patients reveal a variety of fungal and bacterial species, although some were more prominent than others. The fungal genera more prevalent in AD patients were Alternaria, Botrytis, Candida, and Malassezia. We also compared these genera with those found in elderly and younger subjects. One of the most prominent genera in control subjects was Fusarium. Principal component analysis clearly indicated that fungi from frontal cortex samples of AD brains clustered together and differed from those of equivalent control subjects. Regarding bacterial infection, the phylum Proteobacteria was the most prominent in both AD patients and controls, followed by Firmicutes, Actinobacteria, and Bacteroides. At the family level, Burkholderiaceae and Staphylococcaceae exhibited higher percentages in AD brains than in control brains. These findings could be of interest to guide targeted antimicrobial therapy for AD patients. Moreover, the variety of microbial species in each patient may constitute a basis for a better understanding of the evolution and severity of clinical symptoms in each patient.

Fungal infection in neural tissue of patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the main cause of motor neuron pathology. The etiology of the disease remains unknown, and no effective therapy exists to halt the disease or improve the quality of life. Here, we provide compelling evidence for the existence of fungal infection in ALS. Immunohistochemistry analysis using a battery of antifungal antibodies revealed fungal structures such as yeast and hyphae in the motor cortex, the medulla and the spinal cord, in eleven patients with ALS. Some fungal structures were localized intracellularly and even intranuclearly, indicating that this infection is not the result of post-mortem colonization. By contrast, this burden of fungal infection cannot be observed in several CNS areas of control subjects. PCR analysis and next generation sequencing of DNA extracted from frozen neural tissue identified a variety of fungal genera including Candida, Malassezia, Fusarium, Botrytis, Trichoderma and Cryptococcus. Overall, our present observations provide strong evidence for mixed fungal infections in ALS patients. The exact mixed infection varies from patient to patient consistent with the different evolution and severity of symptoms in each ALS patient. These novel findings provide a logical explanation for the neuropathological observations of this disease, such as neuroinflammation and elevated chitinase levels, and could help to implement appropriate therapies.

Polymicrobial Infections In Brain Tissue From Alzheimer's Disease Patients.

Several studies have advanced the idea that the etiology of Alzheimer's disease (AD) could be microbial in origin. In the present study, we tested the possibility that polymicrobial infections exist in tissue from the entorhinal cortex/hippocampus region of patients with AD using immunohistochemistry (confocal laser scanning microscopy) and highly sensitive (nested) PCR. We found no evidence for expression of early (ICP0) or late (ICP5) proteins of herpes simplex virus type 1 (HSV-1) in brain sections. A polyclonal antibody against Borrelia detected structures that appeared not related to spirochetes, but rather to fungi. These structures were not found with a monoclonal antibody. Also, Borrelia DNA was undetectable by nested PCR in the ten patients analyzed. By contrast, two independent Chlamydophila antibodies revealed several structures that resembled fungal cells and hyphae, and prokaryotic cells, but most probably were unrelated to Chlamydophila spp. Finally, several structures that could belong to fungi or prokaryotes were detected using peptidoglycan and Clostridium antibodies, and PCR analysis revealed the presence of several bacteria in frozen brain tissue from AD patients. Thus, our results show that polymicrobial infections consisting of fungi and bacteria can be revealed in brain tissue from AD patients.

Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease.

The synthesis, biochemical evaluation, ADMET, toxicity and molecular modeling of novel multi-target-directed Donepezil + Propargylamine + 8-Hydroxyquinoline (DPH) hybrids 1-7 for the potential prevention and treatment of Alzheimer's disease is described. The most interesting derivative was racemic α-aminotrile4-(1-benzylpiperidin-4-yl)-2-(((8-hydroxyquinolin-5-yl)methyl)(prop-2-yn-1-yl)amino) butanenitrile (DPH6) [MAO A (IC50 = 6.2 ± 0.7 µM; MAO B (IC50 = 10.2 ± 0.9 µM); AChE (IC50 = 1.8 ± 0.1 µM); BuChE (IC50 = 1.6 ± 0.25 µM)], an irreversible MAO A/B inhibitor and mixed-type AChE inhibitor with metal-chelating properties. According to docking studies, both DPH6 enantiomers interact simultaneously with the catalytic and peripheral site of EeAChE through a linker of appropriate length, supporting the observed mixed-type AChE inhibition. Both enantiomers exhibited a relatively similar position of both hydroxyquinoline and benzyl moieties with the rest of the molecule easily accommodated in the relatively large cavity of MAO A. For MAO B, the quinoline system was hosted at the cavity entrance whereas for MAO A this system occupied the substrate cavity. In this disposition the quinoline moiety interacted directly with the FAD aromatic ring. Very similar binding affinity values were also observed for both enantiomers with ChE and MAO enzymes. DPH derivatives exhibited moderate to good ADMET properties and brain penetration capacity for CNS activity. DPH6 was less toxic than donepezil at high concentrations; while at low concentrations both displayed a similar cell viability profile. Finally, in a passive avoidance task, the antiamnesic effect of DPH6 was tested on mice with experimentally induced amnesia. DPH6 was capable to significantly decrease scopolamine-induced learning deficits in healthy adult mice.

Relación entre analgesia epidural y tipo de parto / The relationship between epidural analgesia and the type of childbirth

Objetivo: Estudiar la relación que existe entre administración de analgesia epidural durante el trabajo de parto y parto instrumentado (con fórceps o ventosa) en el Hospital Materno-Infantil Teresa Herrera de A Coruña para los casos estudiados que tuvieron lugar en 1999. Material y Métodos: Se seleccionaron 380 casos aleatoriamente a partir de la revisión de historias clínicas, de los cuales 190 habían recibido analgesia epidural y el resto (190) no la habían recibido. Resultados: De la asociación aislada entre analgesia epidural y parto instrumentado encontramos que el riesgo de parto instrumentado cuando se administra analgesia epidural es alto (OR de 2,7). Sin embargo, cuando analizamos por efecto confusor de las diferentes variables encontramos que el ser primípara, el peso del recién nacido > de 3500 g y la analgesia epidural por este orden tienen un efecto independiente sobre la presencia de un parto instrumentado. Por otra parte, se registró una frecuencia similar de casos de sufrimiento fetal intraparto para ambos grupos (5,8 por ciento de los partos con analgesia epidural y 5,3 por ciento de los casos sin analgesia epidural); relación no significativa estadísticamente (según p de 3500 g, tendencia a abreviar expulsivo sin sufrimiento fetal…), que a la analgesia en sí misma. El impacto de ésta sobre el desarrollo último del parto podría verse influido por un cambio en la práctica obstétrica (AU)

[Relationship between epidural analgesia and type of delivery]. / Relación entre analgesia epidural y tipo de parto.

OBJECTIVE: To study the relationship which exists between the administration of an epidural analgesic during labor and an instrument-aided, either with forceps or a suction cup, childbirth in the Teresa Herrera Maternity-Infant Care Hospital in A Coruña for the clinical cases studied during 1999. MATERIALS AND METHODS: 380 cases were selected by lot by going through clinical files; of these 190 had received epidural analgesia while the other 190 had not. RESULTS: Regarding isolated association between epidural analgesic usage and instrument-aided childbirth, we found that the risk of an instrument-aided childbirth is high (OR 2.7) when an epidural analgesic is administered. However, when we analyze our results weighing various factors which may cause confusion, we discover that if it is a woman's first birth, if the newborn's weight is greater than or equal to 3500 g and if an epidural analgesic is administered have an independent effect, in this order, on the presence of an instrument-aided childbirth. At the same time, this study showed a similar occurrence of cases of intra-labor fetal suffering for both groups (5.8% among childbirths in which epidural analgesia was administered and 5.3% among childbirths in which epidural analgesia was not administered); a statistically insignificant relationship (since is less than 0.05%). CONCLUSION: The increase of an instrument-aided childbirth when an epidural analgesic is administered is due more to factors related to the aforementioned analgesia (such as first child birth, fetal weight greater than or equal to 3500 g or a tendency to shorten labor without fetal suffering,...) than to the analgesic itself. The impact of this on the latest developments in childbirth could be affected by a change in obstetrics practices.