Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront ...AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ± 15 nM) is associated to a 30.7 ± 8.6% inhibition of the proaggregating action of AChE on the Aβ and a moderate inhibition of Aβ self-aggregation (34.9 ± 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood−brain barrier, emerging as lead candidates for treating AD.
Novel multifunctional compounds have been designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer’s disease (AD). With an l-glutamic moiety as a suitable biocompatible ...linker, three pharmacophoric groups were joined: (1) an N-benzylpiperidine fragment selected to inhibit acetylcholinesterase by interacting with the catalytic active site (CAS), (2) an N-protecting group of the amino acid, capable of interacting with the acetylcholinesterase (AChE)-peripheral anionic site (PAS) and protecting neurons against oxidative stress, and (3) a lipophilic alkyl ester that would facilitate penetration into the central nervous system by crossing the blood−brain barrier. At submicromolar concentration, they inhibit AChE and butyrylcholinesterase (BuChE) of human origin, displace the binding of propidium iodide from the PAS of AChE, and could thus inhibit Aβ aggregation promoted by AChE. They also display neuroprotective properties against mitochondrial free radicals, show low toxicity, and could be able to penetrate into the CNS.
Potential explanations point to a lack of pandemic preparedness (ie, weak surveillance systems, low capacity for PCR tests, and scarcity of personal protective equipment and critical care equipment), ...a delayed reaction by central and regional authorities, slow decision-making processes, high levels of population mobility and migration, poor coordination among central and regional authorities, low reliance on scientific advice, an ageing population, vulnerable groups experiencing health and social inequalities, and a lack of preparedness in nursing homes. ...the social and economic circumstances that have contributed to making Spain more vulnerable, including rising inequalities, must be considered. Specific concerns include public health functions, leadership and governance, financing, health and social workforce, health information systems, service delivery, access to diagnosis and treatment, the role of scientific research, and the experience and values of individuals, communities, and vulnerable groups.
Abstract Background Pre-reperfusion administration of intravenous (IV) metoprolol reduces infarct size in ST-segment elevation myocardial infarction (STEMI). Objectives This study sought to determine ...how this cardioprotective effect is influenced by the timing of metoprolol therapy having either a long or short metoprolol bolus-to-reperfusion interval. Methods We performed a post hoc analysis of the METOCARD-CNIC (effect of METOprolol of CARDioproteCtioN during an acute myocardial InfarCtion) trial, which randomized anterior STEMI patients to IV metoprolol or control before mechanical reperfusion. Treated patients were divided into short- and long-interval groups, split by the median time from 15 mg metoprolol bolus to reperfusion. We also performed a controlled validation study in 51 pigs subjected to 45 min ischemia/reperfusion. Pigs were allocated to IV metoprolol with a long (−25 min) or short (−5 min) pre-perfusion interval, IV metoprolol post-reperfusion (+60 min), or IV vehicle. Cardiac magnetic resonance (CMR) was performed in the acute and chronic phases in both clinical and experimental settings. Results For 218 patients (105 receiving IV metoprolol), the median time from 15 mg metoprolol bolus to reperfusion was 53 min. Compared with patients in the short-interval group, those with longer metoprolol exposure had smaller infarcts (22.9 g vs. 28.1 g; p = 0.06) and higher left ventricular ejection fraction (LVEF) (48.3% vs. 43.9%; p = 0.019) on day 5 CMR. These differences occurred despite total ischemic time being significantly longer in the long-interval group (214 min vs. 160 min; p < 0.001). There was no between-group difference in the time from symptom onset to metoprolol bolus. In the animal study, the long-interval group (IV metoprolol 25 min before reperfusion) had the smallest infarcts (day 7 CMR) and highest long-term LVEF (day 45 CMR). Conclusions In anterior STEMI patients undergoing primary angioplasty, the sooner IV metoprolol is administered in the course of infarction, the smaller the infarct and the higher the LVEF. These hypothesis-generating clinical data are supported by a dedicated experimental large animal study.
Photosensitivity is a neurological disorder in which a person's brain produces epileptic discharges, known as Photoparoxysmal Responses (PPRs), when it receives certain visual stimuli. The current ...standardized diagnosis process used in hospitals consists of submitting the subject to the Intermittent Photic Stimulation process and attempting to trigger these phenomena. The brain activity is measured by an Electroencephalogram (EEG), and the clinical specialists manually look for the PPRs that were provoked during the session. Due to the nature of this disorder, long EEG recordings may contain very few PPR segments, meaning that a highly imbalanced dataset is available. To tackle this problem, this research focused on applying Data Augmentation (DA) to create synthetic PPR segments from the real ones, improving the balance of the dataset and, thus, the global performance of the Machine Learning techniques applied for automatic PPR detection. K-Nearest Neighbors and a One-Hidden-Dense-Layer Neural Network were employed to evaluate the performance of this DA stage. The results showed that DA is able to improve the models, making them more robust and more able to generalize. A comparison with the results obtained from a previous experiment also showed a performance improvement of around 20% for the Accuracy and Specificity measurements without Sensitivity suffering any losses. This project is currently being carried out with subjects at Burgos University Hospital, Spain.
The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been ...reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We aimed to identify biomarkers of MS in an accessible sample, such as blood, by quantifying the relative expression of 91 Th17-related genes in CD4+ T lymphocytes from patients with MS during a relapse or during a remitting phase. We also compared our findings with those of healthy controls. After confirmation in a validation cohort, expression of
and
mRNAs was decreased in remitting disease (-2.3-fold and -1.3-fold, respectively) and relapsing disease (-2.2-fold and -1.3-fold, respectively). No differential expression was observed for other SMAD7-related genes, namely,
,
, and
. Under-regulation of
and
was also observed in another autoimmune disease, Crohn's disease (CD) (-4.6-fold, -1.6-fold, respectively), suggesting the presence of common markers for autoimmune diseases. In addition, expression of
, and
were also decreased in CD (-2.2-fold, -1.4-fold, -1.6-fold, and -1.6-fold, respectively). Our study suggests that expression of
and
mRNA in blood samples are markers for MS and CD, and
, and
for CD. These genes could prove useful as markers of autoimmune diseases, thus obviating the need for invasive methods.
The SARS-CoV-2 outbreak is posing unprecedented care scenarios, increasing the psychological distress among healthcare workers while reducing the efficiency of health systems. This work evaluated the ...psychological impact of the Covid-19 pandemic on Spanish frontline healthcare workers of two tertiary hospitals.
Healthcare workers were recruited from the medical units designated for the care of Covid-19 patients. The psychological assessment consisted of an individual, face-to-face session where gold-standard psychometric tests were administered to assess stress (VASS & PSS-10), anxiety (STAI), depression (PHQ-2) and posttraumatic stress disorder (PCL-5). Regression models were also fitted to identify predictors of psychological distress.
Overall, almost 13% of healthcare workers showed severe anxiety, while more than 26% had high levels of perceived stress. More than 23% presented severe posttraumatic stress symptoms, and another 13% had PHQ-2 scores equal to or above 3, compatible with Major Depressive Disorder (MDD) diagnosis, respectively. Women, stress-related medication, overworking, performing in Covid-19 wards, and substance abuse were risk factors for increased psychological distress. Instead, practising exercise reduced the burden.
This study outlines the severe psychological impact of the Covid-19 pandemic on Spanish frontline healthcare workers. The stress, depression and anxiety levels found were similar to those reported in similar works but much higher than in Wuhan healthcare workers. Knowledge of risk factors for increased psychological distress may help to develop comprehensive intervention strategies to prevent, control and reduce the mental health exacerbation of healthcare workers, thereby maintaining the effectiveness of health systems in critical scenarios.
•Almost 13% of healthcare workers presented severe anxiety.•The prevalence of severe posttraumatic stress symptoms was over 23%.•Nearly 13% of healthcare workers had PHQ-2 scores consistent with Major Depressive Disorder.•Women and overworking were risk factors for higher psychological distress.•The practice of physical exercise reduced the psychological burden.
AHCC® is a standardized extract of cultured mushroom (Lentinula edodes) mycelia with a wide variety of therapeutic effects including anti-inflammatory, antitumor and antiviral effects. ...Trichinellosis, a food-borne parasitic zoonosis is caused by the nematode Trichinella spp. Infection with Trichinella is characterized by the induction of a Th1-type response at the beginning of the intestinal phase, followed by a dominant Th2-type response which is essential for parasite expulsion. The aim of this study was to evaluate the immunomodulatory effect of AHCC® in a murine model of Trichinella spiralis infection. Swiss CD1 mice were infected with T. spiralis larvae and treated with AHCC®. Standard treatment with albendazole (ABZ) was used as control in the assessment of parasite burden. The small intestine was taken out and the proximal segment was evaluated for several parameters: gene expression of immune and stress-reticulum mediators, histological damage score, goblet cell count and Mucin 2 (Muc2) gene expression. AHCC® modulated expression levels of both Th1 and Th2 cytokines and reduced histological damage score. In addition, AHCC® diminished the number of adults of T. spiralis in treated animals. AHCC® treatment anticipates T. spiralis expulsion and increases goblet cell number and Muc2 gene expression.
Display omitted
•ABZ + AHCC® reduces parasite burden assessment similarly to standard treatment.•AHCC® anticipates T. spiralis expulsion regarding the natural course of infection.•AHCC® restores MUC-2 gene expression levels with respect to non-treated mice.•AHCC® increases Goblet cell number regarding non-treated mice at day 7 p.i.
Tuberculosis (TB) of the central nervous system (CNS) presents high mortality due to brain damage and inflammation events. The formation and deposition of immune complexes (ICs) in the brain ...microvasculature during
(Mtb) infection are crucial for its pathobiology. The relevance of ICs to Mtb antigens in the pathogenesis of CNS-TB has been poorly explored. Here, we aimed to establish a murine experimental model of ICs-mediated brain vasculitis induced by cell wall antigens of Mtb. We administered a cell wall extract of the prototype pathogenic Mtb strain H37Rv to male BALB/c mice by subcutaneous and intravenous routes. Serum concentration and deposition of ICs onto blood vessels were determined by polyethylene glycol precipitation, ELISA, and immunofluorescence. Histopathological changes in the brain, lung, spleen, liver, and kidney were evaluated by hematoxylin and eosin staining. Our results evidenced that vasculitis developed in the studied tissues. High serum levels of ICs and vascular deposition were evident in the brain, lung, and kidneys early after the last cell wall antigen administration. Cell wall Mtb antigens induce strong type III hypersensitivity reactions and the development of systemic vasculitis with brain vascular changes and meningitis, supporting a role for ICs in the pathogenesis of TB.
PDF
