Age-Related Effects of AT1 Receptor Antagonist Losartan on Cognitive Decline in Spontaneously Hypertensive Rats.

Both hypertension and aging are known to increase the vulnerability of the brain to neurovascular damage, resulting in cognitive impairment. The present study investigated the efficacy of the antihypertensive drug losartan on age- and hypertension-associated cognitive decline and the possible mechanism underlying its effect in spontaneously hypertensive rats (SHRs). Losartan was administered (10 mg/kg, i.p. for 19 days) to 3- and 14-month-old SHRs. Age-matched Wistar rats were used as controls. Working memory, short-term object recognition, and spatial memory were assessed using the Y-maze, object recognition test (ORT) and radial arm maze (RAM) test. The expression of markers associated with aging, oxidative stress, and memory-related signaling was assessed in the frontal cortex (FC) and hippocampus. Motor activity measured over 24 h was not different between groups. Middle-aged vehicle-treated SHRs showed poorer performance in spontaneous alternation behavior (SAB) and activity in the first Y-maze test than their younger counterparts, suggesting age-related reduced "decision making" and reactivity in a novel environment. Losartan improved the age- and hypertension-induced decline in short-term recognition and spatial memory measured in the ORT and the second Y-maze test, particularly in the middle-aged rats, but was ineffective in the young adult rats. Changes in memory and age-related markers such as cAMP response element-binding protein (CREB) and amyloid-ß1-42 (Aß1-42) and increased oxidative stress were observed in the hippocampus but not in the FC between young adult and middle-aged vehicle-treated SHRs. Losartan increased CREB expression while reducing Aß1-42 levels and concomitant oxidative stress in middle-aged SHRs compared with vehicle-treated SHRs. In conclusion, our study highlights the complex interplay between hypertension, aging, and cognitive impairment. It suggests that there is a critical time window for therapeutic intervention with angiotensin II type 1 receptor blockers.

Tailored Melatonin- and Donepezil-Based Hybrids Targeting Pathognomonic Changes in Alzheimer's Disease: An In Vitro and In Vivo Investigation.

A plethora of pathophysiological events have been shown to play a synergistic role in neurodegeneration, revealing multiple potential targets for the pharmacological modulation of Alzheimer's disease (AD). In continuation to our previous work on new indole- and/or donepezil-based hybrids as neuroprotective agents, the present study reports on the beneficial effects of lead compounds of the series on key pathognomonic features of AD in both cellular and in vivo models. An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the anti-fibrillogenic properties of 15 selected derivatives and identify quantitative changes in the formation of neurotoxic ß-amyloid (Aß42) species in human neuronal cells in response to treatment. Among the most promising compounds were 3a and 3c, which have recently shown excellent antioxidant and anticholinesterase activities, and, therefore, have been subjected to further in vivo investigation in mice. An acute toxicity study was performed after intraperitoneal (i.p.) administration of both compounds, and 1/10 of the LD50 (35 mg/kg) was selected for subacute treatment (14 days) with scopolamine in mice. Donepezil (DNPZ) and/or galantamine (GAL) were used as reference drugs, aiming to establish any pharmacological superiority of the multifaceted approach in battling hallmark features of neurodegeneration. Our promising results give first insights into emerging disease-modifying strategies to combine multiple synergistic activities in a single molecule.

A digital patient-reported outcome (electronic patient-reported outcome) system for patients with severe psychiatric disorders: User-centered development study and study protocol of a multicenter-controlled trial.

Background: The effective treatment of patients with severe psychiatric disorders primarily relies on subjective reporting of symptoms and side-effects. This information is crucial for a clinician's decision regarding medication adjustment. Treatment adjustment usually happens at a low frequency (∼4-8 weeks). In between points of care, patients are left alone with their symptoms and side-effects. This leads to uncertainty regarding the treatment, non-adherence, possible relapse, and rehospitalization. Objectives: We aim to design a flexible electronic patient-reported outcome (ePRO) system, which allows patients with severe psychiatric disorders to: (a) record their symptoms using an app; (b) share the data with the clinical team at points of care; and (c) utilize the data to support therapy decisions. Methods: In this article, we describe the development process which included the following steps: (a) formation of a co-design team; (b) stakeholder interviews with patients, practitioners, and digital health experts to access needs, requirements, and barriers; (c) prototype conceptualization and design; (d) user acceptance testing and refinement; and (e) finalization of the system for testing in a pilottrial. Results: We included input from patients with lived experience of psychiatric disorders, clinical team members, software engineers, and researchers. A prototype system was refined, and iterative changes were made before finalization during a series of operational meetings. The system allows patients to digitally self-report their symptoms and provides longitudinal ePRO symptom data for export into the electronic health record. Conclusions: Routine ePRO collection has the potential to improve outcomes and hereby also reduce health service costs. We have successfully developed a trial-ready ePRO system for severe psychiatric disorders. The findings were incorporated in the planning of a feasibility pilot trial. Assuming feasibility will be established, the system might be subjected to a certification process evaluation of safety and efficacy including a randomized controlled trial.

Surveillance, control and management of infections in intensive care units in Southern Europe, Turkey and Iran--a prospective multicenter point prevalence study.

OBJECTIVE: We aimed to compare the features of intensive care units (ICUs), their antimicrobial resistance patterns, infection control policies, and distribution of infectious diseases from central Europe to Mid-West Asia. METHODS: A cross-sectional point prevalence study was performed in 88 ICUs from 12 countries. Characteristics of ICUs, patient and antibiotic therapy data were collected with a standard form by infectious diseases specialists. RESULTS: Out of 749, 305 patients at least with one infectious disease were assessed and 254 patients were reported to have coexistent medical problems. When primary infectious diseases diagnoses of the patients were evaluated, 69 had community-acquired, 61 had healthcare-associated, and 176 had hospital-acquired infections. Pneumonia was the most frequent ICU infection seen in half of the patients. Distribution of frequent pathogens was as follows: Enteric Gram-negatives (n = 62, 28.8%), Acinetobacter spp. (n = 47, 21.9%), Pseudomonas aeruginosa (n = 29, 13.5%). Multidrug resistance profiles of the infecting microorganisms seem to have a uniform pattern throughout Southern Europe and Turkey. On the other hand, active and device-associated infection surveillance was performed in Turkey more than Iran and Southeastern Europe (p < 0.05). However, designing antibiotic treatment according to culture results was highest in Southeastern Europe (p < 0.05). The most frequently used antibiotics were carbapenems (n = 92, 30.2%), followed by anti-gram positive agents (vancomycin, teicoplanin, linezolid, daptomycin, and tigecycline; n = 79, 25.9%), beta-lactam/beta lactamase inhibitors (n = 78, 25.6%), and extended-spectrum cephalosporins (n = 73, 23.9%). CONCLUSION: ICU features appears to have similar characteristics from the infectious diseases perspective, although variability seems to exist in this large geographical area.