Reducing loneliness and depressive symptoms in older adults during the COVID-19 pandemic: A pre-post evaluation of a psychosocial online intervention.

Background: Loneliness is related to worse mental health, particularly in people with poor social support. The COVID-19 pandemic altered our lives and ways of social interaction, especially among vulnerable populations such as older adults.

Methods: We designed a group-based psychosocial online intervention for older adults (≥ 65 years) facilitated by gerontologists addressing loneliness consisting of: (i) sharing experiences and promoting peer support to overcome feelings of loneliness and (ii) increasing the chances of establishing successful social relationships.

β-Lactamase and Macrolide Resistance Gene Carriage in Isolates Among Children Discharged From Inpatient Care in Western Kenya: A Cross-sectional Study.

Background: Antimicrobial resistance (AMR) is a global threat to infectious disease control, particularly among recently hospitalized children. We sought to determine the prevalence and mitigating factors of resistance in enteric among children discharged from health facilities in western Kenya.

Methods: Between June 2016 and November 2019, children aged 1 to 59 months were enrolled at the point of discharge from the hospital.

Circadian rhythms mediate malaria transmission potential.

Malaria transmission begins when infected female mosquitos deposit parasites into the mammalian host's skin during a bloodmeal. The salivary gland-resident sporozoite parasites migrate to the bloodstream, subsequently invading and replicating within hepatocytes. As mosquitos are more active at night, with a 24-hour rhythm, we investigated whether their salivary glands are under circadian control, anticipating bloodmeals and modulating sporozoite biology for host encounters.

WLB-87848, a Selective σ Receptor Agonist, with an Unusually Positioned NH Group as Positive Ionizable Moiety and Showing Neuroprotective Activity.

The synthesis and pharmacological activity of a new series of thieno[2,3-]pyrimidin-4(3)-one derivatives as sigma-1 receptor (σR) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σR agonist () that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σR. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σR association assay, induces neuron viability in an in vitro model of β-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aβ peptide in rats after oral treatment, altogether making (WLB-87848) an interesting candidate for neuroprotection.

Lead exerts a depression of neurotransmitter release through a blockade of voltage dependent calcium channels in chromaffin cells.

The present work, using chromaffin cells of bovine adrenal medullae (BCCs), aims to describe what type of ionic current alterations induced by lead (Pb) underlies its effects reported on synaptic transmission. We observed that the acute application of Pb lead to a drastic depression of neurotransmitters release in a concentration-dependent manner when the cells were stimulated with both K or acetylcholine, with an IC of 119,57 μM and of 5,19 μM, respectively. This effect was fully recovered after washout.

Identification of aberrant luminal progenitors and mTORC1 as a potential breast cancer prevention target in BRCA2 mutation carriers.

Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2 tissue, including expansion of aberrant ERBB3 luminal progenitor and mature cells, and the presence of atypical oestrogen receptor (ER)-positive lesions.

Mediterranean springs: Keystone ecosystems and biodiversity refugia threatened by global change.

Mediterranean spring ecosystems are unique habitats at the interface between surface water and groundwater. These ecosystems support a remarkable array of biodiversity and provide important ecological functions and ecosystem services. Spring ecosystems are influenced by abiotic, biotic, and anthropogenic factors such as the lithology of their draining aquifers, their climate, and the land use of their recharge area, all of which affect the water chemistry of the aquifer and the spring discharges.

Environmental enrichment accelerates the acquisition of schedule-induced drinking in rats.

Environmental enrichment (EE) provides an improvement in the housing conditions of experimental animals, such as laboratory rats, with greater physical and social stimulation through toys and company in the home cages. Its use is known to influence performance of experimental protocols, but these effects have not been well determined in the schedule-induced drinking (SID) procedure. The main goal of this study was to investigate the effects of EE on the acquisition of SID in 24 12-week-old male Wistar rats, divided into two groups, a group with EE housed with toys and companions, and a group without enrichment in individual housing conditions without toys (social isolation and no environmental enrichment, INEE).

Discovery of WLB-89462, a New Drug-like and Highly Selective σ Receptor Ligand with Neuroprotective Properties.

The synthesis and pharmacological activity of a new series of isoxazolylpyrimidines as sigma-2 receptor (σR) ligands are reported. Modification of a new hit retrieved in an HTS campaign allowed the identification of the compound WLB-89462 () with good σR affinity ( = 13 nM) and high selectivity vs both the σR ( = 1777 nM) and a general panel of 180 targets. It represents one of the first σR ligands with drug-like properties, linked to a good physicochemical and ADMET profile (good solubility, no CYP inhibition, good metabolic stability, high permeability, brain penetration, and high oral exposure in rodents).

Effect of indexed glomerular filtration rate according to age.

Background: To find out up to what age there is dispersion in glomerular filtration rate (GFR) values when normalised by body surface area (BSA) and extracellular fluid volume (ECFV), based on the hypothesis that these values differ in childhood age.

Methods: A retrospective study was performed on patients aged 0-85 years, with renal pathology, who were administered i.v.

Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.

Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, chronic, irreversible fibrotic lung disease. IPF is associated with increased senescent cells burden, which may be alleviated with administration of senescent cell targeting drugs termed 'senolytics'. We previously conducted an open-label single-arm pilot study of the senolytic combination of dasatinib and quercetin (D + Q) in patients with IPF but lack of control group limited interpretation and next-stage trial planning.

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids.

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R.

Aluminum alters excitability by inhibiting calcium, sodium, and potassium currents in bovine chromaffin cells.

Aluminum (Al ) has long been related to neurotoxicity and neurological diseases. This study aims to describe the specific actions of this metal on cellular excitability and neurotransmitter release in primary culture of bovine chromaffin cells. Using voltage-clamp and current-clamp recordings with the whole-cell configuration of the patch clamp technique, online measurement of catecholamine release, and measurements of [Ca ] with Fluo-4-AM, we have observed that Al reduced intracellular calcium concentrations around 25% and decreased catecholamine secretion in a dose-dependent manner, with an IC of 89.

Clinical usefulness of cerebrospinal fluid biomarkers in Alzheimer's disease.

Background: Alzheimer's disease (AD) is a complex disease that shares clinical features with other dementias. It is important to establish a specific and reliable diagnosis. Nowadays, AD diagnosis is based on cerebrospinal fluid (CSF) biomarkers.

Environmental enrichment reverses cerebellar impairments caused by prenatal exposure to a synthetic glucocorticoid.

During prenatal life, exposure to synthetic glucocorticoids (SGCs) can alter normal foetal development, resulting in disease later in life. Previously, we have shown alterations in the dendritic cytoarchitecture of Purkinje cells in adolescent rat progeny prenatally exposed to glucocorticoids. However, the molecular mechanisms underlying these alterations remain unclear.

Real Time Recording of Perifused Chromaffin Cells.

Amperometry is an electrochemical method based on the oxidation or reduction of molecules. Many secretion products, including catecholamines, contain in their molecule chemical groups with the ability to yield (oxidize) or capture (reduce) electrons upon its exposure to an electrical field. In order to measure the secretion of catecholamines, they are oxidized at +650 mV with a carbon electrode, releasing every molecule of catecholamine that is oxidized two electrons (e) that are recorded as an electrical current.

The Influence of ASD Severity on Parental Overload: The Moderating Role of Parental Well-Being and the ASD Pragmatic Level.

The aim of the present study is to analyze the relation between the severity of symptoms in people with ASD on their parents' overload, moderated by parental well-being and the ASD pragmatic level. A sample consisted of 28 fathers and mothers whose children had ASD. The obtained results showed that the higher the ASD severity, the better the parental overload was perceived if parents had low well-being levels.

Alterations of the Sympathoadrenal Axis Related to the Development of Alzheimer's Disease in the 3xTg Mouse Model.

Alzheimer's disease (AD), the most common form of dementia, is becoming a global health problem and public health priority. In the advanced stages of AD, besides the initial cognitive symptoms, behavioral problems, particularly agitation and aggressiveness, become prevalent in AD patients. These non-cognitive symptoms could be related to a noradrenergic overactivation.

Novel Purine Derivative ITH15004 Facilitates Exocytosis through a Mitochondrial Calcium-Mediated Mechanism.

Upon depolarization of chromaffin cells (CCs), a prompt release of catecholamines occurs. This event is triggered by a subplasmalemmal high-Ca microdomain (HCMD) generated by Ca entry through nearby voltage-activated calcium channels. HCMD is efficiently cleared by local mitochondria that avidly take up Ca through their uniporter (MICU), then released back to the cytosol through mitochondrial Na/Ca exchanger (MNCX).

Pro-arrhythmogenic effects of conditioned medium proteins in a model of bovine chromaffin cells.

Asymptomatic sudden death is the principal cause of mortality in Chagas disease. There is little information about molecular mechanisms involved in the pathophysiology of malignant arrhythmias in Chagasic patients. Previous studies have involved Trypanosoma cruzi secretion proteins in the genesis of arrhythmias ex vivo, but the molecular mechanisms involved are still unresolved.

[Hemophagocytic syndrome at a pediatric specialty hospital. Underdiagnosis and overdiagnosis].

Background: The hemophagocytic syndrome is a serious complication of several systemic illnesses.

Objective: To define the characteristics of the hemophagocytic syndrome at a pediatric specialty hospital in Tuxtla Gutiérrez, Chiapas, Mexico; incidences, underdiagnosis and overdiagnosis, associated conditions, treatment, and prognosis were included.

Methods: 214 cases of probable hemophagocytic syndrome that were seen between January 2011 and May 2019 were analyzed.

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter.

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Caα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Caα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5-pyrimido[4,5-][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality.

Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation.

The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists.