The enormous societal impact of the ongoing COVID‐19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play ...a central role in pathogenesis by exacerbating the pro‐inflammatory immune response against SARS‐CoV‐2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID‐19 in some cases. Using the established COVID‐19 murine model K18‐hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS‐CoV‐2‐related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS‐CoV‐2 may be related to the post‐COVID‐19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID‐19, and make D/Q a new and promising therapeutic tool.
New treatments are necessary to reduce the social impact of COVID‐19. Using the murine model K18‐hACE2, we demonstrated that senolytics (D/Q) reduced SARS‐CoV‐2‐related mortality, delayed its onset, and reduced the number of other clinical symptoms.
A comprehensive understanding of gut microbiota in a clearly defined group of healthy individuals is essential when making meaningful comparisons with various diseases. The Mediterranean diet (MD), ...renowned for its potential health benefits, and the influence of adherence thereto on gut microbiota have become a focus of research. Our aim was to elucidate the impact of adherence to the MD on gut microbiota composition in a well-defined cohort. In this prospective study, healthy volunteers completed a questionnaire to provide demographic data, medical history, and dietary intake. Adherence was evaluated using the Med-DQI. The V4 region of the 16S rRNA gene was sequenced. Analysis of sequencing data and statistical analysis were performed using MOTHUR software and R. The study included 60 patients (51.7% females). Adherence correlated with alpha diversity, and higher values were recorded in good adherers. Good adherers had a higher abundance of
and
(
< 0.001). Alpha diversity correlated inversely with fat intake and positively with non-starch polysaccharides (NSPs). Evenness correlated inversely with red meat intake and positively with NSPs. Predicted functional analysis highlighted metabolic pathway differences based on adherence to the MD. In conclusion, our study adds useful information on the relationship between the MD and the gut microbiome.
Replication of SARS-CoV-2 in the human population is defined by distributions of mutants that are present at different frequencies within the infected host and can be detected by ultra-deep ...sequencing techniques. In this study, we examined the SARS-CoV-2 mutant spectra of amplicons from the spike-coding (S-coding) region of 5 nasopharyngeal isolates derived from patients with vaccine breakthrough. Interestingly, all patients became infected with the Alpha variant, but amino acid substitutions that correspond to the Delta Plus, Iota, and Omicron variants were present in the mutant spectra of the resident virus. Deep sequencing analysis of SARS-CoV-2 from patients with vaccine breakthrough revealed a rich reservoir of mutant types and may also identify tolerated substitutions that can be represented in epidemiologically dominant variants.
Seventy-one healthy subjects with sleep disturbances participated in a randomized, double-blind controlled trial in which dietary supplementation with an extract of
(lemon verbena) (
= 33) or placebo ...(
= 38) was administered for 90 days. There were between-group differences in favor of the experimental group in the visual analogue scale (VAS) for sleep quality (6.5 ± 1.6 vs. 5.5 ± 2.1,
= 0.021) as well as in the overall score (5.8 ± 2.4,
= 0.008) and scores for sleep latency (1.6 ± 1.0 vs. 1.9 ± 0.7,
= 0.027) and sleep efficiency (84.5 ± 12.8 vs. 79.8 ± 13.6,
= 0.023) in the Pittsburgh Sleep Quality Index (PSQI). Sleep-related variables (latency, efficiency, wakefulness after sleep onset, awakenings) assessed by actigraphy also showed better scores in the experimental group (
= 0.001). Plasma nocturnal melatonin levels also increased significantly in the experimental group (199.7 ± 135.3 vs. 174.7 ± 115.4 pg/mL,
= 0.048). Changes in anthropometric parameters and physical activity levels were not found. In summary, a dietary supplement of lemon verbena administered for 3 months was associated with a significant improvement in sleep quality as compared with placebo in a population of healthy subjects with sleep problems.
Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagenic agent, often a nucleotide ...analogue. One of its advantages is its broad spectrum nature that renders the strategy potentially effective against emergent RNA viral infections. Here we describe synergistic lethal mutagenesis of hepatitis C virus (HCV) by a combination of favipiravir (T-705) and ribavirin. Synergy has been documented over a broad range of analogue concentrations using the Chou-Talalay method as implemented in the CompuSyn graphics, with average dose reduction index (DRI) above 1 (68.02±101.6 for favipiravir, and 5.83±6.07 for ribavirin), and average combination indices (CI) below 1 (0.52±0.28). Furthermore, analogue concentrations that individually did not extinguish high fitness HCV in ten serial infections, when used in combination they extinguished high fitness HCV in one to two passages. Although both analogues display a preference for G→A and C→U transitions, deep sequencing analysis of mutant spectra indicated a different preference of the two analogues for the mutation sites, thus unveiling a new possible synergy mechanism in lethal mutagenesis. Prospects of synergy among mutagenic nucleotides as a strategy to confront emerging viral infections are discussed.
ABSTRACT
Lupus nephritis (LN) is the most frequent serious manifestation of patients with systemic lupus erythematosus (SLE). Up to 60% of SLE patients develop LN, which has a significant impact on ...their quality of life and prognosis. Recent advances have improved the diagnostic approach to LN, and new drugs that block specific pathways and kidney damage progression have been developed. Several randomized and well-powered clinical trials have confirmed the efficacy of these agents in terms of proteinuria remission and preservation of kidney function in the medium and long term, with an acceptable safety profile and good tolerance. The combination of different therapies allows for reduction of the dose and duration of corticosteroids and other potentially toxic therapies and leads to an increase in the number of patients achieving complete remission of the disease. This consensus document carried out by the Spanish Group for the Study of Glomerular Diseases (GLOSEN) provides practical and updated recommendations, based on the best available evidence and clinical expertise of participating nephrologists.
Lay Summary
This abridged version of the 2023 GLOSEN Consensus Document on Lupus Nephritis provides practical and up-to-date recommendations on the diagnosis, monitoring and treatment of patients with lupus nephritis (LN), including special situations such as frequently relapsing patients, refractory LN, pregnancy and thrombotic microangiopathy. These recommendations are based on the best available evidence and on the clinical experience of authors. The text is accompanied by tables and algorithms aiming to provide an easy-to-read document useful for the diagnosis and management of LN patients.
Research in Macaronesia has led to substantial advances in ecology, evolution and conservation biology. We review the scientific developments achieved in this region, and outline promising research ...avenues enhancing conservation. Some of these discoveries indicate that the Macaronesian flora and fauna are composed of rather young lineages, not Tertiary relicts, predominantly of European origin. Macaronesia also seems to be an important source region for back-colonisation of continental fringe regions on both sides of the Atlantic. This group of archipelagos (Azores, Madeira, Selvagens, Canary Islands, and Cabo Verde) has been crucial to learn about the particularities of macroecological patterns and interaction networks on islands, providing evidence for the development of the General Dynamic Model of oceanic island biogeography and subsequent updates. However, in addition to exceptionally high richness of endemic species, Macaronesia is also home to a growing number of threatened species, along with invasive alien plants and animals. Several innovative conservation and management actions are in place to protect its biodiversity from these and other drivers of global change. The Macaronesian Islands are a well-suited field of study for island ecology and evolution research, mostly due to its special geological layout with 40 islands grouped within five archipelagos differing in geological age, climate and isolation. A large amount of data is now available for several groups of organisms on and around many of these islands. However, continued efforts should be made toward compiling new information on their biodiversity, to pursue various fruitful research avenues and develop appropriate conservation management tools.
A significant number of patients with systemic lupus erythematosus (between 20% and 60% according to different reported series) develop lupus nephritis in the course of its evolution, which directly ...influences their quality of life and vital prognosis. In recent years, the greater knowledge about the pathogenesis of systemic lupus and lupus nephritis has allowed relevant advances in the diagnostic approach and treatment of these patients, achieving the development of drugs specifically aimed at blocking key pathogenic pathways of the disease. Encouragingly, these immunomodulatory agents have shown in well-powered, randomized clinical trials good clinical efficacy in the medium-term, defined as proteinuria remission and preservation of kidney function, with an acceptable safety profile and good patient tolerability. All this has made it possible to reduce the use of corticosteroids and other potentially more toxic therapies, as well as to increase the use of combined therapies. The present consensus document carried out by the Glomerular Diseases Working Group of the Spanish Society of Nephrology (GLOSEN), collects in a practical and summarized, but rigorous way, the best currently available evidence about the diagnosis, treatment, and follow-up of lupus nephritis patients, including cases of special situations, with the main objective of providing updated information and well-founded clinical recommendations to treating physicians, to improve the diagnostic and therapeutic approach to our patients.
Un número importante de pacientes con lupus eritematoso sistémico (entre un 20% a 60%, según diferentes series), desarrolla nefritis lúpica en el curso de su evolución, lo que influye directamente en su calidad de vida y pronóstico vital. En años recientes, el mayor conocimiento sobre la patogénesis del lupus sistémico y de la nefritis lúpica, ha permitido avances relevantes en el abordaje diagnóstico y en el tratamiento de estos pacientes, lográndose desarrollar fármacos dirigidos específicamente a bloquear vías patogénicas claves de la enfermedad. Alentadoramente, estos agentes inmunomoduladores han demostrado en ensayos clínicos aleatorizados y bien ponderados, buena eficacia clínica a mediano plazo, definida como remisión de proteinuria y preservación de la función renal, con un aceptable perfil de seguridad y buena tolerabilidad del paciente. Todo esto ha permitido reducir el uso de corticoides y de otras terapias potencialmente más tóxicas, así como incrementar el uso de terapias combinadas. El presento documento de consenso realizado por el Grupo de Trabajo de Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN), recoge de manera práctica y resumida, pero rigurosa, la mejor evidencia actual disponible acerca del diagnóstico, tratamiento y seguimiento del paciente con nefritis lúpica, incluyendo casos de situaciones especiales, con el objetivo principal de brindar información actualizada y recomendaciones clínicas bien fundamentadas a los médicos tratantes, para mejorar el enfoque diagnóstico y terapéutico a nuestro pacientes.
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•The non-ionic surfactant has the lowest risk of skin irritation.•Non-ionic/anionic combinations reduced skin irritability by 24–67 % over the single anionic surfactant.•Silica ...nanoparticles (NP) increased the skin irritation potential of single surfactants.•The formulation stability of surfactant mixtures improves with the addition of NP.•The irritation potential of anionic/non-ionic mixtures of surfactants can be further reduced by adding silica NPs.
There has been a notable upswing in the adoption of product formulations based on nanotechnology within the cosmetics industry. By using nanocarriers, such as solid or micellar nanoparticles, the quality and performance of cosmetics can be improved, allowing for better transport of bioactive components into the skin. However, it is important to note that the interaction between these compounds may lead to skin irritation. To mitigate skin irritability, nano-formulation strategies should be implemented in cosmetics. A proof-of-concept study was therefore conducted to investigate if low-toxicity nanoparticles (silica) could be used in combination with a mixture of anionic surfactants and a low-irritant cosurfactant (non-ionic) to develop safer cosmetic formulations that reduce skin damage. The skin irritation potential of the formulations was assessed in vitro using the well-known Zein method.
As anticipated, non-ionic surfactants pose the lowest risk for skin irritation. When compared to single anionic surfactants, non-ionic/anionic mixtures were found to decrease skin irritability by 24–67 %. However, when silica nanoparticles (NPs) were added to single surfactants, the potential for skin irritation increased, particularly when the anionic surfactant molecules were arranged in a spherical core-shell structure around the surface of the NPs. On the other hand, incorporating NPs in surfactant mixtures enhanced their formulation stability. While all three-component formulations were found to decrease skin irritability, those that formed spherical core-shell structures demonstrated the most significant reduction, likely related to a reduction in charge density caused by the non-ionic surfactant which may decrease protein solubilisation. Therefore, the inclusion of silica NPs can potentially result in a further reduction of the skin irritation potential caused by mixtures of anionic and non-ionic surfactants.
Cardioembolic stroke is one of the most devastating complications of non-ischemic dilated cardiomyopathy (NIDCM). However, in clinical trials of primary prevention, the benefits of anticoagulation ...are hampered by the risk of bleeding. Indices of cardiac blood stasis may account for the risk of stroke and be useful to individualize primary prevention treatments. We performed a cross-sectional study in patients with NIDCM and no history of atrial fibrillation (AF) from two sources: 1) a prospective enrollment of unselected patients with left ventricular (LV) ejection fraction <45% and 2) a retrospective identification of patients with a history of previous cardioembolic neurological event. The primary endpoint integrated a history of ischemic stroke or the presence intraventricular thrombus, or a silent brain infarction (SBI) by imaging. From echocardiography, we calculated blood flow inside the LV, its residence time ( R T ) maps and its derived stasis indices. Of the 89 recruited patients, 18 showed a positive endpoint: 9 had a history stroke or TIA and 9 were diagnosed with SBIs in the brain imaging. Averaged R T , performed good to identify the primary endpoint (AUC (95% CI)= 0.75 (0.61-0.89), p= 0.001). When accounting only for identifying a history of stroke or TIA, AUC for was 0.92 (0.85-1.00) with and odds ratio= 7.2 (2.3 - 22.3) per cycle, p< 0.001. These results suggest that, in patients with NIDCM in sinus rhythm, stasis imaging derived from echocardiography may account for the burden of stroke.
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