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Introduction: Frailty is characterized by vulnerability and decline in physical, mental, and social activity, significantly contributing to adverse health outcomes. Frailty encompasses nutritional status, muscle strength, inflammation, and hormones. Dehydroepiandrosterone sulfate (DHEAS) is one of the hormones hypothesized to play a role in frailty. Handgrip strength (HGS) correlates with overall muscle strength. The fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) scale can be used to readily screen frailty. Identifying markers associated with frailty can facilitate its early diagnosis, risk stratification, and target interventions to prevent or mitigate its negative consequences. This study sought to evaluate the associations between frailty, HGS, and DHEAS in a Portuguese frailty unit (FU)., Methods: We developed an observational retrospective study in an FU. Patients admitted to the FU underwent a rehabilitation program. We assessed frailty with the FRAIL scale. We assayed DHEAS upon admission to the FU. We measured HGS at admission (i-HGS) and discharge (f-HGS). We also considered HGS variation (∆ HGS) and length of stay., Results: Out of 119 subjects, 97 fulfilled the eligibility criteria (mean age 78.35 ± 9.58 years; 44.33% men). Overall, 88 (90.72%) patients had a FRAIL scale score of 3 or more. DHEAS values were not significantly different in either the categories of the FRAIL scale or frailty status. DHEAS values were also not significantly correlated with either i-HGS, f-HGS, ∆ HGS, age, or FU length of stay. Frail patients had a significantly lower i-HGS (p = 0.002) and f-HGS (p = 0.001) and a significantly higher length of stay (p = 0.006). Also, the i-HGS and f-HGS significantly decreased with the increase of the FRAIL scale score (p < 0.0001 for both). The cut-off values of the i-HGS and the f-HGS for detecting frail patients in our study were 13.3 kg and 19.1 kg, respectively (p < 0.0001 for both). The i-HGS was significantly and independently associated with the frailty status of frail (p = 0.001), with a 15% probability reduction of a patient being frail for every kilogram increase in the i-HGS., Conclusion: Frail patients assessed with the FRAIL scale had a significantly lower i-HGS and f-HGS and a higher length of stay. In this study, we found frailty and DHEAS to be not associated and DHEAS values to be not correlated with i-HGS or f-HGS. In our opinion, the creation of an FU with an initial FRAIL scale screening and HGS measurement might have a significant impact on identifying frail people and ensuring the implementation of a multimodal multidisciplinary approach., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of the Autonomous Region of Madeira Health Care System issued approval nº38/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Caires et al.)

Parkin (PK) is an E3-ligase harboring tumor suppressor properties that has been associated to various cancer types including glioblastoma (GBM). However, PK is also a transcription factor (TF), the contribution of which to GBM etiology remains to be established. Methods: The impact of PK on GBM cells proliferation was analyzed by real-time impedance measurement and flow cytometry. Cyclins A and B proteins, promoter activities and mRNA levels were measured by western blot, luciferase assay and quantitative real-time PCR. Protein-protein and protein-promoter interactions were performed by co-immunoprecipitation and by ChIP approaches. The contribution of endogenous PK to tumor progression in vivo was performed by allografts of GL261 GBM cells in wild-type and PK knockout mice. Results: We show that overexpressed and endogenous PK control GBM cells proliferation by modulating the S and G2/M phases of the cell cycle via the trans-repression of cyclin A and cyclin B genes. We establish that cyclin B is regulated by both E3-ligase and TF PK functions while cyclin A is exclusively regulated by PK TF function. PK invalidation leads to enhanced tumor progression in immunocompetent mice suggesting an impact of PK-dependent tumor environment to tumor development. We show that PK is secreted by neuronal cells and recaptured by tumor cells. Recaptured PK lowered cyclins levels and decreased GBM cells proliferation. Further, PK expression is decreased in human GBM biopsies and its expression is inversely correlated to both cyclins A and B expressions. Conclusion: Our work demonstrates that PK tumor suppressor function contributes to the control of tumor by its cellular environment. It also shows a key role of PK TF function in GBM development via the control of cyclins in vitro and in vivo . It suggests that therapeutic strategies aimed at controlling PK shuttling to the nucleus may prove useful to treat GBM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Heart failure is a disease with high direct and indirect costs. Current treatment includes drugs that alter disease progression and drugs that to improve symptoms. Loop diuretics are the cornerstone of congestion relief for acute management, as well as for chronic stabilization. In heart failure patients, maximal diuretic response is reduced by many individual factors. Diuretic resistance is defined as failure to achieve effective congestion relief despite appropriate or escalating diuretic doses. Its causes include impaired delivery of the diuretic to its luminal site of action, neurohormonal activation, tubular compensatory adaptation and drug interactions. Several strategies can be employed to aid decongestion of patients with impaired diuretic response. These include salt restriction, a higher effective single dose or higher dose frequency of loop diuretics, continuous infusion of diuretics and/or sequential nephron blockade through a synergistic combination of two or more diuretics from different classes. Ultrafiltration has also been found to be another effective and safe therapeutic option and should be considered in patients with refractory diuretic resistance. Overall, there is a lack of high-quality clinical data to guide the choice of treatment strategy and therapy should be tailored on a case-by-case basis., (Copyright © 2018 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Genome-wide association study (GWAS) has identified several novel genes associated with the risk of Alzheimer's disease (AD), which is a progressive neurodegenerative disease in elders. However, most of the novel genes have not been validated through replication in separated populations. Among them, the BIN1 gene is involved in endocytosis and intracellular trafficking as well as in the formation of β amyloid plaques and neurofibrillary tangles, which are the main pathological hallmarks of AD. The IL-6 gene has also been frequently associated with AD; however, consistent results have not been found. IL-6, a cytokine from the immune system, is implicated in the pathogenesis of several degenerative diseases. Similar to BIN1, it is suggested that IL-6 is also involved in the formation of β amyloid plaques. In this case-control study, we aimed to investigate whether single nucleotide polymorphisms in the BIN1 (rs744373) and IL-6 (rs1800795) genes are associated with AD. Genotype frequencies were evaluated via PCR-RFLP in 82 late-onset AD patients and 159 elderly healthy controls, who were matched by age and gender. In this study, no association was found for either polymorphism, suggesting that these genes are not implicated in the aetiology of AD in all populations., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)