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The training of hospital pharmacists in the coming years must adapt and respond to constant current and future social and technological challenges, without neglecting the basic areas of the profession. It is necessary to acquire knowledge in what is known as digital comprehensive health: Artificial intelligence, technology and automation, digital skills, and new forms of communication with patients, such as telemedicine and telepharmacy that are already a reality in many hospitals. We must provide knowledge in automated systems for the distribution and dispensing of medicines, robots for preparing sterile preparations, traceability systems, the use of drones in clinical care, etc., as well as including training in the application of technology in pharmaceutical care, through devices and applications that help identify patients who require specific care early and effectively. In this digital scenario, new risks and challenges must be faced, such as cybersecurity and cyber-resilience, which makes the training and education of healthcare professionals in general, and hospital pharmacists in particular, essential. On the other hand, the appearance of increasingly complex and innovative therapies has a great impact not only on health population but also on economic and environmental issues, which makes new competencies and skills essential to develop and implement disruptive and competent financing, equity, and sustainability strategies. In this demanding and hyper-connected environment, it is understandable that the well-known "burned out worker syndrome" appears, which prevents the correct personal and professional development of the team and highlights the importance of quality training for its prevention and management. In short, in the next decade, the training of hospital pharmacists must be aimed at providing knowledge in innovation and in basic skills needed to adapt and succeed to current demands and changes.
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Farmacêuticos , Serviço de Farmácia Hospitalar , Humanos , Educação em Farmácia , Telemedicina , Inteligência ArtificialRESUMO
The training of hospital pharmacists in the coming years must adapt and respond to constant current and future social and technological challenges, without neglecting the basic areas of the profession. It is necessary to acquire knowledge in what is known as digital comprehensive health: artificial intelligence, technology and automation, digital skills, and new forms of communication with patients, such as telemedicine and telepharmacy that are already a reality in many hospitals. We must provide knowledge in automated systems for the distribution and dispensing of medicines, robots for preparing sterile preparations, traceability systems, the use of drones in clinical care, etc. as well as training in the application of technology in pharmaceutical care, through devices and applications that help identify patients who require specific care early and effectively. In this digital scenario, new risks and challenges must be faced, such as cybersecurity and cyber resilience, which makes the training and education of healthcare professionals in general, and hospital pharmacists in particular, inexcusable. On the other hand, the appearance of increasingly complex and innovative therapies has a great impact not only on health population but also on economic and environmental issues, which makes new competencies and skills essential to develop and implement disruptive and competent financing, equity, and sustainability strategies. In this demanding and hyper-connected environment, it is understandable that the well-known "burned out worker syndrome" appears, which prevents the correct personal and professional development of the team and highlights the importance of quality training for its prevention and management. In short, in the next decade, the training of hospital pharmacists must be aimed at providing knowledge in innovation and in basic skills needed to adapt and succeed to current demands and changes.
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Farmacêuticos , Serviço de Farmácia Hospitalar , Humanos , Educação em Farmácia , Telemedicina , Inteligência Artificial , PrevisõesRESUMO
Hippocampal seizures mimicking mesial temporal lobe epilepsy cause a profound disruption of the adult neurogenic niche in mice. Seizures provoke neural stem cells to switch to a reactive phenotype (reactive neural stem cells, React-NSCs) characterized by multibranched hypertrophic morphology, massive activation to enter mitosis, symmetric division, and final differentiation into reactive astrocytes. As a result, neurogenesis is chronically impaired. Here, using a mouse model of mesial temporal lobe epilepsy, we show that the epidermal growth factor receptor (EGFR) signaling pathway is key for the induction of React-NSCs and that its inhibition exerts a beneficial effect on the neurogenic niche. We show that during the initial days after the induction of seizures by a single intrahippocampal injection of kainic acid, a strong release of zinc and heparin-binding epidermal growth factor, both activators of the EGFR signaling pathway in neural stem cells, is produced. Administration of the EGFR inhibitor gefitinib, a chemotherapeutic in clinical phase IV, prevents the induction of React-NSCs and preserves neurogenesis.
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Receptores ErbB , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Hipocampo , Células-Tronco Neurais , Neurogênese , Convulsões , Transdução de Sinais , Animais , Receptores ErbB/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Convulsões/metabolismo , Neurogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Masculino , Modelos Animais de Doenças , Gefitinibe/farmacologia , Epilepsia do Lobo Temporal/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ácido Caínico/farmacologia , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: To evaluate cognitive function in patients with rheumatoid arthritis (RA) and inflammatory activity. PATIENTS AND METHODS: We performed a cross-sectional study of a cohort of patients with RA initiating their first biological treatment due to moderate-to-high inflammation and a healthy control group (no inflammatory diseases) matched for age, sex and educational level. All participants underwent a comprehensive neuropsychological assessment, with cognitive impairment defined as a Montreal Cognitive Assessment (MoCA) score<26. Additional assessments included various cognitive tests (STROOP, forward and backward digit spans), anxiety and depression scales (Hospital Anxiety and Depression Scale), quality of life measures (Quality of Life-Rheumatoid Arthritis) and average inflammatory activity according to the 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP) into high activity (DAS28≥3.2) and low activity (DAS28<3.2) groups, also CRP levels and interleukin 6 (IL-6) levels were measured using an ELISA. RESULTS: The study population comprised 140 participants, 70 patients with RA and 70 controls. Patients more frequently experienced cognitive impairment than controls (60% vs 40%; p=0.019) and had lower mean (SD) values in the MoCA (23.6 (3.9) vs 25.1 (3.4); p=0.019. As for subtests of the MoCA, involvement was more marked in patients than in controls for the visuospatial-executive (p=0.030), memory (p=0.026) and abstraction (p=0.039) domains. Additionally, patients scored lower on executive function, as assessed by the backward digit span test (4.0 (1.7) vs 4.7 (1.9); p=0.039). Cognitive impairment is associated with age and a lower educational level in the general population, and among patients with RA with educational level, obesity and average inflammatory activity (DAS28, CRP, and IL-6). CONCLUSIONS: Patients with RA with high inflammatory activity are more susceptible to cognitive impairment, which specifically affects the domains of visuospatial, memory, abstraction and executive function.
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Artrite Reumatoide , Proteína C-Reativa , Cognição , Disfunção Cognitiva , Inflamação , Testes Neuropsicológicos , Humanos , Artrite Reumatoide/psicologia , Artrite Reumatoide/complicações , Artrite Reumatoide/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Transversais , Inflamação/sangue , Inflamação/etiologia , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Idoso , Qualidade de Vida , Biomarcadores/sangue , Índice de Gravidade de Doença , Estudos de Casos e Controles , Interleucina-6/sangue , AdultoRESUMO
Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic lowgrade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloidderived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesityassociated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesityassociated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSCdriven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesityrelated cancer.
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Progressão da Doença , Células Supressoras Mieloides , Neoplasias , Obesidade , Microambiente Tumoral , Humanos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Obesidade/complicações , Obesidade/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/etiologia , Microambiente Tumoral/imunologia , Animais , Leptina/metabolismo , Inflamação/imunologia , Inflamação/patologiaAssuntos
COVID-19 , Transplante de Rim , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/complicações , COVID-19/complicações , Tratamento Farmacológico da COVID-19 , Masculino , Pessoa de Meia-Idade , Feminino , Índice de Gravidade de Doença , Idoso , SARS-CoV-2 , Antivirais/uso terapêuticoRESUMO
This study explored the interconnections between sociodemographic elements, depression, fatigue, and exercise in patients suffering from incurable neoplasm, particularly emphasizing the mediating influence of exercise on the relationship between depression and fatigue This was a prospective, multicenter, observational study involving 15 hospitals across Spain. After three months of systemic cancer treatment, participants completed the Brief Symptom Inventory (BSI), the Godin-Shephard Leisure-Time Physical Activity Questionnaire (GSLTPAQ) and the Fatigue Assessment Scale (FAS) to measure levels of depression, fatigue, and exercise, respectively. A total of 616 subjects participated in this study. Activity levels differed markedly according to educational attainment, marital, and work status. There was a negative correlation between physical activity and depression, and a positive correlation between depression and fatigue (ß = -0.18, and ß = 0.46, respectively). Additionally, physical activity inversely influenced fatigue levels (ß = 0.21). Physical activity served as a partial intermediary in the link between depression and fatigue among patients with advanced, unresectable cancer. Healthcare providers are urged to consider both the physical and emotional dimensions of cancer treatment, implementing physical activity programs to enhance overall patient quality of life and mental health.
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Depressão , Exercício Físico , Fadiga , Neoplasias , Humanos , Fadiga/etiologia , Neoplasias/complicações , Neoplasias/psicologia , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Adulto , Inquéritos e Questionários , Qualidade de Vida , EspanhaRESUMO
This study presents the development of a sandwich ELISA method for gluten detection in foods, using recombinant Fab antibody fragments against gliadin. The Fabs were chemically biotinylated and immobilized on streptavidin-coated plates as capture antibodies, while alkaline phosphatase-conjugated Fabs were used as detection antibodies. Four different gliadin-binding Fabs were tested and the Fab pair Fab8E-4 and Fab-C showed the best compatibility. An indirect sandwich immunoassay, using unmodified Fab8E-4 for capture and Fab-C as the detection antibody, achieved a detection limit of 26 ng/mL of gliadin, corresponding to 10 mg/kg of gluten in foods. No cross-reactivity was observed against 60 gluten-free species commonly used in the food industry. Analysis of 50 commercial products demonstrated consistent results compared to the standard method for gluten detection. The complete lack of cross-reactivity of the developed immunoassay with oat products potentially provides an advantage over other gluten detection systems.
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Artificial intelligence (AI) is revolutionizing the field of medical imaging, holding the potential to shift medicine from a reactive "sick-care" approach to a proactive focus on healthcare and prevention. The successful development of AI in this domain relies on access to large, comprehensive, and standardized real-world datasets that accurately represent diverse populations and diseases. However, images and data are sensitive, and as such, before using them in any way the data needs to be modified to protect the privacy of the patients. This paper explores the approaches in the domain of five EU projects working on the creation of ethically compliant and GDPR-regulated European medical imaging platforms, focused on cancer-related data. It presents the individual approaches to the de-identification of imaging data, and describes the problems and the solutions adopted in each case. Further, lessons learned are provided, enabling future projects to optimally handle the problem of data de-identification. CRITICAL RELEVANCE STATEMENT: This paper presents key approaches from five flagship EU projects for the de-identification of imaging and clinical data offering valuable insights and guidelines in the domain. KEY POINTS: ΑΙ models for health imaging require access to large amounts of data. Access to large imaging datasets requires an appropriate de-identification process. This paper provides de-identification guidelines from the AI for health imaging (AI4HI) projects.
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OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive, and longitudinal study. All human immunodeficiency virus (HIV) patients over 18â¯years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (p=.001). Persistence with DGT/3TC was 1237â¯days (IC95% 1216-1258) and persistence with BIC/FTC/TAF was 986â¯days [(IC95% 950-1021); p<.001]. The difference was remained after adjusting for covariates with the cox regression model [HR=8.2 (IC95% 1.03-64.9), p=.047]. The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study, patients have a high persistence. Patients on DTG/3TC treatment are more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF is tolerability/toxicity.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , Estudos Retrospectivos , Masculino , Piridonas/uso terapêutico , Feminino , Lamivudina/uso terapêutico , Piperazinas/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Adulto , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Tenofovir/uso terapêutico , Alanina/uso terapêutico , Alanina/análogos & derivados , Estudos Longitudinais , Combinação de Medicamentos , Amidas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Adenina/análogos & derivados , Adenina/uso terapêuticoRESUMO
Directed evolution is a pivotal strategy for new antibody discovery, which allowed the generation of high-affinity Fabs against gliadin from two antibody libraries in our previous studies. One of the libraries was exclusively derived from celiac patients' mRNA (immune library) while the other was obtained through a protein engineering approach (semi-immune library). Recent advances in high-throughput DNA sequencing techniques are revolutionizing research across genomics, epigenomics, and transcriptomics. In the present work, an Oxford Nanopore in-lab sequencing device was used to comprehensively characterize the composition of the constructed libraries, both at the beginning and throughout the phage-mediated selection processes against gliadin. A customized analysis pipeline was used to select high-quality reads, annotate chain distribution, perform sequence analysis, and conduct statistical comparisons between the different selection rounds. Some immunological attributes of the most representative phage variants after the selection process were also determined. Sequencing results revealed the successful transfer of the celiac immune response features to the immune library and the antibodies derived from it, suggesting the crucial role of these features in guiding the selection of high-affinity recombinant Fabs against gliadin. In summary, high-throughput DNA sequencing has improved our understanding of the selection processes aimed at generating molecular binders against gliadin.
Assuntos
Gliadina , Fragmentos Fab das Imunoglobulinas , Sequenciamento por Nanoporos , Biblioteca de Peptídeos , Humanos , Doença Celíaca/imunologia , Doença Celíaca/genética , Técnicas de Visualização da Superfície Celular/métodos , Gliadina/imunologia , Gliadina/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Fragmentos Fab das Imunoglobulinas/genética , Fragmentos Fab das Imunoglobulinas/imunologiaRESUMO
PURPOSE: Allogeneic hematopoietic stem cell transplantation (HSCT) can have a long-term impact on patients' sexual functioning and consequently, their relationship satisfaction. This study aimed to examine the feasibility and acceptability of a 5-session psychosexual intervention for HSCT survivors and their partners. METHODS: To be eligible patients were required to be more than 3 months post-allogeneic HSCT. The intervention comprised 2 components: (1) A psychosexual education session exploring medical/behavioral treatment options for sexual dysfunction, delivered by a specialist nurse; (2) A 4-session Emotionally-Focused Therapy-based relationship education program for couples delivered by a clinical psychologist. Measures assessing relationship quality, sexual functioning, anxiety, and depression were administered pre- and post-intervention. Feasibility was measured via participation rate, adherence and compliance with completing main measures. Acceptability of the intervention was assessed via patient/partner satisfaction surveys. RESULTS: Eight of 85 (9.4%) eligible patients and their partners participated in the study. Reasons for declining participation included: feeling uncomfortable due to sensitive nature of intervention; did not have any relationship/sexual function issues; and experiencing ongoing medical issues. Six of 8 couples (75%) attended at least 4 intervention sessions and 5 of 8 (62.5%) completed the main study measures post-intervention. Four couples reported that sexual satisfaction and relationship satisfaction was somewhat or much better post-intervention; 1 reported no change. CONCLUSION: Feasibility criteria were not met, with low enrolment rate, however the intervention was deemed acceptable. Couples who participated adhered to the intervention and considered it beneficial. Further strategies to identify and manage sexual concerns are required.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Disfunções Sexuais Fisiológicas , Humanos , Estudos de Viabilidade , Comportamento Sexual , SobreviventesRESUMO
Inflammation causes a wide range of health disorders. In this process, the formation of inflammasome complexes plays a key role. Although inflammasomes have been extensively studied during kidney disease, their role in kidney transplantation has not been fully elucidated. In this study, we evaluate the gene and protein expression of several components of the inflammasome pathway before and at several time points after kidney transplantation in a cohort of patients of different ages and receiving an organ from older or younger donors. Our findings indicate the activation of the NLRP1 inflammasome in several immune cell population, monocytes and CD4+ and CD8+ cells mainly, in renal transplant, and its level increases gradually in patients who receive an older organ, whereas it has the opposite effect on older patients who receive a younger organ. Despite treatment with immunosuppressants, inflammation persists in some patients. These results lead to the hypothesis that the donor's age is a critical factor in post-transplant inflammasome activation and that specific NLRP1 inflammasome inhibitors should be considered to increase the success of kidney transplantation long-term.
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INTRODUCTION: Religious leaders have the potential to play a significant role in the identification and referral of individuals with mental health problems. OBJECTIVE: This study sought to understand the perceptions of religious leaders in regards to identifying and referring parishioners with mental health issues to healthcare professionals, in Chimbote, Peru. METHODS: We performed a cross-sectional study that covered religious leaders of different religious groups in Chimbote. The leaders completed a survey that assessed their characteristics, past experiences of detecting and referring those with mental health problems to healthcare professionals, and perceptions of four clinical cases (for which we used the Clergy's Perception of Mental Illness Survey instrument). RESULTS: We included 109 religious' leaders of four religious groups (11 Catholics, 70 Evangelicals, 21 Mormons, and 7 Adventists). Of these, 50.5% had received at least one request for help with mental health issues from a parishioner in the previous month, over 85% expressed a desire for training in identifying mental health problems, and 22-30% reported receiving any training. While the majority of leaders were able to correctly identify cases of depression, alcohol dependence, and drug problems, only 62% correctly classified a case of schizophrenia. Despite this, 80% stated that they would refer their parishioners to healthcare professionals. CONCLUSION: Parishioners tend to consult their religious leaders regarding their mental health and approximately 80% stated they would refer such cases to a healthcare professional. However, less than one-third of the leaders had received training to detect mental health problems. These results suggest that there is a need for training programs to improve the ability of religious leaders to identify and refer individuals with mental health issues.
Assuntos
Saúde Mental , Religião , Humanos , Estudos Transversais , Peru , Encaminhamento e ConsultaRESUMO
OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive and longitudinal study. All human immunodeficiency virus (HIV) patients over 18 years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (pâ¯=â¯0.001). Persistence with DGT/3TC was 1,237 days (IC95% 1,216-1,258) and persistence with BIC/FTC/TAF was 986 days ([IC95% 950-1,021]; pâ¯<â¯0.001). The difference was remained after adjusting for covariates with the cox regression model (HR= 8.2 [IC95% 1.03-64.9], pâ¯=â¯0.047). The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study patients had a high persistence. Patients on DTG/3TC treatment were more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF was tolerability/toxicity.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Humanos , Estudos Retrospectivos , Infecções por HIV/tratamento farmacológico , Masculino , Feminino , Piridonas/uso terapêutico , Lamivudina/uso terapêutico , Oxazinas/uso terapêutico , Adulto , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Piperazinas/uso terapêutico , Pessoa de Meia-Idade , Fármacos Anti-HIV/uso terapêutico , Tenofovir/uso terapêutico , Emtricitabina/uso terapêutico , Estudos Longitudinais , Alanina/uso terapêutico , Alanina/análogos & derivados , Amidas/uso terapêutico , Combinação de MedicamentosAssuntos
Anticorpos Monoclonais Humanizados , Anticolesterolemiantes , Dislipidemias , Transplante de Rim , Pró-Proteína Convertase 9 , Humanos , Transplante de Rim/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Dislipidemias/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/diagnóstico , Anticolesterolemiantes/uso terapêutico , Masculino , Resultado do Tratamento , Pessoa de Meia-Idade , Feminino , Inibidores de PCSK9RESUMO
Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Leptina , Obesidade , Adulto , Humanos , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Leptina/metabolismo , Obesidade/metabolismoRESUMO
Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence of polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, the extent to which intrinsic structural tendencies of tau amyloid cores contribute to fibril polymorphism remains uncertain. Using a combination of experimental approaches, we here identify a new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif of Repeat 4), as a significant contributor to tau polymorphism. Calculation of per-residue contributions to the stability of the fibril cores of different pathologic tau structures suggests that PAM4 plays a central role in preserving structural integrity across amyloid polymorphs. Consistent with this, cryo-EM structural analysis of fibrils formed from a synthetic PAM4 peptide shows that the sequence adopts alternative structures that closely correspond to distinct disease-associated tau strains. Furthermore, in-cell experiments revealed that PAM4 deletion hampers the cellular seeding efficiency of tau aggregates extracted from Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy patients, underscoring PAM4's pivotal role in these tauopathies. Together, our results highlight the importance of the intrinsic structural propensity of amyloid core segments to determine the structure of tau in cells, and in propagating amyloid structures in disease.
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Doença de Alzheimer , Paralisia Supranuclear Progressiva , Tauopatias , Humanos , Doença de Alzheimer/genética , Amiloide/química , Proteínas Amiloidogênicas , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/genética , Proteínas tau/química , Tauopatias/genética , Tauopatias/patologiaRESUMO
Renal transplantation is an effective treatment for severe chronic kidney diseases. However, young patients often face a scarcity of kidneys from donors of similar age, resulting in the transplantation of older organs, which increase the risk of graft rejection and several complications compared with older individuals who receive kidneys from donors of similar age or younger. This article focuses on studying different senescence biomarkers in donors and patients who received kidneys from various age ranges complying with the STROBE requirements. We studied 61 patients subjected to renal transplant isolating blood samples 24 h before, and 24 h, 3 days, 7 days, 3 months, and 6 months after transplant. The patients were divided into three groups: older donor than the patient (Old Donor), younger donor than the patient (Young Donor), and similar age (Matched). We studied different senescence markers such as p16, p21, interleukin 6 (IL-6), and senescence-associated secretory phenotype (SASP) release. Young patients who receive older organs showed increased mRNA and protein expression of the senescence makers. Hence, increased SASP release was also observed in patients from older donor. In contrast, older patients who receive younger organs showed a slow but consistent improvement in their initial senescent phenotype. In addition, macrophage cell model treated with blood-derived serum from patients 6 months after the transplant showed a pro-senescence environment in macrophages proposed by the SASP from the patients. These results lead the hypothesis that senolytics could reduce the presence of senescent cells and mitigate the complications associated with the transplantation of older organs in young patients.