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Maintenance of stemness is tightly linked to cell cycle regulation through protein phosphorylation by cyclin-dependent kinases (CDKs). However, how this process is reversed during differentiation is unknown. We report here that exit from stemness and differentiation of pluripotent cells along the neural lineage are controlled by CDC14, a CDK-counteracting phosphatase whose function in mammals remains obscure. Lack of the two CDC14 family members, CDC14A and CDC14B, results in deficient development of the neural system in the mouse and impairs neural differentiation from embryonic stem cells (ESCs). Mechanistically, CDC14 directly dephosphorylates specific proline-directed Ser/Thr residues of undifferentiated embryonic transcription Factor 1 (UTF1) during the exit from stemness, triggering its proteasome-dependent degradation. Multiomic single-cell analysis of transcription and chromatin accessibility in differentiating ESCs suggests that increased UTF1 levels in the absence of CDC14 prevent the proper firing of bivalent promoters required for differentiation. CDC14 phosphatases are dispensable for mitotic exit, suggesting that CDC14 phosphatases have evolved to control stemness rather than cell cycle exit and establish the CDK-CDC14 axis as a critical molecular switch for linking cell cycle regulation and self-renewal.
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Proteínas de Ciclo Celular , Proteínas de Saccharomyces cerevisiae , Animales , Ratones , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Ciclo Celular , Fosforilación/fisiología , Mitosis , Proteínas de Saccharomyces cerevisiae/metabolismo , MamíferosRESUMEN
Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.
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Mucopolisacaridosis I , Humanos , Mucopolisacaridosis I/terapia , Mucopolisacaridosis I/tratamiento farmacológico , Iduronidasa/efectos adversos , Iduronidasa/genética , Iduronidasa/metabolismo , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Receptores de Transferrina/genética , Heparitina Sulfato/metabolismoRESUMEN
The successful translation of therapeutic nucleic acids (NAs) for the treatment of neurological disorders depends on their safe and efficient delivery to neural cells, in particular neurons. DNA nanostructures can be a promising NAs delivery vehicle. Nonetheless, the potential of DNA nanostructures for neuronal cell delivery of therapeutic NAs is unexplored. Here, tetrahedral DNA nanostructures (TDN) as siRNA delivery scaffolds to neuronal cells, exploring the influence of functionalization with two different reported neuronal targeting ligands: C4-3 RNA aptamer and Tet1 peptide are investigated. Nanostructures are characterized in vitro, as well as in silico using molecular dynamic simulations to better understand the overall TDN structural stability. Enhancement of neuronal cell uptake of TDN functionalized with the C4-3 Aptamer (TDN-Apt), not only in neuronal cell lines but also in primary neuronal cell cultures is demonstrated. Additionally, TDN and TDN-Apt nanostructures carrying siRNA are shown to promote silencing in a process aided by chloroquine-induced endosomal disruption. This work presents a thorough workflow for the structural and functional characterization of the proposed TDN as a nano-scaffold for neuronal delivery of therapeutic NAs and for targeting ligands evaluation, contributing to the future development of new neuronal drug delivery systems based on DNA nanostructures.
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ADN , Nanoestructuras , Neuronas , ARN Interferente Pequeño , Nanoestructuras/química , Neuronas/metabolismo , ADN/química , ADN/metabolismo , Animales , Humanos , Aptámeros de Nucleótidos/química , Ácidos Nucleicos/química , Simulación de Dinámica MolecularRESUMEN
BACKGROUND: The age at onset (AO) of Machado-Joseph disease (SCA3/MJD), a disorder due to an expanded CAG repeat (CAGexp) in ATXN3, is quite variable and the role of environmental factors is still unknown. Caffeine was associated with protective effects against other neurodegenerative diseases, and against SCA3/MJD in transgenic mouse models. We aimed to evaluate whether caffeine consumption and its interaction with variants of caffeine signaling/metabolization genes impact the AO of this disease. METHODS: a questionnaire on caffeine consumption was applied to adult patients and unrelated controls living in Rio Grande do Sul, Brazil. AO and CAGexp were previously determined. SNPs rs5751876 (ADORA2A), rs2298383 (ADORA2A), rs762551 (CYP1A2) and rs478597 (NOS1) were genotyped. AO of subgroups were compared, adjusting the CAGexp to 75 repeats (p < 0.05). RESULTS: 171/179 cases and 98/100 controls consumed caffeine. Cases with high and low caffeine consumption (more or less than 314.5 mg of caffeine/day) had mean (SD) AO of 35.05 (11.44) and 35.43 (10.08) years (p = 0.40). The mean (SD) AO of the subgroups produced by the presence or absence of caffeine-enhancing alleles in ADORA2A (T allele at rs5751876 and rs2298383), CYP1A2 (C allele) and NOS1 (C allele) were all similar (p between 0.069 and 0.516). DISCUSSION: Caffeine consumption was not related to changes in the AO of SCA3/MJD, either alone or in interaction with protective genotypes at ADORA2A, CYP1A2 and NOS1.
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BACKGROUND: This study delves into the States' accountability for health-related Sustainable Development Goal (SDG) indicators from 2016 to 2020. An analysis of Voluntary National Reviews (VNR) is employed as an instrument to scrutinize the alignment of States' indicators with the global indicator framework, shedding light on global health governance within the context of the 2030 Agenda and States' strategic prioritization. A curation of 60 health-related indicators from 195 VNRs, produced during the aforementioned period, is organized into thematic groups. RESULTS: Our results highlight a concerning discrepancy in the reporting frequency of various health-related themes. The findings reveal a paradoxical coexistence characterized by the concurrent strengthening and diminution of the global health governance articulated in the Agenda's global health governance. This manifests in the increased utilization and consistency of health-related indicators over the study years, coupled with an emphasis on infectious diseases and child and maternal health indicators. Conversely, a discernible governance decline is evidenced by the inadequate representation of health-related indicators in VNRs, notably within the domains of universal health coverage and health system indicators. Furthermore, High-Income States exhibit diminished accountability. CONCLUSIONS: The VNRs unveil a paradox wherein burgeoning technical capacity coexists with governance deficits, a phenomenon attributable to both statistical capabilities and political preferences. The prevalent use of proxy indicators in VNRs oversimplifies the presentation of official indicators, thereby compromising the aspirational goal of pioneering statistical innovations for measuring intricate issues in the SDGs. In light of our conceptualization of the 2030 Agenda's global health as a regime complex governance, we advocate for comprehensive investigations into each health regime cluster. This approach aims to unravel disputes, discern patterns, and elucidate States' preferences concerning specific thematic areas. Functioning as an accountability mechanism for the Agenda's governance, VNRs underscore States' adaptability and short-term learning capabilities, offering valuable insights for identifying harmful goal prioritization. The discretionary nature of indicator selection by States in the VNRs, enabled by the Agenda's proposition of a contextual adaptation of the SDGs and a blind eye to the guideline's request to review all SDG indicators, highlights a critical flaw in the VNR as an accountability mechanism.
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Salud Global , Desarrollo Sostenible , Humanos , Indicadores de Salud , Responsabilidad SocialRESUMEN
INTRODUCTION: A transformation of food systems is urgently needed, given their contribution to three ongoing and interlinked global health pandemics: (1) undernutrition and food insecurity, (2) obesity and non-communicable diseases (NCDs), and (3) climate change and biodiversity loss. As policymakers make decisions that shape food systems, this study aimed to identify and prioritise policies with double- or triple-duty potential to achieve healthier and more environmentally sustainable food systems. METHODS: This study undertook a 4-step methodological approach, including (i) a compilation of international policy recommendations, (ii) an online survey, (iii) four regional workshops with international experts and (iv) a ranking for prioritisation. Policies were identified and prioritised based on their double- or triple-duty potential, synergies and trade-offs. Using participatory and transdisciplinary approaches, policies were identified to have double- or triple-duty potential if they were deemed effective in tackling two or three of the primary outcomes of interest: (1) undernutrition, (2) obesity/NCDs and (3) environmental degradation. RESULTS: The desk review identified 291 recommendations for governments, which were merged and classified into 46 initially proposed policies. Based on the results from the online survey, 61% of those policies were perceived to have double- or triple-duty potential. During the workshops, 4 potential synergies and 31 trade-offs of these policies were identified. The final list of 44 proposed policies for healthier and more environmentally sustainable food systems created was divided into two main policy domains: 'food supply chains' and 'food environments'. The outcome with the most trade-offs identified was 'undernutrition', followed by 'environmental sustainability', and 'obesity/NCDs'. Of the top five expert-ranked food supply chain policies, two were perceived to have triple-duty potential: (a) incentives for crop diversification; (b) support for start-ups, and small- and medium-sized enterprises. For food environments, three of the top five ranked policies had perceived triple-duty potential: (a) affordability of healthier and more sustainable diets; (b) subsidies for healthier and more sustainable foods; (c) restrictions on children's exposure to marketing through all media. CONCLUSION: This study identified and prioritised a comprehensive list of double- and triple-duty government policies for creating healthier and more environmentally sustainable food systems. As some proposed policies may have trade-offs across outcomes, they should be carefully contextualised, designed, implemented and monitored.
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Desnutrición , Obesidad , Humanos , Obesidad/prevención & control , Obesidad/epidemiología , Desnutrición/prevención & control , Desnutrición/epidemiología , Desarrollo Sostenible , Abastecimiento de Alimentos , Salud Global , Conservación de los Recursos Naturales , Política Nutricional , Cambio ClimáticoRESUMEN
BACKGROUND: With the COVID-19 pandemic and the restrictions imposed to contain the spread of SARS-CoV-2, the Brazilian population has increased the time spent at home and watching television (TV). Since food advertising exposure is a key driver of food choices, this study described the content of food advertisements (ads) on Brazilian TV during the COVID-19 pandemic. METHODS: This is an exploratory study. A total of 684 h of TV programming comprised of three free-to-air channels and two pay-per-view channels was recorded from 06 a.m. to 12 a.m. for eight non-consecutive days in June 2020. A content analysis of all the food-related ads was carried out. The data collection process followed INFORMAS Protocol for TV food advertising monitoring. RESULTS: The sample was composed of 7,083 ads, 752 (10.6%) of which were food-related and 487 (6.9%) were promoting ultra-processed foods. The content analysis indicated seven thematic categories, all of them with reference to the COVID-19 pandemic: brand and product differentials (79.8%); visual and sound effects (70.2%); thematic campaigns (56.0%); digitization (22.9%); convenience (16.5%); economic benefits (11.9%); and commensality and social interaction (6.1%). Ads content varied according to the day of the week, the time of the day, the length of the ad, and the channel type. CONCLUSIONS: The thematic of food advertising on Brazilian TV during the COVID-19 pandemic is aligned with the country's health crisis context and varied during the programming.
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Publicidad , COVID-19 , Humanos , Brasil/epidemiología , Pandemias , COVID-19/epidemiología , Televisión , SARS-CoV-2 , Alimentos , Industria de Alimentos , BebidasRESUMEN
BACKGROUND: Expenditure of healthcare services has been growing over the past decades. Lean and agile are two popular paradigms that could potentially contain cost and improve proficiency of the healthcare system. However no systematic review was found on leagilty in the healthcare research. This study aims at synthesizing the extant literature of leagility in the healthcare area to consolidate its potential and identify research gaps for future study in the field. METHODS: A systematic literature review is conducted following the PRISMA checklist approach. Studies were searched in multiple databases. The selection of articles was executed by dual-scanning of two researchers to ensure quality of data and relevance to the topic. Scientific articles published between January 1999 and November 2023 concerning leagile healthcare are analysed using Microsoft Excel and VOSviewer (version 1.6.18). RESULTS: Out of 270 articles identified from the inclusion and exclusion criteria, 24 were included in the review. A total of 11 target areas were identified in leagility applications in healthcare. Success and limiting factors of leagile healthcare were classified into macro and micro aspects and further categorized into six dimensions: policy, organization, human resources, marketing, operation management and technology. Moreover, four research gaps were revealed and suggestions were provided for future study. CONCLUSION: Leagility in the healthcare context is still being in its infancy. Few empirical validation was found in leagile healthcare literature. Further exploration into the application of theory in various sectors under the scope of healthcare is appealed for. Standardization and modularization, leadership support, skillfulness of professionals and staff training are the factors most frequently mentioned for a successful implementation of leagility in the healthcare sector.
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Atención a la Salud , Investigación sobre Servicios de Salud , Humanos , Gastos en Salud , Instituciones de Salud , LiderazgoRESUMEN
We describe the composition of endoparasites associated with leaf litter anurans from an Atlantic Forest area, in southeastern Brazil. We tested if body size, sex, and reproductive modes of anuran hosts influence endoparasite abundance and richness. We sampled 583 individuals from 11 anuran species and recorded 1,600 helminths from 14 taxa. The helminths that infected the greatest number of anuran host species were the nematodes Cosmocerca parva (8 spp.), Physaloptera sp. (8 spp.), and Cosmocerca brasiliense (7 spp.), and the most abundant helminth species were Physaloptera sp. (14.6%), Cosmocerca brasiliense (13.7%) and Cosmocerca parva (12.6%). Both helminth abundance and richness were positively affected by anuran body size and dependence on water for reproduction. Larger hosts can contain a higher abundance of parasites because they may provide more physical space than smaller ones, or it can simply be a function of age. Besides, parasite species richness can be highly correlated with the amount of time a host spends in association with aquatic habitats, a conservative aspect of both parasite and host natural history. Within host species, there was a positive and significant influence of body size on helminth abundance. Haddadus binotatus females had greater helminth abundance than males, probably due to sex-related differences in behavior and/or in physiology. Our data suggest that reproductive modes could also influence helminth infection parameters in other anuran communities and should be considered in detail in future analyses.
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Anuros , Tamaño Corporal , Helmintos , Reproducción , Animales , Anuros/parasitología , Brasil , Femenino , Masculino , Helmintos/clasificación , Helmintos/fisiología , Helmintos/aislamiento & purificación , Biodiversidad , Interacciones Huésped-ParásitosRESUMEN
To review current literature and synthesize clinical outcomes related to different low-level laser techniques as a complement to basic periodontal therapy (BPT). Electronic searches were conducted in PubMed, Cochrane, and Scopus, and clinical trials published from January 2013 to August 2023 using photobiomodulation as a complement to basic periodontal therapy, with a clear description of the laser technique, were included. The risk of bias was assessed using the Joanna Briggs Institute Critical Assessment Checklist. Estimates of interest were calculated using random effects meta-analyses. A total of 947 references were retrieved, and 22 studies were included for qualitative synthesis. Ten studies used intrasulcular laser techniques, with 89% using infrared wavelength, and 12 studies used transgingival techniques, with 61.5% using red wavelength. The frequency of photobiomodulation after BPT ranged from 1 to 9 sessions, with follow-up periods ranging from 5 days to 12 months. Risk of bias was considered low in 16 studies and moderate in six studies. Meta-analysis of 13 studies showed that BPT reduced probing depth at 4-, 12- and 24-weeks post-treatment, and improved clinical level attachment at 6-, 12- and 24-weeks post-treatment. Studies suggest that photobiomodulation may be a valuable complement in the treatment of periodontitis, especially using transgingival application technique.
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Terapia por Luz de Baja Intensidad , Humanos , Terapia por Luz de Baja Intensidad/métodos , Enfermedades Periodontales/radioterapia , Enfermedades Periodontales/terapia , Resultado del TratamientoRESUMEN
Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are the main causes of nephrotic syndrome in the world. The complement system appears to play an important role in the pathogenesis of these diseases. To evaluate the deposition of immunoglobulins and particles of the complement system in renal biopsies of patients with FSGS and MCD and relate to laboratory data, we selected 59 renal biopsies from patients with podocytopathies, 31 from patients with FSGS and 28 with MCD. Epidemiological, clinical, laboratory information and the prognosis of these patients were evaluated. Analysis of the deposition of IgM, IgG, C3, C1q and C4d in renal biopsies was performed. We related IgM and C3 deposition with laboratory parameters. Statistical analysis was performed using GraphPad Prism version 7.0. Glomerular deposition of IgM was significantly higher in the FSGS group, as was codeposition of IgM and C3. The clinical course of patients and laboratory data were also worse in cases of FSGS, with a higher percentage progressing to chronic kidney disease and death. Patients with C3 deposition had significantly higher mean serum creatinine and significantly lower eGFR, regardless of disease. Patients with FSGS had more IgM and C3 deposition in renal biopsies, worse laboratory data and prognosis than patients with MCD. C3 deposition, both in FSGS and MCD, appears to be related to worsening renal function.
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Complemento C3 , Glomeruloesclerosis Focal y Segmentaria , Inmunoglobulina M , Glomérulos Renales , Nefrosis Lipoidea , Humanos , Inmunoglobulina M/metabolismo , Complemento C3/metabolismo , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Glomeruloesclerosis Focal y Segmentaria/inmunología , Femenino , Masculino , Adulto , Glomérulos Renales/patología , Glomérulos Renales/metabolismo , Persona de Mediana Edad , Nefrosis Lipoidea/patología , Nefrosis Lipoidea/metabolismo , Podocitos/patología , Podocitos/metabolismo , Adulto Joven , Adolescente , Pronóstico , Biopsia , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Síndrome Nefrótico/inmunología , AncianoRESUMEN
Mangrove habitats can serve as nursery areas for sharks and rays. Such environments can be thermally dynamic and extreme; yet, the physiological and behavioural mechanisms sharks and rays use to exploit such habitats are understudied. This study aimed to define the thermal niche of juvenile mangrove whiprays, Urogymnus granulatus. First, temperature tolerance limits were determined via the critical thermal maximum (CTMax) and minimum (CTMin) of mangrove whiprays at summer acclimation temperatures (28 °C), which were 17.5 °C and 39.9 °C, respectively. Then, maximum and routine oxygen uptake rates (MO2max and MO2routine, respectively), post-exercise oxygen debt, and recovery were estimated at current (28 °C) and heatwave (32 °C) temperatures, revealing moderate temperature sensitivities (i.e., Q10) of 2.4 (MO2max) and 1.6 (MO2routine), but opposing effects on post-exercise oxygen uptake. Finally, body temperatures (Tb) of mangrove whiprays were recorded using external temperature loggers, and environmental temperatures (Te) were recorded using stationary temperature loggers moored in three habitat zones (mangrove, reef flat, and reef crest). As expected, environmental temperatures varied between sites depending on depth. Individual mangrove whiprays presented significantly lower Tb relative to Te during the hottest times of the day. Electivity analysis showed tagged individuals selected temperatures from 24.0 to 37.0 °C in habitats that ranged from 21.1 to 43.5 °C. These data demonstrate that mangrove whiprays employ thermotaxic behaviours and a thermally insensitive aerobic metabolism to thrive in thermally dynamic and extreme habitats. Tropical nursery areas may, therefore, offer important thermal refugia for young rays. However, these tropical nursery areas could become threatened by mangrove and coral habitat loss, and climate change.
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Severe malarial anemia (SMA) increases the morbidity and mortality of Plasmodium, the causative agent of malaria. SMA is mainly developed by children and pregnant women in response to the infection. It is characterized by ineffective erythropoiesis caused by impaired erythropoietin (EPO) signaling. To gain new insights into the pathogenesis of SMA, we investigated the relationship between the immune system and erythropoiesis, conducting comparative analyses in a mouse model of malaria. Red blood cell (RBC) production was evaluated in infected and reinfected animals to mimic endemic occurrences. Higher levels of circulating EPO were observed in response to (re)infection. Despite no major differences in bone marrow erythropoiesis, compensatory mechanisms of splenic RBC production were significantly reduced in reinfected mice. Concomitantly, a pronounced immune response activation was observed in erythropoietic organs of reinfected animals in relation to single-infected mice. Aged mice were also used to mimic the occurrence of malaria in the elderly. The increase in symptom severity was correlated with the enhanced activation of the immune system, which significantly impaired erythropoiesis. Immunocompromised mice further support the existence of an immune-shaping regulation of RBC production. Overall, our data reveal the strict correlation between erythropoiesis and immune cells, which ultimately dictates the severity of SMA.
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Anemia , Eritropoyesis , Inmunomodulación , Malaria , Animales , Ratones , Malaria/inmunología , Malaria/parasitología , Anemia/inmunología , Eritrocitos/parasitología , Eritrocitos/inmunología , Eritrocitos/metabolismo , Modelos Animales de Enfermedad , Eritropoyetina/metabolismo , Femenino , Bazo/inmunología , Bazo/patología , Bazo/metabolismo , Ratones Endogámicos C57BLRESUMEN
Positional vertigo poses a diagnostic challenge in people with multiple sclerosis (MS). The characteristics of positional nystagmus and its response to repositioning manoeuvres are usually sufficient to diagnose benign paroxysmal positional vertigo (BPPV). However, certain BPPV variants respond poorly to repositioning manoeuvres and their nystagmus pattern can resemble that of central positional vertigo caused by infratentorial demyelination. This diagnostic difficulty is particularly challenging if positional vertigo occurs during an MS relapse. We describe a woman with MS who developed a sixth nerve palsy and gaze-evoked nystagmus, caused by demyelination near or within areas classically involved in central positional vertigo. However, she also had positional vertigo from coincident BPPV (and not central positional vertigo). This was initially a treatment resistant-posterior semicircular canal cupulolithiasis but it later progressed to a posterior semicircular canal canalolithiasis, with symptoms promptly resolving after a repositioning manoeuvre.
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Enfermedades del Nervio Abducens , Enfermedades Desmielinizantes , Nistagmo Patológico , Femenino , Humanos , Vértigo Posicional Paroxístico Benigno/terapia , Canales Semicirculares , Nistagmo Patológico/diagnósticoRESUMEN
The main aim of this study was to validate and adapt the Centrality of Religiosity Scale to the Portuguese population. A total of 1018 subjects participated in this study. The metric qualities demonstrated in the analyses suggested that the factor structure was based on five dimensions identical to those proposed by its authors. After analysing its psychometric qualities, we concluded that this instrument can be applied to the Portuguese population and is a valuable tool in studies related to the psychology of religion and spirituality.
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INTRODUCTION: Fertility rates in developing countries have declined over the past decades, and the trend of delayed fatherhood is rising as societies develop. The reasons behind the decline in male fertility with advancing age remain mysterious, making it a compelling and crucial area for further research. However, the limited number of studies dedicated to unraveling this enigma poses a challenge. Thus, our objective is to illuminate some of the upregulated and downregulated mechanisms in the male testis during the aging process. AREAS COVERED: Herein, we present a critical overview of the studies addressing the alterations of testicular proteome through the aging process, starting from sexually matured young males to end-of-life-expectancy aged males. The comparative studies of the proteomic testicular profile of men with and without spermatogenic impairment are also discussed and key proteins and pathways involved are highlighted. EXPERT OPINION: The difficulty of making age-comparative studies, especially of advanced-age study subjects, makes this topic of study quite challenging. Another topic worth mentioning is the heterogeneous nature and vast cellular composition of testicular tissue, which makes proteome data interpretation tricky. The cell type sorting and comorbidities testing in the testicular tissue of the studied subjects would help mitigate these problems.
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Infertilidad Masculina , Testículo , Masculino , Humanos , Anciano , Proteoma/genética , Proteómica , Espermatogénesis/genética , Infertilidad Masculina/genéticaRESUMEN
Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements.
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Enfermedad de Fabry , Femenino , Humanos , Enfermedad de Fabry/tratamiento farmacológico , Enfermedad de Fabry/epidemiología , Enfermedad de Fabry/genética , alfa-Galactosidasa/genética , alfa-Galactosidasa/uso terapéutico , Terapia de Reemplazo Enzimático/métodos , Sistema de Registros , Fenotipo , Atención Dirigida al Paciente , Estudios Observacionales como AsuntoRESUMEN
BACKGROUND: Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). METHODS: Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-database.org. Linear mixed models were conducted to assess changes over ≥2-year follow-up in the estimated glomerular filtration rate (eGFR) stratified by low (LRI) and high (HRI) renal involvement (defined by proteinuria/albuminuria levels), and changes in interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) Z-scores stratified by median age at first treatment. Self-reports ('yes'/'no') of abdominal pain, diarrhea, chronic peripheral pain (denoting neuropathic pain), and acute pain crises at baseline were compared with reports after ≥0.5-year and ≥2.5-year follow-up using McNemar's test. RESULTS: Male (n = 117) and female patients (n = 59) with LRI initiated treatment at a median age of 19.9 and 23.6 years, respectively, and were followed for a median of 6.3 and 5.0 years, respectively. The eGFR slopes were -1.18 (Pfrom 0 <0.001) and -0.92 mL/min/1.73 m2/year (Pfrom 0 = 0.040), respectively. Males with HRI (n = 23, median UPCR 1.0 g/g), who started treatment at a median age of 26.7 years, had an eGFR slope of -2.39 mL/min/1.73 m2/year (Pfrom 0 <0.001; Pdifference = 0.055, as compared with the slope of -1.18 mL/min/1.73 m2/year for LRI males) during a median follow-up of 5.6 years. Echocardiographic variables were stable among males, regardless of age, and among young females (median follow-up >5.5 years and ≥4.5 years, respectively). Older females (treatment initiation at median age 27.5 years) had a slope of LVPWT Z-scores of 0.18/year (n = 12, Pfrom 0 = 0.028), whereas IVST Z-scores remained stable (n = 13, 0.10/year, Pfrom 0 = 0.304) during a median follow-up of ≥3.7 years. These slopes did not significantly differ from slopes of younger females. Reports of chronic peripheral pain and acute pain crises by males, and of diarrhea and acute pain crises by females, significantly reduced after a median follow-up of ≥4.0 years. After a median follow-up of ≥5.4 years, reports of all four symptoms significantly decreased among males, whereas among females only reports of abdominal pain significantly decreased. CONCLUSIONS: During sustained treatment with agalsidase beta in young Fabry patients with a predicted classic phenotype or with unclassified GLA variants with similar characteristics, the decline in eGFR was modest among male and female patients with LRI. The greater decline in eGFR among older, proteinuric (i.e., HRI) males may suggest a benefit of earlier treatment. Overall, echocardiographic variables remained stable, particularly among males and younger females. Significant reductions in symptom reports occurred primarily among males after longer follow-up and were less noticeable among females. These observed trends are suggestive of an overall improvement after treatment in young patients, but warrant larger longitudinal studies.
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Dolor Agudo , Enfermedad de Fabry , Masculino , Femenino , Humanos , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/tratamiento farmacológico , Dolor Agudo/inducido químicamente , Dolor Agudo/tratamiento farmacológico , alfa-Galactosidasa/genética , alfa-Galactosidasa/efectos adversos , Dolor Abdominal/inducido químicamente , Dolor Abdominal/tratamiento farmacológico , Sistema de Registros , Terapia de Reemplazo Enzimático/efectos adversosRESUMEN
BACKGROUND: Long-term success of peritoneal dialysis relies on the integrity of the peritoneal membrane. This proof-of-concept study addressed the hypothesis that fibrosis is already present in the membrane at pre-dialysis and that the membrane status is related to the individual's uraemic fingerprint. METHODS: A clinical-mechanistic, transversal, single-centre study was conducted. Pre-dialysis peritoneal biopsies were scored considering the submesothelial compact zone thickness (STM), vasculopathy and inflammation. We investigated if the membrane status could be inferred from a panel of proteins (α-Klotho, Galectin-3, FGF21, FGF23, Tweak, TNFα and hsPCR) in blood. RESULTS: A total 58 incident patients aged 56 ± 15 years old were included, 31% female, 55% hypertension, 29% diabetic and 24% obese. Person-to-person STM was found to be highly variable and 38% of patients were fibrosis positive. Both α-Klotho (Spearman r = -.7491, p < 0.001) and FGF21 (Spearman r = -.5102, p < 0.001) were negatively associated with STM. α-Klotho, but not FGF21, was able to discriminate fibrosis from nonfibrosis with/without inflammation and vasculopathy. PLS models identified α-Klotho as the protein most relevant for fibrosis. α-Klotho was independently associated with fibrosis of the peritoneal membrane (OR = .991 (.896-.997), p = 0.002). CONCLUSION: Before the start of dialysis in incident patients, some patients already present fibrosis of the peritoneal membrane and other patients do not. Our findings suggest that α-Klotho may be implicated in fibrosis of the peritoneal membrane.
Asunto(s)
Diálisis Peritoneal , Peritoneo , Humanos , Femenino , Adulto , Persona de Mediana Edad , Anciano , Masculino , Peritoneo/metabolismo , Peritoneo/patología , Fibrosis , Diálisis Renal , Inflamación/metabolismoRESUMEN
OBJECTIVE: Continuous Spike-Wave during slow Sleep (CSWS) syndrome associates a clinically important neurocognitive regression with strong activation of non-REM sleep spikes. Its mechanisms remain unknown, but a contribution of rare perinatal thalamic injuries has been highlighted. We determine the incidence of such lesions in a cohort of CSWS patients. METHODS: N = 65 patients with CSWS and a control group (N = 51) were studied. Spikes were quantified in long-term ambulatory EEGs, brain Magnetic Ressonance Imaging (MRI) structural lesions were assessed and thalamic volumetry was performed. A neurocognitive scale was used to assess dysfunction. RESULTS: The most common etiologies in the control patients were not represented in the CSWS group. Structural lesions were detected in a minority of CSWS patients (25/53) but included a thalamic injury in the large majority (24/25). This ratio was 4/40 in controls. Lesions belonged to one of five types: 1. Circumscribed to the thalamus (N = 11); 2. Extending beyond the thalamus (N = 3); 3. Hypothalamic-Hamartomas (N = 4); 4. Periventricular-Leukomalacia (N = 4); 5. Hypoplasia-Polymicrogyria (N = 1). Most lesions were lateralized to one hemisphere, which in all cases corresponded to the lateralization of the CSWS. SIGNIFICANCE: Thalamic lesions are present in most CSWS patients with abnormal MRIs, supporting an important role in its genesis.