RESUMO
The electron transport chain (ETC) of mitochondria, bacteria, and archaea couples electron flow to proton pumping and is adapted to diverse oxygen environments. Remarkably, in mice, neurological disease due to ETC complex I dysfunction is rescued by hypoxia through unknown mechanisms. Here, we show that hypoxia rescue and hyperoxia sensitivity of complex I deficiency are evolutionarily conserved to C. elegans and are specific to mutants that compromise the electron-conducting matrix arm. We show that hypoxia rescue does not involve the hypoxia-inducible factor pathway or attenuation of reactive oxygen species. To discover the mechanism, we use C. elegans genetic screens to identify suppressor mutations in the complex I accessory subunit NDUFA6/nuo-3 that phenocopy hypoxia rescue. We show that NDUFA6/nuo-3(G60D) or hypoxia directly restores complex I forward activity, with downstream rescue of ETC flux and, in some cases, complex I levels. Additional screens identify residues within the ubiquinone binding pocket as being required for the rescue by NDUFA6/nuo-3(G60D) or hypoxia. This reveals oxygen-sensitive coupling between an accessory subunit and the quinone binding pocket of complex I that can restore forward activity in the same manner as hypoxia.
Assuntos
Caenorhabditis elegans , Complexo I de Transporte de Elétrons , Hipóxia , Animais , Camundongos , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oxigênio/metabolismoRESUMO
PURA is mapped to chromosome 5q31 and plays a vital role in neuronal development and synapse formation. Here, we aim to explore PURA's impact on cognitive development and epilepsy phenotype by comparing patients with single nucleotide variants (SNPs) in the PURA gene (PURA-SNP patients) to those with 5q31 microdeletions including PURA (5q31del + PURA) and those with 5q31 microdeletions not including the PURA gene (5q31del-PURA). A systematic literature search was conducted in PubMed. Two separate searches were performed in order to find patients with PURA SNPs and 5q31 microdeletions. This review includes data from 191 patients collected from a total of 18 articles; 174 of the patients had PURA SNPs, 13 had 5q31 microdeletions involving the PURA gene, and 4 had 5q31 microdeletions without PURA gene implication. All patients exhibited hypotonia, feeding difficulties and dysmorphic features, however epilepsy was primarily present in patients with PURA syndrome, that is, groups PURA-SNP and 5q31del + PURA. Regarding the developmental milestones the 5q31del + PURA group stood out as being the most severe, while the 5q31del-PURA group showed a relatively mild phenotype. Our findings support the hypothesis of PURA being the key contributor of developmental delay and epilepsy among patients with PURA syndrome.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Deficiências do Desenvolvimento , Epilepsia , Humanos , Cromossomos Humanos Par 5/genética , Deficiências do Desenvolvimento/genética , Epilepsia/genética , Polimorfismo de Nucleotídeo Único , Fenótipo , Proteínas de Ligação a DNA/genética , Masculino , Feminino , Fatores de Transcrição/genética , Síndrome , Pré-EscolarRESUMO
OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.
RESUMO
BACKGROUND: Defects in GNAO1, the gene encoding the major neuronal G-protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes. OBJECTIVES: We aimed to analyze the clinical phenotype and the molecular characterization of GNAO1-related disorders. METHODS: Patients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade-videos, and an online questionnaire completed by families were analyzed. We studied Gαo cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G-protein-coupled receptors (GPCRs). RESULTS: Eighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic Gαo were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of Gαo in the plasma membrane was correlated with the phenotype of "developmental and epileptic encephalopathy 17." We observed a genotype-phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del. CONCLUSION: We highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post-hyperkinetic crisis state. We confirm a molecular-based genotype-phenotype correlation for specific variants. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMO
MPZL2-related hearing loss is a rare form of autosomal recessive hearing loss characterized by progressive, mild sloping to severe sensorineural hearing loss. Thirty-five previously reported patients had biallelic truncating variants in MPZL2, with the exception of one patient with a missense variant of uncertain significance and a truncating variant. Here, we describe the clinical characteristics and genotypes of five patients from four families with confirmed MPZL2-related hearing loss. A rare missense likely pathogenic variant [NM_005797.4(MPZL2):c.280C>T,p.(Arg94Trp)] located in exon 3 was confirmed to be in trans with a recurrent pathogenic truncating variant that segregated with hearing loss in three of the patients from two unrelated families. This is the first recurrent likely pathogenic missense variant identified in MPZL2. Apparently milder or later-onset hearing loss associated with rare missense variants in MPZL2 indicates that some missense variants in this gene may cause a milder phenotype than that resulting from homozygous or compound heterozygous truncating variants. This study, along with the identification of truncating loss of function and missense MPZL2 variants in several diverse populations, suggests that MPZL2-related hearing loss may be more common than previously appreciated and demonstrates the need for MPZL2 inclusion in hearing loss testing panels.
Assuntos
Moléculas de Adesão Celular , Perda Auditiva Neurossensorial , Humanos , Moléculas de Adesão Celular/genética , Surdez/genética , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Mutação de Sentido Incorreto/genética , Linhagem , FenótipoRESUMO
BACKGROUND AND AIMS: To investigate the efficacy and feasibility of three different 8 h time-restricted eating (TRE) schedules (i.e., early, late, and self-selected) compared to each other and to a usual-care (UC) intervention on visceral adipose tissue (VAT) and cardiometabolic health in men and women. METHODS AND RESULTS: Anticipated 208 adults (50% women) aged 30-60 years, with overweight/obesity (25 ≤ BMI<40 kg/m2) and with mild metabolic impairments will be recruited for this parallel-group, multicenter randomized controlled trial. Participants will be randomly allocated (1:1:1:1) to one of four groups for 12 weeks: UC, early TRE, late TRE or self-selected TRE. The UC group will maintain their habitual eating window and receive, as well as the TRE groups, healthy lifestyle education for weight management. The early TRE group will start eating not later than 10:00, and the late TRE group not before 13:00. The self-selected TRE group will select an 8 h eating window before the intervention and maintain it over the intervention. The primary outcome is changes in VAT, whereas secondary outcomes include body composition and cardiometabolic risk factors. CONCLUSION: This study will determine whether the timing of the eating window during TRE impacts its efficacy on VAT, body composition and cardiometabolic risk factors and provide insights about its feasibility.
Assuntos
Doenças Cardiovasculares , Gordura Intra-Abdominal , Adulto , Masculino , Humanos , Feminino , Composição Corporal , Fatores de Risco Cardiometabólico , Escolaridade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Jejum , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
PURPOSE: To analyse the time-to-surgery of a centre of excellence in hip fractures of the elderly and its influence on inpatient mortality and postoperative complications. METHODS: A cross-sectional cohort study was conducted. The sample universe consisted of 4,364 patients admitted to a university clinic in Chía, Colombia during the year 2018 to 2023 with ICD-10 diagnoses corresponding to femur fractures. After eliminating duplicates and application of inclusion and exclusion criteria, the final sample included was 269 patients. Qualitative and quantitative variables were analysed, such as: sex, age, age group, type of fracture, type of surgical procedure, time-to-surgery, time to discharge, inpatient mortality and postoperative complications. RESULTS: The mean time-to-surgery from admission was 70.16 h or 2.92 days (IQR 37-87). Patients were divided into three subgroups of time in which they were taken to surgery: <24 h (11.89%), 24-48 h (33.82%) and > 48 h (54.27%). The overall mortality rate was 1.85% for a total of five deceased patients, two of whom belonged to the 24-48-hour group and three to the > 48 h group. Higher rates of postoperative complications were observed in the > 48-hours group (n: 39, 14.49%), followed by the 24-48-hour group (n: 25, 9.29%) and the < 24-hour group (n: 7, 2.6%). CONCLUSIONS: Patients operated for a hip fracture in > 48 h since admission had a slightly higher rate of postoperative complications. No significant difference was observed regarding inpatient mortality when compared to the 24-48-hour group.
RESUMO
This review focuses on the role of small extracellular vesicles in the pathophysiological mechanisms of retinal degenerative diseases. Many of these mechanisms are related to or modulated by the oxidative burden of retinal cells. It has been recently demonstrated that cellular communication in the retina involves extracellular vesicles and that their rate of release and cargo features might be affected by the cellular environment, and in some instances, they might also be mediated by autophagy. The fate of these vesicles is diverse: they could end up in circulation being used as markers, or target neighbor cells modulating gene and protein expression, or eventually, in angiogenesis. Neovascularization in the retina promotes vision loss in diseases such as diabetic retinopathy and age-related macular degeneration. The importance of micro RNAs, either as small extracellular vesicles' cargo or free circulating, in the regulation of retinal angiogenesis is also discussed.
Assuntos
Vesículas Extracelulares , MicroRNAs , Degeneração Retiniana , Humanos , Retina/metabolismo , Degeneração Retiniana/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse OxidativoRESUMO
BACKGROUND: Advanced practice nursing has emerged as a result of the evolution of healthcare systems, the changing needs of the population and the academic development of nursing, as well as sociodemographic and epidemiological changes. The aim of this study is to describe the professional experiences of Spanish advanced practice nurses in specific positions within the healthcare system in order to better understand the development and characteristics of this specialised nursing role. METHODS: A descriptive qualitative study was conducted. Fourteen advanced practice nurses from healthcare centres participated. Semi-structured interviews were carried out. Braun and Clarke's method for reflexive thematic analysis was followed. The Atlas. Ti version 22 program was used for technological support. The COREQ checklist was used to optimise the reporting of this qualitative study. RESULTS: From the analysis of the data collected, three themes and six subthemes were extracted: 1) Advanced practice nursing on the rise: (a) The driving forces in the development of advanced practice nursing, (b) Barriers to the development of advanced practice nursing; 2) Advanced practice nurses as a response to the population's needs: (a) The development of a new professional nursing role, (b) The patient at the centre of care in advanced practice nursing; 3) Training as the foundation for advanced practice nursing: (a) Expert nurses in a specific context, (b) Differences in the level of training depending on the context. CONCLUSION: Advanced practice nurses have faced countless barriers and difficulties that have impeded them from demonstrating their importance and effectiveness within the healthcare system. A stable regulatory framework for the functions of advanced practice nurses is required to promote care, training and research in the field of advanced practice nursing. Health institutions need to promote the role of advanced practice nurses, facilitate the employment of new professionals, and establish new areas of practice. TRIAL REGISTRATION: Not applicable.
RESUMO
The objective of this research was to analyze the risk of adverse effects in patients older than 65 years with dementia and in concomitant treatment with antidementia and antipsychotic drugs and who are cared for by community nurses. A retrospective cross-sectional descriptive study was carried out. A total of 332 patients who were cared for by primary care teams participated. Most of the patients were women, totally dependent for the basic activities of daily living and residing in the family home. They were polymedicated and there was poor therapeutic adherence. The risk of adverse effects was higher in polymedicated patients who had been taking antipsychotics for longer periods and in those who had a main caregiver. However, those patients who had been assessed by the community nurse were protected from suffering adverse effects. This study demonstrates how integrated and continuous nursing care can reduce adverse effects in this type of patient.
Assuntos
Antipsicóticos , Demência , Humanos , Feminino , Idoso , Masculino , Antipsicóticos/efeitos adversos , Vida Independente , Estudos Transversais , Estudos Retrospectivos , Atividades CotidianasRESUMO
The present study examined the association of mothers' and fathers' individualism, collectivism and conformity values with parenting behaviours and child adjustment during middle childhood in an Italian sample. Children (n = 194; 95 from Naples and 99 from Rome; 49% girls) were 10.93 years old (SD = .61) at the time of data collection. Their mothers (n = 194) and fathers (n = 152) also participated. Mother and father reports were collected about parental individualism and collectivism, conformity values, warmth, family obligations expectations and their children's internalising and externalising problems. Child reports were collected about their parents' warmth, psychological control, rules/limit-setting, family obligations expectations and their own internalising and externalising behaviours. Multiple regressions predicted each of the parenting and child adjustment variables from the value variables, controlling for child gender and parent education. Results showed that maternal collectivism was associated with high psychological control, parental collectivism was associated with high expectations regarding children's family obligations and fathers' conformity values were associated with more child internalising behaviours. Overall, the present study shed light on how parents' cultural values are related to some parenting practices and children's internalising problems in Italy.
Assuntos
Poder Familiar , Valores Sociais , Humanos , Feminino , Masculino , Poder Familiar/psicologia , Poder Familiar/etnologia , Itália/etnologia , Criança , Adulto , Comparação Transcultural , Relações Pais-Filho/etnologia , Conformidade Social , Controle Interno-ExternoRESUMO
INTRODUCTION: Endoscopy plays a fundamental role in inflammatory bowel disease (IBD), and becomes essential in diagnosis, treatment monitoring, and detection and management of complications. MATERIALS AND METHODS: The Pan American Crohn's and Colitis Organization (PANCCO) and the Inter-American Society of Endoscopy (SIED) appointed 22 Latin American experts in IBD to develop a consensus study using the modified Delphi method, based on the best available evidence. A working group of 22 members from 9 countries identified 15 topics and formulated 98 statements, who participated in 2 rounds of voting. It was defined as agreement of ≥80% of experts for each statement. RESULTS: After the voting of all the statements, 8 statements were obtained that did not reach 80% consensus among the participants, so the questions were reconsidered in the Coordinating Committee of the consensus with the participation of the expert reviewers of these questions and 7 final statements were voted again by all the experts in a second round and 1 was eliminated with consensus. After two rounds of voting, the experts reached consensus with literature review with the best available evidence, the most important issues were developed with scientific evidence supporting each of the statements around the topic of endoscopy in IBD. CONCLUSIONS: Consensus statements were developed and based on the best available evidence about endoscopy in inflammatory bowel disease.
Assuntos
Técnica Delphi , Doenças Inflamatórias Intestinais , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Endoscopia Gastrointestinal/normas , Doença de Crohn/diagnóstico , América Latina , Sociedades Médicas , ConsensoRESUMO
The expressions of ion channels by Müller glial cells (MGCs) may change in response to various retinal pathophysiological conditions. There remains a gap in our understanding of MGCs' responses to photoreceptor degeneration towards finding therapies. The study explores how an inhibition of store-operated Ca2+ entry (SOCE) and its major component, Orai1 channel, in MGCs protects photoreceptors from degeneration. The study revealed increased Orai1 expression in the MGCs of retinal degeneration 10 (rd10) mice. Enhanced expression of oxidative stress markers was confirmed as a crucial pathological mechanism in rd10 retina. Inducing oxidative stress in rat MGCs resulted in increasing SOCE and Ca2+ release-activated Ca2+ (CRAC) currents. SOCE inhibition by 2-Aminoethoxydiphenyl borate (2-APB) protected photoreceptors in degenerated retinas. Finally, molecular simulations proved the structural and dynamical features of 2-APB to the target structure Orai1. Our results provide new insights into the physiology of MGCs regarding retinal degeneration and shed a light on SOCE and Orai1 as new therapeutic targets.
Assuntos
Canais de Cálcio , Degeneração Retiniana , Ratos , Camundongos , Animais , Canais de Cálcio/metabolismo , Células Ependimogliais/metabolismo , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/prevenção & controle , Cálcio/metabolismo , Proteína ORAI1/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Sinalização do Cálcio/fisiologiaRESUMO
OBJECTIVE: To evaluate factors influencing the diagnostic yield of comprehensive gene panel testing (CGPT) for hearing loss (HL) in children and to understand the characteristics of undiagnosed probands. STUDY DESIGN: This was a retrospective cohort study of 474 probands with childhood-onset HL who underwent CGPT between 2016 and 2020 at a single center. Main outcomes and measures included the association between clinical variables and diagnostic yield and the genetic and clinical characteristics of undiagnosed probands. RESULTS: The overall diagnostic yield was 44% (209/474) with causative variants involving 41 genes. While the diagnostic yield was high in the probands with congenital, bilateral, and severe HL, it was low in those with unilateral, noncongenital, or mild HL; cochlear nerve deficiency; preterm birth; neonatal intensive care unit admittance; certain ancestry; and developmental delay. Follow-up studies on 49 probands with initially inconclusive CGPT results changed the diagnostic status to likely positive or negative outcomes in 39 of them (80%). Reflex to exome sequencing on 128 undiagnosed probands by CGPT revealed diagnostic findings in 8 individuals, 5 of whom had developmental delays. The remaining 255 probands were undiagnosed, with 173 (173/255) having only a single variant in the gene(s) associated with autosomal recessive HL and 28% (48/173) having a matched phenotype. CONCLUSION: CGPT efficiently identifies the genetic etiologies of HL in children. CGPT-undiagnosed probands may benefit from follow-up studies or expanded testing.
Assuntos
Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Nascimento Prematuro , Feminino , Humanos , Criança , Recém-Nascido , Estudos Retrospectivos , Nascimento Prematuro/genética , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Surdez/genética , Fenótipo , Perda Auditiva Neurossensorial/diagnóstico , Testes Genéticos/métodosRESUMO
OBJECTIVES: To characterize the clinical presentation and outcomes of LN in a Hispanic cohort from Mexico. METHODS: We studied 440 subjects with systemic lupus erythematosus and biopsy-proven LN followed for >36 months. We obtained demographic, clinical, laboratory, histopathological and treatment variables. All outcomes were analysed by survival analysis and included response to therapy, renal relapses, progression of kidney disease (decline in eGFR ≥ 30%, doubling of serum creatinine, end-stage kidney disease) and patient survival. RESULTS: The median age of the study cohort was 29 years (IQR 23-37) and 96% were female. The median eGFR at inclusion was 81 mL/min/1.73m2 (IQR 48-118) and 24 h-uPCR was 3.4 g/g (IQR 1.9-5.6). Mixed class LN (III/IV+V) was the most frequently observed (69%). Over a median follow-up of 79 months, complete response rates were 22.3%, 40.5% and 51.6%, at 6, 12 and 24 months, respectively. Renal relapse rates were 32.3% and 50.6% at 3 and 5 years. By 3 and 5 years, 20.7% and 31.4% had decline in eGFR ≥30%, 14.4% and 22.5% doubled their serum creatinine, and 9.1% and 17.7% progressed to ESKD. The factors associated with loss of kidney function were age, eGFR at presentation, the histologic chronicity index in the kidney biopsy, and the type of response to therapy. Patient survival was 98.2% and 97.1% at 3 and 5 years. CONCLUSION: Although the response to treatment and patient survival in this Latin American cohort is comparable to that observed in other regions, there is still a high rate of renal relapses and progression to decline in kidney function.
Assuntos
Falência Renal Crônica , Nefrite Lúpica , Humanos , Feminino , Adulto Jovem , Adulto , Masculino , Nefrite Lúpica/tratamento farmacológico , México , Creatinina , Prognóstico , Seguimentos , Estudos Retrospectivos , Rim/patologia , Falência Renal Crônica/complicações , Hispânico ou LatinoRESUMO
OBJECTIVES: To evaluate the effect of antimalarial drugs in response to therapy, incidence of LN flares, and progression of kidney disease in a large LN cohort. METHODS: We retrospectively studied 424 biopsy-proven LN patients followed for >3 years. We obtained demographic, clinical, laboratory, histopathological, and treatment variables. Antimalarial use was approached as 1) users versus no users, 2) according to prevalent vs incident use regarding the LN flare, and 3) according to the type of antimalarial. All outcomes were evaluated by time-to-event analyses. Adjusted hazard ratios were obtained by Cox regression. RESULTS: The cohort included 424 patients, median age of 29 years (IQR 23-37), 96% female, with a median eGFR of 81 ml/min/1.73m2 (IQR 48-118) and proteinuria of 3.4 g/g (IQR 1.9-5.5). Antimalarial use was associated with higher complete response (aHR 1.57, 1.08-2.27), lower incidence of kidney flares (aHR 0.63, 0.43-0.92), and lower progression to kidney failure (aHR 0.37, 0.23-0.53). The effect on these outcomes was modified by the presentation eGFR, histological class, and/or concomitant initial immunosuppressor. These protective effects were observed in patients with prevalent or incident use regarding the LN flare and patients using hydroxychloroquine. The incidence of toxic retinopathy was 1.7%, 5.7%, and 8.8% by 3-, 5-, and 7 years of continued antimalarial use. CONCLUSION: The use of antimalarial drugs is associated with increased response to therapy, lower incidence of kidney flares, and lower progression to kidney failure in LN patients. Conversely, this population is at high risk of toxic maculopathy, and yearly ophthalmologic examination is recommended.
RESUMO
BACKGROUND: Baby-led weaning (BLW) is an alternative method to spoon-feeding to introduce solid foods. This study aimed to describe and understand the experiences and opinions of pediatricians and pediatric nurse specialists of the implementation of the BLW approach. METHODS: An interpretive descriptive qualitative research was carried out. A focus group with 7 participants and 13 face-to-face interviews were conducted between February and May 2022 (17 females and 3 males). All were audio-recorded, transcribed, and analyzed with the supported by Atlas.Ti qualitative data analysis software. RESULTS: From the data, two themes developed: (1) BLW as an ideal method of introducing solid food, with the subthemes: "a natural method of introducing complementary feeding" and "BLW is a safe method"; (2) Perceived barriers to the uptake of the BLW method, with the subthemes: "a lack of BLW training prevents the best practice" and "the influence of family and social context on parents." CONCLUSIONS: Healthcare professionals perceive BLW to be a safe and natural weaning approach. The lack of training of healthcare professionals and the influence of family social context on parents may limit the implementation of BLW. IMPACT: Baby-led weaning is perceived by healthcare professionals as a safe complementary feeding method that promotes chewing, improves growth, and the development of fine motor skills. However, lack of training of healthcare professionals and the family social context of the parents hinders the uptake of baby-led weaning. The views of the family and parents' social context about baby-led weaning may restrict their willingness to use the method. Family education delivered by healthcare professionals may avoid risks and allay parental anxieties about safety.
Assuntos
Comportamento Alimentar , Fenômenos Fisiológicos da Nutrição do Lactente , Masculino , Lactente , Feminino , Criança , Humanos , Desmame , Pesquisa Qualitativa , Atenção à Saúde , Alimentos InfantisRESUMO
BACKGROUND: Repeated renal flares in lupus nephritis (LN) have been associated with worse long-term kidney function. This study aimed to assess the impact of repeated LN flares in response to therapy, kidney and patient prognosis. METHODS: All patients from a biopsy-proven LN cohort between 2008 and 2018 were segregated into three groups according to the number of LN flares when they entered our cohort: first LN flare, second LN flare or third LN flare. The following outcomes were evaluated by unadjusted and adjusted time-to-event analyses: complete and partial response, disease relapses, progression to decline of 30% of the estimated glomerular filtration rate (eGFR), doubling of serum creatinine, end-stage kidney disease and patient survival. RESULTS: A total of 441 patients were included: 257 (58%) in their first LN flare, 102 (23%) in their second LN flare and 82 (19%) in their third LN flare. There were significant differences in LN flare presentation in age, eGFR, serum albumin, pyuria and hematuria among groups. The National Institutes of Health chronicity indices and the percentage of patients with vascular lesions were higher in groups at progressive LN flares. In the adjusted analyses, complete and partial response rates decreased, as well as kidney and patient survival, at a progressive number of LN flares. No differences in the dynamic course of all surveillance laboratory parameters were observed in the first year after initial therapy among LN flare groups. CONCLUSIONS: A progressive number of LN flares is associated with a lower response to therapy and an adverse prognosis for kidney function and patient survival.
Assuntos
Falência Renal Crônica , Nefrite Lúpica , Humanos , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/tratamento farmacológico , Rim/patologia , Prognóstico , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Falência Renal Crônica/epidemiologia , Biópsia , Estudos RetrospectivosRESUMO
The mammalian mitochondrial proteome is under dual genomic control, with 99% of proteins encoded by the nuclear genome and 13 originating from the mitochondrial DNA (mtDNA). We previously developed MitoCarta, a catalogue of over 1000 genes encoding the mammalian mitochondrial proteome. This catalogue was compiled using a Bayesian integration of multiple sequence features and experimental datasets, notably protein mass spectrometry of mitochondria isolated from fourteen murine tissues. Here, we introduce MitoCarta3.0. Beginning with the MitoCarta2.0 inventory, we performed manual review to remove 100 genes and introduce 78 additional genes, arriving at an updated inventory of 1136 human genes. We now include manually curated annotations of sub-mitochondrial localization (matrix, inner membrane, intermembrane space, outer membrane) as well as assignment to 149 hierarchical 'MitoPathways' spanning seven broad functional categories relevant to mitochondria. MitoCarta3.0, including sub-mitochondrial localization and MitoPathway annotations, is freely available at http://www.broadinstitute.org/mitocarta and should serve as a continued community resource for mitochondrial biology and medicine.
Assuntos
Bases de Dados de Proteínas , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Anotação de Sequência Molecular , Proteoma/metabolismo , Animais , Teorema de Bayes , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Conjuntos de Dados como Assunto , Humanos , Internet , Aprendizado de Máquina , Espectrometria de Massas , Camundongos , Mitocôndrias/genética , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais/classificação , Proteínas Mitocondriais/genética , Proteoma/classificação , Proteoma/genética , SoftwareRESUMO
Connexins (Cx) are a family of transmembrane proteins that form gap junction intercellular channels that connect neighboring cells. These channels allow the passage of ions and other biomolecules smaller than 1 kDa, thereby synchronizing the cells both electrically and metabolically. Cxs are expressed in all retinal cell types and the diversity of Cx isoforms involved in the assembly of the channels provides a functional syncytium required for visual transduction. In this chapter, we summarize the status of current knowledge regarding Cx biology in retinal tissues and discuss how Cx dysfunction is associated with retinal disease pathophysiology. Although the contribution of Cx deficiency to retinal degeneration is not well understood, recent findings present Cx as a potential therapeutic target. Therefore, we will briefly discuss pharmacological approaches and gene therapies that are being explored to modulate Cx function and fight sight-threatening eye diseases.