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Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8+ T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+ cells, which drove expression of Wnt10b. Reducing Treg cell numbers, or reconstitution of TCRß-/- mice with CD8+ T cells from Wnt10b-/- mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell-mediated regulation of CD8+ T cell Wnt10b production.
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Butiratos/farmacologia , Osteogênese/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Proteínas Wnt/metabolismo , Animais , Butiratos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Comunicação Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Lacticaseibacillus rhamnosus/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Probióticos/administração & dosagem , Probióticos/metabolismo , Linfócitos T Reguladores/citologia , Proteínas Wnt/genéticaRESUMO
INTRODUCTION: Joubert syndrome (JS) arises from defects of primary cilia resulting in potential malformations of the brain, kidneys, eyes, liver, and limbs. Several of the 35+ genes associated with JS have recognized genotype/phenotype correlations, but most genes have not had enough reported individuals to draw meaningful conclusions. METHODS: A PubMed literature review identified 688 individuals with JS across 32 genes and 112 publications to bolster known genotype/phenotype relationships and identify new correlations. All included patients had the "molar tooth sign" and a confirmed genetic diagnosis. Individuals were categorized by age, ethnicity, sex and the presence of developmental disability/intellectual disability, hypotonia, abnormal eye movements, ataxia, visual impairment, renal impairment, polydactyly, and liver abnormalities. RESULTS: Most genes demonstrated unique phenotypic profiles. Grouping proteins based on physiologic interactions established stronger phenotypic relationships that reflect known ciliary pathophysiology. Age-stratified data demonstrated that end-organ disease is progressive in JS. Most genes demonstrated a significant skew towards having variants with either residual protein function or no residual protein function. CONCLUSION: This cohort demonstrates that clinically meaningful genotype/phenotype relationships exist within most JS-related genes and can be referenced to allow for more personalized clinical care.
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Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Humanos , Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Doenças Renais Císticas/genética , Anormalidades do Olho/genética , Retina/anormalidades , Proteínas/genética , Variação Biológica da PopulaçãoRESUMO
PURPOSE: ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. METHODS: We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. RESULTS: De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. CONCLUSION: We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.
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Deficiência Intelectual , Microcefalia , Heterotopia Nodular Periventricular , Humanos , Encéfalo/diagnóstico por imagem , Genótipo , Deficiência Intelectual/genética , Fenótipo , Convulsões/genéticaRESUMO
BACKGROUND: Maternal diet during pregnancy can impact progeny health and disease by influencing the offspring's gut microbiome and immune development. Gut microbial metabolism generates butyrate, a short-chain fatty acid that benefits intestinal health. Here we assess the effects of antenatal butyrate on the offspring's gastrointestinal health. We hypothesized that antenatal butyrate supplementation will induce protection against colitis in the offspring. METHODS: C57BL/6 mice received butyrate during pregnancy and a series of experiments were performed on their offspring. RNA sequencing was performed on colonic tissue of 3-week-old offspring. Six-8-week-old offspring were subjected to dextran sulfate sodium-induced colitis. Fecal microbiome analysis was performed on the 6-8-week-old offspring. RESULTS: Antenatal butyrate supplementation dampened transcript enrichment of inflammation-associated colonic genes and prevented colonic injury in the offspring. Antenatal butyrate increased the offspring's stool microbiome diversity and expanded the prevalence of specific gut microbes. CONCLUSIONS: Antenatal butyrate supplementation resulted in downregulation of genes in the offspring's colon that function in inflammatory signaling. In addition, antenatal butyrate supplementation was associated with protection against colitis and an expanded fecal microbiome taxonomic diversity in the offspring. IMPACT: Dietary butyrate supplementation to pregnant mice led to downregulation of colonic genes involved in inflammatory signaling and cholesterol synthesis, changes in the fecal microbiome composition of the offspring, and protection against experimentally induced colitis in the offspring. These data support the mounting evidence that the maternal diet during pregnancy has enduring effects on the offspring's long-term health and disease risk. Although further investigations are needed to identify the mechanism of butyrate's effects on fetal gut development, the current study substantiates the approach of dietary intervention during pregnancy to optimize the long-term gastrointestinal health of the offspring.
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Butiratos , Colite , Animais , Butiratos/efeitos adversos , Colite/induzido quimicamente , Colite/prevenção & controle , Citoproteção , Suplementos Nutricionais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , GravidezRESUMO
BACKGROUND & AIMS: A Western-style diet, which is high in fat and sugar, can cause significant dyslipidemia and nonalcoholic fatty liver disease; the diet has an especially strong effect in women, regardless of total calorie intake. Dietary supplementation with beneficial microbes might reduce the detrimental effects of a Western-style diet. We assessed the effects of Lactococcus lactis subspecies (subsp) cremoris on weight gain, liver fat, serum cholesterol, and insulin resistance in female mice on a high-fat, high-carbohydrate diet. METHODS: Female C57BL/6 mice were fed either a high-fat, high-carbohydrate (Western-style) diet that contained 40% fat (mostly milk fat) and 43% carbohydrate (mostly sucrose) or a calorie-matched-per-gram control diet. The diets of mice were supplemented with 1 × 109 colony-forming units of L lactis subsp cremoris ATCC 19257 or Lactobacillus rhamnosus GG ATCC 53103 (control bacteria) 3 times per week for 16 weeks. Body weights were measured, and fecal, blood, and liver tissues were collected and analyzed. Livers were analyzed for fat accumulation and inflammation, and blood samples were analyzed for cholesterol and glucose levels. Mice were housed within Comprehensive Lab Animal Monitoring System cages, and respiratory exchange ratio and activity were measured. Hepatic lipid profiles of L lactis subsp cremoris-supplemented mice were characterized by lipidomics mass spectrometry analysis. RESULTS: Mice fed L lactis subsp cremoris while on the Western-style diet gained less weight, developed less hepatic steatosis and inflammation, and had a lower mean serum level of cholesterol and body mass index than mice fed the control bacteria. Mice fed the L lactis subsp cremoris had increased glucose tolerance while on the Western-style diet compared to mice fed control bacteria and had alterations in hepatic lipids, including oxylipins. CONCLUSIONS: Dietary supplementation with L lactis subsp cremoris in female mice on a high-fat, high-carbohydrate (Western-style) diet caused them to gain less weight, develop less liver fat and inflammation, reduce serum cholesterol levels, and increase glucose tolerance compared with mice on the same diet fed control bacteria. L lactis subsp cremoris is safe for oral ingestion and might be developed for persons with metabolic and liver disorders caused by a Western-style diet.
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Dieta Ocidental/efeitos adversos , Dislipidemias/prevenção & controle , Lactococcus , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Probióticos/administração & dosagem , Animais , Colesterol/sangue , Colesterol/metabolismo , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/metabolismo , Feminino , Humanos , Resistência à Insulina , Fígado/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Aumento de PesoRESUMO
Accurate diagnosis of acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical for appropriate management of patients with this disease. We examined the possible complementary role of laboratory-developed class-specific clinical serology in assessing SARS-CoV-2 infection in hospitalized patients. Serological tests for immunoglobulin G (IgG), IgA, and IgM antibodies against the receptor binding domain (RBD) of SARS-CoV-2 were evaluated using samples from real-time reverse transcription-quantitative PCR (qRT-PCR)-confirmed inpatient coronavirus disease 2019 (COVID-19) cases. We analyzed the influence of timing and clinical severity on the diagnostic value of class-specific COVID-19 serology testing. Cross-sectional analysis revealed higher sensitivity and specificity at lower optical density cutoffs for IgA in hospitalized patients than for IgG and IgM serology (IgG area under the curve [AUC] of 0.91 [95% confidence interval {CI}, 0.89 to 0.93] versus IgA AUC of 0.97 [95% CI, 0.96 to 0.98] versus IgM AUC of 0.95 [95% CI, 0.92 to 0.97]). The enhanced performance of IgA serology was apparent in the first 2 weeks after symptom onset and the first week after PCR testing. In patients requiring intubation, all three tests exhibit enhanced sensitivity. Among PCR-negative patients under investigation for SARS-CoV-2 infection, 2 out of 61 showed clear evidence of seroconversion IgG, IgA, and IgM. Suspected false-positive results in the latter population were most frequently observed in IgG and IgM serology tests. Our findings suggest the potential utility of IgA serology in the acute setting and explore the benefits and limitations of class-specific serology as a complementary diagnostic tool to PCR for COVID-19 in the acute setting.
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COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Estudos Transversais , Humanos , Imunoglobulina M , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: While convalescent plasma (CP) may benefit patients with COVID-19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG-specific anti-SARS-CoV-2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP. STUDY DESIGN AND METHODS: Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti-SARS-CoV-2 antibody titers against the receptor-binding domain responsible for viral entry. Symptom onset was obtained by chart review. RESULTS: Increased IgA anti-SARS-CoV-2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID-19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation. CONCLUSIONS: IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID-19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity.
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COVID-19/imunologia , COVID-19/terapia , Convalescença , Imunoglobulina A/sangue , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , Doadores de Sangue , Síndrome de Down/complicações , Síndrome de Down/imunologia , Síndrome de Down/terapia , Feminino , Defeitos dos Septos Cardíacos/complicações , Defeitos dos Septos Cardíacos/imunologia , Defeitos dos Septos Cardíacos/terapia , Humanos , Imunidade Humoral/imunologia , Imunização Passiva/métodos , Imunoglobulina A/análise , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lactente , Estudos Retrospectivos , Testes Sorológicos , Estados Unidos , Soroterapia para COVID-19RESUMO
Recent evidence has demonstrated that reactive oxygen (eg, hydrogen peroxide) can activate host cell signaling pathways that function in repair. We show that mice deficient in their capacity to generate reactive oxygen by the NADPH oxidase 2 holoenzyme, an enzyme complex highly expressed in neutrophils and macrophages, have disrupted capacity to orchestrate signaling events that function in mucosal repair. Similar observations were made for mice after neutrophil depletion, pinpointing this cell type as the source of the reactive oxygen driving oxidation-reduction protein signaling in the epithelium. To simulate epithelial exposure to high levels of reactive oxygen produced by neutrophils and gain new insight into this oxidation-reduction signaling, epithelial cells were treated with hydrogen peroxide, biochemical experiments were conducted, and a proteome-wide screen was performed using isotope-coded affinity tags to detect proteins oxidized after exposure. This analysis implicated signaling pathways regulating focal adhesions, cell junctions, and maintenance of the cytoskeleton. These pathways are also known to act via coordinated phosphorylation events within proteins that constitute the focal adhesion complex, including focal adhesion kinase and Crk-associated substrate. We identified the Rho family small GTP-binding protein Ras-related C3 botulinum toxin substrate 1 and p21 activated kinases 2 as operational in these signaling and localization pathways. These data support the hypothesis that reactive oxygen species from neutrophils can orchestrate epithelial cell-signaling events functioning in intestinal repair.
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Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Intestinos/lesões , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Células Cultivadas , Células Epiteliais/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiologia , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 2/genética , Espécies Reativas de Oxigênio/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Cicatrização/fisiologiaRESUMO
Introduction: Lateral meningocele syndrome (LMS), also known as Lehman syndrome, is caused by pathogenic variants in exon 33 of NOTCH3. Variants in this final exon of NOTCH3 interrupt the regulatory PEST domain, leading to enhanced NOTCH3 signaling due to prolonged cellular half-life. Individuals with LMS are expected to have multiple lateral meningoceles, developmental delay, neonatal hypotonia, dysmorphic facial features, and feeding difficulties. Case Presentation: We report an 8-year-old male with a history of autism, feeding difficulties, developmental delay, severe intellectual disability, and self-injurious behavior. Genetic testing revealed a NOTCH3 c.6663C>G (p.Y2221*) pathogenic variant in exon 33, consistent with a diagnosis of LMS. A follow-up spine MRI showed a ventral sacral extradural arachnoid cyst but no lateral meningoceles. This individual's most recent exam noted multiple dysmorphic features including prominent metopic ridging, broad forehead, downslanting palpebral fissures, high-arched palate, long narrow philtrum, mild pectus excavatum, and wide-based gait. Discussion/Conclusion: This individual shares the dysmorphic facial features, ongoing G-tube dependence, failure to thrive, and developmental delay seen in other individuals with LMS. His lack of lateral meningoceles expands the phenotype for this condition, as all previously reported individuals with molecularly confirmed LMS had multiple lateral meningoceles before age 8 years with an average age of identification at 4 years.
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X-linked creatine transporter deficiency is caused by hemizygous or heterozygous pathogenic variants in SLC6A8 that cause neuropsychiatric symptoms because of impaired uptake of creatine into tissues throughout the body. Small cohorts have suggested that supplementation of creatine, arginine, and glycine can stop disease progression in males, but only six cases of supplementation in females have been published. Here, we present a female with a de-novo pathogenic SLC6A8 variant who had ongoing weight loss, mild intellectual disability, and neuropsychiatric symptoms. Magnetic resonance spectroscopy of the brain showed reduced creatine on all acquired spectra. The patient was started on creatine-monohydrate, l -arginine, and l -glycine supplementation, and she had significant symptomatic improvement within the following 3 weeks. After 8 months of supplementation, magnetic resonance spectroscopy showed improved creatine concentrations with normalizing semiquantitative ratios with other brain metabolites. Current data supports clinicians trialing creatine, arginine, and glycine supplements for female patients with creatine transporter deficiency.
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Arginina , Creatina , Suplementos Nutricionais , Glicina , Deficiência Intelectual Ligada ao Cromossomo X , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Humanos , Feminino , Creatina/metabolismo , Creatina/deficiência , Glicina/metabolismo , Arginina/metabolismo , Arginina/uso terapêutico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/tratamento farmacológico , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo , Encéfalo/metabolismo , Adulto , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Espectroscopia de Ressonância Magnética , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/tratamento farmacológico , Encefalopatias Metabólicas Congênitas , Proteínas de Membrana TransportadorasRESUMO
This study examined educational and occupational inequality as two aspects of social determinants of health that might mediate the longitudinal relationship between racialization and late life cognitive level and change. Participants were 2371 individuals racialized as Black and White from the ACTIVE study who provided occupational data. Data were analyzed from baseline and five assessments over 10-years using structural equation modeling. Black/White race served as the predictor, occupational complexity (OC) and years of education as mediators, and cognitive (memory, reasoning, and speed of processing) intercept, linear slope, and quadratic slope as the dependent variables. Black/White race showed significant indirect associations through education and OC on level of performance in cognition, linear change in reasoning and memory, and quadratic change in reasoning. Education and OC accounted for 11-16% of the association between race and cognitive level and represent modifiable social determinants of health that are associated with disparities in cognitive aging.
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The diet during pregnancy, or antenatal diet, influences the offspring's intestinal health. We previously showed that antenatal butyrate supplementation reduces injury in adult murine offspring with dextran sulfate sodium (DSS)-induced colitis. Potential modulators of butyrate levels in the intestine include a high fiber diet or dietary supplementation with probiotics. To test this, we supplemented the diet of pregnant mice with high fiber, or with the probiotic bacteria Lactococcus lactis subspecies cremoris or Lactobacillus rhamnosus GG. We then induced chronic colitis with DSS in their adult offspring. We demonstrate that a high fiber antenatal diet, or supplementation with Lactococcus lactis subspecies cremoris during pregnancy diminished the injury from DSS-induced colitis in offspring. These data are evidence that antenatal dietary interventions impact offspring gut health and define the antenatal diet as a therapeutic modality to enhance offspring intestinal health.
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Colite , Microbioma Gastrointestinal , Lactococcus lactis , Lactococcus , Feminino , Gravidez , Animais , Camundongos , Lactococcus lactis/genética , Suplementos Nutricionais , ButiratosRESUMO
Objectives: This article sought to determine (1) whether occupational complexity (OC) explains individual differences in cognition at baseline, (2) whether this relationship is differentially related to cognition by Black/White race, and (3) whether OC mediates some or all of the Black/White race-related variance in late life cognition. Methods: 2371 participants from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study reported longest held jobs and received OC ratings based on a factor analysis of 63 variables from the Dictionary of Occupational Titles. Results: We found that multiple dimensions of OC are related to cognition, but there were relatively few Black/White differences in these associations. Across all cognitive dimensions except for useful field of view, a history of having jobs lower in substantive complexity and fine motor skills and higher in physical demands may explain some of the Black/White race differences in elder's cognition. Discussion: We conclude that occupations can be a target to reduce social disparities in late life cognition.
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Cognição , Ocupações , Idoso , Humanos , EnvelhecimentoRESUMO
OBJECTIVE: To assess domains of social determinants of health (SDoH) and their associations with cognition and quality of life. METHOD: This investigation uses baseline data from individuals participating in the ACTIVE trial (n = 2505) to reproduce the SDoH domains described in Healthy People 2030 (economic stability, health care, education, neighborhood and built environment, and social and community context). Results: Results support using data from the ACTIVE trial to assess all five SDoH domains, and the ability of the composites to predict baseline performance on measures of cognition and self-reported quality of life within a sample of older adults. Additionally, higher SDoH domain scores were associated with better functioning on composite measures of cognition and higher scores for mental and general health-related quality of life with Access to Healthcare associated with all outcomes. Discussion: These findings can inform investigators interested in assessing multiple domains of SDoH and highlight the importance of access to health care within older Black/African American and White older adults.
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Cognição , Qualidade de Vida , Determinantes Sociais da Saúde , Idoso , Humanos , Negro ou Afro-Americano , Nível de Saúde , Brancos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Core decompression and placement of the Trabecular Metal Osteonecrosis Intervention Implant have shown to be initially successful in treating early osteonecrosis. When treatment fails, however, patients often undergo primary total hip arthroplasty (THA) requiring removal of a previously inserted trabecular metal implant. We describe a technical tip for removal of a well-ingrown trabecular metal screw. A metal-cutting trephine placed over the screw allows for removal in an efficient manner while minimizing additional dissection and bone loss during conversion to THA.
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Artroplastia de Quadril , Parafusos Ósseos , Remoção de Dispositivo/métodos , Necrose da Cabeça do Fêmur/cirurgia , Metais , Próteses e Implantes , Adulto , Perda do Osso Alveolar/prevenção & controle , Artroplastia de Quadril/instrumentação , Progressão da Doença , Necrose da Cabeça do Fêmur/diagnóstico por imagem , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/cirurgia , Prótese de Quadril , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , ReoperaçãoRESUMO
Introduction: Given prior work showing racial differences on baseline social determinants of health (SDoH) and 10-year trajectories of everyday functioning, we examined associations between SDoH and longitudinal everyday functioning performance in Black/African American and White older adults. Methods: Participants were 2505 older adults (Mage = 73.5; 28% Black/African American) without dementia. SDoH included economic stability/status, education access/quality, health-care access, neighborhood/built environment, and social/community contexts. The Observed Tasks of Daily Living (OTDL) measured everyday functioning and was administered at baseline and 1-, 2-, 3-, 5-, and 10-year visits. Results: Across the sample, social and community context and economic stability/status were associated with steeper age-related OTDL declines (ßs = 0.05 to 0.07, Ps < 0.001). Lower levels of social and community context (ß = 0.08, P = 0.002) and economic stability/status (ß = 0.07, P = 0.04) were associated with OTDL linear age declines in Black/African American participants, but not in White participants (Ps > 0.30). Discussion: Inequities across SDoH accelerate age-related declines in everyday functioning among Black/African American older adults.
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We have demonstrated that neuropeptide Y (NPY) can regulate pro-inflammatory signaling in the gut via cross-talk with the pro-inflammatory cytokine tumor necrosis factor (TNF). Here, we investigated if selective blocking of NPY receptors, NPY1R or NPY2R, using small molecule non-peptide antagonists (BIBP-3222 for NPY1R and BIIE-0246 for NPY2R) in the colon could attenuate intestinal inflammation by lowering TNF levels (BIBP - N-[(1R)]-4-[(Aminoiminomethyl)amino-1-[[[(4-hydroxyphenyl)methyl]amino]carbonyl]butyl-α-phenylbenzeneacetamide; BIIE - N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide). Colitis was induced using dextran sodium sulfate in drinking water for 7 days, or by adoptive T-cell transfer in RAG-/- mice. Colonic biopsies from healthy subjects (n = 10) and IBD patients (n = 34, UC = 20, CD = 14) were cultured ex vivo in presence or absence of NPY antagonists (100 µM, 20 h), and cytokine release into culture supernatants was measured by ELISA. Intracolonic administration of BIBP (but not BIIE) significantly reduced clinical, endoscopic, and histological scores, and serum TNF, interleukin (IL)-6, and IL-12p70 in DSS colitis; it also significantly attenuated histological damage and serum IL-6 in T-cell colitis (P < .05). Intracolonic administration of BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). Our data suggest a promising therapeutic value for NPY1R inhibition in alleviating intestinal inflammation in UC, possibly as enemas to IBD patients.
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Colite , Doenças Inflamatórias Intestinais , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Biópsia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Humanos , Inflamação/patologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/patologia , CamundongosRESUMO
Gut mucosal immune cells play an essential role in health due to their ability to orchestrate host signaling events in response to exogenous antigens. These antigens may originate from microorganisms including viruses, commensal or pathogenic bacteria, or single-celled eukaryotes, as well as from dietary foodstuff-derived proteins or products. A critical technological capacity to understand host responses to antigens is the ability to efficiently isolate and functionally characterize immune cells from intestinal tissues. Additionally, after characterization, it is of paramount importance to understand the exact functions of these immune cells under different disease states or genetic variables. Here, we outline methods for immune cell isolation from murine small and large intestines with the goal of undertaking a functional analysis of isolated cell types using antibody array platforms.
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Citometria de Fluxo/métodos , Mucosa Intestinal/citologia , Linfócitos/imunologia , Análise Serial de Proteínas/métodos , Animais , Imunoensaio/métodos , Linfócitos/citologia , CamundongosRESUMO
Cardiometabolic syndrome encompasses intertwined risk factors such as hypertension, dyslipidemia, elevated triglycerides, abdominal obesity, and other maladaptive metabolic and inflammatory aberrations. As the molecular mechanisms linking cardiovascular disease and metabolic disorders are investigated, endocannabinoids have emerged as molecules of interest. The endocannabinoid system (ECS) of biologically active lipids has been implicated in several conditions, including chronic liver disease, osteoporosis, and more recently in cardiovascular diseases. The gut microbiome is a major regulator of inflammatory and metabolic signaling in the host, and if disrupted, has the potential to drive metabolic and cardiovascular diseases. Extensive studies have unraveled the impact of the gut microbiome on host physiology, with recent reports showing that gut microbes exquisitely control the ECS, with significant influences on host metabolic and cardiac health. In this review, we outline how modulation of the gut microbiome affects host metabolism and cardiovascular health via the ECS, and how these findings could be exploited as novel therapeutic targets for various metabolic and cardiac diseases.