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1.
Cell ; 184(21): 5338-5356.e21, 2021 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-34624222

RESUMEN

The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.


Asunto(s)
Interferón Tipo I/metabolismo , Proteínas de la Membrana/metabolismo , Microbiota , Monocitos/metabolismo , Microambiente Tumoral , Akkermansia/efectos de los fármacos , Akkermansia/fisiología , Animales , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Fibras de la Dieta/farmacología , Fosfatos de Dinucleósidos/administración & dosificación , Fosfatos de Dinucleósidos/farmacología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunomodulación/efectos de los fármacos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Melanoma/inmunología , Melanoma/patología , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Monocitos/efectos de los fármacos , Fagocitos/efectos de los fármacos , Fagocitos/metabolismo , Transcripción Genética/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
2.
Cell ; 171(6): 1437-1452.e17, 2017 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-29195078

RESUMEN

We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Línea Celular Tumoral , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica/economía , Humanos , Neoplasias/tratamiento farmacológico , Especificidad de Órganos , Preparaciones Farmacéuticas/metabolismo , Análisis de Secuencia de ARN/economía , Análisis de Secuencia de ARN/métodos , Bibliotecas de Moléculas Pequeñas
3.
Nature ; 617(7960): 377-385, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37138075

RESUMEN

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2-RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2-RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2-RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.


Asunto(s)
Resistencia a Antineoplásicos , Inmunoterapia , Melanoma , Microbiota , Animales , Humanos , Ratones , Moléculas de Adhesión Celular Neuronal , Modelos Animales de Enfermedad , Regulación hacia Abajo , Resistencia a Antineoplásicos/efectos de los fármacos , Trasplante de Microbiota Fecal , Vida Libre de Gérmenes , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/inmunología , Melanoma/microbiología , Melanoma/terapia , Unión Proteica/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología
4.
Nature ; 620(7974): 651-659, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37468627

RESUMEN

Even among genetically identical cancer cells, resistance to therapy frequently emerges from a small subset of those cells1-7. Molecular differences in rare individual cells in the initial population enable certain cells to become resistant to therapy7-9; however, comparatively little is known about the variability in the resistance outcomes. Here we develop and apply FateMap, a framework that combines DNA barcoding with single-cell RNA sequencing, to reveal the fates of hundreds of thousands of clones exposed to anti-cancer therapies. We show that resistant clones emerging from single-cell-derived cancer cells adopt molecularly, morphologically and functionally distinct resistant types. These resistant types are largely predetermined by molecular differences between cells before drug addition and not by extrinsic factors. Changes in the dose and type of drug can switch the resistant type of an initial cell, resulting in the generation and elimination of certain resistant types. Samples from patients show evidence for the existence of these resistant types in a clinical context. We observed diversity in resistant types across several single-cell-derived cancer cell lines and cell types treated with a variety of drugs. The diversity of resistant types as a result of the variability in intrinsic cell states may be a generic feature of responses to external cues.


Asunto(s)
Antineoplásicos , Células Clonales , Resistencia a Antineoplásicos , Neoplasias , Humanos , Células Clonales/efectos de los fármacos , Células Clonales/metabolismo , Células Clonales/patología , Código de Barras del ADN Taxonómico , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , RNA-Seq , Análisis de Expresión Génica de una Sola Célula , Células Tumorales Cultivadas , Antineoplásicos/farmacología
5.
EMBO J ; 42(10): e111587, 2023 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-37063065

RESUMEN

Cancer cells display persistent underlying chromosomal instability, with individual tumour types intriguingly exhibiting characteristic subsets of whole, and subchromosomal aneuploidies. Few methods to induce specific aneuploidies will exist, hampering investigation of functional consequences of recurrent aneuploidies, as well as the acute consequences of specific chromosome mis-segregation. We therefore investigated the possibility of sabotaging the mitotic segregation of specific chromosomes using nuclease-dead CRISPR-Cas9 (dCas9) as a cargo carrier to specific genomic loci. We recruited the kinetochore-nucleating domain of centromere protein CENP-T to assemble ectopic kinetochores either near the centromere of chromosome 9, or the telomere of chromosome 1. Ectopic kinetochore assembly led to increased chromosome instability and partial aneuploidy of the target chromosomes, providing the potential to induce specific chromosome mis-segregation events in a range of cell types. We also provide an analysis of putative endogenous repeats that could support ectopic kinetochore formation. Overall, our findings provide new insights into ectopic kinetochore biology and represent an important step towards investigating the role of specific aneuploidy and chromosome mis-segregation events in diseases associated with aneuploidy.


Asunto(s)
Proteínas Cromosómicas no Histona , Cinetocoros , Humanos , Cinetocoros/metabolismo , Proteína A Centromérica/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Mitosis , Centrómero/genética , Centrómero/metabolismo , Aneuploidia , Segregación Cromosómica
6.
Nature ; 592(7852): 138-143, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33731925

RESUMEN

A variety of species of bacteria are known to colonize human tumours1-11, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12-14. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.


Asunto(s)
Antígenos Bacterianos/análisis , Antígenos Bacterianos/inmunología , Bacterias/inmunología , Antígenos HLA/inmunología , Melanoma/inmunología , Melanoma/microbiología , Péptidos/análisis , Péptidos/inmunología , Presentación de Antígeno , Bacterias/clasificación , Bacterias/genética , Línea Celular Tumoral , Técnicas de Cocultivo , Antígenos HLA/análisis , Humanos , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/patología , Metástasis de la Neoplasia/inmunología , Filogenia , ARN Ribosómico 16S/genética
7.
Blood ; 144(4): 392-401, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38643491

RESUMEN

ABSTRACT: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607.


Asunto(s)
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Trastornos Linfoproliferativos , Piperidinas , Rituximab , Humanos , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Persona de Mediana Edad , Femenino , Masculino , Adenina/análogos & derivados , Adenina/uso terapéutico , Trastornos Linfoproliferativos/tratamiento farmacológico , Trastornos Linfoproliferativos/etiología , Anciano , Adulto , Rituximab/efectos adversos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Órganos/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Ciclofosfamida/efectos adversos , Vincristina/administración & dosificación , Vincristina/efectos adversos , Vincristina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Doxorrubicina/administración & dosificación , Prednisona/administración & dosificación , Prednisona/efectos adversos , Prednisona/uso terapéutico , Estudios Prospectivos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificación
8.
Am J Physiol Endocrinol Metab ; 326(4): E493-E502, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38381399

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum ß-hydroxybutyrate (ß-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum ß-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum ß-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum ß-HB correlated with liver mitochondrial ß-hydroxyacyl-CoA dehydrogenase (ß-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum ß-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD.NEW & NOTEWORTHY Serum ß-hydroxybutyrate (ß-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating ß-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum ß-HB. Our work supports serum ß-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Hígado/metabolismo , Obesidad/metabolismo , Cuerpos Cetónicos/metabolismo , Biomarcadores/metabolismo , ARN Mensajero/metabolismo , Palmitatos/metabolismo
9.
Am J Med Genet A ; 194(5): e63542, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38234180

RESUMEN

Axenfeld-Rieger Syndrome (ARS) type 1 is a rare autosomal dominant condition characterized by anterior chamber anomalies, umbilical defects, dental hypoplasia, and craniofacial anomalies, with Meckel's diverticulum in some individuals. Here, we describe a clinically ascertained female of childbearing age with ARS for whom clinical targeted sequencing and deletion/duplication analysis followed by clinical exome and genome sequencing resulted in no pathogenic variants or variants of unknown significance in PITX2 or FOXC1. Advanced bioinformatic analysis of the genome data identified a complex, balanced rearrangement disrupting PITX2. This case is the first reported intrachromosomal rearrangement leading to ARS, illustrating that for patients with compelling clinical phenotypes but negative genomic testing, additional bioinformatic analysis are essential to identify subtle genomic abnormalities in target genes.


Asunto(s)
Segmento Anterior del Ojo , Anomalías del Ojo , Enfermedades Hereditarias del Ojo , Proteína del Homeodomínio PITX2 , Femenino , Humanos , Segmento Anterior del Ojo/anomalías , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Enfermedades Hereditarias del Ojo/diagnóstico , Enfermedades Hereditarias del Ojo/genética , Enfermedades Hereditarias del Ojo/patología , Factores de Transcripción Forkhead/genética , Proteínas de Homeodominio/genética
11.
Pediatr Radiol ; 54(4): 530-547, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37589764

RESUMEN

Pulmonary infection is the leading cause of infectious morbidity and mortality in children with immune defects. We provide a comprehensive review of lung infections in immunocompromised children, with a focus on imaging findings and imaging-based management. We include an overview of the immune defences of the respiratory tract, the aetiologies of immune defects in children, the features of specific infections and important differential diagnoses and describe diagnostic strategies using imaging and non-imaging-based techniques.


Asunto(s)
Neumonía , Infecciones del Sistema Respiratorio , Niño , Humanos , Infecciones del Sistema Respiratorio/diagnóstico por imagen , Huésped Inmunocomprometido , Pulmón
12.
Curr Cardiol Rep ; 26(6): 483-495, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38568339

RESUMEN

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. It has been associated with metabolic, reproductive, and psychiatric disorders. Despite its association with insulin resistance (IR) and cardiovascular disease (CVD) risk factors, the association between PCOS and CVD outcomes has been conflicting. This review reports the updated evidence between PCOS, insulin resistance, and CVD events. RECENT FINDINGS: IR is highly prevalent occurring in 50 to 95% of general and obese PCOS women. The etiology of PCOS involves IR and hyperandrogenism, which lead to CVD risk factors, subclinical CVD, and CVD outcomes. Multiple studies including meta-analysis confirmed a strong association between PCOS and CVD events including ischemic heart disease, stroke, atrial fibrillation, and diabetes, particularly among premenopausal women, and these associations were mediated by metabolic abnormalities. PCOS is highly familial and has substantial CVD risk and transgenerational effects regardless of obesity. A personalized approach to the CVD risk assessment and management of symptom manifestations should be conducted according to its phenotypes. Lifestyle modifications and reduction in environmental stressors should be encouraged for CVD prevention among PCOS women.


Asunto(s)
Enfermedades Cardiovasculares , Resistencia a la Insulina , Síndrome del Ovario Poliquístico , Humanos , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/fisiopatología , Femenino , Enfermedades Cardiovasculares/etiología , Obesidad/complicaciones , Obesidad/fisiopatología , Factores de Riesgo , Medición de Riesgo , Factores de Riesgo de Enfermedad Cardiaca , Prevalencia , Hiperandrogenismo/complicaciones , Hiperandrogenismo/fisiopatología
13.
Prev Sci ; 25(5): 760-773, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38653943

RESUMEN

Service engagement is critical when working with children and families experiencing chronic adversities because of their socially marginalized status. Further, sociodemographic disparities exist in service engagement within service systems including Community-Based Behavioral Health; likely in part, a result of structural issues driving unresponsive service systems. Despite this knowledge, a large proportion of the family engagement literature continues to be approached through a deficit-based and family-centric lens leaving out important systemic considerations and furthering health inequities. Drawing from a Socio-Ecological Framework (Stokols, 1996), this study focuses on exploring the value of peer support providers (PSPs) to understand how sociocultural responsiveness functions under this service model. Individual interviews and focus group data were collected from both families and PSPs. Thematic analysis (Braun & Clarke in Qualitative Research in Psychology, 3(2), 77-101, 2006) was utilized to code and synthetize the data collected. Findings highlight the importance of capitalizing on meaningful and trusting relationships to foster family engagement in services. These findings solidify the understanding that family engagement is a function of crucial relationships between family, provider, and systems. This work also illustrates how PSPs organic embodiment of sociocultural responsiveness through cultural humility is an avenue through which family engagement can be sustained.


Asunto(s)
Grupos Focales , Grupo Paritario , Humanos , Femenino , Masculino , Niño , Investigación Cualitativa
14.
J Clin Microbiol ; 61(10): e0042623, 2023 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-37702495

RESUMEN

Rapid identification of the causative pathogens of central nervous system infections is essential for providing appropriate management and improving patient outcomes. The performance of QIAstat-Dx Meningitis/Encephalitis (ME) Panel-a multiplex PCR testing platform-in detecting pathogens implicated in meningitis and/or encephalitis was evaluated using BioFire FilmArray ME Panel as a comparator method. This multicenter study analyzed 585 retrospective residual cerebrospinal fluid specimens and 367 contrived specimens. The QIAstat-Dx ME Panel showed positive percent agreement (PPA) values of 100% for Neisseria meningitidis, Streptococcus agalactiae, Escherichia coli K1, Listeria monocytogenes, and Cryptococcus gattii/neoformans on clinical samples compared to the BioFire FilmArray ME Panel. The PPA values observed for Haemophilus influenzae and Streptococcus pneumoniae were 80% and 88.24%, respectively. Negative percent agreement (NPA) values were >99.0% for each of the six bacterial targets and one fungal target tested with clinical samples. One viral target, herpes simplex virus 1, exhibited a PPA value of 100.0%, while the remaining viral targets-human parechovirus, herpes simplex virus 2, human herpes virus 6, and varicella zoster virus-were >90.0%, with the exception of enterovirus, which had a PPA value of 77.8%. The QIAstat-Dx ME Panel detected five true-positive and four true-negative cases compared to BioFire FilmArray ME Panel. The NPA values for all viral pathogens were >99.0%. Overall, the QIAstat-Dx ME Panel showed comparable performance to the BioFire FilmArray ME Panel as a rapid diagnostic tool for community-acquired meningitis and encephalitis.


Asunto(s)
Encefalitis , Meningitis , Meningoencefalitis , Humanos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Estudios Retrospectivos , Meningitis/diagnóstico , Encefalitis/diagnóstico , Meningoencefalitis/diagnóstico
15.
Hepatology ; 76(5): 1452-1465, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35000203

RESUMEN

BACKGROUND AND AIMS: NAFLD and its more-advanced form, steatohepatitis (NASH), is associated with obesity and is an independent risk factor for cardiovascular, liver-related, and all-cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation (FAO) and hepatic mitochondrial turnover in NAFLD and NASH are scant. APPROACH AND RESULTS: To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (CTRL; no disease); NAFL (steatosis only); Borderline-NASH (steatosis with lobular inflammation or hepatocellular ballooning); and Definite-NASH (D-NASH; steatosis, lobular inflammation, and hepatocellular ballooning). Hepatic mitochondrial complete FAO to CO2 and the rate-limiting enzyme in ß-oxidation (ß-hydroxyacyl-CoA dehydrogenase activity) were reduced by ~40%-50% with D-NASH compared with CTRL. This corresponded with increased hepatic mitochondrial reactive oxygen species production, as well as dramatic reductions in markers of mitochondrial biogenesis, autophagy, mitophagy, fission, and fusion in NAFL and NASH. CONCLUSIONS: These findings suggest that compromised hepatic FAO and mitochondrial turnover are intimately linked to increasing NAFLD severity in patients with obesity.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/patología , Especies Reactivas de Oxígeno , Dióxido de Carbono , Hígado/patología , Biomarcadores , Obesidad/patología , Inflamación/patología , Recambio Mitocondrial , Ácidos Grasos , Oxidorreductasas , Coenzima A
16.
Int J Eat Disord ; 56(9): 1801-1806, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37158635

RESUMEN

OBJECTIVE: Loss-of-control and overeating are common in adolescents with high body mass index (BMI). Mindfulness may affect negative affect, and both may relate to loss-of-control and overeating. Yet, there is limited understanding of these associations in adolescents' daily lives. METHODS: Forty-five adolescents (77% female; Mage = 14.4 years, SDage = 1.7 years) with high weight (92% with BMI [kg/m2 ] ≥85th percentile for age/sex) provided daily, repeated measurements of mindfulness, negative affect, loss-of-control, and overeating for ~7 days (M = 5.6 days; range = 1-13). Multilevel mixed modeling was conducted to test within-person (intraindividual) and between-person (interindividual) associations for the same-day (concurrent) and next-day (time-ordered/prospective). RESULTS: There were within-person and between-person associations of higher mindfulness with lower negative affect on the same-day and next-day. Greater between-person mindfulness related to lower odds of adolescents' loss-of-control occurrence (same-day) and conversely, more perceived control over eating (same-day and next-day). Greater within-person mindfulness related to less odds of next-day overeating. DISCUSSION: Dynamic relations exist among mindfulness, negative affect, and eating in adolescents at-risk for excess weight gain. Mindfulness may be an important element to consider in loss-of-control and overeating. Future work using momentary-data within an experimental design would help disentangle the intraindividual effects of increasing mindfulness/decreasing negative affect on disordered eating. PUBLIC SIGNIFICANCE: Loss-of-control and overeating are common in teenagers with high weight. Greater mindfulness-present-moment, non-judgmental attention-and less negative emotions may relate to healthier eating, but we do not know how these processes play out in teenagers' daily lives. Addressing this knowledge gap, the current findings showed that greater daily mindfulness, but not negative affect, related to less loss-of-control/overeating, suggesting the importance of mindfulness for eating patterns in teenagers' daily lives.


Asunto(s)
Atención Plena , Humanos , Adolescente , Femenino , Lactante , Recién Nacido , Masculino , Estudios Prospectivos , Conducta Alimentaria/psicología , Aumento de Peso , Hiperfagia/psicología , Sobrepeso
17.
J Nurs Adm ; 53(3): 175-180, 2023 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-36753439

RESUMEN

OBJECTIVES: The aim of this study was to increase patient safety during care transitions through the development of a new process and electronic screening tool. BACKGROUND: Direct hospital admissions that are not clinically triaged can put the patient at an increased safety risk. METHODS: Utilizing the electronic medical record and mnemonic situation, background, assessment, and recommendation (SBAR), an admission module was created to intake direct admission requests by transfer center nurses to ensure clinical triage and accurate bed placement. RESULTS: One hundred eighty-nine direct admissions met inclusion criteria. Thirteen patients were clinically screened, deemed not stable for the acute care setting, and sent to the emergency department. One direct admission safety event occurred involving a hypoglycemic patient upon arrival. Results indicate the new clinical screening program offered a safer way to directly admit patients to the inpatient setting. CONCLUSION: Implementation of the electronic SBAR handoff tool meets the Joint Commission standard of care transitions compliance. The significant workflow changes increased patient safety and will be expanded in the future to all service lines.


Asunto(s)
Hospitalización , Pase de Guardia , Humanos , Servicio de Urgencia en Hospital , Triaje , Cuidados Críticos , Pacientes Internos , Admisión del Paciente
18.
Int J Mol Sci ; 24(14)2023 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-37511466

RESUMEN

Clopidogrel, which is one of the most prescribed antiplatelet medications in the world, is given to stroke survivors for the prevention of secondary cardiovascular events. Clopidogrel exerts its antiplatelet activity via antagonism of the P2Y12 receptor (P2RY12). Although not widely known or considered during the initial clinical trials for clopidogrel, P2RY12 is also expressed on microglia, which are the brain's immune cells, where the receptor facilitates chemotactic migration toward sites of cellular damage. If microglial P2RY12 is blocked, microglia lose the ability to migrate to damaged sites and carry out essential repair processes. We aimed to investigate whether administering clopidogrel to mice post-stroke was associated with (i) impaired motor skills and cognitive recovery; (ii) physiological changes, such as survival rate and body weight; (iii) changes in the neurovascular unit, including blood vessels, microglia, and neurons; and (iv) changes in immune cells. Photothrombotic stroke (or sham surgery) was induced in adult male mice. From 24 h post-stroke, mice were treated daily for 14 days with either clopidogrel or a control. Cognitive performance (memory and learning) was assessed using a mouse touchscreen platform (paired associated learning task), while motor impairment was assessed using the cylinder task for paw asymmetry. On day 15, the mice were euthanized and their brains were collected for immunohistochemistry analysis. Clopidogrel administration significantly impaired learning and memory recovery, reduced mouse survival rates, and reduced body weight post-stroke. Furthermore, clopidogrel significantly increased vascular leakage, significantly increased the number and appearance of microglia, and significantly reduced the number of T cells within the peri-infarct region post-stroke. These data suggest that clopidogrel hampers cognitive performance post-stroke. This effect is potentially mediated by an increase in vascular permeability post-stroke, providing a pathway for clopidogrel to access the central nervous system, and thus, interfere in repair and recovery processes.


Asunto(s)
Accidente Cerebrovascular , Masculino , Humanos , Clopidogrel/farmacología , Clopidogrel/uso terapéutico , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Cognición , Peso Corporal
19.
Fam Process ; 62(4): 1687-1708, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-36347267

RESUMEN

Adolescent disordered eating and obesity are interrelated and adversely relate to mental and metabolic health. Parental feeding practices have been associated with adolescent disordered eating and obesity. Yet, observable interactions related to food parenting have not been well characterized. To address this gap, N = 30 adolescents (M ± SD 14 ± 2 year) at risk for adult obesity due to above-average body mass index (BMI ≥70th percentile) or parental obesity (BMI ≥30 kg/m2 ) participated in a video-recorded parent-adolescent task to discuss a food/eating-related disagreement. Interactions were coded for individual/dyadic affect/content using the Interactional Dimensions Coding System. We examined associations of interaction qualities with parent-reported food practices, adolescent disordered eating behaviors/attitudes, and insulin resistance. Reported parenting practices were correlated with multiple interaction qualities (p-values <0.05), with the most consistent correspondence between parent-reported pressure to eat (e.g., pressure to eat more healthy foods) and negative aspects of parent-adolescent interactions. Also, after accounting for adolescent age, sex, and BMI-standard score, parent-adolescent interaction qualities were associated with adolescents' disordered eating and insulin resistance. Specifically, greater adolescent problem-solving related to less adolescent global disordered eating, shape, and weight concern (p-values <0.05); adolescent autonomy related to less weight concern (p = 0.03). Better parent communication skills were associated with less adolescent eating concern (p = 0.04), and observed dyadic mutuality related to adolescents' lower insulin resistance (p = 0.03). Parent-adolescent interaction qualities during food/eating-related disagreements show associations with parent-reported food practices and adolescent disordered eating. This method may offer a tool for measuring the qualities of parent-adolescent food/eating-related interactions. A nuanced understanding of conversations about food/eating may inform family-based intervention in youth at-risk for adult obesity.


Asunto(s)
Trastornos de Alimentación y de la Ingestión de Alimentos , Resistencia a la Insulina , Adulto , Humanos , Adolescente , Responsabilidad Parental , Padres , Obesidad , Relaciones Padres-Hijo , Encuestas y Cuestionarios
20.
Med Ref Serv Q ; 42(1): 16-30, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36862614

RESUMEN

This research article examines data from an in-person 2017 survey on LibGuides usage, perceptions, and awareness of health professions students seeking bachelor and graduate-level degrees. Almost 45% (n = 20, N = 45) of participants who visited the library's website at least once per week indicated awareness of library-created LibGuides. Nearly 90% (n = 8, N = 9) of health professions students who had not visited the library's website were unaware of the guides. The statistical analysis shows significant associations between various variables (academic level, library workshop attendance, research guide type usage, research guide page usage) and library guide awareness. The data did not reveal any significant relationships between other variables (undergraduate class level, field of study, and library website visit frequency) and guide awareness. The authors discuss implications for health sciences libraries and suggestions for future research.


Asunto(s)
Educación de Postgrado , Bibliotecas Médicas , Humanos , Proyectos de Investigación , Empleos en Salud , Estudiantes
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