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1.
Cell ; 155(6): 1296-308, 2013 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-24315099

RESUMEN

Bacteria that cause disease rely on their ability to counteract and overcome host defenses. Here, we present a genome-scale study of Mycobacterium tuberculosis (Mtb) that uncovers the bacterial determinants of surviving host immunity, sets of genes we term "counteractomes." Through this analysis, we found that CD4 T cells attempt to contain Mtb growth by starving it of tryptophan--a mechanism that successfully limits infections by Chlamydia and Leishmania, natural tryptophan auxotrophs. Mtb, however, can synthesize tryptophan under stress conditions, and thus, starvation fails as an Mtb-killing mechanism. We then identify a small-molecule inhibitor of Mtb tryptophan synthesis, which converts Mtb into a tryptophan auxotroph and restores the efficacy of a failed host defense. Together, our findings demonstrate that the Mtb immune counteractomes serve as probes of host immunity, uncovering immune-mediated stresses that can be leveraged for therapeutic discovery.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Mycobacterium tuberculosis/metabolismo , Triptófano/biosíntesis , Tuberculosis/inmunología , Tuberculosis/microbiología , Animales , Vías Biosintéticas/efectos de los fármacos , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferón gamma/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Mycobacterium smegmatis/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidad , Tuberculosis/tratamiento farmacológico , Factores de Virulencia/metabolismo , ortoaminobenzoatos/farmacología
2.
J Neurooncol ; 169(1): 105-117, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38837019

RESUMEN

INTRODUCTION: This study compares four management paradigms for large brain metastasis (LMB): fractionated SRS (FSRS), staged SRS (SSRS), resection and postoperative-FSRS (postop-FSRS) or preoperative-SRS (preop-SRS). METHODS: Patients with LBM (≥ 2 cm) between July 2017 and January 2022 at a single tertiary institution were evaluated. Primary endpoints were local failure (LF), radiation necrosis (RN), leptomeningeal disease (LMD), a composite of these variables, and distant intracranial failure (DIF). Gray's test compared cumulative incidence, treating death as a competing risk with a random survival forests (RSF) machine-learning model also used to evaluate the data. RESULTS: 183 patients were treated to 234 LBMs: 31.6% for postop-FSRS, 28.2% for SSRS, 20.1% for FSRS, and 20.1% for preop-SRS. The overall 1-year composite endpoint rates were comparable (21 vs 20%) between nonoperative and operative strategies, but 1-year RN rate was 8 vs 4% (p = 0.012), 1-year overall survival (OS) was 48 vs. 69% (p = 0.001), and 1-year LMD rate was 5 vs 10% (p = 0.052). There were differences in the 1-year RN rates (7% FSRS, 3% postop-FSRS, 5% preop-SRS, 10% SSRS, p = 0.037). With RSF analysis, the out-of-bag error rate for the composite endpoint was 47%, with identified top-risk factors including widespread extracranial disease, > 5 total lesions, and breast cancer histology. CONCLUSION: This is the first study to conduct a head-to-head retrospective comparison of four SRS methods, addressing the lack of randomized data in LBM literature amongst treatment paradigms. Despite patient characteristic trends, no significant differences were found in LF, composite endpoint, and DIF rates between non-operative and operative approaches.


Asunto(s)
Neoplasias Encefálicas , Radiocirugia , Humanos , Radiocirugia/métodos , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/mortalidad , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Adulto , Resultado del Tratamiento , Tasa de Supervivencia , Estudios de Seguimiento
3.
South Med J ; 117(2): 75-79, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38307502

RESUMEN

OBJECTIVES: Many epidemiological studies have shown that coronavirus disease 2019 (COVID-19) disproportionately affects males, compared with females, although other studies show that there were no such differences. The aim of the present study was to assess differences in the prevalence of hospitalizations and in-hospital outcomes between the sexes, using a larger administrative database. METHODS: We used the 2020 California State Inpatient Database for this retrospective analysis. International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis code U07.1 was used to identify COVID-19 hospitalizations. These hospitalizations were subsequently stratified by male and female sex. Diagnosis and procedures were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. The primary outcome of the study was hospitalization rate, and secondary outcomes were in-hospital mortality, prolonged length of stay, vasopressor use, mechanical ventilation, and intensive care unit (ICU) admission. RESULTS: There were 95,180 COVID-19 hospitalizations among patients 18 years and older, 52,465 (55.1%) of which were among men and 42,715 (44.9%) were among women. In-hospital mortality (12.4% vs 10.1%), prolonged length of hospital stays (30.6% vs 25.8%), vasopressor use (2.6% vs 1.6%), mechanical ventilation (11.8% vs 8.0%), and ICU admission rates (11.4% versus 7.8%) were significantly higher among male compared with female hospitalizations. Conditional logistic regression analysis showed that the odds of mortality (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.38-1.44), hospital lengths of stay (OR 1.35, 95% CI 1.31-1.39), vasopressor use (OR 1.59, 95% CI 1.51-1.66), mechanical ventilation (OR 1.62, 95% CI 1.47-1.78), and ICU admission rates (OR 1.58, 95% CI 1.51-1.66) were significantly higher among male hospitalizations. CONCLUSION: Our findings show that male sex is an independent and strong risk factor associated with COVID-19 severity.


Asunto(s)
COVID-19 , Humanos , Masculino , Femenino , COVID-19/epidemiología , COVID-19/terapia , Estudios Retrospectivos , Factores Sexuales , Hospitalización , Unidades de Cuidados Intensivos , Hospitales , Mortalidad Hospitalaria
4.
Anal Chem ; 95(32): 11885-11891, 2023 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-37348197

RESUMEN

As a biomarker of hepatocellular carcinoma (HCC) biopsy, circulating tumor cells (CTCs) are often used in the diagnosis of cancer and treatment guidance. For CTCs detection, immuno-magnetic nanoparticles (IMNs) are one of the most commonly used platforms. However, the nonspecific adsorption of proteins and non-tumor cells weakens the performance of IMNs to capture CTCs. In this work, we developed an IMNs platform which was constructed by a biomimetic protein corona precoating and a polyethylene glycol (PEG) spacer to form the PEG and corona-coated IMNs (IP-CMNs). Due to the dual stealth effect of protein corona precoating and PEG spacer, the nonspecific protein adsorption and cell binding of P-CMNs could reduce by ∼5.5- and ∼5.4-fold, respectively, compared with those of unmodified particles. Furthermore, the PEG spacer could not only reduce the interaction between IP-CMNs and leukocytes but also enhance the capture performance toward tumor cells. By using artificial blood samples, the capture efficiency of IP-CMNs toward rare CTCs was found to be 88.3%, while it was 70.5% by using commercial IMNs. Finally, CTCs were successfully isolated in all HCC patient blood samples (7/7) using IP-CMNs. These results provide insight into the use of the multifunctional nanoplatform as a useful tool for CTCs detection.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Células Neoplásicas Circulantes , Corona de Proteínas , Humanos , Carcinoma Hepatocelular/diagnóstico , Células MCF-7 , Células Neoplásicas Circulantes/patología , Neoplasias Hepáticas/diagnóstico , Polietilenglicoles , Separación Celular
5.
Reproduction ; 166(1): 27-36, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37140983

RESUMEN

In brief: The current declining trend in male fertility parallels the increasing prevalence of obesity worldwide. This paper revealed that the poor in vitro fertilization rates and decreased sperm motility in obese mice due to excessive oxidative stress enhanced apoptosis and impaired glucose metabolism in the testes. Abstract: Obesity is an urgent public health problem in recent decades, linked to reduced reproductive potential, and negatively affects the success of assisted reproduction technology. The aim of this study is to investigate the mechanisms underlying impaired male fertility caused by obesity. Male C57BL/6 mice fed a high-fat diet for 20 weeks served as mouse models with moderate (20% < body fat rate (BFR) < 30%) and severe obesity (BFR > 30%). Our results showed poor in vitro fertilization rates and decreased sperm motility in obese mice. Abnormal testicular structures were identified in male mice with moderate and severe obesity. The expression level of malondialdehyde increased with obesity severity. This finding indicates that oxidative stress plays a role in male infertility caused by obesity, which was further confirmed by the decreased expression of nuclear factor erythroid 2-related factor 2, superoxide dismutase, and glutathione peroxidases. Our study also found that the expression of cleaved caspase-3 and B-cell lymphoma-2 showed an obesity severity-dependent manner indicating that apoptosis is highly correlated with male infertility caused by obesity. Moreover, the expression of glycolysis-related proteins, including glucose transporter 8, lactate dehydrogenase A, monocarboxylate transporter 2 (MCT2), and MCT4, decreased significantly in the testes of obese male mice, suggesting energy supply for spermatogenesis is impaired by obesity. Taken together, our findings provide evidence that obesity impairs male fertility through oxidative stress, apoptosis, and blockage of energy supply in the testes and suggest that male obesity influences fertility through complex and multiple mechanisms.


Asunto(s)
Infertilidad Masculina , Obesidad Mórbida , Humanos , Masculino , Ratones , Animales , Obesidad Mórbida/complicaciones , Obesidad Mórbida/metabolismo , Ratones Obesos , Motilidad Espermática , Ratones Endogámicos C57BL , Obesidad/complicaciones , Obesidad/metabolismo , Testículo/metabolismo , Infertilidad Masculina/etiología , Infertilidad Masculina/metabolismo , Estrés Oxidativo , Apoptosis , Glucólisis
6.
J Youth Adolesc ; 52(9): 1873-1886, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37296270

RESUMEN

There is growing evidence of a clear association between students' perceived stress and their adjustment to life at college. However, the predictors and implications of distinct changing patterns of perceived stress during the transition to college life are less clear. To address these research gaps, the current study aims to identify distinct patterns of perceived stress trajectories among 582 Chinese first-year college students (Mage = 18.11, SDage = 0.65; 69.40% female) across the first 6 months upon enrollment. Three distinct profiles of perceived stress trajectories, i.e., low-stable (15.63%), middle-decreasing (69.07%), and high-decreasing (15.29%), were identified. Moreover, individuals who followed the low-stable trajectory showed better distal outcomes (specifically, higher levels of well-being and academic adjustment) 8 months after enrollment than those who followed the other two trajectories. Furthermore, two types of positive mindset (a growth mindset of intelligence and a stress-is-enhancing mindset) contributed to differences in perceived stress trajectory, either independently or jointly. These findings highlight the significance of identifying different patterns of perceived stress among students during the transition to college, as well as the protective roles of both a stress mindset and a mindset of intelligence.


Asunto(s)
Inteligencia , Estudiantes , Adolescente , Femenino , Humanos , Masculino , Pueblo Asiatico , Estrés Psicológico , Universidades , Adaptación Psicológica
7.
Curr Psychol ; : 1-15, 2022 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-36468161

RESUMEN

Drastically disrupting daily routines, the global pandemic of COVID-19 has posed critical mental health threats to adolescents and young adults worldwide. Many of the extant empirical findings, however, have focused on individuals' psychological adjustment during the initial phase of the pandemic. It is less clear how COVID-19 stressful experiences impact young people's daily lives in the post-pandemic "new normal." Drawing on 7-day diary reports, the present study fills this gap by examining: (1) how daily perceived stress impacted daily emotional adjustment; and (2) the moderating effects of COVID-19 stressful experiences on these associations among 582 Chinese young adults (M age = 18.12, SD = .65; 69% females). Results indicated that higher levels of both trait (i.e., average levels) and state (i.e., daily fluctuations) perceived stress were associated with greater negative and anxious moods, and that prior pandemic-related experiences exacerbated the adverse impact of both trait and state perceived stress on daily moods. Specifically, young adults reporting greater COVID-19 stressful experiences demonstrated poorer emotional adjustment (i.e., lower levels of positive mood and higher levels of negative mood) on days when they had more fluctuations in perceived stress; the aggravating impact was stronger when the average levels of perceived stress were higher. By illuminating the moderating effects of COVID-19 stressful experiences, this study contributes to the limited, but burgeoning, research examining the prolonged impact of the COVID-19 health crisis on daily emotional adjustment in post-pandemic life.

9.
PLoS Genet ; 10(11): e1004782, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25375795

RESUMEN

Transposon-insertion sequencing (TIS) is a powerful approach for deciphering genetic requirements for bacterial growth in different conditions, as it enables simultaneous genome-wide analysis of the fitness of thousands of mutants. However, current methods for comparative analysis of TIS data do not adjust for stochastic experimental variation between datasets and are limited to interrogation of annotated genomic elements. Here, we present ARTIST, an accessible TIS analysis pipeline for identifying essential regions that are required for growth under optimal conditions as well as conditionally essential loci that participate in survival only under specific conditions. ARTIST uses simulation-based normalization to model and compensate for experimental noise, and thereby enhances the statistical power in conditional TIS analyses. ARTIST also employs a novel adaptation of the hidden Markov model to generate statistically robust, high-resolution, annotation-independent maps of fitness-linked loci across the entire genome. Using ARTIST, we sensitively and comprehensively define Mycobacterium tuberculosis and Vibrio cholerae loci required for host infection while limiting inclusion of false positive loci. ARTIST is applicable to a broad range of organisms and will facilitate TIS-based dissection of pathways required for microbial growth and survival under a multitude of conditions.


Asunto(s)
Elementos Transponibles de ADN/genética , Interacciones Huésped-Patógeno/genética , Mutagénesis Insercional/genética , Programas Informáticos , Simulación por Computador , Flujo Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Cadenas de Markov , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidad , Vibrio cholerae/genética , Vibrio cholerae/patogenicidad
10.
Proc Natl Acad Sci U S A ; 111(22): 8037-42, 2014 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-24843173

RESUMEN

Bacterial growth and cell division are coordinated with hydrolysis of the peptidoglycan (PG) layer of the cell wall, but the mechanisms of regulation of extracellular PG hydrolases are not well understood. Here we report the biochemical, structural, and genetic analysis of the Mycobacterium tuberculosis homolog of the transmembrane PG-hydrolase regulator, FtsX. The purified FtsX extracellular domain binds the PG peptidase Rv2190c/RipC N-terminal segment, causing a conformational change that activates the enzyme. Deletion of ftsEX and ripC caused similar phenotypes in Mycobacterium smegmatis, as expected for genes in a single pathway. The crystal structure of the FtsX extracellular domain reveals an unprecedented fold containing two lobes connected by a flexible hinge. Mutations in the hydrophobic cleft between the lobes reduce RipC binding in vitro and inhibit FtsX function in M. smegmatis. These studies suggest how FtsX recognizes RipC and support a model in which a conformational change in FtsX links the cell division apparatus with PG hydrolysis.


Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Mycobacterium smegmatis/enzimología , Mycobacterium tuberculosis/enzimología , N-Acetil Muramoil-L-Alanina Amidasa/metabolismo , Factores de Virulencia/metabolismo , Sustitución de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Sitios de Unión , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Pared Celular/enzimología , Cristalografía por Rayos X , Activación Enzimática/fisiología , Hidrólisis , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/genética , N-Acetil Muramoil-L-Alanina Amidasa/química , N-Acetil Muramoil-L-Alanina Amidasa/genética , Fenotipo , Conformación Proteica , Estructura Terciaria de Proteína , Transducción de Señal/fisiología , Factores de Virulencia/química , Factores de Virulencia/genética
11.
Proc Natl Acad Sci U S A ; 111(34): 12510-5, 2014 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-25104751

RESUMEN

Staphylococcus aureus contains two distinct teichoic acid (TA) polymers, lipoteichoic acid (LTA) and wall teichoic acid (WTA), which are proposed to play redundant roles in regulating cell division. To gain insight into the underlying biology of S. aureus TAs, we used a small molecule inhibitor to screen a highly saturated transposon library for cellular factors that become essential when WTA is depleted. We constructed an interaction network connecting WTAs with genes involved in LTA synthesis, peptidoglycan synthesis, surface protein display, and D-alanine cell envelope modifications. Although LTAs and WTAs are synthetically lethal, we report that they do not have the same synthetic interactions with other cell envelope genes. For example, D-alanylation, a tailoring modification of both WTAs and LTAs, becomes essential when the former, but not the latter, are removed. Therefore, D-alanine-tailored LTAs are required for survival when WTAs are absent. Examination of terminal phenotoypes led to the unexpected discovery that cells lacking both LTAs and WTAs lose their ability to form Z rings and can no longer divide. We have concluded that the presence of either LTAs or WTAs on the cell surface is required for initiation of S. aureus cell division, but these polymers act as part of distinct cellular networks.


Asunto(s)
Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Ácidos Teicoicos/metabolismo , Alanina/metabolismo , División Celular , Pared Celular/metabolismo , Mapeo Cromosómico , Elementos Transponibles de ADN/genética , Técnicas de Inactivación de Genes , Redes Reguladoras de Genes , Genes Bacterianos , Lipopolisacáridos/metabolismo , Mutación , Fenotipo
12.
Nucleic Acids Res ; 41(19): 9033-48, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23901011

RESUMEN

The coupling of high-density transposon mutagenesis to high-throughput DNA sequencing (transposon-insertion sequencing) enables simultaneous and genome-wide assessment of the contributions of individual loci to bacterial growth and survival. We have refined analysis of transposon-insertion sequencing data by normalizing for the effect of DNA replication on sequencing output and using a hidden Markov model (HMM)-based filter to exploit heretofore unappreciated information inherent in all transposon-insertion sequencing data sets. The HMM can smooth variations in read abundance and thereby reduce the effects of read noise, as well as permit fine scale mapping that is independent of genomic annotation and enable classification of loci into several functional categories (e.g. essential, domain essential or 'sick'). We generated a high-resolution map of genomic loci (encompassing both intra- and intergenic sequences) that are required or beneficial for in vitro growth of the cholera pathogen, Vibrio cholerae. This work uncovered new metabolic and physiologic requirements for V. cholerae survival, and by combining transposon-insertion sequencing and transcriptomic data sets, we also identified several novel noncoding RNA species that contribute to V. cholerae growth. Our findings suggest that HMM-based approaches will enhance extraction of biological meaning from transposon-insertion sequencing genomic data.


Asunto(s)
Elementos Transponibles de ADN , Genes Bacterianos , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia de ADN , Vibrio cholerae/genética , Regiones no Traducidas 5' , Escherichia coli/genética , Biblioteca de Genes , Genes Esenciales , Sitios Genéticos , Cadenas de Markov , ARN no Traducido/genética , Vibrio cholerae/crecimiento & desarrollo
13.
Bioinformatics ; 29(6): 695-703, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23361328

RESUMEN

MOTIVATION: Next-generation sequencing affords an efficient analysis of transposon insertion libraries, which can be used to identify essential genes in bacteria. To analyse this high-resolution data, we present a formal Bayesian framework for estimating the posterior probability of essentiality for each gene, using the extreme-value distribution to characterize the statistical significance of the longest region lacking insertions within a gene. We describe a sampling procedure based on the Metropolis-Hastings algorithm to calculate posterior probabilities of essentiality while simultaneously integrating over unknown internal parameters. RESULTS: Using a sequence dataset from a transposon library for Mycobacterium tuberculosis, we show that this Bayesian approach predicts essential genes that correspond well with genes shown to be essential in previous studies. Furthermore, we show that by using the extreme-value distribution to characterize genomic regions lacking transposon insertions, this method is capable of identifying essential domains within genes. This approach can be used for analysing transposon libraries in other organisms and augmenting essentiality predictions with statistical confidence scores.


Asunto(s)
Elementos Transponibles de ADN , Genes Bacterianos , Secuenciación de Nucleótidos de Alto Rendimiento , Mutagénesis Insercional , Algoritmos , Teorema de Bayes , Biblioteca de Genes , Genes Esenciales , Genómica , Modelos Estadísticos , Mycobacterium tuberculosis/genética , Estructura Terciaria de Proteína
14.
PLoS Pathog ; 8(9): e1002946, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23028335

RESUMEN

Identifying genomic elements required for viability is central to our understanding of the basic physiology of bacterial pathogens. Recently, the combination of high-density mutagenesis and deep sequencing has allowed for the identification of required and conditionally required genes in many bacteria. Genes, however, make up only a part of the complex genomes of important bacterial pathogens. Here, we use an unbiased analysis to comprehensively identify genomic regions, including genes, domains, and intergenic elements, required for the optimal growth of Mycobacterium tuberculosis, a major global health pathogen. We found that several proteins jointly contain both domains required for optimal growth and domains that are dispensable. In addition, many non-coding regions, including regulatory elements and non-coding RNAs, are critical for mycobacterial growth. Our analysis shows that the genetic requirements for growth are more complex than can be appreciated using gene-centric analysis.


Asunto(s)
Proteínas Bacterianas/genética , Genoma Bacteriano , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/genética , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Perfilación de la Expresión Génica , Genoma , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Mycobacterium tuberculosis/metabolismo , ARN no Traducido/genética , Secuencias Reguladoras de Ácidos Nucleicos , Análisis de Secuencia de ADN
15.
Cell Microbiol ; 15(7): 1079-87, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23521858

RESUMEN

Intracellular bacterial pathogens often rely on their hosts for essential nutrients. Host cells, in turn, attempt to limit nutrient availability, using starvation as a mechanism of innate immunity. Here we discuss both host mechanisms of amino acid starvation and the diverse adaptations of pathogens to their nutrient-deprived environments. These processes provide both key insights into immune subversion and new targets for drug development.


Asunto(s)
Aminoácidos/metabolismo , Bacterias/metabolismo , Bacterias/patogenicidad , Fenómenos Fisiológicos Celulares , Citoplasma/metabolismo , Citoplasma/microbiología , Interacciones Huésped-Patógeno , Animales , Humanos
16.
Artículo en Inglés | MEDLINE | ID: mdl-38624107

RESUMEN

INTRODUCTION: Proton pump inhibitor (PPI) use has been associated with an increased risk of gastrointestinal and upper respiratory infections in children. There are limited longitudinal data on the effect of PPI in children. The goal of this prospective observational study was to compare the stool and oropharyngeal microbiome of children before and after starting PPIs. METHODS: We prospectively recruited participants from a gastroenterology clinic. Consented participants provided stool samples and oropharyngeal swabs at baseline and after 8 weeks of PPI therapy. Microbiome changes were measured by analyzing 16S sequencing from both body sites at both time points. RESULTS: Thirty-four participants completed the study and provided samples both at baseline and after 8 weeks on PPI therapy. Of those, 24 participants had sufficient sequencing from both stool and oropharyngeal samples at both time points. There were no differences between the pre-PPI and post-PPI samples using beta-diversity metrics in either the oropharynx or stool. There were, however, significant changes in specific taxa. There was an enrichment of Streptococcus in the stool after PPI use and a reduction in the relative abundance of Bifidobacterium , Peptostreptococcus , and Turicibacter ( P -values < 0.01). Furthermore, there was an increase in the relative abundance of oropharyngeal bacteria in the stool after PPI therapy. This enrichment of oropharyngeal bacteria in the stool was most prominent in younger participants. DISCUSSION: Further investigation is needed to determine the clinical and microbial factors that predispose or protect against microbiome changes due to PPI use and why young children are more susceptible to this PPI effect.

17.
Curr Mol Pharmacol ; 17: e18761429282063, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38389418

RESUMEN

BACKGROUND: Nicosulfuron, a widely used herbicide in crops, has raised concerns due to its escalating presence as an environmental pollutant, particularly in soil and water. The potential adverse effects of nicosulfuron on animals, including reproductive toxicity, have garnered attention. OBJECTIVE: The study aimed to evaluate the reproductive toxicity of nicosulfuron in male mice. METHODS: Male mice were orally administrated with three different concentration gradients (350, 700, and 1400 mg/kg) of nicosulfuron for 35 days. The investigation delved into sperm quality, testicular structures, and expression of cleaved caspase-3 and NF-κB p65 of the testes. RESULTS: The finding unveiled a correlation between nicosulfuron exposure and detrimental effects on sperm quality and alteration of testicular structure. Notably, parameters, such as sperm survival rate (SUR) and sperm motility (MOT), exhibited a decline in relation to increasing nicosulfuron dosages. Moreover, in the mice subjected to higher doses of nicosulfuron, elevated expression of cleaved caspase-3 and NF-κB p65 was observed in the testes. Interestingly, we also observed an increase of NF-κB p65 expression in the mice exposed to the nicosulfuron. CONCLUSION: Our research revealed that exposure to nicosulfuron resulted in compromised sperm quality and alterations in testicular structure. The correlation between nicosulfuron and apoptosis, especially via the NF-κB pathway, provided significant insights into the mechanisms underpinning these detrimental effects. These findings significantly enhance our comprehension of the potential hazards associated with nicosulfuron exposure and its impacts on the reproductive health of animals.


Asunto(s)
FN-kappa B , Piridinas , Compuestos de Sulfonilurea , Testículo , Masculino , Ratones , Animales , FN-kappa B/metabolismo , Caspasa 3/metabolismo , Caspasa 3/farmacología , Estrés Oxidativo , Motilidad Espermática , Semen/metabolismo , Espermatozoides/metabolismo , Transducción de Señal , Apoptosis
18.
Ann Epidemiol ; 94: 81-90, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38710239

RESUMEN

PURPOSE: Identifying predictors of opioid overdose following release from prison is critical for opioid overdose prevention. METHODS: We leveraged an individually linked, state-wide database from 2015-2020 to predict the risk of opioid overdose within 90 days of release from Massachusetts state prisons. We developed two decision tree modeling schemes: a model fit on all individuals with a single weight for those that experienced an opioid overdose and models stratified by race/ethnicity. We compared the performance of each model using several performance measures and identified factors that were most predictive of opioid overdose within racial/ethnic groups and across models. RESULTS: We found that out of 44,246 prison releases in Massachusetts between 2015-2020, 2237 (5.1%) resulted in opioid overdose in the 90 days following release. The performance of the two predictive models varied. The single weight model had high sensitivity (79%) and low specificity (56%) for predicting opioid overdose and was more sensitive for White non-Hispanic individuals (sensitivity = 84%) than for racial/ethnic minority individuals. CONCLUSIONS: Stratified models had better balanced performance metrics for both White non-Hispanic and racial/ethnic minority groups and identified different predictors of overdose between racial/ethnic groups. Across racial/ethnic groups and models, involuntary commitment (involuntary treatment for alcohol/substance use disorder) was an important predictor of opioid overdose.


Asunto(s)
Árboles de Decisión , Sobredosis de Opiáceos , Humanos , Masculino , Sobredosis de Opiáceos/epidemiología , Adulto , Femenino , Massachusetts/epidemiología , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/etnología , Prisioneros/estadística & datos numéricos , Prisiones/estadística & datos numéricos , Persona de Mediana Edad , Analgésicos Opioides/envenenamiento , Analgésicos Opioides/efectos adversos , Etnicidad/estadística & datos numéricos , Adulto Joven
19.
ACS Biomater Sci Eng ; 10(3): 1494-1506, 2024 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-38414275

RESUMEN

The use of hemoperfusion adsorbents for the removal of bilirubin in patients with liver failure has become a critical treatment. However, the insufficient clearance of bilirubin and the possibility of bacterial infection during hemoperfusion limit the application. In this work, we designed a novel antibacterial bilirubin adsorbent (PSVT) through the suspension polymerization reaction between double-bond functionalized TiO2 nanoparticles and styrene. PSVT showed an excellent bilirubin adsorption ability and antibacterial performance, ensuring efficient clearance of bilirubin in liver failure patients during hemoperfusion and preventing bacterial infection. The experimental results indicated that TiO2 was uniformly dispersed in the microspheres, which improved the mesoporous structure and increased the specific surface area. Composite adsorbent PSVT showed an exceptional bilirubin adsorption capacity, with the maximum adsorption capacity reaching 24.3 mg/g. In addition, the introduction of TiO2 endowed PSVT with excellent antibacterial ability; the ultimate antibacterial rates against Escherichia coli and Staphylococcus aureus reached 97.31 and 96.47%, respectively. In summary, PSVT served as a novel antibacterial bilirubin adsorbent with excellent bilirubin clearance capacity and antibacterial performance, providing excellent application prospects for treating liver failure patients.


Asunto(s)
Infecciones Bacterianas , Hemoperfusión , Fallo Hepático , Nanocompuestos , Humanos , Bilirrubina/química , Poliestirenos/química , Hemoperfusión/métodos , Nanocompuestos/uso terapéutico
20.
Artículo en Inglés | MEDLINE | ID: mdl-39051622

RESUMEN

The clearance of urea poses a formidable challenge, and its excessive accumulation can cause various renal diseases. Urease demonstrates remarkable efficacy in eliminating urea, but cannot be reused. This study aimed to develop a composite vector system comprising microcrystalline cellulose (MCC) immobilized with urease and metal-organic framework (MOF) UiO-66-NH2, denoted as MCC@UiO/U, through the dynamic defect generation strategy. By utilizing competitive coordination, effective immobilization of urease into MCC@UiO was achieved for efficient urea removal. Within 2 h, the urea removal efficiency could reach up to 1500 mg/g, surpassing an 80% clearance rate. Furthermore, an 80% clearance rate can also be attained in peritoneal dialyzate from patients. MCC@UiO/U also exhibits an exceptional bioactivity even after undergoing 5 cycles of perfusion, demonstrating remarkable stability and biocompatibility. This innovative approach and methodology provide a novel avenue and a wide range of immobilized enzyme vectors for clinical urea removal and treatment of kidney diseases, presenting immense potential for future clinical applications.

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