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1.
Malays J Pathol ; 46(1): 95-102, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38682849

RESUMO

Borderline oxacillin-resistant Staphylococcus aureus (BORSA) are mecA-negative strains with oxacillin minimum inhibitor concentration (MIC) close to the resistance breakpoint of ≥ 4µg/mL. Instead of producing penicillin-binding protein with low affinity to methicillin (oxacillin) mediated by mecA gene as in methicillin-resistant S. aureus (MRSA), BORSA strains are characterised by the hyperproduction of ß-lactamase enzymes, thus able to break down methicillin. Common laboratory methods to detect MRSA such as cefoxitin disk diffusion alone may fail to detect methicillin resistance due to BORSA. We report five cases of BORSA blood-stream infections in a university teaching hospital. All isolates were found to be susceptible to cefoxitin using disk diffusion, resistant to oxacillin using automated MIC method, and did not harbour mecA gene. All patients were suscessfully treated with anti-MRSA antibiotics, and removal of primary sources were done if identified. A more cost-effective method for screening and diagnosis of BORSA is needed in addition to cefoxitin disk diffusion test, in order to monitor the spread, and to enable routine detection and treatment of this pathogen.


Assuntos
Antibacterianos , Oxacilina , Infecções Estafilocócicas , Humanos , Oxacilina/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/diagnóstico , Masculino , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Feminino , Pessoa de Meia-Idade , Testes de Sensibilidade Microbiana , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Adulto , Idoso , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , Cefoxitina/farmacologia , Cefoxitina/uso terapêutico
2.
Ann Surg Oncol ; 31(6): 4005-4017, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38526832

RESUMO

BACKGROUND: Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the cost impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging. MATERIALS AND METHODS: In this cost analysis, four staging strategies were modeled in a decision tree: (1) 18FFDG-PET/CT first, then SL, (2) SL only, (3) 18FFDG-PET/CT only, and (4) neither SL nor 18FFDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding 18FFDG-PET/CT and SL to staging advanced gastric cancer (cT3-4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided 18FFDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations). RESULTS: 18FFDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding 18FFDG-PET/CT to SL increased costs by €1058 per patient; IQR €870-1253 in the sensitivity analysis. CONCLUSIONS: For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine 18FFDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs. TRIAL REGISTRATION: NCT03208621. This trial was registered prospectively on 30-06-2017.


Assuntos
Fluordesoxiglucose F18 , Gastrectomia , Laparoscopia , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Neoplasias Gástricas , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/economia , Humanos , Laparoscopia/economia , Laparoscopia/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/economia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Prospectivos , Gastrectomia/economia , Fluordesoxiglucose F18/economia , Compostos Radiofarmacêuticos/economia , Análise Custo-Benefício , Seguimentos , Prognóstico , Custos e Análise de Custo , Masculino , Feminino
3.
ACS Med Chem Lett ; 15(2): 258-264, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38352843

RESUMO

Glioblastoma, a prevalent malignant CNS tumor, presents a therapeutic challenge because of resistance to standard treatments, including radiation therapy and temozolomide. Both modalities induce autophagy, thereby paradoxically promoting tumor survival. The cysteine protease ATG4B is implicated in this cellular process, which highlights the enzyme as a viable therapeutic target for glioblastoma. We have developed streamlined syntheses for ATG4B inhibitor NSC185058, its derivatives, and fluorogenic ATG4B substrate pim-FG-PABA-AMC. We leveraged these findings to rapidly identify novel compound MJO445, which demonstrates markedly greater potency biochemically and in cells.

5.
Neuropsychologia ; 191: 108726, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37931746

RESUMO

Investigations of grasping real, 3D objects subjected to illusory effects from a pictorial background often choose in-flight grasp aperture as the primary variable to test the hypothesis that the visuomotor system resists the illusion. Here we test an equally important feature of grasps that has received less attention: in-flight grasp orientation. The current study tested a variant of the simultaneous tilt illusion using a mirror-apparatus to manipulate the availability of haptic feedback. Participants performed grasps with haptic feedback (real grasps) and without it (pantomime grasps), reaching for the reflection of a real, 3D bar atop a background grating that induced a 1.1° bias in the perceived orientation of the bar in a separate sample of participants. Analysis of the hand's in-flight grasp orientation at early, late, and end stages of the reach showed that at no point were the real grasps biased by the illusion. In contrast, pantomimed grasps were affected by the illusion at the late and end stages of the reach. At each stage, the effect on the real grasps was significantly weaker than the effect of the illusion as measured by the mean point of subjective equality (PSE) in a two-alternative forced-choice task. In contrast, the effect on the pantomime grasps was statistically indistinguishable from the mean PSE at all three stages of the reach. These findings reinforce the idea that in-flight grasp orientation, like grasp aperture to pictorial illusions of target size, is refractory to pictorial backgrounds that bias perceived orientation.


Assuntos
Ilusões , Humanos , Desempenho Psicomotor , Percepção Visual , Atenção , Força da Mão
6.
Pathog Glob Health ; : 1-23, 2023 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-38006316

RESUMO

Staphylococcus aureus is a Gram-positive bacterium and one of the most prevalent infectious disease-related causes of morbidity and mortality in adults. This pathogen can trigger a broad spectrum of diseases, from sepsis and pneumonia to severe skin infections that can be fatal. In this review, we will provide an overview of S. aureus and discuss the extensive literature on epidemiology, transmission, genetic diversity, evolution and antibiotic resistance strains, particularly methicillin resistant S. aureus (MRSA). While many different virulence factors that S. aureus produces have been investigated as therapeutic targets, this review examines recent nanotechnology approaches, which employ materials with atomic or molecular dimensions and are being used to diagnose, treat, or eliminate the activity of S. aureus. Finally, having a deeper understanding and clearer grasp of the roles and contributions of S. aureus determinants, antibiotic resistance, and nanotechnology will aid us in developing anti-virulence strategies to combat the growing scarcity of effective antibiotics against S. aureus.

7.
Genes (Basel) ; 14(10)2023 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-37895233

RESUMO

Prostate cancer (PCa) is the most common cause of cancer death among African men. The presence of tumor-specific variations in cell-free DNA (cfDNA), such as mutations, microsatellite instability, and DNA methylation, has been explored as a source of biomarkers for cancer diagnosis. In this study, we investigated the diagnostic role of cfDNA among South African PCa patients. We performed whole exome sequencing (WES) of urinary cfDNA. We identified a novel panel of 31 significantly deregulated somatic mutated genes between PCa and benign prostatic hyperplasia (BPH). Additionally, we performed whole-genome sequencing (WGS) on matching PCa and normal prostate tissue in an independent PCa cohort from South Africa. Our results suggest that the mutations are of germline origin as they were also found in the normal prostate tissue. In conclusion, our study contributes to the knowledge of cfDNA as a biomarker for diagnosing PCa in the South African population.


Assuntos
Ácidos Nucleicos Livres , Hiperplasia Prostática , Neoplasias da Próstata , Masculino , Humanos , Ácidos Nucleicos Livres/genética , África do Sul , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/genética , Mutação , Biomarcadores
8.
Biomolecules ; 13(9)2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37759795

RESUMO

Delirium is a common postoperative complication among older patients with many adverse outcomes. Due to a lack of validated biomarkers, prediction and monitoring of delirium by biological testing is not currently feasible. Circulating proteins in cerebrospinal fluid (CSF) may reflect biological processes causing delirium. Our goal was to discover and investigate candidate protein biomarkers in preoperative CSF that were associated with the development of postoperative delirium in older surgical patients. We employed a nested case-control study design coupled with high multiplex affinity proteomics analysis to measure 1305 proteins in preoperative CSF. Twenty-four matched delirium cases and non-delirium controls were selected from the Healthier Postoperative Recovery (HiPOR) cohort, and the associations between preoperative protein levels and postoperative delirium were assessed using t-test statistics with further analysis by systems biology to elucidate delirium pathophysiology. Proteomics analysis identified 32 proteins in preoperative CSF that significantly associate with delirium (t-test p < 0.05). Due to the limited sample size, these proteins did not remain significant by multiple hypothesis testing using the Benjamini-Hochberg correction and q-value method. Three algorithms were applied to separate delirium cases from non-delirium controls. Hierarchical clustering classified 40/48 case-control samples correctly, and principal components analysis separated 43/48. The receiver operating characteristic curve yielded an area under the curve [95% confidence interval] of 0.91 [0.80-0.97]. Systems biology analysis identified several key pathways associated with risk of delirium: inflammation, immune cell migration, apoptosis, angiogenesis, synaptic depression and neuronal cell death. Proteomics analysis of preoperative CSF identified 32 proteins that might discriminate individuals who subsequently develop postoperative delirium from matched control samples. These proteins are potential candidate biomarkers for delirium and may play a role in its pathophysiology.


Assuntos
Delírio do Despertar , Humanos , Idoso , Proteínas do Líquido Cefalorraquidiano , Estudos de Casos e Controles , Proteômica , Complicações Pós-Operatórias , Oligonucleotídeos
9.
Cancers (Basel) ; 15(15)2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37568783

RESUMO

Prostate cancer (PCa) is the most common cause of cancer death among African men. The analysis of microRNAs (miRNAs) in plasma extracellular vesicles (EVs) can be utilized as a non-invasive tool for the diagnosis of PCa. In this study, we used small RNA sequencing to profile miRNAs cargo in plasma EVs from South African PCa patients. We evaluated the differential expression of miRNAs between low and high Gleason scores in the plasma EVs of South African patients and in the prostatic tissue from data available in the Cancer Genome Atlas (TCGA) Data Portal. We identified 7 miRNAs differently expressed in both EVs and prostatic tissues. We evaluated their expression using qPCR in a larger cohort of 10 patients with benign prostatic hyperplasia (BPH) and 24 patients with PCa. Here, we reported that the ratio between two of these miRNAs (i.e., miR-194-5p/miR-16-5p) showed a higher concentration in PCa compared to BPH and in metastatic PCa compared to localized PCa. We explored for the first time the profiling of miRNAs cargo in plasma EVs as a tool for the identification of putative markers in the South African population. Our finding indicated the ratio miR-194-5p/miR-16-5p as a non-invasive marker for the evaluation of PCa aggressiveness in this population.

10.
Cells ; 12(15)2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-37566077

RESUMO

Multi-omics has the promise to provide a detailed molecular picture of biological systems. Although obtaining multi-omics data is relatively easy, methods that analyze such data have been lagging. In this paper, we present an algorithm that uses probabilistic graph representations and external knowledge to perform optimal structure learning and deduce a multifarious interaction network for multi-omics data from a bacterial community. Kefir grain, a microbial community that ferments milk and creates kefir, represents a self-renewing, stable, natural microbial community. Kefir has been shown to have a wide range of health benefits. We obtained a controlled bacterial community using the two most abundant and well-studied species in kefir grains: Lentilactobacillus kefiri and Lactobacillus kefiranofaciens. We applied growth temperatures of 30 °C and 37 °C and obtained transcriptomic, metabolomic, and proteomic data for the same 20 samples (10 samples per temperature). We obtained a multi-omics interaction network, which generated insights that would not have been possible with single-omics analysis. We identified interactions among transcripts, proteins, and metabolites, suggesting active toxin/antitoxin systems. We also observed multifarious interactions that involved the shikimate pathway. These observations helped explain bacterial adaptation to different stress conditions, co-aggregation, and increased activation of L. kefiranofaciens at 37 °C.


Assuntos
Produtos Fermentados do Leite , Produtos Fermentados do Leite/microbiologia , Multiômica , Proteômica , Bactérias/genética
11.
Magn Reson Med ; 90(5): 1874-1888, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37392412

RESUMO

PURPOSE: Clinical use of transcranial electrical stimulation (TES) requires accurate knowledge of the injected current distribution in the brain. MR current density imaging (MRCDI) uses measurements of the TES-induced magnetic fields to provide this information. However, sufficient sensitivity and image quality in humans in vivo has only been documented for single-slice imaging. METHODS: A recently developed, optimally spoiled, acquisition-weighted, gradient echo-based 2D-MRCDI method has now been advanced for volume coverage with densely or sparsely distributed slices: The 3D rectilinear sampling (3D-DENSE) and simultaneous multislice acquisition (SMS-SPARSE) were optimized and verified by cable-loop experiments and tested with 1-mA TES experiments for two common electrode montages. RESULTS: Comparisons between the volumetric methods against the 2D-MRCDI showed that relatively long acquisition times of 3D-DENSE using a single slab with six slices hindered the expected sensitivity improvement in the current-induced field measurements but improved sensitivity by 61% in the Laplacian of the field, on which some MRCDI reconstruction methods rely. Also, SMS-SPARSE acquisition of three slices, with a factor 2 CAIPIRINHA (controlled aliasing in parallel imaging results in higher acceleration) acceleration, performed best against the 2D-MRCDI with sensitivity improvements for the ∆ B z , c $$ \Delta {B}_{z,c} $$ and Laplacian noise floors of 56% and 78% (baseline without current flow) as well as 43% and 55% (current injection into head). SMS-SPARSE reached a sensitivity of 67 pT for three distant slices at 2 × 2 × 3 mm3 resolution in 10 min of total scan time, and consistently improved image quality. CONCLUSION: Volumetric MRCDI measurements with high sensitivity and image quality are well suited to characterize the TES field distribution in the human brain.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Humanos , Encéfalo/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Cabeça , Imagens de Fantasmas , Campos Magnéticos , Processamento de Imagem Assistida por Computador/métodos
12.
Cureus ; 15(6): e40943, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37503477

RESUMO

INTRODUCTION: Obesity (Obe) is a chronic metabolic disorder usually complicated by impaired fibrinolytic activity. Apigenin (Api) is one of the flavonoids that have anti-adiposity effects. This study aimed to explore the therapeutic potential of Api in high-fat diet (HFD)-induced obese rats. METHODS: Twenty-four Wistar adult male rats were randomly allocated into control group, supplemented with a normal pellet diet (NPD); Api group, supplemented with Api (10 mg/kg) for eight weeks; Obe group, obesity was induced by feeding HFD for eight weeks; and Obe/Api group, obese rats supplemented with Api for eight weeks. Body mass index (BMI), homeostatic model assessment of insulin resistance (HOMA-IR), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), total superoxide dismutase (t-SOD) activity, and plasminogen activator inhibitor-1 (PAI-1) were measured. RESULTS: Compared to the control group, Obe group exhibited a significant increase in BMI, HOMA-IR, TNF-α, MDA, and PAI-1. These results were also associated with a significant decrease in serum t-SOD activity. Supplementation of Api alleviated the measured deteriorated parameters and ameliorated visceral adiposity in obese rats. CONCLUSION: This study provides compelling evidence regarding a promising role for Api in ameliorating the impairment of fibrinolytic activity in an Obe animal model. The observed effects are likely mediated through Api's anti-obesity properties, as well as its indirect modulation of PAI-1, oxidative stress, and inflammation. Future clinical studies are recommended that may make benefit of the preclinical therapeutic use of apigenin in obesity-associated fibrinolytic dysfunctions.

13.
Reumatismo ; 75(1)2023 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-37154255

RESUMO

cleredema of Buschke is a rare pathological disorder of connective tissue, which is characterized by a woody, diffuse induration of the skin, most often in the upper extremities. We report an extremely rare complication of post-streptococcal infection in a six-year-old male complaining of gradually progressing, painless skin thickening and tightness which was preceded by a one-month history of fever, cough, and tonsillitis. By reporting this case, we hope to contribute to the creation of a database for future research aimed at better understanding the incidence, pathophysiology, and management of this extremely rare complication.


Assuntos
Escleredema do Adulto , Masculino , Humanos , Criança , Escleredema do Adulto/etiologia , Escleredema do Adulto/complicações , Pele/patologia
14.
J Vasc Surg ; 78(2): 490-497, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37150486

RESUMO

OBJECTIVE: Optimizing medical management and risk factor modification are underused strategies in patients with chronic limb-threatening ischemia (CLTI), despite evidence of improved outcomes. The Vascular Quality Initiative (VQI) registry is a tool to improve quality of vascular care. In this study, we used the VQI to evaluate trends in medical management in patients with CLTI undergoing peripheral vascular interventions (PVI), and the impact of changes in management on overall survival (OS), amputation-free survival (AFS), and limb salvage (LS). METHODS: Patients undergoing index PVI for CLTI between 2012 and 2016, with ≥24 months of follow-up were identified from the national VQI registry. Patient details including smoking status and medication use, OS, LS, and AFS were analyzed with linear-by-linear association, t test, and logistic regression. RESULTS: There were 12,370 PVI completed in 11,466 patients. There was a significant increase in infrapopliteal interventions (from 29.8% to 39.0%; P < .001) and PVI performed for tissue loss (from 59.1% to 66.5%; P < .001). The percentage of current smokers at time of PVI decreased (from 36.2% to 30.7%; P = .036). At discharge, statins were initiated in 25%, aspirin in 45%, and P2Y12 therapy in 58% of patients not receiving these medications before PVI. Over the course of follow-up, dual antiplatelet therapy (DAPT) (from 41.1% to 48.0%; P < .001), angiotensin-converting enzyme (ACE) inhibitor (from 46.2% to 51.3%; P < .001), and statin (from 70.4% to 77.5%; P < .001) use increased. Combined DAPT, ACE inhibitor and statin use increased from 33.6% to 39.6% (P ≤ .001). Significant improvement in 24-month OS and AFS was noted (OS, from 90.9% to 93.7% [P = .002]: AFS, from 81.2% to 83.1% [P = .046]), but not LS (from 89.6% to 89.0%; P = .83). Combined therapy with P2Y12 inhibitors, statins and ACE inhibitors was an independent predictor of improved OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.96; P = .034). DAPT was independent predictor of improved LS (hazard ratio, 0.83; 95% confidence interval, 0.79-0.87; P < .007). CONCLUSIONS: Antiplatelet, ACE inhibitor, and statin use increased over the study period and was associated with improved OS and AFS. LS trends did not change significantly over time, possibly owing to the inclusion of patients with a greater disease burden or inadequate medical management. Medical management, although improved, remained far from optimal and represents an area for continued development.


Assuntos
Procedimentos Endovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Doença Arterial Periférica , Humanos , Isquemia Crônica Crítica de Membro , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Medição de Risco , Procedimentos Endovasculares/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/terapia , Isquemia/diagnóstico , Isquemia/terapia , Fatores de Risco , Salvamento de Membro , Inibidores da Enzima Conversora de Angiotensina , Estudos Retrospectivos , Resultado do Tratamento
15.
ACS Med Chem Lett ; 14(5): 606-613, 2023 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-37197477

RESUMO

The mitogen-activated protein kinase signaling cascade is conserved across eukaryotes, where it plays a critical role in the regulation of activities including proliferation, differentiation, and stress responses. This pathway propagates external stimuli through a series of phosphorylation events, which allows external signals to influence metabolic and transcriptional activities. Within the cascade, MEK, or MAP2K, enzymes occupy a molecular crossroads immediately upstream to significant signal divergence and cross-talk. One such kinase, MAP2K7, also known as MEK7 and MKK7, is a protein of great interest in the molecular pathophysiology underlying pediatric T cell acute lymphoblastic leukemia (T-ALL). Herein, we describe the rational design, synthesis, evaluation, and optimization of a novel class of irreversible MAP2K7 inhibitors. With a streamlined one-pot synthesis, favorable in vitro potency and selectivity, and promising cellular activity, this novel class of compounds wields promise as a powerful tool in the study of pediatric T-ALL.

16.
J Biochem Mol Toxicol ; 37(2): e23257, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36419211

RESUMO

The fatty liver syndrome caused by nutritional factors is a common cause of hepatic dysfunction globally. This research was designed to study the shielding effect of boron in rats fed a diet having high fat. Overall, 40 Wistar albino male rats were placed into one control and four treatment groups, that is, each having eight rats. Group I was provided with a standard rat diet while group II was only provided a high-fat diet for 60 days. Groups III, IV, and V were provided with 5, 10, and 20 mg/kg/day boron, respectively, by gastric gavage besides a high-fat diet for 60 days. Malondialdehyde was increased significantly in rats' blood and tissue because of high-fat diets. Glutathione was decreased significantly in blood and tissues because of a high-fat diet. Moreover, the activities of superoxide dismutase (SOD) and catalase (CAT) were decreased in the blood and tissues of the high-fat-fed rats. The genes expression for C-reactive protein, interleukin-1ß, leptin, and tumor necrosis factor-α were increased while gene expression for peroxisome proliferator-activated receptors was decreased in the liver of rats fed with a high-fat diet. Contrariwise, boron supplementation improves antioxidative response in terms of increased SOD and CAT activities, gene expression regulation, and improved anti-inflammatory activities. In a nutshell, boron has dose-dependent shielding antioxidative and tissue regenerative effects in rats.


Assuntos
Antioxidantes , Boro , Ratos , Animais , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Boro/farmacologia , Ratos Wistar , Adipogenia , Estresse Oxidativo , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Superóxido Dismutase/metabolismo , Expressão Gênica , Anti-Inflamatórios/farmacologia
17.
Anesth Analg ; 136(1): 163-175, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35389379

RESUMO

BACKGROUND: The neuroinflammatory response to surgery can be characterized by peripheral acute plasma protein changes in blood, but corresponding, persisting alterations in cerebrospinal fluid (CSF) proteins remain mostly unknown. Using the SOMAscan assay, we define acute and longer-term proteome changes associated with surgery in plasma and CSF. We hypothesized that biological pathways identified by these proteins would be in the categories of neuroinflammation and neuronal function and define neuroinflammatory proteome changes associated with surgery in older patients. METHODS: SOMAscan analyzed 1305 proteins in blood plasma (n = 14) and CSF (n = 15) samples from older patients enrolled in the Role of Inflammation after Surgery for Elders (RISE) study undergoing elective hip and knee replacement surgery with spinal anesthesia. Systems biology analysis identified biological pathways enriched among the surgery-associated differentially expressed proteins in plasma and CSF. RESULTS: Comparison of postoperative day 1 (POD1) to preoperative (PREOP) plasma protein levels identified 343 proteins with postsurgical changes ( P < .05; absolute value of the fold change [|FC|] > 1.2). Comparing postoperative 1-month (PO1MO) plasma and CSF with PREOP identified 67 proteins in plasma and 79 proteins in CSF with altered levels ( P < .05; |FC| > 1.2). In plasma, 21 proteins, primarily linked to immune response and inflammation, were similarly changed at POD1 and PO1MO. Comparison of plasma to CSF at PO1MO identified 8 shared proteins. Comparison of plasma at POD1 to CSF at PO1MO identified a larger number, 15 proteins in common, most of which are regulated by interleukin-6 (IL-6) or transforming growth factor beta-1 (TGFB1) and linked to the inflammatory response. Of the 79 CSF PO1MO-specific proteins, many are involved in neuronal function and neuroinflammation. CONCLUSIONS: SOMAscan can characterize both short- and long-term surgery-induced protein alterations in plasma and CSF. Acute plasma protein changes at POD1 parallel changes in PO1MO CSF and suggest 15 potential biomarkers for longer-term neuroinflammation that warrant further investigation.


Assuntos
Doenças Neuroinflamatórias , Procedimentos Ortopédicos , Humanos , Idoso , Proteoma , Biomarcadores , Inflamação , Proteínas Sanguíneas , Plasma
18.
Cell Rep ; 41(11): 111797, 2022 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-36516754

RESUMO

Persistent neutrophil-dominated lung inflammation contributes to lung damage in cystic fibrosis (CF). However, the mechanisms that drive persistent lung neutrophilia and tissue deterioration in CF are not well characterized. Starting from the observation that, in patients with CF, c-c motif chemokine receptor 2 (CCR2)+ monocytes/macrophages are abundant in the lungs, we investigate the interplay between monocytes/macrophages and neutrophils in perpetuating lung tissue damage in CF. Here we show that CCR2+ monocytes in murine CF lungs drive pathogenic transforming growth factor ß (TGF-ß) signaling and sustain a pro-inflammatory environment by facilitating neutrophil recruitment. Targeting CCR2 to lower the numbers of monocytes in CF lungs ameliorates neutrophil inflammation and pathogenic TGF-ß signaling and prevents lung tissue damage. This study identifies CCR2+ monocytes as a neglected contributor to the pathogenesis of CF lung disease and as a therapeutic target for patients with CF, for whom lung hyperinflammation and tissue damage remain an issue despite recent advances in CF transmembrane conductance regulator (CFTR)-specific therapeutic agents.


Assuntos
Fibrose Cística , Pneumonia , Humanos , Camundongos , Animais , Fibrose Cística/patologia , Monócitos/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística , Pneumonia/patologia , Pulmão/patologia , Inflamação/patologia , Receptores de Quimiocinas/metabolismo , Macrófagos/metabolismo , Fator de Crescimento Transformador beta/metabolismo
19.
Proc Natl Acad Sci U S A ; 119(43): e2121077119, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36269862

RESUMO

Mice with a functional human immune system serve as an invaluable tool to study the development and function of the human immune system in vivo. A major technological limitation of all current humanized mouse models is the lack of mature and functional human neutrophils in circulation and tissues. To overcome this, we generated a humanized mouse model named MISTRGGR, in which the mouse granulocyte colony-stimulating factor (G-CSF) was replaced with human G-CSF and the mouse G-CSF receptor gene was deleted in existing MISTRG mice. By targeting the G-CSF cytokine-receptor axis, we dramatically improved the reconstitution of mature circulating and tissue-infiltrating human neutrophils in MISTRGGR mice. Moreover, these functional human neutrophils in MISTRGGR are recruited upon inflammatory and infectious challenges and help reduce bacterial burden. MISTRGGR mice represent a unique mouse model that finally permits the study of human neutrophils in health and disease.


Assuntos
Neutrófilos , Receptores de Fator Estimulador de Colônias de Granulócitos , Humanos , Camundongos , Animais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos/genética , Citocinas
20.
JAMA Surg ; 157(9): e222935, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35947375

RESUMO

Importance: Patients with abdominal aortic aneurysm (AAA) can choose open repair or endovascular repair (EVAR). While EVAR is less invasive, it requires lifelong surveillance and more frequent aneurysm-related reinterventions than open repair. A decision aid may help patients receive their preferred type of AAA repair. Objective: To determine the effect of a decision aid on agreement between patient preference for AAA repair type and the repair type they receive. Design, Setting, and Participants: In this cluster randomized trial, 235 patients were randomized at 22 VA vascular surgery clinics. All patients had AAAs greater than 5.0 cm in diameter and were candidates for both open repair and EVAR. Data were collected from August 2017 to December 2020, and data were analyzed from December 2020 to June 2021. Interventions: Presurgical consultation using a decision aid vs usual care. Main Outcomes and Measures: The primary outcome was the proportion of patients who had agreement between their preference and their repair type, measured using χ2 analyses, κ statistics, and adjusted odds ratios. Results: Of 235 included patients, 234 (99.6%) were male, and the mean (SD) age was 73 (5.9) years. A total of 126 patients were enrolled in the decision aid group, and 109 were enrolled in the control group. Within 2 years after enrollment, 192 (81.7%) underwent repair. Patients were similar between the decision aid and control groups by age, sex, aneurysm size, iliac artery involvement, and Charlson Comorbidity Index score. Patients preferred EVAR over open repair in both groups (96 of 122 [79%] in the decision aid group; 81 of 106 [76%] in the control group; P = .60). Patients in the decision aid group were more likely to receive their preferred repair type than patients in the control group (95% agreement [93 of 98] vs 86% agreement [81 of 94]; P = .03), and κ statistics were higher in the decision aid group (κ = 0.78; 95% CI, 0.60-0.95) compared with the control group (κ = 0.53; 95% CI, 0.32-0.74). Adjusted models confirmed this association (odds ratio of agreement in the decision aid group relative to control group, 2.93; 95% CI, 1.10-7.70). Conclusions and Relevance: Patients exposed to a decision aid were more likely to receive their preferred AAA repair type, suggesting that decision aids can help better align patient preferences and treatments in major cardiovascular procedures. Trial Registration: ClinicalTrials.gov Identifier: NCT03115346.


Assuntos
Aneurisma da Aorta Abdominal , Procedimentos Endovasculares , Idoso , Aneurisma da Aorta Abdominal/cirurgia , Técnicas de Apoio para a Decisão , Procedimentos Endovasculares/métodos , Feminino , Humanos , Masculino , Preferência do Paciente
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