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1.
ACS Infect Dis ; 9(10): 1949-1963, 2023 10 13.
Article in English | MEDLINE | ID: mdl-37646612

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) infections are some of the most common antibiotic-resistant infections, often exacerbated by the formation of biofilms. Here, we evaluated six compounds, three common antibiotics used against MRSA and three antibiofilm compounds, in nine combinations to investigate the mechanisms of synergistic eradication of MRSA biofilms. Using metabolic assessment, colony enumeration, confocal fluorescence microscopy, and scanning electron microscopy, we identified two promising combinations of antibiotics with antibiofilm agents against preformed MRSA biofilms. The broad-spectrum protease, proteinase K, and membrane-targeting antibiotic, daptomycin, worked in synergy against MRSA biofilms by manipulating the protein content, increasing access to the cell membrane of biofilm bacteria. We also found that the combination of cationic peptide, IDR-1018, with the cell wall cross-linking inhibitor, vancomycin, exhibited synergy against MRSA biofilms by causing bacterial damage and preventing repair. Our findings identify synergistic combinations of antibiotics and antibiofilm agents, providing insight into mechanisms that may be explored further for the development of effective treatments against MRSA biofilm.


Subject(s)
Anti-Bacterial Agents , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Microbial Sensitivity Tests , Vancomycin/pharmacology , Biofilms
2.
Am J Sports Med ; 49(10): 2760-2770, 2021 08.
Article in English | MEDLINE | ID: mdl-34283947

ABSTRACT

BACKGROUND: Impaired healing after rotator cuff repair is a major concern, with retear rates as high as 94%. A method to predict whether patients are likely to experience poor surgical outcomes would change clinical practice. While various patient factors, such as age and tear size, have been linked to poor functional outcomes, it is currently very challenging to predict outcomes before surgery. PURPOSE: To evaluate gene expression differences in tissue collected during surgery between patients who ultimately went on to have good outcomes and those who experienced a retear, in an effort to determine if surgical outcomes can be predicted. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Rotator cuff tissue was collected at the time of surgery from 140 patients. Patients were tracked for a minimum of 6 months to identify those with good or poor outcomes, using clinical functional scores and follow-up magnetic resonance imaging to confirm failure to heal or retear. Gene expression differences between 8 patients with poor outcomes and 28 patients with good outcomes were assessed using a multiplex gene expression analysis via NanoString and a custom-curated panel of 145 genes related to various stages of rotator cuff healing. RESULTS: Although significant differences in the expression of individual genes were not observed, gene set enrichment analysis highlighted major differences in gene sets. Patients who had poor healing outcomes showed greater expression of gene sets related to extracellular matrix production (P < .0001) and cellular biosynthetic pathways (P < .001), while patients who had good healing outcomes showed greater expression of genes associated with the proinflammatory (M1) macrophage phenotype (P < .05). CONCLUSION: These results suggest that a more proinflammatory, fibrotic environment before repair may play a role in poor healing outcome. With validation in a larger cohort, these results may ultimately lead to diagnostic methods to preoperatively predict those at risk for poor surgical outcomes.


Subject(s)
Rotator Cuff Injuries , Rotator Cuff , Arthroscopy , Case-Control Studies , Humans , Magnetic Resonance Imaging , Rotator Cuff/surgery , Rotator Cuff Injuries/genetics , Rotator Cuff Injuries/surgery , Transcriptome , Treatment Outcome
3.
ACS Infect Dis ; 7(4): 695-720, 2021 04 09.
Article in English | MEDLINE | ID: mdl-33733747

ABSTRACT

Bacterial infections are a major threat to human health, exacerbated by increasing antibiotic resistance. These infections can result in tremendous morbidity and mortality, emphasizing the need to identify and treat pathogenic bacteria quickly and effectively. Recent developments in detection methods have focused on electrochemical, optical, and mass-based biosensors. Advances in these systems include implementing multifunctional materials, microfluidic sampling, and portable data-processing to improve sensitivity, specificity, and ease of operation. Concurrently, advances in antibacterial treatment have largely focused on targeted and responsive delivery for both antibiotics and antibiotic alternatives. Antibiotic alternatives described here include repurposed drugs, antimicrobial peptides and polymers, nucleic acids, small molecules, living systems, and bacteriophages. Finally, closed-loop therapies are combining advances in the fields of both detection and treatment. This review provides a comprehensive summary of the current trends in detection and treatment systems for bacterial infections.


Subject(s)
Bacterial Infections , Biosensing Techniques , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteria , Bacterial Infections/diagnosis , Bacterial Infections/drug therapy , Drug Resistance, Microbial , Humans
4.
Wound Repair Regen ; 27(6): 598-608, 2019 11.
Article in English | MEDLINE | ID: mdl-31343792

ABSTRACT

Diabetic foot ulcers (DFUs) are a major clinical problem exacerbated by prolonged bacterial infection. Macrophages, the primary innate immune cells, are multifunctional cells that regulate diverse processes throughout multiple phases of wound healing. To better understand the influence of microbial species on macrophage behavior, we cultured primary human monocyte-derived macrophages from four donors for 24 hours in media conditioned by bacteria and fungi (Pseudomonas aeruginosa, Corynebacterium amycolatum, Corynebacterium striatum, Staphylococcus aureus, Staphylococcus simulans, and Candida albicans) isolated from the DFUs of six patients. The effects of these microbe-derived signals on macrophage behavior were assessed by measuring the gene expression of a panel of 25 genes related to macrophage phenotype, angiogenesis, bacterial recognition, and cell survival, as well as secretion of two inflammatory cytokines using NanoString multiplex analysis. Principal component analysis showed that macrophage gene expression and protein secretion were affected by both microbial species as well as human donor. S. simulans and C. albicans caused up-regulation of genes associated with a proinflammatory (M1) phenotype, and P. aeruginosa caused an increase in the secretion of the proinflammatory cytokine and M1 marker tumor necrosis factor-alpha (TNFα). Together, these results suggest that macrophages respond to secreted factors from microbes by up-regulating inflammatory markers, and that the effects are strongly dependent on the monocyte donor. Ultimately, increased understanding of macrophage-microbe interactions will lead to the development of more targeted therapies for DFU healing.


Subject(s)
Anti-Infective Agents/pharmacology , Bacterial Infections/mortality , Diabetic Foot/microbiology , Macrophages/metabolism , Microbiota/genetics , Wound Healing/drug effects , Adult , Aged , Bacterial Infections/pathology , Biopsy, Needle , Cells, Cultured , Cohort Studies , Culture Media , Diabetic Foot/physiopathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Microbiota/drug effects , Middle Aged , Sensitivity and Specificity , Wound Healing/genetics
5.
J Clin Endocrinol Metab ; 101(9): 3401-8, 2016 09.
Article in English | MEDLINE | ID: mdl-27399351

ABSTRACT

CONTEXT: Cardiovascular risk factors are well-known predictors of the development of diabetic peripheral neuropathy (DPN), which has traditionally been considered as a manifestation of diabetes-associated microangiopathy. Because endothelial dysfunction is strongly associated with all cardiovascular risk factors, we hypothesized that it may be a link between cardiovascular risk factors and DPN. OBJECTIVE: The primary objective of this study was to test whether endothelial dysfunction is a predictor of DPN. DESIGN AND SETTING: This is a cross-sectional analysis of a cohort composed of patients followed at the Microcirculatory Laboratory, Beth Israel Deaconess Medical Center. PATIENTS: Participants with diabetes without DPN (n = 192) and with DPN (n = 166), subjects with prediabetes (n = 75), and nondiabetic controls (n = 59) were included. INTERVENTIONS: Endothelial function was assessed with flow-mediated dilation (FMD) of the brachial artery. Inflammatory cytokines and biomarkers of endothelial function (soluble intercellular and vascular cell adhesion molecules) were quantified using a multiplex bead-based immunoassay. Neurological assessment included the neuropathy disability score (NDS). MAIN OUTCOME MEASURE: The relationship between FMD and NDS assessed using multiple linear regression. RESULTS: In addition to already known risk factors of DPN, FMD was strongly associated with NDS (ß = -0.24; P < .001). Sensitivity analysis that removed FMD from the model provided similar results for soluble intercellular cell adhesion molecule-1, another biomarker of endothelial function. Confirmatory factor analysis further showed that endothelial dysfunction is a significant mediator between glycosylated hemoglobin and diabetes duration and diabetic complications. CONCLUSIONS: This study shows that endothelial dysfunction occurs early in the pathophysiology of diabetes and is a link between cardiovascular risk factors and DPN.


Subject(s)
Cardiovascular Diseases/pathology , Diabetes Complications/pathology , Diabetes Mellitus/physiopathology , Diabetic Neuropathies/pathology , Endothelium, Vascular/pathology , Vascular Diseases/pathology , Biomarkers/analysis , Cardiovascular Diseases/etiology , Cardiovascular Diseases/metabolism , Case-Control Studies , Cohort Studies , Cross-Sectional Studies , Diabetes Complications/etiology , Diabetes Complications/metabolism , Diabetic Neuropathies/etiology , Diabetic Neuropathies/metabolism , Endothelium, Vascular/metabolism , Female , Follow-Up Studies , Humans , Israel , Male , Microcirculation , Middle Aged , Prognosis , Risk Factors , Vascular Diseases/etiology , Vascular Diseases/metabolism
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