Abstract:The purpose of this study was to investigate flexible nanoliposomes for mediating topical delivery of daptomycin, and to document permeation rates and bacteriostatic activity towards skin infections. Response surface methodology was used to optimize the daptomycinloaded flexible nanoliposomes (DAP-FL), and the amount of drug loaded into the particles was evaluated as the investigation index. The optimal lipid ratio was lecithin to sodium cholate 17:1 (w/w) and the lipid to drug ratio was 14:1 (w/w). The hydration temperature was set at 37°C and the duration of treatment with ultrasound was 20 minutes. The DAP-FL obtained had a small mean particle size (55.4 nm) with a narrow size distribution (polydispersity index 0.15). The mean entrapment efficiency was 87.85% ± 2.15% and the mean percent drug loading was 5.61% ± 0.14%. Using skin mounted between the donor and receptor compartments of a modified Franz diffusion cell, the percentage and quantity of cumulative daptomycin permeation from DAP-FL within 12 hours were measured at 96.28% ± 0.70% and (132.23 ± 17.73) μg/cm 2 *5 = 661.15 ± 88.65 μg/cm 2 , directly, showing rapid and efficient antibacterial activity against Staphylococcus aureus. Following local administration of DAP-FL, daptomycin was detected in multilayer tissues within the skin and underlying structures in the dorsal skin of the mouse. Effective therapeutic concentrations were maintained for several hours, and significantly inhibited bacterial growth and injury-induced biofilms. These results demonstrate that the DAP-FL can enhance the ability of daptomycin to permeate the skin efficiently, where it has a powerful antibacterial action and activity against biofilms. This novel formulation of daptomycin has potential as a new approach in the clinical application of daptomycin.
Adipose and endothelial dysfunction is associated with cardiovascular disease. Perivascular adipose tissue (PVAT) directly surrounds vessels and influences vessel function via a paracrine effect, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) modulates the metabolic pathway, thus, the present study hypothesized that activation of AMPK in PVAT may regulate endothelial function in pathological settings. The present study investigated the effect of methotrexate (MTX) on adipocytokine expression in PVAT with an emphasis on the regulation of endothelial function. The effects of MTX and the mechanisms involved were investigated using a relaxation assay and western blot analysis. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the mRNA and protein expression levels. ELISA assay was used to quantify the level of TNF‑α and IL‑6. Palmitic acid (PA) stimulation induced inflammation and dysregulation of adipocytokine expression in PVAT. MTX treatment inhibited nuclear factor‑κB p65 phosphorylation and downregulated expression of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin-6, whereas adiponectin expression increased. MTX increased AMPK phosphorylation under basal and inflammatory conditions in PVAT, whereas knockdown of AMPK via small interfering RNA diminished its modulatory effect, indicating that MTX inhibits inflammation in an AMPK‑dependent manner. The present study prepared conditioned medium from PA‑stimulated PVAT to induce endothelial dysfunction and observed that pre‑treatment of PVAT with MTX effectively restored the loss of acetylcholine‑induced vasodilation and increased endothelial nitric oxide synthase phosphorylation in the rat aorta. The results of the present study demonstrated that MTX ameliorated inflammation-associated adipocytokine dysregulation and thus prevented endothelial dysfunction. These data provide further pharmacological evidence regarding the beneficial effects of MTX in cardiovascular diseases.
Objective. Depression is a prevalent (24-30%) and significant comorbidity in patients with systemic lupus erythematosus (SLE). In the present study, we leveraged the longitudinal SLE cohort at the Washington University Lupus Clinic to address 1) what is the longitudinal course of depressed affect among outpatients with SLE and 2) what is the longitudinal relationship between SLE disease activity and depressed affect?Methods. Longitudinal data from patients with American College of Rheumatology-or Systemic Lupus International Collaborating Clinics-classified SLE were analyzed. Depressed symptoms were assessed at each visit using the Center for Epidemiologic Studies Depression Scale, Revised (CESD-R), and SLE disease activity was measured via the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Group-based trajectory modeling (GBTM) and linear mixed models were used for analysis.Results. The study sample (n = 144) was 56.3% Black and 38.9% White. GBTM revealed 5 distinct groups of patients who demonstrated consistent trends in depression over time. Members of groups 4 (n = 44, 30.6%) and 5 (n = 44, 30.6%) demonstrated CESD-R scores consistent with depression. Of note, Black patients were much more common in group 5 (n = 32, 72.7%, P < 0.02). Analyses identified an association between SLEDAI disease activity and depression scores in multivariate analysis but did not show significance in GBTM and univariate analysis.Conclusions. The majority (61.2%) of patients had CESD-R scores consistent with persistent depressed affect or major depression over a period of up to 4 years. The lack of a consistent relationship of CESD-R with SLE disease activity highlights the need to regularly monitor, treat, and better understand the causes behind this comorbidity.
Objective International Classification of Diseases (ICD) codes are commonly used to identify patients with rare diseases in electronic health records (EHRs). However, misclassification is common, impacting the validity of study results. In this study, we compared the accuracies of several ICD-based case definitions of lupus nephritis (LN) in identifying United States veterans with LN. Methods Using the Department of Veterans Affairs (VA) EHR, we identified all veterans with ≥1 ICD-9 or 10 diagnostic codes for systemic lupus erythematosus (SLE) between October 1, 1999 and September 30, 2017. A cohort was randomly selected for diagnostic validation and 9 ICD-based LN case definitions were applied to this cohort. The diagnostic accuracy of each definition was assessed against gold standard criterion of biopsy-proven LN. Results 18,420 veterans had ≥1 ICD-9 or 10 diagnostic codes for SLE; 981 were randomly selected for diagnostic validation. 95 veterans (9.7%) had biopsy-proven LN. The case definitions had high specificity and NPV but variable sensitivity and PPV. The definition containing ≥2 ICD -9 codes for SLE and ≥2 nephritis indicators had the highest combination of sensitivity and specificity (87.4% and 94.6% respectively). ICD-10 code for LN had high specificity (99.8%) and PPV (93.9%). Conclusion ICD-based case definitions of LN in the VA population have high specificity and NPV but variable sensitivity and PPV. Our results may help guide the design of future LN studies in VA cohorts. The choice of specific case definitions depends on the relative importance of different accuracy measures to individual studies.
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