Proteomic profiles in serum and sputum distinguished controlled and poorly controlled asthmatics, and were maintained over time. Findings support a link between sputum neutrophil markers and loss of asthma control.
As the global population continues to grow, food needs will increase as well. The amount of land and other resources devoted to agriculture production is not expected to grow significantly, leading most to agree that the substantial increases in food production to meet food security needs will come through the development of technologies that improve production efficiency. Diseases are constant threats to efficiency in all segments of agriculture. In livestock production, many of the bacterial pathogens that infect food animals are controlled through the use of antimicrobials. Antimicrobials are currently used in the United States not only to treat specific diseases, but also as feed additives to prevent bacterial disease in general or to improve growth performance. In recent years, there have been several proposals in the United States, both at state and federal levels, aimed at curtailing or dramatically reducing the use antimicrobials as feed additives, creating a policy similar to that of the European Union. Here we review the current policies on antimicrobial use in the European Union and their impact on food animal production. In addition, we discuss the future of antimicrobial use in food animal production in the United States and the increasing role of biosecurity programs. Finally, we discuss the role of Cooperative Extension Service in creating improved biosecurity programs and extension programs that provide policy makers and voters information on modern food animal production practices and technologies so that policies and regulations are effective and appropriate.
SummaryBackground. Psoriasis is a systemic inflammatory disease with a pathophysiology involving interleukin (IL)-17. Tofacitinib is an oral Janus kinase inhibitor. Etanercept is a tumour necrosis factor-a inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17 directly. Aim. To evaluate correlations between circulating IL-17A and clinical efficacy in patients with psoriasis treated with tofacitinib or etanercept. Methods. Serum concentrations of IL-17A homodimer and IL-17A/F heterodimer were determined by immunoassays at weeks 0, 4 and 12 in patients with moderate to severe psoriasis treated with placebo (n = 60), tofacitinib 5 mg twice daily (n = 184), tofacitinib 10 mg twice daily (n = 190), or etanercept 50 mg subcutaneously twice weekly (n = 190). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) and clinical response was defined as patients achieving ≥ 75% improvement from baseline PASI (PASI75). Results. Serum levels of IL-17A homodimer at week 0 showed moderate correlation with PASI, with a Spearman correlation coefficient of 0.43. Furthermore, serum levels of IL-17A homodimer showed a clear correlation with clinical response, with a decrease of 57.1% in patients achieving PASI75 at week 12, but only 15.9% decrease in nonresponders. PASI75 responders had lower median concentrations of IL-17A (range across treatments: 0.24-0.27 pg/mL) at week 12 vs. nonresponders (0.37-0.62 pg/mL), regardless of the treatment. Serum IL-17A/F heterodimer showed similar decreases at week 12 in responders and nonresponders. Conclusions. Baseline serum IL-17A correlates moderately with psoriasis severity. Reduction in circulating IL-17A is required for disease remission regardless of therapeutic agent.
We previously showed that delphinidin, a dietary small molecule, possesses prodifferentiation and anti-proliferative properties with unknown mechanism, and recently observed deregulated PI3K/Akt/mTOR signaling in human psoriasis and imiquimod (IMQ)induced murine psoriasis-like skin lesions. Using KINOMEscan, a competitive kinase binding assay platform and subsequent K d determinations we observed that from a panel of 104 kinases screened delphinidin bound to several lipid (PIK3CG, PIK3C2B, and PIK3CA) and serine/threonine (PIM1, PIM3, mTOR, S6K1, PLK1, and PLK2) kinases (P< 0.05). We further corroborated these data using Surface Plasmon Resonance and in silico molecular modeling and observed kinetic (P<0.05) and high affinity direct interactions of delphinidin with PI3K (a, and g), mTOR and p70S6K with favorable free energy values and little affinity for Akt. Delphinidin treatment of interleukin 22 or TPA pre-stimulated human epidermal keratinocytes (NHEK), significantly (p<0.05) inhibited proliferation, expression of PI3Ks and phosphorylated Akt, mTOR and p70S6K, and secretion of pro-inflammatory cytokines. Further, we established the in vivo relevance of these findings using tissues derived from topically treated delphinidin (1mg/cm 2 skin) on IMQ-induced mouse psoriasis-like skin lesions. qPCR, western blot and multiplex ELISA analyses demonstrated significant (p<0.05) decrease in; i) PI3Ks, phosphorylated Akt, mTOR and p70S6K expression, ii) proliferation, epidermal thicknesses and skin inflammation, and iii) psoriasis-related inflammatory cytokines/chemokines (P<0.01) when compared with IMQ-treated skin. Taken together, our data demonstrate that delphinidin potently binds and inhibits key kinases including the PI3/Akt/mTOR signaling involved in psoriasis pathophysiology, and alleviates (IMQ)-induced murine psoriasis-like disease. We suggest further studies to develop delphinidin either alone or as an adjuvant to current therapies, as specific PI3K/AKT/mTOR kinase inhibitor for the treatment of psoriasis.
Severe psoriasis is associated with an increase in cardiovascular mortality. Cardiovascular disease has a strong inflammatory pathophysiology, so agents used to treat psoriasis skin disease might have beneficial effects on systemic inflammatory pathways that are associated with increased risk of cardiovascular diseases. Tofacitinib is an oral JAK inhibitor that is being investigated for psoriasis. To understand the influence of psoriasis medications on systemic inflammation, we studied proteins related to cardiovascular disease in blood archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. 156 proteins were quantified by a proximity extension assay from blood of 269 patients at baseline and week 4. Protein changes in blood after 1 month of treatment were compared between tofacitinib (10 mg BID) vs. etanercept (50 mg BIW), and by response status at week 12. Differentially expressed proteins were detected by empirical Bayes methods. Ingenuity Pathway Analysis showed that cardiovascular proteins were enriched within proteins that decreased upon treatment. 20 cardiovascular proteins decreased after tofacitinib treatment in PASI75 responders, while only 1 cardiovascular protein decreased in non-responders. In contrast, 6 proteins were reduced in both responders and non-responders upon etanercept treatment, with little overlap between the two groups. Furthermore, all 6 affected proteins in etanercept responders were cytokines and chemokines, whereas those reduced in tofacitinib responders included proteins involved angiogenesis and metabolism. Our study suggests the possibility that the broad cytokine signaling modulation caused by tofacitinib might have a beneficial effect on cardiovascular pathophysiology in psoriasis.
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