Invasive aspergillosis (IA), primarily caused by Aspergillus fumigatus, is an opportunistic fungal infection predominantly affecting immunocompromised and neutropenic patients that is difficult to treat and results in high mortality. Investigations of neutrophil-hypha interaction in vitro and in animal models of IA are limited by lack of temporal and spatial control over interactions. This study presents a new approach for studying neutrophil-hypha interaction at single cell resolution over time, which revealed an evasive fungal behavior triggered by interaction with neutrophils: Interacting hyphae performed de novo tip formation to generate new hyphal branches, allowing the fungi to avoid the interaction point and continue invasive growth. Induction of this mechanism was independent of neutrophil NADPH oxidase activity and neutrophil extracellular trap (NET) formation, but could be phenocopied by iron chelation and mechanical or physiological stalling of hyphal tip extension. The consequence of branch induction upon interaction outcome depends on the number and activity of neutrophils available: In the presence of sufficient neutrophils branching makes hyphae more vulnerable to destruction, while in the presence of limited neutrophils the interaction increases the number of hyphal tips, potentially making the infection more aggressive. This has direct implications for infections in neutrophil-deficient patients and opens new avenues for treatments targeting fungal branching.
Idiopathic thrombocytopenic purpura (ITP) is typically a diagnosis of exclusion, assigned by clinicians after ruling out other identifiable etiologies. Since a report by Gasbarrini et al. in 1998, an accumulating body of evidence has proposed a pathophysiological link between ITP and chronic Helicobacter pylori (H. pylori) infection. Clinical reports have described a spontaneous resolution of ITP symptoms in about 50% of chronic ITP patients following empirical treatment of H. pylori infection, but response appears to be geography dependent. Studies have also documented that ITP patients in East Asian countries are more likely to express positive antibody titers against H. pylori-specific cytotoxic-associated gene A (CagA), a virulence factor that is associated with an increased risk for gastric diseases including carcinoma. While a definitive mechanism by which H. pylori may induce thrombocytopenia remains elusive, proposed pathways include molecular mimicry of CagA by host autoantibodies against platelet surface glycoproteins, as well as perturbations in the phagocytic activity of monocytes. Traditional treatments of ITP have been largely empirical, involving the use of immunosuppressive agents and immunoglobulin therapy. However, based on the findings of clinical reports emerging over the past 20 years, health organizations around the world increasingly suggest the detection and eradication of H. pylori as a treatment for ITP. Elucidating the exact molecular mechanisms of platelet activation in H. pylori-positive ITP patients, while considering biogeographical differences in response rates, could offer insight into how best to use clinical H. pylori eradication to treat ITP, but will require well-designed studies to confirm the suggested causative relationship between bacterial infection and an autoimmune disease state.
Manuka honey (MH) is currently used as a wound treatment and suggested to be effective in Methicillin-resistant Staphylococcus aureus (MRSA) elimination. We sought to optimize the synthesis of MH microneedles (MHMs) while maintaining the MH therapeutic effects. MHMs were synthesized using multiple methods and evaluated with in vitro assays. MHMs demonstrated excellent bactericidal activity against MRSA at concentrations ≥ 10% of honey, with vacuum-prepared honey appearing to be the most bactericidal, killing bacterial concentrations as high as 8 × 10 7 CFU/mL. The woundhealing assay demonstrated that, at concentrations of 0.1%, while the cooked honey had incomplete wound closure, the vacuum-treated honey trended towards faster wound closure. In this study, we demonstrate that the method of MHM synthesis is crucial to maintaining MH properties. We optimized the synthesis of MHMs and demonstrated their potential utility in the treatment of MRSA infections as well as in wound healing. This is the first report of using MH as a substrate for the formation of dissolvable microneedles. this data supports the need for further exploration of this new approach in a wound-healing model and opens the door for the future use of MH as a component of microneedle scaffolds. Surgical site infections (SSIs) have historically been associated with increased morbidity and mortality but remain an issue in modern day healthcare. As of 2017, the Centers for Disease Control and Prevention (CDC) estimated that SSIs occurred in at least 1.9% of all surgical patients; however, this number is most likely not representative of the total number of SSI cases since about 50% of SSIs occur after hospital discharge 1,2. MRSA is the most common cause of SSIs leading in an increased morbidity in patients and increased hospital charges 3,4. In a study evaluating the 90-day mortality rate in patients with SSI, it was discovered that patients with a methicillin-resistant Staphylococcus aureus (MRSA) SSI had a 3.40 times increased mortality rate (95% CI, 1.5-7.2) than patients infected with a methicillin-susceptible S. aureus strain 5. Given the health and economic burden attributable,
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