Enrichment of T-lymphocytes from leukemic blood using inertial microfluidics toward improved chimeric antigen receptor-T cell manufacturing.

Chimeric antigen receptor cell therapy is a successful immunotherapy for the treatment of blood cancers. However, hurdles in their manufacturing remain including efficient isolation and purification of the T-cell starting material. Herein, we describe a one-step separation based on inertial spiral microfluidics for efficient enrichment of T-cells in B-cell acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia patient's samples. In healthy donors used to optimize the process, the lymphocyte purity was enriched from 65% (SD ± 0.2) to 91% (SD ± 0.06) and T-cell purity was enriched from 45% (SD ± 0.1) to 73% (SD ± 0.02). Leukemic samples had higher starting B-cells compared to the healthy donor samples. Efficient enrichment and recovery of lymphocytes and T-cells were achieved in ALL samples with B-cells, monocytes and leukemic blasts depleted by 80% (SD ± 0.09), 89% (SD ± 0.1) and 74% (SD ± 0.09), respectively, and a 70% (SD ± 0.1) T-cell recovery. Chronic lymphocytic leukemia samples had lower T-cell numbers, and the separation process was less efficient compared to the ALL. This study demonstrates the use of inertial microfluidics for T-cell enrichment and depletion of B-cell blasts in ALL, suggesting its potential to address a key bottleneck of the chimeric antigen receptor-T manufacturing workflow.

Testing a modified electronic version of the Edmonton symptom assessment system-revised for remote online completion with ambulatory cancer patients in Alberta, Canada.

Objective: The cancer program in Alberta, Canada routinely collects patient-reported outcomes using the Edmonton symptom assessment system-revised (ESAS-r). The program recently launched the province's new clinical information system which has expanded functionality, allowing patients to complete symptom questionnaires remotely online, instead of completing a paper form at the clinic. This study aimed to test a modified electronic version of the ESAS-r [(e)ESAS-r] with patients, to assess the feasibility of completion and questionnaire clarity. Methods: Staff, patients, and other stakeholders worked to create modified definitions for ESAS-r symptoms, to aid in patient understanding. Patient and family advisors were recruited to test the questionnaire. Participants completed an online mock-up of the (e)ESAS-r and answered questions about technical issues. One-to-one cognitive interviews were held to discuss each symptom definition in detail. Modifications were made based on the feedback and a second round of interviews was held to finalize the wording. Results: In total, 19 patients and 7 family advisors participated. All but one (96.2%) completed the questionnaire without assistance and had no technical issues. Participants requested certain wording modifications and that definitions be added for all symptoms for consistency. Very few participants reported any confusion with the final definitions. Conclusions: The (e)ESAS-r was tested for clarity and ease of completion and was determined to be suitable for remote online use with ambulatory cancer patients. The enhanced definitions on the new questionnaire were clear to patients and helped ensure they understood the meaning of each symptom they were asked to rate.

Rheumatoid arthritis is a preventable disease: 11 ways to reduce your patients' risk.

New evidence shows that up to 40% of rheumatoid arthritis (RA) cases are attributable to exposure to potentially modifiable factors. We can now identify people at higher risk of RA (pre-RA) through their family history, risk factors, autoantibodies and symptoms. Counselling these patients to act to modify factors known to be associated with RA risk could prevent the development of RA, and evidence shows that informing individuals of their risk and of ways to reduce it leads to positive behavioural change and is not harmful. This consumer-focussed narrative review is targeted at primary care providers and physicians to describe 11 changes that can be made, based on current evidence linking potentially modifiable factors to RA risk. These evidence-based recommendations are: (i) cease smoking; (ii) reduce exposure to inhaled silica, dusts and occupational risks; (iii) maintain a healthy weight; (iv) increase leisure time physical activity; (v) maintain good dental hygiene; (vi) maximise breastfeeding if able; (vii) maximise dietary quality and avoid high-salt diets; (viii) consume high levels of omega-3 fatty acids and fish; (ix) reduce consumption of sugar-sweetened soft drinks; (x) consume moderate levels of alcohol; and (xi) remain vitamin D replete.

Inertial Microfluidic Purification of CAR-T-Cell Products.

Chimeric antigen receptor T (CAR-T) cell therapy is rapidly becoming a frontline cancer therapy. However, the manufacturing process is time-, labor- and cost-intensive, and it suffers from significant bottlenecks. Many CAR-T products fail to reach the viability release criteria set by regulators for commercial cell therapy products. This results in non-recoupable costs for the manufacturer and is detrimental to patients who may not receive their scheduled treatment or receive out-of-specification suboptimal formulation. It is demonstrated here that inertial microfluidics can, within minutes, efficiently deplete nonviable cells from low-viability CAR-T cell products. The percentage of viable cells increases from 40% (SD ± 0.12) to 71% (SD ± 0.09) for untransduced T cells and from 51% (SD ± 0.12) to 71% (SD ± 0.09) for CAR-T cells, which meets the clinical trials' release parameters. In addition, the processing of CAR-T cells formulated in CryStor yields a 91% reduction in the amount of the cryoprotectant dimethyl sulfoxide. Inertial microfluidic processing has no detrimental effects on the proliferation and cytotoxicity of CAR-T cells. Interestingly, ≈50% of T-regulatory and T-suppressor cells are depleted, suggesting the potential for inertial microfluidic processing to tune the phenotypical composition of T-cell products.

Atypical Fibroxanthoma Within a Melanoma: A Case Report.

The finding of a pigmented lesion within another distinct lesion is rare but not unheard of. Here, we describe the presence of an atypical fibroxanthoma within a melanoma in a 72-year-old female referred to the plastics surgery department with a pigmented lesion on her left knee. It was excised in view of clinical suspicion of melanoma. The histopathology report documented a single lesion with two distinct components, namely a melanoma of superficial spreading type with a Breslow thickness of 3.0mm, and a central nodule of atypical fibroxanthoma.

Utilizing Patient Reported Outcome Measures (PROMs) in ambulatory oncology in Alberta: Digital reporting at the micro, meso and macro level.

Cancer patients experience numerous distressing symptoms and concerns across the course of their illness, which negatively influence their quality of life. Regardless of cancer type, unmanaged symptoms can lead to adverse downstream consequences. Patient Reported Outcome Measures (PROMs) can be used to inform patient care and lead to targeted symptom management but simply gathering this information does not improve outcomes for the patient. Patient generated information must be easy for the clinicians to access and interpret if it is to be used to inform care delivery in ambulatory oncology facilities. This pragmatic work responded to this need. One Canadian provincial ambulatory oncology jurisdiction implemented digital tracking of PROMs over time in the provincial Electronic Medical Record (EMR) to support full integration of PROMs into standard care workflows and processes. Due to an inability within the EMR for direct patient entry, a hybrid data-entry was designed where the patient completes a paper-based PROM in the waiting room, and after clinical review, a clinician documents this along with their clinical assessment in the EMR. Several digital dashboards were developed which report PROMs data at the micro (individual), meso (clinic) and macro (program) levels. Using PROMs routinely in these provincial practice settings has numerous benefits including enhanced patient-clinician communication, assisting with problem detection, management of symptoms, and improving outcomes for patients. There are over 60,000 unique patients represented in our PROMs database, and over 300,000 unique screening events captured. The PROMs data is now used at all levels of the provincial cancer jurisdiction to provide targeted person centred care (micro), to staff appropriately at a clinic or program level (meso), and for capacity planning for provincial programs (macro). A new provincial EMR is currently being implemented which has an associated patient portal. Based on the success of this work, integration of direct entry of PROMs by the patient prior to the appointment and an associated workflow for symptom management is underway in this jurisdiction.

Gas Phase Glycerol Valorization over Ceria Nanostructures with Well-Defined Morphologies.

Glycerol solutions were vaporized and reacted over ceria catalysts with different morphologies to investigate the relationship of product distribution to the surface facets exposed, particularly, the yield of bio-renewable methanol. Ceria was prepared with cubic, rodlike, and polyhedral morphologies via hydrothermal synthesis by altering the concentration of the precipitating agent or synthesis temperature. Glycerol conversion was found to be low over the ceria with a cubic morphology, and this was ascribed to both a low surface area and relatively high acidity. Density functional theory calculations also showed that the (100) surface is likely to be hydroxylated under reaction conditions which could limit the availability of basic sites. Methanol space-time-yields over the polyhedral ceria samples were more than four times that for the cubic material at 400 °C, where 201 g of methanol was produced per hour per kilogram of the catalyst. Under comparable glycerol conversions, we show that the rodlike and polyhedral catalysts produce a major intermediate to methanol, hydroxyacetone (HA), with a selectivity of ca. 45%, but that over the cubic sample, this was found to be 15%. This equates to a 13-fold increase in the space-time-yield of HA over the polyhedral samples compared to the cubes at 320 °C. The implications of this difference are discussed with respect to the reaction mechanism, suggesting that a different mechanism dominates over the cubic catalysts to that for rodlike and polyhedral catalysts. The strong association between exposed surface facets of ceria to high methanol yields is an important consideration for future catalyst design in this area.

Validating a Patient-Reported Outcomes-Derived Algorithm for Classifying Symptom Complexity Levels Among Patients With Cancer.

BACKGROUND: The patient-reported outcomes (PROs) symptom complexity algorithm, derived from self-reported symptom scores using the Edmonton Symptom Assessment System and concerns indicated on the Canadian Problem Checklist, has not been validated extensively. METHODS: This is a retrospective chart review study using data from the Alberta Cancer Registry and electronic medical records from Alberta Health Services. The sample includes patients with cancer who visited a cancer facility in Alberta, Canada, from February 2016 through November 2017 (n=1,466). RESULTS: The effect size (d=1.2) indicates that the magnitude of difference in health status between the severe- and low-complexity groups is large. The symptom complexity algorithm effectively classified subgroups of patients with cancer with distinct health status. Using Karnofsky performance status, the algorithm shows a sensitivity of 70.3%, specificity of 84.1%, positive predictive value of 79.1%, negative predictive value of 76.7%, and accuracy of 77.7%. An area under the receiver operating characteristic of 0.824 was found for the complexity algorithm, which is generally regarded as good, This same finding was also regarded as superior to the alternative algorithm generated by 2-step cluster analysis (area under the curve, 0.721). CONCLUSIONS: The validity of the PRO-derived symptom complexity algorithm is established in this study. The algorithm demonstrated satisfactory accuracy against a clinician-driven complexity assessment and a strong correlation with the known group analysis. Furthermore, the algorithm showed a higher screening capacity compared with the algorithm generated from 2-step cluster analysis, reinforcing the importance of contextualization when classifying patients' symptoms, rather than purely relying on statistical outcomes. The algorithm carries importance in clinical settings, acting as a symptom complexity flag, helping healthcare teams identify which patients may need more timely, targeted, and individualized patient symptom management.

Probiotics Modulate a Novel Amphibian Skin Defense Peptide That Is Antifungal and Facilitates Growth of Antifungal Bacteria.

Probiotics can ameliorate diseases of humans and wildlife, but the mechanisms remain unclear. Host responses to interventions that change their microbiota are largely uncharacterized. We applied a consortium of four natural antifungal bacteria to the skin of endangered Sierra Nevada yellow-legged frogs, Rana sierrae, before experimental exposure to the pathogenic fungus Batrachochytrium dendrobatidis (Bd). The probiotic microbes did not persist, nor did they protect hosts, and skin peptide sampling indicated immune modulation. We characterized a novel skin defense peptide brevinin-1Ma (FLPILAGLAANLVPKLICSITKKC) that was downregulated by the probiotic treatment. Brevinin-1Ma was tested against a range of amphibian skin cultures and found to inhibit growth of fungal pathogens Bd and B. salamandrivorans, but enhanced the growth of probiotic bacteria including Janthinobacterium lividum, Chryseobacterium ureilyticum, Serratia grimesii, and Pseudomonas sp. While commonly thought of as antimicrobial peptides, here brevinin-1Ma showed promicrobial function, facilitating microbial growth. Thus, skin exposure to probiotic bacterial cultures induced a shift in skin defense peptide profiles that appeared to act as an immune response functioning to regulate the microbiome. In addition to direct microbial antagonism, probiotic-host interactions may be a critical mechanism affecting disease resistance.

Multiparameter toxicity screening on a chip: Effects of UV radiation and titanium dioxide nanoparticles on HaCaT cells.

Microfluidic screening is gaining attention as an efficient method for evaluating nanomaterial toxicity. Here, we consider a multiparameter treatment where nanomaterials interact with cells in the presence of a secondary exposure (UV radiation). The microfluidic device contains channels that permit immobilization of HaCaT cells (human skin cell line), delivery of titanium dioxide nanoparticles (TNPs), and exposure to a known dose of UV radiation. The effect of single-parameter exposures (UV or TNP) was first studied as a benchmark, and then multiparameter toxicity (UV and TNP) at different concentrations was explored. The results demonstrate a concentration-dependent protective effect of TNP when exposed to UV irradiation.

Microbiota and skin defense peptides may facilitate coexistence of two sympatric Andean frog species with a lethal pathogen.

Management of hyper-virulent generalist pathogens is an emergent global challenge, yet for most disease systems we lack a basic understanding as to why some host species suffer mass mortalities, while others resist epizootics. We studied two sympatric species of frogs from the Colombian Andes, which coexist with the amphibian pathogen Batrachochytrium dendrobatidis (Bd), to understand why some species did not succumb to the infection. We found high Bd prevalence in juveniles for both species, yet infection intensities remained low. We also found that bacterial community composition and host defense peptides are specific to amphibian life stages. We detected abundant Bd-inhibitory skin bacteria across life stages and Bd-inhibitory defense peptides post-metamorphosis in both species. Bd-inhibitory bacteria were proportionally more abundant in adults of both species than in earlier developmental stages. We tested for activity of peptides against the skin microbiota and found that in general peptides did not negatively affect bacterial growth and in some instances facilitated growth. Our results suggest that symbiotic bacteria and antimicrobial peptides may be co-selected for, and that together they contribute to the ability of Andean amphibian species to coexist with the global pandemic lineage of Bd.

Nutritional screening, assessment and implementation strategies for adults in an Australian acute tertiary hospital: a best practice implementation report.

OBJECTIVE: The project aimed to improve the effectiveness of nutritional screening and assessment practices through clinical audits and the implementation of evidence-based practice recommendations. INTRODUCTION: In the absence of optimal nutrition, health may decline and potentially manifest as adverse health outcomes. In a hospitalized person, poor nutrition may adversely impact on the person's outcome. If the nutritional status can be ascertained, nutritional needs can be addressed and potential risks minimized.The overall purpose of this project was to review and monitor staff compliance with nutritional screening and assessment best practice recommendations ensuring there is timely, relevant and structured nutritional therapeutic practices that support safe, compassionate and person-centered care in adults in a tertiary hospital in South Western Sydney, Australia, in the acute care setting. METHODS: A baseline retrospective chart audit was conducted and measured against 10 best practice criteria in relation to nutritional screening and assessment practices. This was followed by a facilitated multidisciplinary focus group to identify targeted strategies, implementation of targeted strategies, and a post strategy implementation chart audit.The project utilized the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) and Getting Research into Practice (GRIP) tool, including evidence from other available supporting literature, for promoting change in healthcare practice. RESULTS: The baseline audit revealed deficits between current practice and best practice across the 10 criteria. Barriers for implementation of nutritional screening and assessment best practice criteria were identified by the focus group and an education strategy was implemented. There were improved outcomes across all best practice criteria in the follow-up audit. CONCLUSIONS: The baseline audit revealed gaps between current practice and best practice. Through the implementation of a targeted education program and resource package, outcomes improved in the follow up audit. The findings indicated that engagement from multidisciplinary team members and consumers was effective in developing tailored education that improved knowledge of best practice. This was demonstrated by an increase in the percentage of compliance across the 10 criteria, although leaving room for more improvement. A policy has been developed for implementation and future audits are planned to measure whether improved practices have been sustained.

Hydroxyurea therapy in UK children with sickle cell anaemia: A single-centre experience.

INTRODUCTION: Despite the demonstrated efficacy of hydroxyurea therapy, children with sickle cell anaemia in the UK are preferentially managed with supportive care or transfusion. Hydroxyurea is reserved for children with severe disease phenotype. This is in contrast to North America and other countries where hydroxyurea is widely used for children of all clinical phenotypes. The conservative UK practice may in part be due to concerns about toxicity, in particular marrow suppression with high doses, and growth in children. METHODS AND RESULTS: We monitored 37 paediatric patients with sickle cell anaemia who were treated with hydroxyurea at a single UK treatment centre. Therapy was well tolerated and mild transient cytopenias were the only toxicity observed. Comparative analysis of patients receiving ≥26 mg/kg/day versus <26 mg/kg/day demonstrates increasing dose has a significant positive effect on foetal haemoglobin (Hb; 29.2% vs. 20.4%, P = 0.0151), mean cell volume (94.4 vs. 86.5, P = 0.0183) and reticulocyte count (99.66 × 109 /l vs. 164.3 × 109 /l, P = 0.0059). Marrow suppression was not a clinical problem with high-dose treatment, Hb 92.25 g/l versus 91.81 g/l (ns), neutrophil count 3.3 × 109 /l versus 4.8 × 109 /l (ns) and platelet count 232.4 × 109 /l versus 302.2 × 109 /l (ns). Normal growth rates were maintained in all children. Good adherence to therapy was a significant factor in reducing hospitalisations. CONCLUSION: This study demonstrates the effectiveness and safety in practice of high-dose hydroxyurea as a disease-modifying therapy, which we advocate for all children with sickle cell anaemia.

Cell sheets in cell therapies.

This review aims to provide a broad introduction to the use of cell sheets and the role of materials in the delivery of cell sheets to patients within a clinical setting. Traditionally, cells sheets have been, and currently are, fabricated using established and accepted cell culture methods within standard formats (e.g., petri dishes) utilizing biological substrates. Synthetic surfaces provide a far more versatile system for culturing and delivering cell sheets. This has the potential to positively affect quality, and efficient, localized cell delivery has a significant impact on patient outcome and on the overall cost of goods. We highlight current applications of these advanced carriers and future applications of these surfaces and cell sheets with an emphasis both on clinical use and regulatory requirements.

Effect of bupivacaine lozenges on oral mucositis pain: a randomized controlled multicenter phase II study.

INTRODUCTION: A nonblinded parallel-group randomized controlled study investigated the efficacy and tolerability of repeated administration of a bupivacaine lozenge (25 mg) as pain management for oral mucositis pain in head and neck cancer patients as add-on to standard systemic pain management. OBJECTIVE: The primary end point was the difference between the intervention group (Lozenge group) and the Control group in daily mean pain scores in the oral cavity or pharynx (whichever was higher). METHOD: Fifty patients from 2 hospitals in Denmark were randomized 1:1 to 7 days of treatment with bupivacaine lozenges (taken up to every 2 hours) plus standard pain treatment minus topical lidocaine (Lozenge group) or standard pain treatment including topical lidocaine (Control group). The efficacy analysis included 38 patients, as 12 patients were excluded because of changes in study design and missing data. RESULTS: Mean pain in the oral cavity or pharynx (whichever was higher) was significantly lower 60 minutes after taking lozenges (35 mm [n = 22]) than for the Control group (51 mm [n = 16]) (difference between groups -16 mm, 95% confidence interval: -26 to -6, P = 0.0032). Pain in the oral cavity was also significantly lower in the Lozenge group (18 mm) vs the Control group (36 mm, P = 0.0002). Pharyngeal mucositis pain did not differ significantly (37 mm [Lozenge group] vs 48 mm [Control group], P = 0.0630). No serious adverse events were reported. CONCLUSION: These results show that the bupivacaine lozenge as an add-on to standard pain treatment had a clinically significant pain-relieving effect in patients with oral mucositis. CLINICALTRIALSGOV: NCT02252926.

Toxins and pharmacologically active compounds from species of the family Bufonidae (Amphibia, Anura).

ETHNOPHARMACOLOGICAL RELEVANCE: Among amphibians, 15 of the 47 species reported to be used in traditional medicines belong to the family Bufonidae, which demonstrates their potential in pharmacological and natural products research. For example, Asian and American tribes use the skin and the parotoid gland secretions of some common toads in the treatment of hemorrhages, bites and stings from venomous animals, skin and stomach disorders, as well as several types of cancers. OVERARCHING OBJECTIVE: In addition to reviewing the occurrence of chemical constituents present in the family Bufonidae, the cytotoxic and biomedical potential of the active compounds produced by different taxa are presented. METHODOLOGY: Available information on bioactive compounds isolated from species of the family Bufonidae was obtained from ACS Publications, Google, Google Scholar, Pubmed, Sciendirect and Springer. Papers written in Chinese, English, German and Spanish were considered. RESULTS: Recent reports show more than 30% of amphibians are in decline and some of bufonid species are considered to be extinct. For centuries, bufonids have been used as traditional folk remedies to treat allergies, inflammation, cancer, infections and other ailments, highlighting their importance as a prolific source for novel drugs and therapies. Toxins and bioactive chemical constituents from skin and parotid gland secretions of bufonid species can be grouped in five families, the guanidine alkaloids isolated and characterized from Atelopus, the lipophilic alkaloids isolated from Melanophryniscus, the indole alkaloids and bufadienolides known to be synthesized by species of bufonids, and peptides and proteins isolated from the skin and gastrointestinal extracts of some common toads. Overall, the bioactive secretions of this family of anurans may have antimicrobial, protease inhibitor and anticancer properties, as well as being active at the neuromuscular level. CONCLUSION: In this article, the traditional uses, toxicity and pharmacological potential of chemical compounds from bufonids have been summarized. In spite of being reported to be used to treat several diseases, neither extracts nor metabolites from bufonids have been tested in such illness like acne, osteoporosis, arthritis and other illnesses. However, the cytotoxicity of these metabolites needs to be evaluated on adequate animal models due to the limited conditions of in vitro assays. Novel qualitative and quantitative tools based on MS spectrometry and Nuclear Magnetic Resonance spectroscopy is now available to study the complex secretions of bufonids.

What Future Role Might N-Acetyl-Cysteine Have in the Treatment of Obsessive Compulsive and Grooming Disorders?: A Systematic Review.

Licensed pharmacological treatments for obsessive-compulsive disorders include selective serotonin reuptake inhibitors and tricyclic antidepressants. However, a large proportion of patients show minimal or no therapeutic response to these treatments. The glutamatergic system has been implicated in the etiology of obsessive-compulsive spectrum disorders, and it has been postulated that n-acetyl-cysteine (NAC) could have a therapeutic effect on these conditions through its actions on the glutamatergic system and the reduction of oxidative stress. A systematic review was conducted on the existing methodologically robust literature regarding the efficacy of NAC on obsessive-compulsive spectrum disorders in adults and children. Four randomized, double-blind placebo-controlled studies were identified, investigating the effects of NAC on obsessive-compulsive disorder, trichotillomania, and onychophagia. Results remain inconclusive, but NAC may still be useful as a treatment for obsessive-compulsive spectrum disorders on an individual level, particularly as the compound has a relatively benign side-effect profile. The dearth of methodologically robust work is clinically important: larger randomized controlled trials are required to inform of any meaningful clinical effectiveness, and to better determine which, if any, clinical populations might most benefit.

Immunomodulatory metabolites released by the frog-killing fungus Batrachochytrium dendrobatidis.

Batrachochytrium dendrobatidis is a fungal pathogen in the phylum Chytridiomycota that causes the skin disease chytridiomycosis. Chytridiomycosis is considered an emerging infectious disease linked to worldwide amphibian declines and extinctions. Although amphibians have well-developed immune defenses, clearance of this pathogen from the skin is often impaired. Previously, we showed that the adaptive immune system is involved in the control of the pathogen, but B. dendrobatidis releases factors that inhibit in vitro and in vivo lymphocyte responses and induce lymphocyte apoptosis. Little is known about the nature of the inhibitory factors released by this fungus. Here, we describe the isolation and characterization of three fungal metabolites produced by B. dendrobatidis but not by the closely related nonpathogenic chytrid Homolaphlyctis polyrhiza. These metabolites are methylthioadenosine (MTA), tryptophan, and an oxidized product of tryptophan, kynurenine (Kyn). Independently, both MTA and Kyn inhibit the survival and proliferation of amphibian lymphocytes and the Jurkat human T cell leukemia cell line. However, working together, they become effective at much lower concentrations. We hypothesize that B. dendrobatidis can adapt its metabolism to release products that alter the local environment in the skin to inhibit immunity and enhance the survival of the pathogen.

Substrate independent silver nanoparticle based antibacterial coatings.

Infections arising from bacterial adhesion and colonization on medical device surfaces are a significant healthcare problem. Silver based antibacterial coatings have attracted a great deal of attention as a potential solution. This paper reports on the development of a silver nanoparticles based antibacterial surface that can be applied to any type of material surface. The silver nanoparticles were surface engineered with a monolayer of 2-mercaptosuccinic acid, which facilitates the immobilization of the nanoparticles to the solid surface, and also reduces the rate of oxidation of the nanoparticles, extending the lifetime of the coatings. The coatings had excellent antibacterial efficacy against three clinically significant pathogenic bacteria i.e. Staphylococcus epidermidis, Staphylococcus aureus and Pseudomonas aeruginosa. Studies with primary human fibroblast cells showed that the coatings had no cytotoxicity in vitro. Innate immune studies in cultures of primary macrophages demonstrated that the coatings do not significantly alter the level of expression of pro-inflammatory cytokines or the adhesion and viability of these cells. Collectively, these coatings have an optimal combination of properties that make them attractive for deposition on medical device surfaces such as wound dressings, catheters and implants.

Alpha-1 acid glycoprotein reduces hepatic leukocyte recruitment in murine models of either early endotoxemia or early sepsis.

OBJECTIVE: To characterize the effect of systemically administered AGP on early leukocyte recruitment in the livers of endotoxemic or septic mice and to determine whether this is influenced by LPS sequestration. METHODS: Endotoxemia was induced in C57Bl/6 mice via intraperitoneal injection of LPS. Sepsis was induced in mice by cecal ligation and perforation. AGP (165 mg/kg) or saline (20 mL/kg) or HAS (200 mg/kg) was administered immediately after surgery or LPS injection and the hepatic microcirculation was examined by intravital microscopy at four hour. RESULTS: Leukocyte adhesion in the PSV was reduced by treatment with AGP in mice subjected to either LPS or CLP protocols compared to either saline or HAS treatment. AGP-treated mice also had significantly higher sinusoidal flow in both models. Pre-incubation of LPS with AGP reduced the ability of LPS to recruit leukocytes to the liver microcirculation. CONCLUSIONS: AGP was more effective in limiting hepatic inflammation and maintaining perfusion than saline or HAS, in both endotoxemic and septic mice. AGP sequestration of LPS may contribute to its anti-inflammatory effects.