A novel apoE-mimetic increases brain apoE levels, reduces Aß pathology and improves memory when treated before onset of pathology in male mice that express APOE3.

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aß). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of the apoE protein could regulate AD progression. In glia, apoE is lipidated via cholesterol efflux from intracellular pools, primarily by the ATP-binding cassette transporter A1 (ABCA1). Therefore, increasing ABCA1 activity is suggested to be a therapeutic approach for AD. CS-6253 (CS) is a novel apoE mimetic peptide that was developed to bind and stabilize ABCA1 and maintain its localization into the plasma membrane therefore promoting cholesterol efflux. The goal of this study was to determine whether CS could modulate apoE levels and lipidation, Aß pathology, and behavior in a model that expresses human APOE and overproduce Aß. METHODS: In vitro, APOE3-glia or APOE4-glia were treated with CS. In vivo, male and female, E3FAD (5xFAD+/-/APOE3+/+) and E4FAD (5xFAD+/-/APOE4+/+) mice were treated with CS via intraperitoneal injection at early (from 4 to 8 months of age) and late ages (from 8 to 10 months of age). ApoE levels, ABCA1 levels and, apoE lipidation were measured by western blot and ELISA. Aß and amyloid levels were assessed by histochemistry and ELISA. Learning and memory were tested by Morris Water Maze and synaptic proteins were measured by Western blot. RESULTS: CS treatment increased apoE levels and cholesterol efflux in primary glial cultures. In young male E3FAD mice, CS treatment increased soluble apoE and lipid-associated apoE, reduced soluble oAß and insoluble Aß levels as well as Aß and amyloid deposition, and improved memory and synaptic protein levels. CS treatment did not induce any therapeutic benefits in young female E3FAD and E4FAD mice or in any groups when treatment was started at later ages. CONCLUSIONS: CS treatment reduced Aß pathology and improved memory only in young male E3FAD, the cohort with the least AD pathology. Therefore, the degree of Aß pathology or Aß overproduction may impact the ability of targeting ABCA1 to be an effective AD therapeutic. This suggests that ABCA1-stabilizing treatment by CS-6253 works best in conditions of modest Aß levels.

United States Medicare Reimbursement Trends for Glaucoma Procedures: 2000-2020.

PURPOSE: The purpose of this study is to investigate US Medicare reimbursement trends for common glaucoma procedures from 2000 to 2020. MATERIALS AND METHODS: Current Procedural Terminology codes for Glaucoma procedures in the US centers for Medicare and Medicaid Services database were used to conduct this economic analysis. Reimbursement data from the Physician Fee Schedule look-up tool from the Centers for Medicare and Medicaid Services were compiled for the selected procedures and compensation trends were investigated after adjusting for inflation in 2020 US dollars from the unadjusted data between 2000 and 2020. RESULTS: The average adjusted reimbursement for the analyzed procedures decreased by 20.5% [95% confidence interval (CI), -15.4% to -25.6%] over the 20-year period. On average, there was a 1.03% decrease in reimbursement rates per year (95% CI, -0.74% to -1.33%), with an adjusted compound annual growth rate of -1.35% (95% CI, -1.07% to -1.64%). The results show an overall declining rate in reimbursement for the glaucoma procedures analyzed in this study. CONCLUSIONS: The US Medicare reimbursement for glaucoma procedures in the United States showed a significant decline between 2000 and 2020. These findings may be relevant to understanding changing practice patterns for glaucoma care.

Diffractive optic intraocular lens exchange: indications and outcomes.

PURPOSE: To assess indications and outcomes of surgical exchange of diffractive optic multifocal and extended depth-of-focus intraocular lenses (IOLs) in favor of monofocal IOLs. SETTING: Private practice, Los Angeles, California. DESIGN: Retrospective chart review. METHODS: All cases of diffractive optic IOL exchange between June 2007 and October 2020 for diffractive optic dysphotopsia (DOD) (ie, light-induced concentric circles and spider web patterns), poor visual quality, or night vision symptoms were evaluated retrospectively regarding surgical indications, comorbidities, surgical methods, surgical complications, and visual outcomes. Ocular surface disease and ametropia were managed prior to consideration of IOL exchange. RESULTS: The charts of 64 eyes of 46 patients were included. 53/64 (83%) had DOD, 50/64 (78%) experienced reduced quality of vision, and 12/64 (19%) complained of night vision difficulties. 27/64 (42%) of eyes had no ocular comorbidities; 15/64 (23%) of eyes had more than 1 comorbid condition, and 12/64 (19%) were post-laser refractive surgery. Laser posterior capsulotomy had been performed in 15/64 (23%) of eyes. There were a variety of inciting diffractive optic IOLs and various monofocal exchange lenses and fixation techniques were used based on symptoms, comorbidities, and status of the posterior capsule. After IOL exchange, all eyes were relieved of DOD, and all eyes had improved or unchanged corrected distance visual acuity. CONCLUSIONS: Diffractive optic IOLs may induce unsatisfactory visual outcomes. However, in this large series of IOL exchanges, DOD and reduced visual function can be overcome with exchange for a monofocal IOL, despite comorbidities or an open posterior capsule.

Femtosecond laser-assisted intraocular lens exchange.

Intraocular lens (IOL) exchange in patients with anterior capsule contraction resulting from phimosis can complicate IOL exchange as the fibrotic anterior capsule must be cut to gain access to the IOL. Maintaining curvilinear capsulotomy is particularly important when the desired outcome is bag-to-bag IOL exchange. Similarly, when the posterior capsule is open, properly sized curvilinear anterior capsulotomy will allow for optic capture and further stability of the exchanged IOL. Secondary capsulotomy size ranged from 4.9 to 5.0 mm, and the energy was set at 4 to 10 µJ depending on diffusiveness of the anterior capsule. The femtosecond laser was adapted to create a secondary anterior capsulotomy to facilitate IOL exchange.

Length of Stay After Transfemoral Transcatheter Aortic Valve Replacement: An Analysis of the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry.

OBJECTIVES: The goal of this study was to investigate the trends, predictors, and outcomes of delayed discharge (>72 h) after transcatheter aortic valve replacement. BACKGROUND: Length of stay post-transcatheter aortic valve replacement may have significant clinical and administrative implications. METHODS: Data from the Transcatheter Valve Therapy Registry were used to identify patients undergoing nonaborted transfemoral transcatheter aortic valve replacement who survived to discharge, and data linked from the Centers for Medicare & Medicaid Services were used to provide 1-year events. Patients were categorized to early discharge (≤72 h) versus delayed discharge (>72 h). The trends, predictors, and adjusted 1-year outcomes were compared in both groups. RESULTS: From 2011 to 2015, a total of 13,389 patients (55.1%) were discharged within 72 h, whereas 10,896 patients (44.9%) were discharged beyond 72 h. There was a significant decline in rates of delayed discharge across the study period (62% vs. 34%; p < 0.01). This remained unchanged when stratified by Transcatheter Valve Therapy risk scores. Several factors were identified as independent predictors of early and delayed discharge. After adjustment for in-hospital complications, delayed discharge was an independent predictor of 1-year all-cause mortality (hazard ratio: 1.45; 95% confidence interval: 1.30 to 1.60; p < 0.01). CONCLUSIONS: Rates of delayed discharge have declined from 2011 to 2015. Delayed discharge is associated with a significant increase in mortality even after adjusting for in-hospital complications. Further work is necessary to determine if predictors of early discharge could be used to develop length of stay scores that might be instrumental in administrative, financial, or clinical policy development.

Multiple environmental stressors induce complex transcriptomic responses indicative of phenotypic outcomes in Western fence lizard.

BACKGROUND: The health and resilience of species in natural environments is increasingly challenged by complex anthropogenic stressor combinations including climate change, habitat encroachment, and chemical contamination. To better understand impacts of these stressors we examined the individual- and combined-stressor impacts of malaria infection, food limitation, and 2,4,6-trinitrotoluene (TNT) exposures on gene expression in livers of Western fence lizards (WFL, Sceloporus occidentalis) using custom WFL transcriptome-based microarrays. RESULTS: Computational analysis including annotation enrichment and correlation analysis identified putative functional mechanisms linking transcript expression and toxicological phenotypes. TNT exposure increased transcript expression for genes involved in erythropoiesis, potentially in response to TNT-induced anemia and/or methemoglobinemia and caused dose-specific effects on genes involved in lipid and overall energy metabolism consistent with a hormesis response of growth stimulation at low doses and adverse decreases in lizard growth at high doses. Functional enrichment results were indicative of inhibited potential for lipid mobilization and catabolism in TNT exposures which corresponded with increased inguinal fat weights and was suggestive of a decreased overall energy budget. Malaria infection elicited enriched expression of multiple immune-related functions likely corresponding to increased white blood cell (WBC) counts. Food limitation alone enriched functions related to cellular energy production and decreased expression of immune responses consistent with a decrease in WBC levels. CONCLUSIONS: Despite these findings, the lizards demonstrated immune resilience to malaria infection under food limitation with transcriptional results indicating a fully competent immune response to malaria, even under bio-energetic constraints. Interestingly, both TNT and malaria individually increased transcriptional expression of immune-related genes and increased overall WBC concentrations in blood; responses that were retained in the TNT x malaria combined exposure. The results demonstrate complex and sometimes unexpected responses to multiple stressors where the lizards displayed remarkable resiliency to the stressor combinations investigated.

Outcomes of beta blocker use in cocaine-associated chest pain: a meta-analysis.

OBJECTIVES: Beta blockers (ß-blockers) remain a standard therapy in the early treatment of acute coronary syndromes. However, ß-blocker therapy in patients with cocaine-associated chest pain (CACP) continues to be an area of debate due to the potential risk of unopposed α-adrenergic stimulation and coronary vasospasm. Therefore, we performed a systematic review and meta-analysis of available studies to compare outcomes of ß-blocker versus no ß-blocker use among patients with CACP. METHODS: We searched the MEDLINE and EMBASE databases through September 2016 using the keywords 'beta blocker', 'cocaine' and commonly used ß-blockers ('atenolol', 'bisoprolol', 'carvedilol', 'esmolol', 'metoprolol' and 'propranolol') to identify studies evaluating ß-blocker use among patients with CACP. We specifically focused on studies comparing outcomes between ß-blocker versus no ß-blocker usage in patients with CACP. Studies without a comparison between ß-blocker and no ß-blocker use were excluded. Outcomes of interest included non-fatal myocardial infarction (MI) and all-cause mortality. Quantitative data synthesis was performed using a random-effects model and heterogeneity was assessed using Q and I2statistics. RESULTS: A total of five studies evaluating 1794 subjects were included. Overall, there was no significant difference on MI in patients with CACP on ß-blocker versus no ß-blocker (OR 1.36, 95% CI 0.68 to 2.75; p=0.39). Similarly, there was no significant difference in all-cause mortality in patients on ß-blocker versus no ß-blocker (OR 0.68, 95% CI 0.26 to 1.79; p=0.43). CONCLUSIONS: In patients presenting with acute chest pain and underlying cocaine, ß-blocker use does not appear to be associated with an increased risk of MI or all-cause mortality.

Surgical management of negative dysphotopsia.

PURPOSE: To evaluate curative and preventative surgical strategies for negative dysphotopsia. SETTING: Private practice, Los Angeles, California, USA. DESIGN: Retrospective case series. METHODS: Patients with self-reported chronic negative dysphotopsia had corrective surgery as the therapeutic group. Second eye surgery, in cases with negative dysphotopsia in the previously operated eye, comprised the preventative group. Chronologically, several surgical strategies were used, including bag-to-bag intraocular lens (IOL) exchange, reducing posterior chamber depth, piggyback secondary IOL placement, bag-to-sulcus IOL exchange, and reverse optic capture. The primary outcome measure was improvement of negative dysphotopsia by 3 months postoperatively. RESULTS: The therapeutic group comprised 40 eyes of 37 patients; 76.6% of causative IOLs were acrylic and 23.4% were silicone and all were bag-fixated. There were 21 eyes in the preventative group of which 11 were second eyes from the therapeutic group; the remaining 10 did not require surgery for the symptomatic eye. Successful outcomes for each surgical strategy were as follows: bag-to-bag IOL exchange (0/5), a reduction in posterior chamber depth with iris suture fixation of the bag-haptic complex (0/1), piggyback secondary IOL (8/11), secondary reverse optic capture (21/22), ciliary sulcus posterior chamber IOL exchange (7/8), and primary reverse optic capture (21/21). CONCLUSIONS: Negative dysphotopsia was associated with acrylic or silicone IOLs of either square- or round-edge design. Negative dysphotopsia was reduced, eliminated, or prevented when the IOL optic overlaid the anterior capsulotomy rather than when the capsule edge overlaid the optic. Bag-to-sulcus IOL exchange and reverse optic capture were highly successful in managing or preventing negative dysphotopsia.

The Role of Intracoronary Plaque Imaging with Intravascular Ultrasound, Optical Coherence Tomography, and Near-Infrared Spectroscopy in Patients with Coronary Artery Disease.

The development of multiple diagnostic intracoronary imaging modalities has increased our understanding of coronary atherosclerotic disease. These imaging modalities, intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near-infrared spectroscopy (NIRS), have provided a method to study plaques and introduced the concept of plaque vulnerability. They are being increasingly used for percutaneous coronary intervention (PCI) optimization and are invaluable tools in research studying the pathophysiology of acute coronary syndrome (ACS), in-stent thrombosis and in-stent restenosis. IVUS has the ability to visualize the intracoronary lumen and the vessel wall and can be used to detect early atherosclerotic disease even in the setting of positive arterial remodeling. Studies supporting the use of IVUS to optimize stent deployment and apposition have shown a significant reduction in cardiovascular events. OCT provides even higher resolution imaging and near microscopic detail of plaques, restenoses, and thromboses; thus, it can identify the etiology of ACS. Ongoing trials are evaluating the role of OCT in PCI and using OCT to study stent endothelialization and neointimal proliferation. NIRS is a modality capable of localizing and quantifying lipid core burden. It is usually combined with IVUS and is used to characterize plaque composition. The benefits of NIRS in the setting of ACS have been limited to case reports and series. The utilization of all these intracoronary imaging modalities will continue to expand as their indications for clinical use and research grow. Studies to support their use for PCI optimization resulting in improved outcomes with potential to prevent downstream events are ongoing.

Physico-Chemical Heterogeneity of Organic-Rich Sediments in the Rifle Aquifer, CO: Impact on Uranium Biogeochemistry.

The Rifle alluvial aquifer along the Colorado River in west central Colorado contains fine-grained, diffusion-limited sediment lenses that are substantially enriched in organic carbon and sulfides, as well as uranium, from previous milling operations. These naturally reduced zones (NRZs) coincide spatially with a persistent uranium groundwater plume. There is concern that uranium release from NRZs is contributing to plume persistence or will do so in the future. To better define the physical extent, heterogeneity and biogeochemistry of these NRZs, we investigated sediment cores from five neighboring wells. The main NRZ body exhibited uranium concentrations up to 100 mg/kg U as U(IV) and contains ca. 286 g of U in total. Uranium accumulated only in areas where organic carbon and reduced sulfur (as iron sulfides) were present, emphasizing the importance of sulfate-reducing conditions to uranium retention and the essential role of organic matter. NRZs further exhibited centimeter-scale variations in both redox status and particle size. Mackinawite, greigite, pyrite and sulfate coexist in the sediments, indicating that dynamic redox cycling occurs within NRZs and that their internal portions can be seasonally oxidized. We show that oxidative U(VI) release to the aquifer has the potential to sustain a groundwater contaminant plume for centuries. NRZs, known to exist in other uranium-contaminated aquifers, may be regionally important to uranium persistence.

Silver nanowire exposure results in internalization and toxicity to Daphnia magna.

Nanowires (NWs), high-aspect-ratio nanomaterials, are increasingly used in technological materials and consumer products and may have toxicological characteristics distinct from nanoparticles. We carried out a comprehensive evaluation of the physicochemical stability of four silver nanowires (AgNWs) of two sizes and coatings and their toxicity to Daphnia magna . Inorganic aluminum-doped silica coatings were less effective than organic poly(vinyl pyrrolidone) coatings at preventing silver oxidation or Ag(+) release and underwent a significant morphological transformation within 1 h following addition to low ionic strength Daphnia growth media. All AgNWs were highly toxic to D. magna but less toxic than ionic silver. Toxicity varied as a function of AgNW dimension, coating, and solution chemistry. Ag(+) release in the media could not account for observed AgNW toxicity. Single-particle inductively coupled plasma mass spectrometry distinguished and quantified dissolved and nanoparticulate silver in microliter-scale volumes of Daphnia magna hemolymph with a limit of detection of approximately 10 ppb. The silver levels within the hemolymph of Daphnia exposed to both Ag(+) and AgNW met or exceeded the initial concentration in the growth medium, indicating effective accumulation during filter feeding. Silver-rich particles were the predominant form of silver in hemolymph following exposure to both AgNWs and Ag(+). Scanning electron microscopy imaging of dried hemolymph found both AgNWs and silver precipitates that were not present in the AgNW stock or the growth medium. Both organic and inorganic coatings on the AgNW were transformed during ingestion or absorption. Pathway, gene ontology, and clustering analyses of gene expression response indicated effects of AgNWs distinct from ionic silver on Daphnia magna .

Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence.

Considerable evidence suggests that transmission at hypocretin-1 (orexin-1) receptors (Hcrt-R1) plays an important role in the reinstatement of extinguished cocaine-seeking behaviors in rodents. However, far less is known about the role for hypocretin transmission in regulating ongoing cocaine-taking behavior. Here, we investigated the effects of the selective Hcrt-R1 antagonist SB-334867 on cocaine intake, as measured by intravenous (IV) cocaine self-administration in rats. The stimulatory effects of cocaine on brain reward systems contribute to the establishment and maintenance of cocaine-taking behaviors. Therefore, we also assessed the effects of SB-334867 on the reward-enhancing properties of cocaine, as measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds. Finally, to definitively establish a role for Hcrt-R1 in regulating cocaine intake, we assessed IV cocaine self-administration in Hcrt-R1 knockout mice. We found that SB-334867 (1-4 mg/kg) dose-dependently decreased cocaine (0.5 mg/kg/infusion) self-administration in rats but did not alter responding for food rewards under the same schedule of reinforcement. This suggests that SB-334867 decreased cocaine reinforcement without negatively impacting operant performance. SB-334867 (1-4 mg/kg) also dose-dependently attenuated the stimulatory effects of cocaine (10 mg/kg) on brain reward systems, as measured by reversal of cocaine-induced lowering of ICSS thresholds in rats. Finally, we found that Hcrt-R1 knockout mice self-administered far less cocaine than wildtype mice across the entire dose-response function. These data demonstrate that Hcrt-R1 play an important role in regulating the reinforcing and reward-enhancing properties of cocaine and suggest that hypocretin transmission is likely essential for establishing and maintaining the cocaine habit in human addicts.

CAPRG: sequence assembling pipeline for next generation sequencing of non-model organisms.

Our goal is to introduce and describe the utility of a new pipeline "Contigs Assembly Pipeline using Reference Genome" (CAPRG), which has been developed to assemble "long sequence reads" for non-model organisms by leveraging a reference genome of a closely related phylogenetic relative. To facilitate this effort, we utilized two avian transcriptomic datasets generated using ROCHE/454 technology as test cases for CAPRG assembly. We compared the results of CAPRG assembly using a reference genome with the results of existing methods that utilize de novo strategies such as VELVET, PAVE, and MIRA by employing parameter space comparisons (intra-assembling comparison). CAPRG performed as well or better than the existing assembly methods based on various benchmarks for "gene-hunting." Further, CAPRG completed the assemblies in a fraction of the time required by the existing assembly algorithms. Additional advantages of CAPRG included reduced contig inflation resulting in lower computational resources for annotation, and functional identification for contigs that may be categorized as "unknowns" by de novo methods. In addition to providing evaluation of CAPRG performance, we observed that the different assembly (inter-assembly) results could be integrated to enhance the putative gene coverage for any transcriptomics study.

Using gene expression to assess the status of fish from anthropogenically influenced estuarine wetlands.

The diverse mixture of contaminants frequently present in estuaries complicates their assessment by routine chemical or biological analyses. We investigated the use of gene expression to assess contaminant exposure and the condition of southern California estuarine fish. Liver gene expression, plasma estradiol concentrations, and gonad histopathology were used to study biological condition in longjaw mudsuckers (Gillichthys mirabilis). Metals, legacy organochlorine pesticides, PCBs, and contaminants of emerging concern were detected in sediments and whole fish. Overall gene expression patterns were characteristic to each of four sites investigated in this study. Differentially expressed genes belonged to several functional categories including xenobiotic metabolism, detoxification, disease, and stress responses. In general, plasma estradiol concentrations were similar among fish from all areas. Some fish gonads had pathologic changes (e.g., infection, inflammation) that could indicate weakened immune systems and chronic stress. The differential expression of some genes involved in stress responses correlated with the prevalence of histologic gonad lesions. This study indicates that gene expression is a promising tool for assessing the biological condition of fish exposed to environmental contaminants.

The PGC-1α-related coactivator promotes mitochondrial and myogenic adaptations in C2C12 myotubes.

The transcriptional coactivator PGC-1α is a potent regulator of skeletal muscle metabolism. Less is known about the structurally similar PGC-1α-related coactivator (PRC) that is enriched in myoblasts and adult skeletal muscle. The present study was designed to determine the effect of PRC on the metabolic profile of C2C12 myotubes. Overexpression of full-length PRC increased PRC gene expression by 2.7 ± 0.3-fold and protein content by 108 ± 5.3%. This modest elevation in PRC resulted in an increased rate of myoblast proliferation (61.5 ± 2.7%) and resulted in myotubes characterized by increased MyoD (18.2 ± 0.52%) and myosin heavy chain (15.4 ± 3.13%) protein. PRC overexpressing myotubes showed increases in mRNA for some-COX4 (2.6 ± 0.18-fold), ATP5B (2.7 ± 0.34-fold) cytochrome c (5.1 ± 0.68-fold)-but not all, MTCO1 (0.61 ± 0.18-fold) and HAD (0.98 ± 0.36-fold) mitochondrial genes, as well as a significant increase in cytochrome-c (28.7 ± 7.02%) protein content. The enzyme activity of the electron transport chain (ETC) complex IV (3.7 ± 0.01-fold) and citrate synthase (2.1 ± 0.14-fold) was increased by PRC, as was the mtDNA:nucDNA ratio (11 ± 0.3%). PRC increased cellular respiration (142%), basal (197%) and insulin-stimulated (253%) glucose uptake, as well as palmitate uptake (28.6 ± 3.31%) and oxidation (31.1 ± 2.17%). Associated with these changes in function, PRC overexpression increased GLUT4 mRNA (4.5 ± 0.22-fold) and protein (13.8 ± 2.08%) and CPT1 protein (28.9 ± 4.23%). Electrical stimulation of C2C12 myotubes resulted in a transient increase in PRC mRNA that was smaller (2.1 ± 0.3-fold vs. 4.4 ± 0.23-fold) and occurred earlier (3 h vs. 6 h) than PGC-1α. Collectively, our data show that PRC promotes skeletal muscle myogenesis and metabolism in vitro, thus identifying PRC as a functional skeletal muscle coactivator capable of regulating mitochondrial substrate utilization and respiration.

Quantification of water solubilized CdSe/ZnS quantum dots in Daphnia magna.

The relative transparency of Daphnia magna (daphnia) and the unique optical properties of quantum dots (QDs) were paired to study the accumulation potential and surface coating effects on uptake of amphiphilic polymer coated CdSe/ZnS QDs. Fluorescence confocal laser scanning microscopy was used to visualize and spectrally distinguish QDs from competing autofluorescent signals arising from the daphnia themselves and their food sources. QDs were found to accumulate within the digestive tracts of daphnia, as well as, in some cases, adhere to the carapace, antennae, and thoracic appendages. After 48 h of gut clearance with and without feeding, QD fluorescence signal was still apparent in the digestive tracts of daphnia, and inductively coupled plasma mass spectrometry (ICP-MS) measurements confirmed that 36-53% of the initial uptake was retained. As surface charge and pegylation can influence the uptake of nanoparticles, uptake of QDs coated with two different amphililic polymers and their polyethylene glycol (PEG) coated counterparts was also examined. Fluorescence microscopy and ICP-MS measurements revealed differences in uptake after 24 h of exposure which were attributed to particle surface coating and stability.

Prophylaxis with lactoferrin, a novel antimicrobial agent, in a neonatal rat model of coinfection.

Lactoferrin has broad-spectrum antimicrobial activity, and the authors hypothesized that recombinant human lactoferrin (Talactoferrin alfa [TLF]) would reduce mortality and morbidity in a coinfection model. The MIC 50 (minimum inhibitory concentration required to inhibit the growth of 50% of organisms) of TLF against Candida albicans and Staphylococcus epidermidis was determined. Neonatal Wistar rats were infected with C albicans or S epidermidis or both, at doses of 2 x10(8) colony-forming units (CFUs) given subcutaneously. Rat pups in each group were randomly given TLF intraperitoneally at 40 mg/kg/dose or 300 mg/kg/dose, or saline in 0.2 mL, once a day for 4 d and were monitored for mortality, weight gain, and blood culture positivity. Trough serum levels of TLF were measured at 24, 48, 72, 96, and 144 h. MIC 50 of TLF was 30 microg/mL and 500 microg/mL for C albicans and S epidermidis, respectively. TLF prophylaxis significantly improved survival in the coinfection group at 40 mg/kg/dose (by 16.1%; P=.019) and at 300 mg/kg/dose (by 15.1%; P=.027) and in the S epidermidis group at a dose of 40 mg/kg/dose (by 18.6%; P=.04). Weight gain was not affected by TLF prophylaxis. Serum trough levels of TLF were 1000-fold lower than in vitro MIC 50. The authors conclude that lactoferrin prophylaxis significantly enhanced survival in coinfection and in the subgroup of S epidermidis infection (40 mg/kg/dose) through indirect mechanisms.

Neonatal coinfection model of coagulase-negative Staphylococcus (Staphylococcus epidermidis) and Candida albicans: fluconazole prophylaxis enhances survival and growth.

Coagulase-negative staphylococci (CoNS) and Candida are among the most common causes of single infections and coinfections in neonates after 72 h of age. In neonates, coinfection increases the rate of mortality threefold and results in significantly greater morbidity compared to those that result from single infections. In an effort to better understand this phenomenon, we developed the first neonatal animal model of coinfection (with CoNS and Candida) and evaluated its effects on mortality and morbidity and the impact of antifungal prophylaxis with fluconazole. Neonatal Wistar rats were infected with Candida albicans and/or Staphylococcus epidermidis with doses of 2x10(8) and 2x10(6) CFU subcutaneously in different combinations and were monitored for mortality, weight gain, and bacteremia. The in vitro sensitivity of C. albicans to fluconazole was evaluated and the MIC was determined. A subset of rats in these experiments received fluconazole at 10 mg/kg of body weight/dose intraperitoneally starting 24 h before infection for 4 days, and the serum trough levels of fluconazole were measured. Coinfection in the suckling rat significantly increased the rate of mortality compared to that after infection with a single species (P<0.001) and resulted in deaths even at sublethal doses. Coinfection also impaired weight gain significantly in severely infected pups compared to that achieved after infection with a single species (P<0.001). Fluconazole prophylaxis significantly reduced mortality by 30% in the Candida group and 36% in the coinfection group and improved weight gain in this neonatal model of coinfection (P<0.001). We developed a neonatal model of coinfection with Candida and CoNS, observed significantly greater mortality and morbidity with coinfection, and found that fluconazole prophylaxis significantly reduced the rates of both mortality and morbidity. Further research on neonatal coinfection is urgently needed to improve clinical outcomes.