Host exposure to a common pollutant can influence diversity-disease relationships.

Hosts and parasites are embedded in communities where species richness and composition can influence disease outcomes (diversity-disease relationships). The direction and magnitude of diversity-disease relationships are influenced by variation in competence (ability to support and transmit infections) of hosts in a community. However, host susceptibility to parasites, which mediates host competence, is not static and is influenced by environmental factors, including pollutants. Despite the role that pollutants can play in augmenting host susceptibility, how pollutants influence diversity-disease dynamics is not well understood. Using an amphibian-trematode model, we tested how NaCl influences diversity-disease dynamics. We predicted that NaCl exposure can alter relative susceptibility of host species to trematodes, leading to cascading effects on the diversity-disease relationship. To test these predictions, we exposed hosts to benign or NaCl environments and generated communities that differed in number and composition of host species. We exposed these communities to trematodes and measured disease outcomes at the community (total infections across all hosts within a community) and species levels (average number of infections per host species within a community). Host species differed in their relative susceptibility to trematodes when exposed to NaCl. Consequently, at the community level (total infections across all hosts within a community), we only detected diversity-disease relationships (dilution effects) in communities where hosts were exposed to NaCl. At the species level, disease outcomes (average number of infections/species) and whether multi-species communities supported lower number of infections relative to single-species communities depended on community composition. Notably, however, as with overall community infection, diversity-disease relationships only emerged when hosts were exposed to NaCl. Synthesis. Pollutants are ubiquitous in nature and can influence disease dynamics across a number of host-parasite systems. Here, we show that NaCl exposure can alter the relative susceptibility of host species to parasites, influencing the relationship between biodiversity and disease at both community and species levels. Collectively, our study contributes to the limited knowledge surrounding environmental mediators of host susceptibility and their influence on diversity-disease dynamics.

Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model.

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Characterization of AAV-mediated dorsal root ganglionopathy.

Recent studies in non-human primates administered recombinant adeno-associated viruses (rAAVs) have shown lesions in the dorsal root ganglia (DRG) of unknown pathogenesis. In this study, rAAV9s manufactured using different purification methods alongside a non-expressing Null AAV9 vector was administered to groups of cynomolgus monkeys followed by neuropathological evaluation after 4 weeks. Lesions, including neuronal degeneration, increased cellularity, and nerve fiber degeneration, were observed in the DRG, regardless of purification methods. Animals did not develop any neurological signs throughout the study, and there was no loss of function observed in neuro-electrophysiological endpoints or clear effects on intraepidermal nerve fiber density. However, magnetic resonance imaging (MRI) of animals with axonopathy showed an increase in short tau inversion recovery (STIR) intensity and decrease in fractional anisotropy. In animals administered the Null AAV9 vector, DRG lesions were not observed despite vector DNA being detected in the DRG at levels equivalent to or greater than rAAV9-treated animals. This study further supports that DRG toxicity is associated with transgene overexpression in DRGs, with particular sensitivity at the lumbar and lumbosacral level. The data from this study also showed that the nerve fiber degeneration did not correlate with any functional effect on nerve conduction but was detectable by MRI.

Effects of Polyester Microplastic Fiber Contamination on Amphibian-Trematode Interactions.

Microplastic contamination poses a global threat to aquatic organisms, yet we know little as to how microplastics may indirectly affect organismal health via their influence on species-species interactions (e.g., host-parasite interactions). This is problematic because microplastic-mediated alterations to host-parasite dynamics could negatively impact individual- population-level health of hosts. Using a larval amphibian (host) and free-living trematode (parasite) model, we asked whether 1) polyester microplastic fibers influence parasite survival; 2) whether polyester microplastic fiber ingestion by amphibians alters amphibian susceptibility to infection; and 3) whether simultaneous exposure of amphibians and trematodes to polyester microplastic fibers influences infection outcomes. Polyester microplastic fibers did not alter trematode survival, nor did their ingestion by amphibians increase amphibian susceptibility to infection. However, when amphibians and trematodes were exposed simultaneously to the fibers, the infection success of the parasite was reduced. Lastly, we conducted a field survey for microfiber contamination across multiple ponds and found microfibers across each of the sampled ponds. Overall, our results contribute to the limited knowledge surrounding the ecological consequences of microplastic contamination. Environ Toxicol Chem 2022;41:869-879. © 2021 SETAC.

MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High-Density Lipoprotein, and Low-Density Lipoprotein Receptor-Mediated Reverse Cholesterol Transport.

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

Amphibian breeding phenology influences offspring size and response to a common wetland contaminant.

BACKGROUND: Increases in temperature variability associated with climate change have critical implications for the phenology of wildlife across the globe. For example, warmer winter temperatures can induce forward shifts in breeding phenology across taxa ("false springs"), which can put organisms at risk of freezing conditions during reproduction or vulnerable early life stages. As human activities continue to encroach on natural ecosystems, it is also important to consider how breeding phenology interacts with other anthropogenic stressors (e.g., pollutants). Using 14 populations of a widespread amphibian (wood frog; Rana sylvatica), we compared 1) growth; 2) tolerance to a common wetland contaminant (NaCl); and 3) the ability of tadpoles to acclimate to lethal NaCl exposure following sublethal exposure earlier in life. We evaluated these metrics across two breeding seasons (2018 and 2019) and across populations of tadpoles whose parents differed in breeding phenology (earlier- versus later-breeding cohorts). In both years, the earlier-breeding cohorts completed breeding activity prior to a winter storm and later-breeding cohorts completed breeding activities after a winter storm. The freezing conditions that later-breeding cohorts were exposed to in 2018 were more severe in both magnitude and duration than those in 2019. RESULTS: In 2018, offspring of the later-breeding cohort were larger but less tolerant of NaCl compared to offspring of the earlier-breeding cohort. The offspring of the earlier-breeding cohort additionally were able to acclimate to a lethal concentration of NaCl following sublethal exposure earlier in life, while the later-breeding cohort became less tolerant of NaCl following acclimation. Interestingly, in 2019, the warmer of the two breeding seasons, we did not detect the negative effects of later breeding phenology on responses to NaCl. CONCLUSIONS: These results suggest that phenological shifts that expose breeding amphibians to freezing conditions can have cascading consequences on offspring mass and ability to tolerate future stressors but likely depends on the severity of the freeze event.

Effects of different roadway deicing salts on host-parasite interactions: The importance of salt type.

The application of roadway deicing salts is increasing the salinity of freshwater systems. Increased salinization from salts, such as NaCl, CaCl2 and MgCl2, can have direct, negative impacts on freshwater organisms at concentrations found in nature. Yet, our understanding of how these salts can indirectly impact freshwater organisms by altering important ecological interactions, such as those between hosts and their parasites, is limited. Using a larval amphibian and infectious free-living helminth (i.e. trematode) model, we examined whether exposure to environmentally relevant concentrations of NaCl, CaCl2 and MgCl2 1) influence trematode mortality; 2) alter amphibian-trematode interactions; and 3) alter larval amphibian activity (a behavior associated with parasite avoidance). We found that exposure to CaCl2 greatly reduced trematode survival across all Cl- concentrations (230, 500, 860 and 1000 mg Cl- L-1) while NaCl and MgCl2 had no effect. When both host and parasites were exposed to the salts, exposure to NaCl, but not MgCl2 or CaCl2, increased infection. The lack of effect of CaCl2 on infection was likely driven by CaCl2 reducing trematode survival. Exposure to NaCl increased infection at 500 mg Cl- L-1, but not 230 or 860 mg Cl- L-1. Increased infection was not due to salt exposure altering tadpole behavior. Our results suggest that NaCl can negatively impact amphibian populations indirectly by increasing trematode infections in tadpole hosts.

Drug-induced myocardial dysfunction - recommendations for assessment in clinical and pre-clinical studies.

Introduction: Drug-induced myocardial dysfunction is an important safety concern during drug development. Oncology compounds can cause myocardial dysfunction, leading to decreased left ventricular ejection fraction and heart failure via several mechanisms. Cardiovascular imaging has a major role in the early detection and monitoring of cardiotoxicity. Echocardiography is the method of choice because of its widespread availability, low cost, and absence of radiation exposure. Cardiac magnetic resonance imaging can provide better reliability, reproducibility, and accuracy in the detection of drug-induced myocardial dysfunction. In addition, it enables assessment of myocardial edema, fibrosis, and necrosis. Cardiac serologic biomarkers such as troponins and B-type natriuretic peptides are used in combination with imaging during drug development. This article provides a general overview of each imaging modality and practical guidance for early detection and monitoring of cardiotoxicity.Areas covered: Cardiovascular imaging modalities and cardiac biomarkers for monitoring of cardiac function and early detection of drug-induced myocardial dysfunction in drug development.Expert opinion: Some new drugs especially in the oncology field, can cause myocardial dysfunction. Depending on the strength of pre-clinical or clinical data, CV imaging modalities and cardiac biomarkers play an important role in the early detection and mitigation plans for such drugs during their development.

AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression.

There has been great progress in ocular gene therapy, but delivery of viral vectors to the retinal pigmented epithelium (RPE) and retina can be challenging. Subretinal injection, the preferred route of delivery for most applications, requires a surgical procedure that has risks. Herein we report a novel gene therapy delivery approach, suprachoroidal injection of AAV8 vectors, which is less invasive and could be done in an outpatient setting. Two weeks after suprachoroidal injection of AAV8.GFP in rats, GFP fluorescence covered 18.9% of RPE flat mounts and extended entirely around sagittal and transverse sections in RPE and photoreceptors. After 2 suprachoroidal injections of AAV8.GFP, GFP fluorescence covered 30.5% of RPE flat mounts. Similarly, widespread expression of GFP occurred in nonhuman primate and pig eyes after suprachoroidal injection of AAV8.GFP. Compared with subretinal injection in rats of RGX-314, an AAV8 vector expressing an anti-VEGF Fab, suprachoroidal injection of the same dose of RGX-314 resulted in similar expression of anti-VEGF Fab and similar suppression of VEGF-induced vascular leakage. Suprachoroidal AAV8 vector injection provides a noninvasive outpatient procedure to obtain widespread transgene expression in retina and RPE.

Direct and indirect effects of a common cyanobacterial toxin on amphibian-trematode dynamics.

Wildlife diseases are emerging at unprecedented rates. While there are likely several factors at play, human-mediated environmental alterations may play a significant role. Of growing interest is the effect that microcystin-LR (MC-LR), a cyanotoxin, may have on disease outcomes. In this study, using an amphibian-trematode model we examined (1) the lethal effects of MC-LR on cercariae of trematodes; (2) the sublethal effects of MC-LR exposure on the ability for trematodes to infect green frog tadpoles; and (3) the sublethal effects of MC-LR on green frog tadpole susceptibility to trematodes. We found that environmentally-relevant concentrations of MC-LR at 50, 100, and 500 µg L-1 increased cercariae rate of mortality (LC50-14h = 134.24 µg L-1). However, sublethal exposure of trematodes to 2 and 10 µg L-1 MC-LR did not alter their infectivity. Conversely, sublethal exposure of tadpoles to 2 µg L-1 increased their susceptibility to trematodes by 147%. However, 10 µg L-1 of MC-LR did not affect tadpole susceptibility to trematodes, indicating a non-linear response to sublethal MC-LR exposure. Overall, our findings suggest that high concentrations of MC-LR (≥50 µg L-1) have the potential to limit trematode transmission to amphibian hosts through MC-LR-induced mortality. However, at lower concentrations (<10 µg L-1) MC-LR's effect on tadpole-cercariae disease outcome is likely driven by its effect on the tadpole host. Collectively, this work highlights the need to consider how toxicants influence both host and parasite at multiple concentrations to better understand the impacts of cyanotoxins on disease dynamics.

Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats.

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.

Nonclinical safety and pharmacokinetics of Miglyol 812: A medium chain triglyceride in exenatide once weekly suspension.

Exenatide, a glucagon-like peptide-1 receptor agonist was originally developed as either a twice daily or once weekly injectable therapeutic for patients with type 2 diabetes. Exenatide QW suspension was developed for use with an autoinjector device, in which the microspheres are suspended in Miglyol 812, a mixture of medium chain triglycerides (MCTs). MCTs are a class of lipids whose fatty acid chains contain from six to 12 carbon atoms (medium chain fatty acids or MCFAs). While MCTs are edible oils present in many foods, including foodstuffs containing coconut and palm kernel oils, limited information is available regarding the oral and subcutaneous bioavailability of MCTs as well as safety following subcutaneous injection. These studies were designed to investigate the non-clinical pharmacokinetics and safety of MCTs. In a single dose pharmacokinetic study, MCFAs were rapidly detected in the plasma of rats following oral administration of either Miglyol 812 or tricaprylin at doses of 10 or 9.48 g kg-1 , respectively. Following subcutaneous dosing with Miglyol 812, MCFAs were rapidly absorbed with a similar profile to that following oral dosing. Furthermore, the toxicity of Miglyol 812 alone was evaluated in a 3 month repeat dose toxicology studies in cynomolgus monkeys. In this study, weekly subcutaneous doses of 0.15 g kg-1 did not elicit any treatment-related effects in cynomolgus monkeys. In conclusion, these studies alongside the available literature data show that Miglyol 812 is a safe excipient for use in subcutaneously administered therapeutics.

Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc Fusion Protein.

Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector functions such as cytokine release and cellular cytotoxicity. We engineered a recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles into a hexameric structure and exerts potent agonist activity following engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was enhanced when the fusion protein was clustered by Fc gamma receptors (FcγRs) on the surface of adjacent cells. The resulting costimulation of OX40 on T cells induced NFκB promoter activity in OX40-expressing T cells and induced Th1-type cytokine production, proliferation, and resistance to regulatory T cell (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of tumor-reactive T cells and reduced tumor growth in the context of an alloreactive human T cell:tumor cell admix model in immunocompromised mice. Consistent with the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 central and effector memory T-cell proliferation as well as B-cell proliferation. Together, these results suggest that OX40 agonism has the potential to enhance antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024-38. ©2018 AACR.

Parasite susceptibility in an amphibian host is modified by salinization and predators.

Secondary salinization represents a global threat to freshwater ecosystems. Salts, such as NaCl, can be toxic to freshwater organisms and may also modify the outcome of species interactions (e.g. host-parasite interactions). In nature, hosts and their parasites are embedded in complex communities where they face anthropogenic and biotic (i.e. predators) stressors that influence host-parasite interactions. As human populations grow, considering how anthropogenic and natural stressors interact to shape host-parasite interactions will become increasingly important. We conducted two experiments investigating: (1) the effects of NaCl on tadpole susceptibility to trematodes and (2) whether density- and trait-mediated effects of a parasite-predator (i.e. damselfly) and a host-predator (i.e. dragonfly), respectively, modify the effects of NaCl on susceptibility to trematode infection. In the first experiment, we exposed tadpoles to three concentrations of NaCl and measured parasite infection in tadpoles. In the second experiment, we conducted a 2 (tadpoles exposed to 0 g L-1 NaCl vs. 1 g L-1 NaCl) x 4 (no predator, free-ranging parasite-predator (damselfly), non-lethal host-predator (dragonfly kairomone), and free-ranging parasite-predator + dragonfly kairomone) factorial experiment. In the absence of predators, exposure to NaCl increased parasite infection. Of the predator treatments, NaCl only caused an increase in parasite infection in the presence of the parasite-predator. However, direct consumption of trematodes caused a reduction in overall infection in the parasite-predator treatment. In the dragonfly kairomone treatment, a reduction in tadpole movement (i.e. trematode avoidance behavior) led to an increase in overall infection. In the parasite-predator + dragonfly kairomone treatment, antagonistic effects of the parasite-predator (reduction in trematode abundance) and dragonfly kairomone (reduction in parasite avoidance behavior) resulted in intermediate parasite infection. Collectively, these findings demonstrate that NaCl can increase amphibian susceptibility to parasites, and underscores the importance of considering predator-mediated interactions in understanding how contaminants influence host-parasite interactions.

Population-specific toxicity of six insecticides to the trematode Echinoparyphium sp.

The ubiquitous use of pesticides has increased concerns over their direct and indirect effects on disease dynamics. While studies examining the effects of pesticides on host-parasite interactions have largely focused on how pesticides influence the host, few studies have considered the effects of pesticides on parasites. We investigated the toxicity of six common insecticides at six environmentally-relevant concentrations to cercariae of the trematode Echinoparyphium from two populations. All six insecticides reduced the survival of cercariae (overall difference between mortality in control vs pesticide exposure = 86·2 ± 8·7%) but not in a predictable dose-dependent manner. These results suggest that Echinoparyphium are sensitive to a broad range of insecticides commonly used in the USA. The lack of a clear dose-dependent response in Echinoparyphium highlights the potential limitations of toxicity assays in predicting pesticide toxicity to parasites. Finally, population-level variation in cercarial susceptibility to pesticides underscores the importance of accounting for population variation as overlooking this variation can limit our ability to predict toxicity in nature. Collectively, this work demonstrates that consideration of pesticide toxicity to parasites is important to understanding how pesticides ultimately shape disease dynamics in nature.

Targeting the annexin 1-formyl peptide receptor 2/ALX pathway affords protection against bacterial LPS-induced pathologic changes in the murine adrenal cortex.

Hypothalamo-pituitary-adrenocortical dysfunction contributes to morbidity and mortality in a high proportion of patients with sepsis. Here, we provide new insights into the underlying adrenal pathology. Using a murine model of endotoxemia (LPS injection), we demonstrate that adrenal insufficiency is triggered early in the disease. LPS induced a local inflammatory response in the adrenal gland within 4 hours of administration, coupled with increased expression of mRNAs for annexin A1 (AnxA1) and the formyl peptide receptors [(Fprs) 1, 2, and 3], a loss of lipid droplets in cortical cells (index of availability of cholesterol, the substrate for steroidogenesis), and a failure to mount a steroidogenic response to ACTH. Deletion of AnxA1 or Fpr2/3 in mice prevented lipid droplet loss, but not leukocyte infiltration. LPS increased adrenal myeloid differentiation primary response gene 88 and TLR2 mRNA expression, but not lymphocyte antigen 96 or TLR4. By contrast, neutrophil depletion prevented leukocyte infiltration and increased AnxA1, Fpr1, and Fpr3 mRNAs but had no impact on lipid droplet loss. Our novel data demonstrate that AnxA1 and Fpr2 have a critical role in the manifestation of adrenal insufficiency in this model, through regulation of cholesterol ester storage, suggesting that pharmacologic interventions targeting the AnxA1/FPR/ALX pathway may provide a new approach for the maintenance of adrenal steroidogenesis in sepsis.

Warfarin for stroke prevention following anterior ST-elevation myocardial infarction.

OBJECTIVES: To assess the benefit of vitamin K antagonist (VKA) therapy for prevention of ischemic stroke following anterior ST-elevation myocardial infarction (STEMI) in patients with reduced ejection fraction. METHODS: A prospective institutional-based registry was used to identify survivors of anterior STEMI with a post-STEMI ejection fraction of 40% or less over a 10-year period. Clinical and procedural characteristics were collected from medical records and vital status from the Social Security Death Index. Outcomes were compared on the basis of VKA use. The primary outcome was a composite of ischemic stroke, death, and clinically relevant bleeding. A secondary analysis examined the effects of low-molecular-weight heparin bridging therapy. RESULTS: The primary outcome occurred in 24.7% (40/162) of VKA patients and 20.5% (22/107) of non-VKA patients [adjusted hazard ratio (HR), 1.30; 95% confidence interval (CI), 0.71-2.31]. Ischemic stroke occurred in 2.5 and 0.9% of VKA patients and non-VKA patients, respectively (adjusted HR, 2.81; 95% CI, 0.31-25.1). There was no significant difference in the rate of bleeding or death between groups. The addition of a low-molecular-weight heparin bridge to VKA therapy was associated with increased bleeding events (adjusted HR, 2.55; 95% CI, 1.04-6.24). CONCLUSION: Ischemic stroke was infrequent in the 6 months following anterior STEMI irrespective of VKA treatment status. The routine use of anticoagulation for prevention of stroke following anterior STEMI may not be warranted.

Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system.

Unregulated inflammation underlies many diseases, including sepsis. Much interest lies in targeting anti-inflammatory mechanisms to develop new treatments. One such target is the anti-inflammatory protein annexin A1 (AnxA1) and its receptor, FPR2/ALX. Using intravital videomicroscopy, we investigated the role of AnxA1 and FPR2/ALX in a murine model of endotoxin-induced cerebral inflammation [intraperitoneal injection of lipopolysaccharide (LPS)]. An inflammatory response was confirmed by elevations in proinflammatory serum cytokines, increased cerebrovascular permeability, elevation in brain myeloperoxidase, and increased leukocyte rolling and adhesion in cerebral venules of wild-type (WT) mice, which were further exacerbated in AnxA1-null mice. mRNA expression of TLR2, TLR4, MyD-88, and Ly96 was also assessed. The AnxA1-mimetic peptide, AnxA1(Ac2-26) (100 µg/mouse, ∼33 µmol) mitigated LPS-induced leukocyte adhesion in WT and AnxA1-null animals without affecting leukocyte rolling, in comparison to saline control. AnxA1(Ac2-26) effects were attenuated by Boc2 (pan-FPR antagonist, 10 µg/mouse, ∼12 nmol), and by minocycline (2.25 mg/mouse, ∼6.3 nmol). The nonselective Fpr agonists, fMLP (6 µg/mouse, ∼17 nmol) and AnxA1(Ac2-26), and the Fpr2-selective agonist ATLa (5 µg/mouse, ∼11 nmol) were without effect in Fpr2/3(-/-) mice. In summary, our novel results demonstrate that the AnxA1/FPR2 system has an important role in effecting the resolution of cerebral inflammation in sepsis and may, therefore, provide a novel therapeutic target.

Monoclonal antibody therapeutics: history and future.

Over the last three decades, monoclonal antibodies have made a dramatic transformation from scientific tools to powerful human therapeutics. At present, approximately 30 therapeutic monoclonal antibodies are marketed in the United States and Europe in a variety of indications, with sales in the US alone reaching approximately $18.5 billion in 2010. This review describes how antibody engineering has revolutionized drug discovery and what are considered the key areas for future development in the monoclonal antibody therapy field.

Annexin A1 and the formyl peptide receptor family: neuroendocrine and metabolic aspects.

Annexin A1 (ANXA1, formerly termed lipocortin 1 or macrocortin) is an important protein mediator of the feedback actions of glucocorticoids within the hypothalamo-pituitary-adrenocortical (HPA) axis. Here we consider the mechanisms by which ANXA1 exerts these actions, with particular reference to the potential role of the formyl peptide receptors (FPRs), a family of G-protein-coupled receptors which has only very recently been implicated in the regulation of neuroendocrine function. In addition, we discuss evidence that ANXA1 contributes to the regulation of other aspects of endocrine and metabolic function and to the aetiology of sexual dimorphisms.