The resolution of inflammation is an active and dynamic process, mediated in large part by the innate immune system. Resolution represents not only an increase in anti-inflammatory actions, but also a paradigm shift in immune cell function to restore homeostasis. PPARγ, a ligand activated transcription factor, has long been studied for its anti-inflammatory actions, but an emerging body of literature is investigating the role of PPARγ and its ligands (including thiazolidinediones, prostaglandins, and oleanolic acids) in all phases of resolution. PPARγ can shift production from pro- to anti-inflammatory mediators by neutrophils, platelets, and macrophages. PPARγ and its ligands further modulate platelet and neutrophil function, decreasing trafficking, promoting neutrophil apoptosis, and preventing platelet-leukocyte interactions. PPARγ alters macrophage trafficking, increases efferocytosis and phagocytosis, and promotes alternative M2 macrophage activation. There are also roles for this receptor in the adaptive immune response, particularly regarding B cells. These effects contribute towards the attenuation of multiple disease states, including COPD, colitis, Alzheimer's disease, and obesity in animal models. Finally, novel specialized proresolving mediators—eicosanoids with critical roles in resolution—may act through PPARγ modulation to promote resolution, providing another exciting area of therapeutic potential for this receptor.

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Influenza viruses remain a critical global health concern. More efficacious vaccines are needed to protect against influenza virus, yet few adjuvants are approved for routine use. Specialized proresolving mediators (SPMs) are powerful endogenous bioactive regulators of inflammation, with great clinical translational properties. Here, we investigated the ability of the SPM 17-HDHA to enhance the adaptive immune response using an OVA immunization model and a pre-clinical influenza vaccination mouse model. Our findings revealed that mice immunized with OVA plus 17-HDHA or with H1N1-derived HA protein plus 17-HDHA increased antigen-specific antibody titers. 17-HDHA increased the number of antibody-secreting cells in vitro as well as the number of HA-specific antibody secreting cells present in the bone marrow. Importantly, the 17-HDHA-mediated increased antibody production was more protective against live pH1N1 influenza infection in mice. This is the first report on the biological effects of omega-3-derived SPMs on the humoral immune response. These findings illustrate a previously unknown biological link between proresolution signals and the adaptive immune system. Furthermore, this work has important implications for the understanding of B cell biology, as well as the development of new potential vaccine adjuvants.

Specialized pro-resolving lipid mediators (SPMs) constitute a recently recognized class of bioactive molecules which promote the resolution of inflammation. We recently reported that the SPMs resolvin D1 (RvD1) and 17-hydroxydocosahexaenoic acid (17-HDHA) promote the differentiation of IgG-secreting B cells and enhance antibody-mediated immune responses. However, there is an important knowledge gap regarding whether or not SPMs regulate human B-cell IgE production, which is the key effector in diseases such as asthma and allergy. Therefore we investigated whether a panel of diverse SPMs influences B-cell IgE production. An important finding was that 17-HDHA and RvD1 inhibit IgE production by human B cells and suppress the differentiation of naïve B cells into IgE-secreting cells by specifically blocking epsilon germline transcription (εGLT). This effect is specific to human IgE, as the SPMs do not inhibit production of IgM and IgG and did not suppress other IL-4-upregulated genes. 17-HDHA and RvD1 act by stabilizing the transcriptional repressor Bcl-6, which competes with STAT6 for binding at the εGLT promoter. Overall, these new findings demonstrate that certain SPMs inhibit the differentiation of IgE-producing B cells, without being broadly immune-suppressive, representing a novel class of potential therapeutics for IgE-driven diseases such as asthma and allergy.

Platelets are small anucleate blood cells derived from megakaryocytes. In addition to their pivotal roles in hemostasis, platelets are the smallest, yet most abundant, immune cells and regulate inflammation, immunity, and disease progression. Although platelets lack DNA, and thus no functional transcriptional activities, they are nonetheless rich sources of RNAs, possess an intact spliceosome, and are thus capable of synthesizing proteins. Previously, it was thought that platelet RNAs and translational machinery were remnants from the megakaryocyte. We now know that the initial description of platelets as “cellular fragments” is an antiquated notion, as mounting evidence suggests otherwise. Therefore, it is reasonable to hypothesize that platelet transcription factors are not vestigial remnants from megakaryocytes, but have important, if only partly understood functions. Proteins play multiple cellular roles to minimize energy expenditure for maximum cellular function; thus, the same can be expected for transcription factors. In fact, numerous transcription factors have non-genomic roles, both in platelets and in nucleated cells. Our lab and others have discovered the presence and non-genomic roles of transcription factors in platelets, such as the nuclear factor kappa β (NFκB) family of proteins and peroxisome proliferator-activated receptor gamma (PPARγ). In addition to numerous roles in regulating platelet activation, functional transcription factors can be transferred to vascular and immune cells through platelet microparticles. This method of transcellular delivery of key immune molecules may be a vital mechanism by which platelet transcription factors regulate inflammation and immunity. At the very least, platelets are an ideal model cell to dissect out the non-genomic roles of transcription factors in nucleated cells. There is abundant evidence to suggest that transcription factors in platelets play key roles in regulating inflammatory and hemostatic functions.

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OBJECTIVE: Appropriate use of drugs to prevent thromboembolism in patients with atrial fibrillation (AF) involves comparing the patient's risk of stroke and risk of hemorrhage. This review summarizes the evidence regarding the efficacy of these medications. METHODS:We conducted a meta-analysis of randomized controlled trials of drugs used to prevent thromboembolism in adults with nonpostoperative AF. Articles were identified through the Cochrane Collaboration's CENTRAL database and MEDLINE until May 1998. A trial fibrillation (AF) is an increasingly common cardiac dysrhythmia affecting over 2 million people in the United States. 1-3 Restoration of sinus rhythm may involve consultation with a cardiologist; however, the prevention of cardioembolic events in patients who remain in AF falls within the domain of the primary care physician. 4 With a recently estimated 3.9 million office visits yearly for patients with AF, 5 internists need to aware of the current evidence regarding prevention of thromboembolic disease in order to provide the best care for their patients. MAIN RESULTS:The estimate that only one third of patients in AF are receiving warfarin is remarkably consistent across studies, 4,6-8 and has raised concerns that warfarin is greatly underutilized in patients with chronic AF. However, for interventions like warfarin that involve significant trade-offs, clinicians need a reliable synthesis of information on risks and benefits in order to make appropriate recommendations to patients. Therefore, we reviewed all of the randomized controlled trials involving anticoagulants and antiplatelet agents in the prevention of thromboembolism in patients with AF. Our aim was to evaluate the strength of the evidence on the efficacy and safety of the drugs used for the prevention of thromboembolic complications in adults with nonpostoperative AF and to report this information in a format useful to clinicians.

isual anosognosia is the lack of awareness and denial of one's blindness. It is often referred to as Anton syndrome (AS), after one of the physicians who described the phenomenon of lacking insight into one's sensory deficit. There are limited numbers of case reports documenting the condition and many refer to the phenomenon in association with bilateral occipital infarcts. We describe a patient who developed visual anosognosia as a result of multiple sclerosis (MS). Case report A 24-year-old left-handed woman presented with right-sided hemiparesis and homonymous hemianopia. Head CT showed a hypodensity spanning the left temporo-parieto-occipital white matter. Brain MRI demonstrated a subcortical lesion with high T2/fluid-attenuated inversion recovery (FLAIR) signal, diffusion restriction, areas of apparent diffusion coefficient (ADC) dropout, no contrast enhancement, and mild mass effect on the lateral ventricle (figure, A). Serologic investigation (erythrocyte sedimentation rate, C-reactive protein, SS-A/B, antineutrophil cytoplasmic antibodies, antinuclear antibodies, angiotensin-converting enzyme, rheumatoid factor, aquaporin-4 antibodies, HIV, hepatitis A, B, and C, JC virus, cytomegalovirus, Epstein-Barr virus, human T-cell lymphotropic virus) was unremarkable. CSF glucose, protein, and cell counts were normal. CSF immunoglobulin G was elevated (.6 mg/dL) and isoelectric focusing reported presence of oligoclonal bands (.2 unique bands) in CSF with absence in serum. The patient was treated with IV methylprednisolone due to the high suspicion of a demyelinating process. She made gradual, incomplete recovery. Follow-up MRI scans performed over the course of 1 year began to show small, asymptomatic juxtacortical and periventricular lesions in addition to one infratentorial pontine lesion (figure, B-D). The initial left-sided tumefactive lesion remained stable with ex vacuo dilation of the left lateral horn adjacent to gliosis in the left hemisphere. Sixteen months after the first attack, the patient presented with global aphasia, left-sided sensorimotor deficiency, and cortical blindness. Brain MRI showed a new right-sided parieto-occipital white matter lesion with T2/FLAIR hyperintensity, restricted diffusion, dropout on ADC, and no contrast enhancement (figure, E). MRI of the total spine did not show any additional lesions. Laboratory studies were again unrevealing. The patient met the revised MacDonald criteria for MS with her 2 attacks and numerous T2 lesions throughout time and space. 1 Due to the aggressive nature of the patient's tumefactive relapsing-remitting MS, she was treated with methylprednisolone and plasmapheresis, and promptly started on alemtuzumab. All her symptoms improved over months except for cortical blindness. Despite being unable to detect light or blink to threat, the patient insisted that her vision was intact and confabulated the presence and placement of objects when asked about her surroundings. Her vision recovered over 2 years; first she gained insight that she was blind, then w...