A Method to Control Epistaxis After Nasal Antrostomy and Caldwell-Luc Procedure

Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. Oct, 2003  |  Pubmed ID: 14586865

Grasshoppers (Orthoptera: Acrididae) Could Serve As Reservoirs and Vectors of Vesicular Stomatitis Virus

Journal of Medical Entomology. Nov, 2003  |  Pubmed ID: 14765676

Vesicular stomatitis (VS) is an economically devastating disease of livestock in the Americas. Despite strong circumstantial evidence for the role of arthropods in epizootics, no hematophagous vector explains the field evidence. Based on the spatiotemporal association of grasshopper outbreaks and VS epizootics, we investigated the potential role of these insects as vectors and reservoirs of the disease. The critical steps in the grasshopper-bovine transmission cycle were demonstrated, including 1) 62% of grasshoppers [Melanoplus sanguinipes (F.)] fed vesicular stomatitis virus (VSV) from cell culture became infected, with titers reaching 40,000 times the inoculative dose; 2) 40% of grasshoppers that cannibalized VSV-infected grasshopper cadavers became infected, amplifying virus up to 1,000-fold; 3) one of three cattle consuming VSV-infected grasshopper cadavers contracted typical VS and shed virus in saliva; and 4) 15% of grasshoppers became infected when fed saliva from this infected cow. The ecological conditions and biological processes necessary for these transmissions to occur are present throughout much of the Americas. Field studies will be required to show these findings are relevant to the natural epidemiology of VSV.

Studies on Overwintering of Bluetongue Viruses in Insects

The Journal of General Virology. Feb, 2005  |  Pubmed ID: 15659765

Bluetongue viruses (BTVs) are economically important arboviruses that affect sheep and cattle. The overwintering mechanism of BTVs in temperate climates has eluded researchers for many years. Many arboviruses overwinter in their invertebrate vectors. To test the hypothesis that BTVs overwinter in their vertically infected insect vectors, Culicoides sonorensis larvae were collected from long-term study sites in northern Colorado, USA, and assayed for the presence of BTV RNA by nested RT-PCR. Sequences from BTV RNA segment 7 were detected in 30 % (17/56) of pools composed of larvae and pupae collected in 1998 and in 10 % (31/319) of pools composed of adults reared from larvae collected in 1996. BTV was not isolated from the insects. Additionally, Culicoides cell-culture lines derived from material collected at one of the sites, or derived from insect samples collected during a BTV outbreak, contained BTV RNA segment 7. In contrast, segment 2 RNA was detected at half the rate of segment 7 RNA in the field-collected larvae and was only detected in the Culicoides cell lines with one of two primer sets. These data suggest that BTVs could overwinter in the insect vector and that there is reduced expression of the outer capsid genes during persistent infection.

Molecular Epidemiology of Bluetongue Virus in Northern Colorado

Virus Research. Jun, 2006  |  Pubmed ID: 16337708

The molecular epidemiology of Bluetongue virus serotype 11 (BTV11) in an enzootic focus in northern Colorado was investigated. Viruses isolated up to 12 years apart, from both vertebrate and invertebrate hosts, were compared by phylogenetic analysis of nucleotide sequence data from three genome segments: L2, S7, and S10. For each segment, viruses isolated from ruminants in the 1980s were more similar to one another than to viruses isolated from Culicoides spp. insects in the 1990s. Nearly identical BTV11-L2 segments were found in all isolates, but over time they were associated with different S7 and S10 genome segments. Therefore, L2-segment-based serologic identification of BTV isolates underestimates the origin and natural evolution of the viruses. In addition, the use of one or even two genome segments is inadequate to define the molecular epidemiology of the viruses in an enzootic focus. This information could influence import/export regulations based on BTV epidemiology in enzootic areas, as well as our view of the natural biology of the viruses.

Pervasive Patient Tracking for Mass Casualty Incident Response

AMIA ... Annual Symposium Proceedings / AMIA Symposium. AMIA Symposium. 2006  |  Pubmed ID: 17238462

Transportation officers at mass casualty incidents are faced with the daunting task of tracking large amounts of patients as they leave the disaster scene. Patients often leave under their own power without notifying any authorities, presenting a problem for personnel attempting to account for every patient they have treated. This paper describes a system of tracking patients at a disaster scene or en route to hospitals using electronic triage tags registered with an external database.

A Novel Fc Gamma Receptor Ligand Augments Humoral Responses by Targeting Antigen to Fc Gamma Receptors

European Journal of Immunology. Apr, 2007  |  Pubmed ID: 17393382

Generating efficient antibody (Ab) responses against weak antigens remains challenging. Ab responses require antigen (Ag) uptake by antigen-presenting cells (APC), followed by presentation of processed Ag to T cells. Limited uptake of antigenic peptides by APC constrains Ab responses. Here we improve vaccine efficacy by targeting Ag to Fcgamma receptors (FcgammaR) using R4, a recombinant FcgammaR ligand. R4 has four repeats per chain of the hinge region and CH2 domain (HCH2) of human IgG1. HCH2 encompasses the FcgammaR binding site. The repeats are linked to the human IgG1 framework. To test R4 in augmenting Ag uptake, we expressed human serum albumin domain 1 (HSA1) at the N terminus of R4 to produce HSA1R4. HSA1R4 (50 microg) administered to mice in Ribi adjuvant induces up to 1100-fold higher HSA1-specific IgG titers than HSA1 (p<0.001). HSA1R4 (250 ng) induces up to 130 times more anti-HSA1 Ab than HSA1Fc, a protein with HSA1 linked to the IgG1 framework (p<0.001). HSA-reactive T cells proliferate more briskly to HSA1R4 than to HSA1Fc (p<0.008). Immunization with HSA1R4 yields greater T cell reactivity to HSA1 ex vivo than immunization with HSA1Fc (p<0.004). Linking antigenic peptides to linear HCH2 polymers may facilitate vaccine development.

Monomeric IgG is Neuroprotective Via Enhancing Microglial Recycling Endocytosis and TNF-alpha

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Nov, 2008  |  Pubmed ID: 19020014

In brain, monomeric immunoglobin G (IgG) is regarded as quiescent and only poised to initiate potentially injurious inflammatory reactions via immune complex formation associated with phagocytosis and tumor necrosis factor alpha (TNF-alpha) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2-20 microg/ml) of monomeric IgG unassociated with disease triggered benign low-level proinflammatory signaling that was neuroprotective against CA1 area excitotoxicity and followed a U-shaped or hormetic dose-response. The data indicate that physiological IgG levels activated microglia by enhancing recycling endocytosis plus TNF-alpha release from these cells to produce the neuroprotection. Minocycline, known for its anti-inflammatory and neuroprotective effects when given after disease onset, abrogated IgG-mediated neuroprotection and related microglial effects when given before injury. In contrast, E-prostanoid receptor subtype 2 (EP2) activation, which served as an exemplary paracrine stimulus like the one expected from neuronal activity, amplified IgG-mediated increased microglial recycling endocytosis and TNF-alpha production. Furthermore, like monomeric IgG these EP2 related effects took days to be effective, suggesting both were adaptive anabolic effects consistent with those seen from other long-term preconditioning stimuli requiring de novo protein synthesis. The data provide the first evidence that brain monomeric IgG at physiological levels can have signaling function via enhanced recycling endocytosis/TNF-alpha production from microglia unassociated with disease and that these IgG-mediated changes may be a means by which paracrine signaling from neuronal activity influences microglia to evoke neuroprotection. The data provide further support that low-level proinflammatory neural immune signaling unassociated with disease enhances brain function.

Immunoglobulin-like Transcript 3, an Inhibitor of T Cell Activation, is Reduced on Blood Monocytes During Multiple Sclerosis Relapses and is Induced by Interferon Beta-1b

Multiple Sclerosis (Houndmills, Basingstoke, England). Jan, 2010  |  Pubmed ID: 20007427

Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3(+)CD14(+) monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon beta-treated relapsing-remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4( +) T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon beta is beneficial in multiple sclerosis; why so remains unclear. Interferon beta-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon beta and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis.

Assessments of Function and Biochemistry of the Anterior Cingulate Cortex in Schizophrenia

Biological Psychiatry. Oct, 2010  |  Pubmed ID: 20570244

Neuroimaging and electrophysiologic studies have consistently provided evidence of impairment in anterior cingulate cortex/medial frontal cortex function in people with schizophrenia. In this study, we sought to clarify the nature of this abnormality by combining proton magnetic resonance spectroscopy (1H-MRS) with functional magnetic resonance imaging (fMRI) at 3T.

White Paper Report of the RAD-AID Conference on International Radiology for Developing Countries: Identifying Challenges, Opportunities, and Strategies for Imaging Services in the Developing World

Journal of the American College of Radiology : JACR. Jul, 2010  |  Pubmed ID: 20630383

The RAD-AID Conference on International Radiology for Developing Countries was an assembly of individuals and organizations interested in improving access to medical imaging services in developing countries where the availability of radiology has been inadequate for both patient care and public health programs. The purpose of the meeting was to discuss data, experiences, and models pertaining to radiology in the developing world and to evaluate potential opportunities for future collaboration. Conference participants included radiologists, technologists, faculty members of academic medical institutions, and leadership of nongovernmental organizations involved in international health care and social entrepreneurship. Four main themes from the conference are presented in this white paper as important factors for the implementation and optimization of radiology in the developing world: (1) ensuring the economic sustainability of radiologic services through financial and administrative training support of health care personnel; (2) designing, testing, and deploying clinical strategies adapted for regions with limited resources; (3) structuring and improving the role of American radiology residents interested in global health service projects; and (4) implementing information technology models to support digital imaging in the developing world.

TNF-α and Microglial Hormetic Involvement in Neurological Health & Migraine

Dose-response : a Publication of International Hormesis Society. 2010  |  Pubmed ID: 21191481

Environmental enrichment, i.e., increased intellectual, social, and physical activity makes brain more resilient to subsequent neurological disease. The mechanisms for this effect remain incompletely defined, but evidence shows tumor necrosis factor-alpha (TNF-α) is involved. TNF-α, at acutely high levels, possesses the intrinsic capacity to enhance injury associated with neurological disease. Conversely, the effect of TNF-α at low-levels is nutritive over time, consistent with physiological conditioning hormesis. Evidence shows that neural activity triggers low-level pro-inflammatory signaling involving TNF-α. This low-level TNF-α signaling alters gene expression, resulting in an enhanced resilience to disease. Brain-immune signaling may become maladaptive when increased activity is chronic without sufficient periods of reduced activity necessary for nutritive adaptation. Such tonically increased activity may explain, for example, the transformation of episodic to chronic migraine with related increased susceptibility to spreading depression, the most likely underlying cause of this malady. Thus, TNF-α, whose function is to alter gene expression, and its principal cellular source, microglia, seem powerfully positioned to orchestrate hormetic immune signaling that establishes the phenotype of neurological health and disease from brain activity.

Rapid Immune Responses to a Botulinum Neurotoxin Hc Subunit Vaccine Through in Vivo Targeting to Antigen-presenting Cells

Infection and Immunity. Aug, 2011  |  Pubmed ID: 21576339

The clostridial botulinum neurotoxins (BoNTs) are the most potent protein toxins known. The carboxyl-terminal fragment of the toxin heavy chain (Hc) has been intensively investigated as a BoNT vaccine immunogen. We sought to determine whether targeting Hc to antigen-presenting cells (APCs) could accelerate the immune responses to vaccination with BoNT serotype A (BoNT/A) Hc. To test this hypothesis, we targeted Hc to the Fc receptors for IgG (FcγRs) expressed by dendritic cells (DCs) and other APCs. Hc was expressed as a fusion protein with a recombinant ligand for human FcγRs (R4) to produce HcR4 or a similar ligand for murine FcγRs to produce HcmR4. HcR4, HcmR4, and Hc were produced as secreted proteins using baculovirus-mediated expression in SF9 insect cells. In vitro receptor binding assays showed that HcR4 effectively targets Hc to all classes of FcγRs. APCs loaded with HcR4 or HcmR4 are substantially more effective at stimulating Hc-reactive T cells than APCs loaded with nontargeted Hc. Mice immunized with a single dose of HcmR4 or HcR4 had earlier and markedly higher Hc-reactive antibody titers than mice immunized with nontargeted Hc. These results extend to BoNT neutralizing antibody titers, which are substantially higher in mice immunized with HcmR4 than in mice immunized with Hc. Our results demonstrate that targeting Hc to FcγRs augments the pace and magnitude of immune responses to Hc.

The Major Determinant of Attenuation in Mice of the Candid1 Vaccine for Argentine Hemorrhagic Fever is Located in the G2 Glycoprotein Transmembrane Domain

Journal of Virology. Oct, 2011  |  Pubmed ID: 21795336

Candid1, a live-attenuated Junin virus vaccine strain, was developed during the early 1980s to control Argentine hemorrhagic fever, a severe and frequently fatal human disease. Six amino acid substitutions were found to be unique to this vaccine strain, and their role in virulence attenuation in mice was analyzed using a series of recombinant viruses. Our results indicate that Candid1 is attenuated in mice through a single amino acid substitution in the transmembrane domain of the G2 glycoprotein. This work provides insight into the molecular mechanisms of attenuation of the only arenavirus vaccine currently available.

Reverse Genetics Generation of Chimeric Infectious Junin/Lassa Virus is Dependent on Interaction of Homologous Glycoprotein Stable Signal Peptide and G2 Cytoplasmic Domains

Journal of Virology. Jan, 2011  |  Pubmed ID: 20980515

The Arenaviridae are a diverse and globally distributed collection of viruses that are maintained primarily by rodent reservoirs. Junin virus (JUNV) and Lassa virus (LASV) can both cause significant outbreaks of severe and often fatal human disease throughout their respective areas of endemicity. In an effort to improve upon the existing live attenuated JUNV Candid1 vaccine, we generated a genetically homogenous stock of this virus from cDNA copies of the virus S and L segments by using a reverse genetics system. Further, these cDNAs were used in combination with LASV cDNAs to successfully generate two recombinant Candid1 JUNV/LASV chimeric viruses (via envelope glycoprotein [GPC] exchange). It was found that while the GPC extravirion domains were readily exchangeable, homologous stable signal peptide (SSP) and G2 transmembrane and cytoplasmic tail domains were essential for correct GPC maturation and production of infectious chimeric viruses. The switching of the JUNV and LASV G1/G2 ectodomains within the Candid1 vaccine background did not alter the attenuated phenotype of the vaccine strain in a lethal mouse model. These recombinant chimeric viruses shed light on the fundamental requirements of arenavirus GPC maturation and may serve as a strategy for the development of bivalent JUNV and LASV vaccine candidates.

Cold Pre-conditioning Neuroprotection Depends on TNF-α and is Enhanced by Blockade of Interleukin-11

Journal of Neurochemistry. Apr, 2011  |  Pubmed ID: 21070241

Cold pre-conditioning reduces subsequent brain injury in small animals but the underlying mechanisms remain undefined. As hypothermia triggers systemic macrophage tumor necrosis factor alpha (TNF-α) production and other neural pre-conditioning stimuli depend on this cytokine, we reasoned that microglia and TNF-α would be similarly involved with cold pre-conditioning neuroprotection. Also, as slice cultures closely approximate their in vivo counterpart and include quiescent microglia, we used rat hippocampal slice cultures to confirm this hypothesis. Furthermore, inflammatory cytokine gene screening with subsequent PCR and immunostaining confirmation of targeted mRNA and related protein changes showed that cold pre-conditioning triggered a significant rise in TNF-α that localized to microglia and a significant rise in interleukin (IL)-11 that localized mainly to hippocampal pyramidal neurons and, more rarely, astrocytes. Importantly, co-stimulation with cold and IL-11, an anti-inflammatory cytokine that inhibits TNF-α expression, abrogated the otherwise evident protection. Instead, cold pre-conditioning coupled with blockade of IL-11 signaling further enhanced neuroprotection from that seen with cold pre-conditioning alone. Thus, physiological activation of brain pro-inflammatory cytokine signaling, and its amplification by inhibition of coincident anti-inflammatory cytokine signaling, may be opportune targets for the development of novel therapeutics that can mimic the protection seen in cold pre-conditioning.