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E-Pub Ahead of Schedule: Bentham Science
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Editorial: Subcellular Trafficking Of Pathogens: Targeting For Therapeutics
Gregory W. Moseley and David A. Jans
[BSP/ID-DT/E-Pub/00021]
Tetraspanins – Gateways for Infection
Peter N. Monk and Lynda J. Partridge
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00022]
Viral Product Trafficking to Mitochondria, Mechanisms and Roles in Pathogenesis
Chad D. Williamson, Roberta L. DeBiasi and Anamaris M. Colberg-Poley
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00023]
Subcellular Trafficking In Rhabdovirus Infection And Immune Evasion: A Novel Target For Therapeutics
Sibil Oksayan, Naoto Ito, Greg Moseley and Danielle Blondel
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00024]
Modulation of Host Cell Nucleocytoplasmic Trafficking During Picornavirus Infection
Parisa Younessi, David A. Jans and Reena Ghildyal
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00025]
Artificial Viruses: Exploiting Viral Trafficking for Therapeutics
Dominic J. Glover
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00026]
Antiretroviral therapy does not block the secretion of the Human Immunodeficiency Virus Tat Protein
Sonia Mediouni, Albert Darque, Gilbert Baillat, Isabelle Ravaux, Catherine Dhiver, Hervé Tissot-Dupont, Malika Mokhtari, Hervé Moreau, Catherine Tamalet, Pascale Paul, Françoise Dignat-George, Andreas Stein, Philippe Brouqui, Stephen A. Spector, Grant R. Campbell and Erwann P. Loret
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00027]
Editorial: RSV Research is Now Close to Providing Solutions to RSV Infection
John Mills
Department of Medicine
Monash University
Melbourne
Australia.
Tel: +61 419 877 472
Fax: +61 398 048 124
Email: mills@monash.edu
[BSP/ID-DT/E-Pub/00028]
Targeting RSV with Vaccines and Small Molecule Drugs
Heather M. Costello, William C. Ray, Supranee Chaiwatpongsakorn and Mark E. Peeples
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00029]
Protein-protein interactions in RSV assembly: potential targets for attenuating RSV strains
Reena Ghildyal, David A. Jans, Philip G. Bardin and John Mills
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00030]
The Burgeoning Burden of Respiratory Syncytial Virus among Children
Caroline Breese Hall
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00031]
The non-structural proteins of RSV: targeting interferon antagonists for vaccine development
Michael N. Teng
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00032]
Respiratory Syncytial Virus Infection in Adult Populations
Edward E. Walsh and Ann R. Falsey
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00033]
Editorial: Pediatric Head and Neck Infections
Udayan K. Shah
Division of Pediatric Otolaryngology
Nemours/Alfred I. duPont Hopsital for Children
P.O. Box 269
Wilmington, DE 19899
Tel: 302-651-5829
Fax: 302-651-6410
ushah@nemours.org
[BSP/ID-DT/E-Pub/00034]
Otitis Media: Epidemiology and Management
Anna Hang and Scott E. Brietzke
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00035]
Complications of Otitis Media
James J. Daniero, Matthew S. Clary and Robert C. O’Reilly
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00036]
Acute Tonsillitis
Doug Sidell and Nina L. Shapiro
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00037]
Pediatric Peritonsillar Abscess: An Overview
Cristina Baldassari and Rahul K. Shah
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00038]
Chronic Streptococcal and Non-Streptococcal Pharyngitis
R.C. Murray and S.K. Chennupati
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00039]
Deep Neck Infections
David E. Conrad and Sanjay R. Parikh
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00040]
Retropharyngeal Abscess: Diagnosis and Treatment Update
Brian K. Reilly and James S. Reilly
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00041]
Airway Management in Pediatric Head and Neck Infections
Nicolas Leboulanger and Eréa-Noël Garabedian
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00042]
Editorial: B lymphocytes as programmers and effectors of Immunity, their roles beyond antibody production
Simon Fillatreau
[BSP/ID-DT/E-Pub/00043]
B cells: programmers of CD4 T cell responses
Tom A. Barr, Mohini Gray and David Gray
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00044]
Unraveling Effector Functions Of B Cells During Infection: The Hidden World Beyond Antibody Production
Beatriz León, André Ballesteros-Tato, Ravi S. Misra, Wojciech Wojciechowski and Frances E. Lund
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00045]
Evolutionary and functional relationships of B cells from fish and mammals: Insights into their novel roles in phagocytosis and presentation of particulate antigen
J. Oriol Sunyer
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00046]
Role of inhibitory BCR co-receptors in immunity
Takeshi Tsubata
[Abstract] [Purchase Article] [BSP/ID-DT/E-Pub/00047]
Reprogramming of B cells into regulatory cells with engineered fusokines
Jiusheng Deng and Jacques Galipeau
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00048]
Functional interactions between B lymphocytes and the innate immune system
Vicky Lampropoulou, Ping Shen, Ellen Hilgenberg, Stefanie Ries, Christian Opitz and Simon Fillatreau
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00049]
B-cell based gene therapy for autoimmune diseases
David W. Scott, Ai-Hong Zhang and Yan Su
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00050]
Primary and secondary B-cell responses to pulmonary virus infection
Yoshimasa Takahashi, Taishi Onodera, Kazuo Kobayashi and Tomohiro Kurosaki
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00051]
Prion Disease: Chemotherapeutic Strategies
Valerie L. Sim
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00052]
Mitochondrial dysfunction and antioxidant therapy in sepsis
Milagros Rocha, R Herance, S Rovira, Antonio Hernández-Mijares and Víctor M Víctor
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00053]
Necrotizing acute pancreatitis Current status - emerging new strategies in surgical management
George H. Sakorafas, Dimitrios Sampanis, Christos Lappas, Panayiotis Kokoropoulos, Aikaterini Mastoraki and Vassilios Smyrniotis
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00054]
Abstracts
Tetraspanins – Gateways for Infection
Peter N. Monk and Lynda J. Partridge
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00022]
The tetraspanins constitute a conserved superfamily of four-span membrane proteins that are widely distributed in multi-cellular organisms. A characteristic property of tetraspanins is their ability to form lateral associations with one another and with other membrane proteins, giving rise to tetraspanin enriched microdomains (TEM) that are involved in the molecular organisation of many membrane-associated functions such as adhesion, fusion and trafficking. Increasing evidence suggests that intracellular pathogens, especially viruses, have “hijacked” tetraspanins as a means of entering, traversing and exiting cells during the course of infection. This article reviews current evidence for the role of tetraspanins in the uptake, trafficking and spread of viruses as well as intracellular bacteria, fungi and parasites. Finally, the prospects of targeting tetraspanins for therapeutic intervention in infections caused by such pathogens are discussed.
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Viral Product Trafficking to Mitochondria, Mechanisms and Roles in Pathogenesis
Chad D. Williamson, Roberta L. DeBiasi and Anamaris M. Colberg-Poley
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00023]
A wide variety of viruses cause significant morbidity and mortality in humans. However, targeted antiviral therapies have been developed for only a subset of these viruses, with the majority of currently licensed antiviral drugs targeting viral entry, replication or exit steps during the viral life cycle. Due to increasing emergence of antiviral drug resistant viruses, the isolation of multiple viral subtypes, and toxicities of existing therapies, there remains an urgent need for the timely development of novel antiviral agents, including those targeting host factors essential for viral replication. This review summarizes viral products that target mitochondria and their effects on common mitochondria regulated pathways. These viral products and the mitochondrial pathways affected by them provide potential novel targets for the rational design of antiviral drugs. Viral products alter oxidative balance, mitochondrial permeability transition pore, mitochondrial membrane potential, electron transport and energy production. Moreover, viruses may cause the Warburg Effect, in which metabolism is reprogrammed to aerobic glycolysis as the main source of energy. Finally, viral products affect proapoptotic and antiapoptotic signaling, as well as mitochondrial innate immune signaling. Because of their importance for the generation of metabolic intermediates and energy as well as cell survival, mitochondrial pathways are targeted by multiple independent viral products. Structural modifications of existing drugs targeted to mitochondrial pathways may lead to the development of novel antiviral drugs with improved efficacy and reduced toxicity.
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Subcellular Trafficking In Rhabdovirus Infection And Immune Evasion: A Novel Target For Therapeutics
Sibil Oksayan, Naoto Ito, Greg Moseley and Danielle Blondel
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00024]
Vesicular stomatitis virus (VSV) and Rabies Virus (RABV) are the prototypic members of the rhabdovirus family. These viruses have a particularly broad host range, and despite the availability of vaccines, RABV still causes more than 50,000 human deaths a year. Trafficking of the virion or viral particles is important at several stages of the replicative life cycle, including cellular entry, localization into the cytoplasmic inclusion bodies which primarily house the transcription and replication of the viral genome, and migration to the plasma membrane from whence the virus is released by budding. Intriguingly, specific viral proteins, VSV M and RABV P have also been shown to undergo intracellular trafficking independent of the other viral apparatus. These proteins are multifunctional, and play roles in antagonism of host processes, namely the IFN system, and as such enable viral evasion of the innate cellular antiviral response. A body of recent research has been aimed at characterizing the mechanisms by which these proteins are able to shuttle between and localize to various subcellular sites, including the nucleus, which is not required during the cytoplasmic replicative life cycle of the virus. This work has indicated that trafficking of these proteins plays a significant role in determining the ability of the viruses to replicate and cause infection, and as such, represents a viable target for development of a new generation of vaccines and prophylactic therapeutics which are required to battle these pathogens of human and agricultural significance.
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Modulation of Host Cell Nucleocytoplasmic Trafficking During Picornavirus Infection
Parisa Younessi, David A. Jans and Reena Ghildyal
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00025]
Picornavirus infection is characterised by host cell shutoff, wherein host transcription and translation processes are severely impaired. Picornavirus proteins interact with host cell proteins, resulting in alterations in the host cell synthetic, signalling and secretory machinery, and facilitating transcription and translation of viral proteins to achieve increased virus replication and assembly. Among the many cellular pathways affected, recent studies have shown that disruption of nucleocytoplasmic trafficking via inhibition of the functions of the nuclear pore may be a common means of picornavirus-induced pathogenesis. Disruption of nuclear pore functions results in nuclear proteins being relocalised to the cytoplasm and reduced export of RNA, and may be a mechanism by which picornaviruses evade host cell defences such as interferon signalling, by blocking signal transduction across the nuclear membrane. However, the mechanisms used and the viral proteins responsible differ between different genera and even between viruses in the same genus. This review aims to summarise current understanding of the mechanisms used by picornaviruses to disrupt host cell nucleocytoplasmic trafficking.
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Artificial Viruses: Exploiting Viral Trafficking for Therapeutics
Dominic J. Glover
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00026]
Improved understanding of the signals that direct the intracellular transport of endogenous mammalian proteins, as well as the means by which viral invaders hijack transport pathways during infection, has revealed a plethora of methods for enhancing drug and gene delivery. Multi-component delivery vectors with virus-like functionality are being developed to assemble with therapeutic DNA into structured nanoparticles that are internalized and actively transported to specific locations within mammalian cells. Furthermore, the mimicking of viral mechanisms can be extended to nuclear maintenance and replication of exogenous DNA, through either site-specific integration into safe genomic regions, or extra-chromosomal maintenance as episomally replicating plasmids. The development of increasingly sophisticated artificial viruses has enormous potential to overcome numerous intracellular barriers that have, thus far, prevented efficient and sustained non-viral gene therapy.
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Antiretroviral therapy does not block the secretion of the Human Immunodeficiency Virus Tat Protein
Sonia Mediouni, Albert Darque, Gilbert Baillat, Isabelle Ravaux, Catherine Dhiver, Hervé Tissot-Dupont, Malika Mokhtari, Hervé Moreau, Catherine Tamalet, Pascale Paul, Françoise Dignat-George, Andreas Stein, Philippe Brouqui, Stephen A. Spector, Grant R. Campbell and Erwann P. Loret
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00027]
The era of antiretroviral therapy (ART) has controlled AIDS and its related disorders considerably; however, the effect of ART on Tat secretion has not been investigated. Tat is secreted from HIV infected cells and induces bystander cell death. In this study, we tested for antibody reactivity against synthetic Tat representative of five HIV subtypes in HIV positive patients receiving ART with undetectable viral loads (< 40 copies/mL) over the course of one year. Anti-Tat IgG were detected in 86% of patients during the course of the study. Anti-Tat IgG appeared transiently in 34% of cases, 32% had anti-Tat IgG appear after the study started and this remained persistent while 20% were persistently positive from the study debut. 14% were consistently negative. No significant correlation was found between anti-Tat IgG and CD4+ T cell, CD8+ T cell and B cell counts. Despite the stable undetectable viral load, the appearance of anti-Tat IgG demonstrates that Tat is actively secreted into the plasma from HIV infected cells.
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Targeting RSV with Vaccines and Small Molecule Drugs
Heather M. Costello, William C. Ray, Supranee Chaiwatpongsakorn and Mark E. Peeples
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00029]
Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis®), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates.
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Protein-protein interactions in RSV assembly: potential targets for attenuating RSV strains
Reena Ghildyal, David A. Jans, Philip G. Bardin and John Mills
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00030]
Respiratory syncytial virus (RSV) is the major respiratory pathogen of infants and children worldwide, with no effective treatment or vaccine available. Steady progress has been made in understanding the respiratory syncytial virus lifecycle and the consequences of infection, but some areas of RSV assembly still remain poorly understood. Although many of the interactions between virus proteins that are required for efficient RSV assembly have been elucidated, many questions still remain regarding viral assembly, as well as the mechanisms of RSV budding. This review will summarise the current understanding of RSV assembly, including the various interactions between virus proteins and the involvement of cellular factors with a view to identifying possible attenuation and/or drug targets within the assembly pathway.
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The Burgeoning Burden of Respiratory Syncytial Virus among Children
Caroline Breese Hall
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00031]
Respiratory syncytial virus (RSV) was first isolated from infants by Chanock and colleagues in 1957. However, control of this ubiquitous agent has yet to be achieved. RSV is recognized as the primary cause of hospitalization for acute lower respiratory tract illness (LRTI) among infants worldwide. Among children <5 years old, annual hospitalization rates in the United States (US) is 3/1000 children, and rates in Canada and European countries are similar. In the US the hospitalization rate is 3 times higher than that from influenza or parainfluenza viral infections.
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The non-structural proteins of RSV: targeting interferon antagonists for vaccine development
Michael N. Teng
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00032]
Over fifty years have passed since the identification of respiratory syncytial virus (RSV) as an important pediatric pathogen. However, an effective vaccine is still lacking. Immunization with formalin-inactivated RSV resulted in vaccine-enhanced disease; thus, a greater focus has been placed more recently on developing live attenuated RSV vaccines. The difficulty in identifying a live attenuated vaccine candidate has been balancing appropriate attenuation with sufficient immunogenicity. With the advent of reverse genetics systems for RSV, researchers have been able to generate recombinant vaccine candidates by introducing specific mutations into the genome of wild-type RSV. These systems provide a means to determine the effects of known attenuating mutations and identifying novel methods of attenuating the virus without decreasing immunogenicity. In addition, different mutations can be combined in a single genome to fine-tune the level of attenuation and immunogenicity to achieve the proper balance in a viable vaccine candidate. Among the targets for attenuation are the small RSV nonstructural (NS) proteins. The NS proteins have multiple functions during the virus life cycle, including antagonizing the antiviral effects of interferon and directly augmenting virus replication. This review will outline the progress in understanding the functions of the NS proteins and how altering these functions by reverse genetic manipulation can be a useful path toward rationally designing a safe and effective live-attenuated RSV vaccine.
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Respiratory Syncytial Virus Infection in Adult Populations
Edward E. Walsh and Ann R. Falsey
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00033]
Respiratory Syncytial Virus, generally recognized for its role as the major respiratory pathogen in newborn infants and young children, is also a significant pathogen in adults. It is a frequent cause of upper and lower respiratory illness among all age groups, although it often goes unrecognized in adults unless highly sensitive molecular diagnostic tests are used. All RSV infections in adults represent re-infection and are generally mild to moderate in severity, although persons with certain high-risk conditions are susceptible to severe disease. These include the frail elderly living at home or in long term care facilities, those with underlying chronic pulmonary disease, and the severely immunocompromised. It is estimated that between 11,000-17,000 adults die of RSV infection annually in the U.S, with ~ ten-fold more admitted to hospital with respiratory symptoms. As in infants, wheezing is often noted during RSV infections and chest radiographs are often normal despite significant lower respiratory symptoms and hypoxia. Treatment of RSV is directed at symptomatic relief, and only rarely is specific antiviral therapy recommended. Exceptions include the severely immunocompromised, in whom inhaled ribavirin has been recommended in hopes of reducing both mortality and long term pulmonary compromise, especially in lung transplant recipients. Immunity to RSV is incomplete. Although there does not appear to be a defect in humoral immunity, there is evidence that CD8+ T cell immunity may be impaired with age. Currently a vaccine for RSV is not available, and many challenges to developing a successful vaccine must be overcome.
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Otitis Media: Epidemiology and Management
Anna Hang and Scott E. Brietzke
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00035]
Otitis media is one of the most common disease entities in children worldwide. This critical review of the literature will focus on the demographics, pathophysiology, diagnosis, and medical and surgical management of the various types of otitis media.
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Complications of Otitis Media
James J. Daniero, Matthew S. Clary and Robert C. O’Reilly
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00036]
Otitis media is the most common reason for antibiotic prescription in the United States. Whether due to disease virulence or growing antimicrobial resistance, complications of otitis media seem to be seen more frequently. These complications may be difficult to identify and treat. This article focuses on the pathophysiology of these complications and address medical and surgical approaches to safe treatment.
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Acute Tonsillitis
Doug Sidell and Nina L. Shapiro
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00037]
Acute tonsillitis is an inflammatory process of the tonsillar tissues and is usually infectious in nature. Acute infections of the palatine tonsils predominantly occur in school-aged children, but patients of any age may be affected. Tonsillitis of viral origin is usually treated with supportive care. Bacterial tonsillitis is most commonly caused by Streptococcus pyogenes. Polymicrobial infections and viral pathogens are also important sources of infection. Penicillins remain the treatment of choice for S. pyogenes tonsillitis, and augmented aminopenicillins have gained utility in concert with the increasing incidence of beta-lactamase producing bacteria. We describe the anatomic features and the immunologic function of the palatine tonsils, including a detailed discussion of history and physical examination findings, treatment recommendations, and possible complications of acute tonsillitis. Establishing an accurate diagnosis and initiating appropriate treatment are key components of managing this common pathologic process.
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Pediatric Peritonsillar Abscess: An Overview
Cristina Baldassari and Rahul K. Shah
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00038]
Peristonsillar abscess (PTA) is a common deep neck space infection in children. Children with PTA often present with sore throat, dysphagia, peritonsillar bulge, uvular deviation, trismus, and a muffled voice. The diagnosis of PTA can be made based on history and physical examination in the majority of children. Treatment of pediatric PTA necessitates aspiration or surgical drainage and antibiotic therapy. Challenges exist with the diagnosis and management of PTA that are unique to pediatric patients. Examples include difficulty with examination of the oropharynx in an uncooperative child and controversy surrounding bedside needle aspiration verses operative incision and drainage. Early identification of PTA and initiation of appropriate treatment can prevent serious complications.
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Chronic Streptococcal and Non-Streptococcal Pharyngitis
R.C. Murray and S.K. Chennupati
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00039]
Pharyngitis is a common medical problem in the outpatient medical setting, resulting in more than seven million pediatric visits each year. Most types of pharyngitis are caused by infectious etiologies. The most common cause of pharyngitis is viral infection; however, some of the more serious types of pharyngitis are attributed to bacterial etiologies, such as group A β-hemolytic Streptococcus pyogenes (GAS). Complications from GAS pharyngitis include rheumatic fever, deep space abscesses, and toxic shock. Although most episodes of pharyngitis are acute in nature, a small percentage becomes recurrent or chronic. With regards to chronic pharyngitis, non-infectious etiologies, such as laryngopharyngeal reflux and periodic fever, aphthous ulcers, pharyngitis, and adenitis syndrome also need to be considered.
Both medical and surgical therapies are effective in managing pharyngitis. First-line medical therapy includes antibiotic therapy. For certain indications, surgical management via adenotonsillectomy is recommended. Adenotonsillectomy has been shown to be effective in reducing disease burden and improving disease-specific and global quality of life. Several techniques for adenotonsillectomy exist, including traditional and intracapsular tonsillectomies.
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Deep Neck Infections
David E. Conrad and Sanjay R. Parikh
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00040]
Deep neck space infections are commonly seen and managed across various medical and surgical specialties. Common presentations permit straightforward management but still pose the risk of severe complications sometimes even with appropriate management.
This article emphasizes the anatomic and physiologic process to heed when managing children with deep neck infections. The roles of radiography and medical versus surgical management are discussed.
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Retropharyngeal Abscess: Diagnosis and Treatment Update
Brian K. Reilly and James S. Reilly
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00041]
Retropharyngeal abscess is a deep neck space infection that may present in various subtle ways permitting potentially lethal complications to occur before appropriate diagnosis is made and expedient management undertaken.
This article reviews in detail the pertinent anatomy, diagnostic pearls, and clinical recommendations to optimally manage these common infections in children.
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Airway Management in Pediatric Head and Neck Infections
Nicolas Leboulanger and Eréa-Noël Garabedian
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00042]
Infectious diseases of the head and neck in children are very common but may sometimes cause upper airway obstruction. Various degrees of respiratory distress are possible, but one will be extra-cautious with newborns and neonates, because the clinical features can evolve especially fast in young children. A child with a respiratory compromise should never be left unattended. Nasal, pharyngeal, and laryngeal airways can be involved and require specific management.
Each time the airway of a child may be compromised, the pediatrician and otolaryngologist have to be prepared for the worst-case scenario: anticipation is essential and allows avoidance of serious troubles.
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B cells: programmers of CD4 T cell responses
Tom A. Barr, Mohini Gray and David Gray
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00044]
B cells are once again gaining prominence as important programmers of CD4 T cell responses. With widespread use of B cell depletion therapy in the clinic, proving effective in treating diseases previously considered T cell-mediated, the time is right for a re-appraisal of the B cell. Though typically considered weak, Th2 driving APC, it is now clear that they are necessary for a robust and long-lived CD4 T cell response in many settings. The sphere of B cell influence extends well beyond that of simply antibody production; antigen presentation, cytokine secretion, costimulation and development of lymphoid tissue architecture are all critical aspects of B cell immunobiology, the absence of which has serious impacts for T cell priming and memory. The aim of this review is to look at non-antibody mediated B cell function and to ask how, where and when do B cells influence the CD4 T cell response?
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Unraveling Effector Functions Of B Cells During Infection: The Hidden World Beyond Antibody Production
Beatriz León, André Ballesteros-Tato, Ravi S. Misra, Wojciech Wojciechowski and Frances E. Lund
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00045]
Antibodies made by B cells are critically important for immune protection to a variety of infectious agents. However, it is becoming increasingly clear that B cells do more than make antibodies and that B cells can both enhance and suppress immune responses. Furthermore, there is growing evidence that B cells modulate cellular immune responses by antibody dependent and independent mechanisms. Although we have a good understanding of the roles played by antibody-secreting effector B cells during immune responses, we know very little about the Ab independent “effector” functions of B cells in either health or disease. Given the recent data suggesting that B cells may contribute to autoimmune disease pathogenesis via an antibody independent mechanism and the increasing use of B cell depletion therapy in autoimmune patients, investigators are beginning to reassess the multiple roles for B cells during immune responses. In this article, we review data describing how B cells mediate protection to pathogens independently of antibody production. In particular, we will focus on the role that B cells play in facilitating dendritic cell and T cell interactions in lymph nodes, the importance of antigen-presenting B cells in sustaining effector T cell and T follicular helper responses to pathogens and the relevance of cytokine-producing effector and regulatory B cells in immune responses.
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Evolutionary and functional relationships of B cells from fish and mammals: Insights into their novel roles in phagocytosis and presentation of particulate antigen
J. Oriol Sunyer
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00046]
The evolutionary origins of Ig-producing B cells appear to be linked to the emergence of fish in this planet. There are three major classes of living fish species, which from most primitive to modern they are referred to as agnathan (e.g., lampreys), Chondrichthyes (e.g., sharks), and teleost fish (e.g., rainbow trout). Agnathans do not have immunoglobulin-producing B cells, however these fish contain a subset of lymphocytes-like cells producing type B variable lymphocyte receptors (VLRBs) that appear to act as functional analogs of immunoglobulins. Chondrichthyes fish represent the most primitive living species containing bona-fide immunoglobulin-producing B cells. Their B cells are known to secrete three types of antibodies, IgM, IgW and IgNAR. Teleost fish are also called bony fish since they represent the most ancient living species containing true bones. Teleost B cells produce three different immunoglobulin isotypes, IgM, IgD and the recently described IgT. While teleost IgM is the principal player in systemic immunity, IgT appears to be a teleost immunoglobulin class specialized in mucosal immune responses. Thus far, three major B cell lineages have been described in teleost, those expressing either IgT or IgD, and the most common lineage which co-expresses IgD and IgM. A few years ago, the study of teleost fish B cells revealed for the first time in vertebrates the existence of B cell subsets with phagocytic and intracellular bactericidal capacities. This finding represented a paradigm shift as professional phagocytosis was believed to be exclusively performed by some cells of the myeloid lineage (i.e., macrophages, monocytes, neutrophils). This phagocytic capacity was also found in amphibians and reptiles, suggesting that this innate capacity was evolutionarily conserved in certain B cell subsets of vertebrates. Recently, the existence of subsets of B cells with phagocytic and bactericidal abilities have also been confirmed in mammals. Moreover, it has been shown that phagocytic B-1 B cells have a potent ability to present particulate antigen to CD4+ T cells. Thus, studies carried out originally on fish B cells have lead to the discovery of new innate and adaptive roles of cells in mammals. This review will concentrate on the evolutionary and functional relationships of fish and mammalian B cells, focusing mainly on the newly discovered roles of these cells in phagocytosis, intracellular killing and presentation of particulate antigen.
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Role of inhibitory BCR co-receptors in immunity
Takeshi Tsubata
[Purchase Article] [BSP/ID-DT/E-Pub/00047]
B lymphocytes (B cells) express a variety of membrane molecules containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region such as FcγRIIB, FCRLs, CD22, mouse Siglec-G/human Siglec-10, PECAM-1, mouse PIR-B/human LIRB1 and LIRB2PD-1 and CD72. When phosphorylated, ITIMs in these molecules recruit and activate phosphatases such as SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1), SHP-2, SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) and SHIP2 depending on receptors. These phosphatases then negatively regulate B cell antigen receptor (BCR) signaling. Because of their ability to inhibit BCR signaling, these ITIM-containing molecules are called inhibitory BCR co-receptors. Studies on mice deficient in an inhibitory co-receptor have demonstrated that the inhibitory co-receptors regulate B cell development, antibody responses and development of autoimmune diseases. Moreover, polymorphisms in some inhibitory co-receptors such as FcγRIIB, FCRL3 and CD72 are associated with autoimmune diseases, suggesting a crucial role of inhibitory co-receptor polymorphisms in the regulation of autoimmune diseases. The ligands for inhibitory co-receptors regulate their inhibitory activity by inducing co-ligation of the co-receptors with BCR or some other regulatory mechanisms. Inhibitory co-receptors and their ligands are therefore good targets for controlling antibody responses and autoimmune diseases.
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Reprogramming of B cells into regulatory cells with engineered fusokines
Jiusheng Deng and Jacques Galipeau
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00048]
B cells play a pivotal role in host adaptive immunity against pathogenic microorganisms, but may also maladaptively contribute to the pathogenesis of autoimmune diseases. In contrast, distinct B cell subsets have the capacity to regulate host immune response, and suppress inflammation. B regulatory cells are a rare population of endogenous B-lymphocytes defined in part by production of the anti-inflammatory cytokine IL-10. Although “natural” B regulatory cells exist in vivo, the low frequency of B regulatory cells may be a limiting factor on their impact in autoimmune ailments. In answer to this unmet need, we have developed a novel strategy for alternate lymphoid activation: fusokines. These wholly engineered chimeric leukines fuse two functionally unrelated cytokines for the purpose of alternate immune modulation. The GM-CSF- and IL-15-derived fusokine: GIFT15, possesses entirely novel and unheralded immune modulating properties mediated through the IL15 receptor which reprograms naïve B cells into B regulatory cells (Bregs). In this article, we review the current approaches to generate Bregs in vitro, and highlight gain-of-function mechanisms by which GIFT15-induced Bregs abrogate pathogenic autoimmunity in mice. We also demonstrate that the human equivalent of inducible Bregs may also serve as a new potent therapeutic tool for treatment of autoimmune disease.
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Functional interactions between B lymphocytes and the innate immune system
Vicky Lampropoulou, Ping Shen, Ellen Hilgenberg, Stefanie Ries, Christian Opitz and Simon Fillatreau
[Abstract] [FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00049]
The immune system is composed of multiple cell types, which together improve the resistance of the organism against infections. The unfolding of a successful host response ensuring effective protection against pathogens requires an appropriate coordination of the different players of the immune system. Innate cells and T cells extensively communicate during immune reactions, providing multiple opportunities for the mutual coordination of these two defense pathways. Little is known about the functional interactions between B and innate cells, and it is generally assumed that they influence each other indirectly through effects on T cells. However, recent studies highlighted important roles for innate cells in initial presentation of antigen to B cells after immunization, and in long-term maintenance of antibody-producing cells in bone marrow after resolution of immune responses. Furthermore, it was found that activated B cells could regulate the activity of innate cells through production of cytokines. Here, we review how direct interactions between innate and B cells can contribute to orchestration of humoral and cellular immunity.
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B-cell based gene therapy for autoimmune diseases
David W. Scott, Ai-Hong Zhang and Yan Su
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00050]
The essence of the adaptive immune system is self tolerance, which is maintained by various central and peripheral check points. However, the tolerance mechanisms can be broken in autoimmune disease conditions due to genetic predisposition and environmental triggers. As a consequence, a patient’s tissue is attacked by his/her own adaptive immune system. An ideal therapy for autoimmune diseases should include methods to re-establish tolerance to the underpinning autoantigen(s). During the last 15 years or so, our lab has been dedicated to developing a novel B-cell gene therapy approach for antigen-specific tolerance induction. This approach has been successfully applied to at least five different animal models for human autoimmune diseases. In this article, we will discuss many of our successful preclinical studies using the B-cell gene therapy approach to induce tolerance, as well as similar studies from others. Particular focus will be given to the tolerance induction mechanisms that have been revealed from these studies.
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Primary and secondary B-cell responses to pulmonary virus infection
Yoshimasa Takahashi, Taishi Onodera, Kazuo Kobayashi and Tomohiro Kurosaki
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00051]
Viruses form particulate structures possessing high-density B-cell epitopes and viral RNA/DNA, which are ligands for multiple Toll-like receptors (TLRs). B cells are able to sense these viral antigenic signatures through B-cell antigen receptors (BCRs) and TLRs, both of which synergistically shape the magnitude and quality of virus-specific B-cell responses. In many viruses, B-cell recognition of these virus signatures is often hampered by tissue tropisms toward nonlymphoid organs. However, ectopic localizations of B cells at virus replication sites facilitate the efficient recognition of intact virus particles. Following pulmonary infection by influenza virus, virus-specific B-cell responses occur in the tertiary lymphoid organs of lungs near the sites of virus replication as well as in the draining lymph nodes. Lungs then begin to support the germinal center response and the formation of niches for plasma cells and memory B cells, thus potentiating B-cell intrinsic recognition of virus particles at these sites. In this review, we discuss how the anatomical location and virus-sensing properties of B cells coordinate protective B-cell responses against pulmonary virus infection.
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Prion Disease: Chemotherapeutic Strategies
Valerie L. Sim
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00052]
Prion diseases, also known as transmissible spongiform encephalopathies, are invariably fatal neurodegenerative diseases for which there are no efficacious treatments. Thousands of compounds have been screened for anti-prion effect, and yet of those that have effect in vitro, very few show effect in vivo, especially if administered in the later stages of disease. However, with new techniques for early diagnosis being developed, and with further insight into the pathogenesis of early disease, including the role of oligomers and the contribution of accessory molecules and signalling cascades, the chance of finding a therapeutic strategy is increasing. Beyond clinical therapy, there is increasing need to find effective decontaminants for blood supplies, as variant Creutzfeldt Jakob Disease (vCJD) is transmissible by blood. Non-toxic preventative therapies are also needed, with ongoing cases of Bovine Spongiform Encephalopathy (BSE) and the spread of Chronic Wasting Disease (CWD) being a growing concern. A primary target for therapy has been the conversion of the normal form of prion protein (PrPC) to its abnormal counterpart (PrPSc). Many of the chemotherapeutic agents with anti-prion effect share structural similarities, often being polyanionic or polycyclic. They may directly bind PrPC or PrPSc, or they may redistribute, sequester, or down-regulate PrPC, thus preventing its conversion. There have also been some novel approaches, including trapping PrPSc in a multimeric form such that it can no longer cause conversion, increasing clearance of PrPSc, targeting accessory molecules which play a role in conversion, targeting pathways which lead to neurodegeneration, and stem cell therapy. It may be that a combination of compounds will be necessary for maximal effect and there is evidence that synergistic responses occur with dual therapy. This updated review focuses primarily on chemical-based treatments in light of developments in diagnostic technologies, including results from recent clinical trials, and proposes some promising new targets for prion therapy.
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Mitochondrial dysfunction and antioxidant therapy in sepsis
Milagros Rocha, R Herance, S Rovira, Antonio Hernández-Mijares and Víctor M Víctor
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00053]
Sepsis and septic shock are the major causes of death in intensive care units. Oxidative damage to mitochondria is involved in the development of organ dysfunction associated with sepsis. This syndrome is caused by an excessive defensive and inflammatory response characterised by a massive increases of reactive oxygen species (ROS), nitric oxide (NO) and inflammatory cytokines. Under normal circumstances, complex interacting antioxidant defense systems control oxidative stress within mitochondria The consequences of sepsis is a systemic damage to the vascular endothelium, impaired tissue and a compromised whole body respiration, antioxidant depletion and mitochondrial respiratory dysfunction with diminished levels of ATP and O2 consumption. In general, ROS are essential to the functions of cells and particularly immune cells, but adequate levels of antioxidant defenses are required to protect against the harmful effects of excessive ROS production. This review considers the process of sepsis from a mitochondrial perspective, discussing strategies for the targeted delivery of antioxidants to mitochondria. We will provide a summary of the following areas: the cellular metabolism of ROS and its role in pathophysiological processes such as sepsis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondria-targeted antioxidants and the future implications for such approaches in patients.
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Necrotizing acute pancreatitis Current status - emerging new strategies in surgical management
George H. Sakorafas, Dimitrios Sampanis, Christos Lappas, Panayiotis Kokoropoulos, Aikaterini Mastoraki and Vassilios Smyrniotis
[FULL-TEXT INQUIRY] [BSP/ID-DT/E-Pub/00054]
Despite that pancreatic necrosis complicates only 15 % of cases of acute pancreatitis (AP), it is associated with high morbidity and considerable mortality. In an attempt to improve prognosis, many surgical strategies have been described during the last few decades. Currently, necrosectomy remains the cornerstone in the surgical treatment of infected pancreatic necrosis and in selected cases of sterile necrotizing pancreatitis. Following necrosectomy, continuous closed lavage is recommended by many authors, while closed abdominal packing /drainage and repeated planned necrosectomies - commonly using the zipper technique - are also acceptable alternative strategies. Open abdomen (laparostomy) is rarely indicated in carefully selected cases (typically in abdominal compartment syndrome associated with necrotizing AP). During the last decade, minimally invasive techniques (including percutaneous drainage, retroperitoneal endoscopic approach, transgastric endoscopic approach etc) have been extensively studied by some groups not only in the management of pancreatic abscesses and / or pseudocysts, but also as primary methods of treatment of necrotizing AP. Results have been impressive, but experience currently is limited to only a few centers around the world.
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