Case study: Managing a case of ankylosing spondylitis for inguinal hernia repair

A 55-year-old man diagnosed with ankylosing spondylitis presented for inguinal hernia repair. The patient was found to have limited neck movement, thoracic kyphosis and restrictive lung disease. Surgery was performed under hernia block, which was inadequate. General anaesthesia was then administered and airway patency was maintained with an endotracheal tube used as a nasopharyngeal airway

Experimental study of coherent synchrotron radiation in the emittance exchange line at the A0-photoinjector

Next generation accelerators will require a high current, low emittance beam with a low energy spread. Such accelerators will employ advanced beam conditioning systems such as emittance exchangers to manipulate high brightness beams. One of the goals of the Fermilab A0 photoinjector is to investigate the transverse to longitudinal emittance exchange principle. Coherent synchrotron radiation could limit high current operation of the emittance exchanger. In this paper, we report on the preliminary experimental and simulation study of the coherent synchroton radiation (CSR) in the emittance exchange line at the A0 photoinjector.Comment: 4 pp. 14th Advanced Accelerator Concepts Workshop, 13-19 Jun 2010: Annapolis, Marylan

There’s Probably a Blackout in Your Television Future: Tracking New Carriage Negotiation Strategies Between Video Content Programmers and Distributors

Video programmers and the satellite and cable operators who distribute their content execute contracts for the mutually profitable offering of services to consumers. However, when programmers and distributors fail to reach closure on new terms and conditions before the end date of an existing agreement, service interruptions (“blackouts”) occur. Video consumers resent having to pay sizable monthly subscriptions for content they temporarily cannot view, and both programmers and distributors risk financial injury. Recognizing the mutual harm to all parties, video programmers and so-called Multichannel Video Programming Distributors (“MVPDs”) usually limit the frequency and duration of blackouts. Heretofore, MVPDs have been able to pass on to subscribers higher programming costs through increased monthly rates without significant declines in subscribership. However, the marketplace for video programming has experienced significant change in recent years, calling into question the continuing ability of MVPDs to raise rates annually at percentages well above measures of general inflation. Additionally, MVPDs have experienced unprecedented declines in subscribership and encountered consumer resentment at having to pay rates, often in excess of $100 monthly, for programming tiers containing dozens of channels, many of which few subscribers have an interest in viewing. Through cord cutting and cord shaving, increasing numbers of video consumers have abandoned an MVPD subscription or downgraded to a less expensive service tier to incur lower monthly rates. Video consumers also have shown greater interest in so-called nonlinear content, available as downloadable files and streaming on demand from new online services, such as Amazon Prime, Hulu, and Netflix, in lieu of conventional live, linear content transmitted by television broadcasters and MVPDs. The marketplace success of nonlinear video content providers demonstrates the growing willingness of consumers to use broadband networks for over-the-top (“OTT”) access to alternative and competitive sources. This Article identifies significant changes in the video marketplace that will trigger more frequent and longer blackouts. The Article will explain how marketplace changes impact the three major sources of video content that MVPDs and broadband networks deliver: (1) broadcast television channels; (2) video content targeted for MVPD subscribers, such as that on CNN, ESPN, and HBO; and (3) video, offered on both a linear and nonlinear basis, by new OTT ventures. For broadcast television, this Article shows how current marketplace conditions challenge the ongoing viability of a legislatively crafted compromise that accords broadcasters the option of electing mandatory carriage of their signal by MVPDs (the “must-carry” requirement) in lieu of contractual “retransmission consent” negotiations. Broadcasters secure guaranteed carriage via MVPDs, and MVPDs benefit by the conferral of a low-cost copyright license to use broadcasters’ content. For competing nonbroadcast video content, MVPDs and the manufacturers of devices, such as Roku, which transfer broadband video content to television sets via broadband networks, negotiate both copyright licenses and delivery rights directly with video programmers. This group also faces market volatility due to changes in consumer preferences and the growing array of video content options available. The Article seeks to answer whether video programmers or MVPDs have overestimated their own negotiating leverage and, in turn, their ability to secure favorable contractual terms and conditions. Broadcasters historically appear to have greater leverage, because they have exclusive control over live, “must-see,” linear content, such as sporting events. This advantage has motivated most broadcasters to eschew the must-carry option and elect retransmission consent negotiations. The Article suggests that a significant increase in blackouts has resulted from reduced opportunities for MVPDs to raise subscription rates without triggering substantial increases in subscriber migration to other broadband-delivered program options. The Article notes that vertically and horizontally integrated MVPDs, such as AT&T and Comcast, are better situated to tolerate more frequent and lengthy blackouts. These companies can offset the adverse financial impact of MVPD subscriber churn with blackout-free alternatives, increased subscribership of their broadband services and unregulated bundling of services and content for subscribers willing to upgrade and pay a higher monthly fee. The Article closely examines a recent antitrust enforcement case that approved AT&T’s acquisition of Time Warner, with an eye toward determining whether reviewing courts understood shifting marketplace conditions that affect the likelihood for more and longer blackouts. The Article concludes that in the AT&T case, both the district and appellate courts woefully underappreciated the ability of this widely diversified venture to trigger and tolerate more blackouts in its capacity as an MVPD and broadband access provider, separate and apart from its capacity as the new owner of Time Warner’s “must-see” CNN and HBO content. The courts concluded that AT&T, having largely abandoned its leverage over access to the Time Warner video content, lacked the ability to trigger blackouts. The courts emphasized the long-term carriage agreements Time Warner had previously negotiated with unaffiliated MVPDs and AT&T’s offer to maintain content access during arbitration of disputes occurring for seven years after merger approval. The courts failed to recognize the significant harm AT&T, in its capacity as a major national MVPD, could inflict on competition and consumers by increasing its use of blackouts for negotiating leverage

A galU mutant of francisella tularensis is attenuated for virulence in a murine pulmonary model of tularemia

<p>Abstract</p> <p>Background</p> <p>A number of studies have revealed that <it>Francisella tularensis </it>(FT) suppresses innate immune responses such as chemokine/cytokine production and neutrophil recruitment in the lungs following pulmonary infection via an unidentified mechanism. The ability of FT to evade early innate immune responses could be a very important virulence mechanism for this highly infectious bacterial pathogen.</p> <p>Results</p> <p>Here we describe the characterization of a <it>galU </it>mutant strain of FT live vaccine strain (LVS). We show that the <it>galU </it>mutant was highly attenuated in a murine model of tularemia and elicited more robust innate immune responses than the wild-type (WT) strain. These studies document that the kinetics of chemokine expression and neutrophil recruitment into the lungs of mice challenged with the <it>galU </it>mutant strain are significantly more rapid than observed with WT FT, despite the fact that there were no observed differences in TLR2 or TLR4 signaling or replication/dissemination kinetics during the early stages of infection. We also show that the <it>galU </it>mutant had a hypercytotoxic phenotype and more rapidly induced the production of IL-1β following infection either <it>in vitro </it>or <it>in vivo</it>, indicating that attenuation of the <it>galU </it>mutant strain may be due (in part) to more rapid activation of the inflammasome and/or earlier death of FT infected cells. Furthermore, we show that infection of mice with the <it>galU </it>mutant strain elicits protective immunity to subsequent challenge with WT FT.</p> <p>Conclusions</p> <p>Disruption of the <it>galU </it>gene of FTLVS has little (if any) effect on <it>in vivo </it>infectivity, replication, or dissemination characteristics, but is highly attenuating for virulence. The attenuated phenotype of this mutant strain of FT appears to be related to its increased ability to induce innate inflammatory responsiveness, resulting in more rapid recruitment of neutrophils to the lungs following pneumonic infection, and/or to its ability to kill infected cells in an accelerated fashion. These results have identified two potentially important virulence mechanisms used by FT. These findings could also have implications for design of a live attenuated vaccine strain of FT because sublethal infection of mice with the <it>galU </it>mutant strain of FTLVS promoted development of protective immunity to WT FTLVS.</p

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals

Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia

Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition

Red Queen Dynamics with Non-Standard Fitness Interactions

Antagonistic coevolution between hosts and parasites can involve rapid fluctuations of genotype frequencies that are known as Red Queen dynamics. Under such dynamics, recombination in the hosts may be advantageous because genetic shuffling can quickly produce disproportionately fit offspring (the Red Queen hypothesis). Previous models investigating these dynamics have assumed rather simple models of genetic interactions between hosts and parasites. Here, we assess the robustness of earlier theoretical predictions about the Red Queen with respect to the underlying host-parasite interactions. To this end, we created large numbers of random interaction matrices, analysed the resulting dynamics through simulation, and ascertained whether recombination was favoured or disfavoured. We observed Red Queen dynamics in many of our simulations provided the interaction matrices exhibited sufficient ‘antagonicity’. In agreement with previous studies, strong selection on either hosts or parasites favours selection for increased recombination. However, fast changes in the sign of linkage disequilibrium or epistasis were only infrequently observed and do not appear to be a necessary condition for the Red Queen hypothesis to work. Indeed, recombination was often favoured even though the linkage disequilibrium remained of constant sign throughout the simulations. We conclude that Red Queen-type dynamics involving persistent fluctuations in host and parasite genotype frequencies appear to not be an artefact of specific assumptions about host-parasite fitness interactions, but emerge readily with the general interactions studied here. Our results also indicate that although recombination is often favoured, some of the factors previously thought to be important in this process such as linkage disequilibrium fluctuations need to be reassessed when fitness interactions between hosts and parasites are complex

Vesicular Stomatitis Virus Infection Promotes Immune Evasion by Preventing NKG2D-Ligand Surface Expression

Vesicular stomatitis virus (VSV) has recently gained attention for its oncolytic ability in cancer treatment. Initially, we hypothesized that VSV infection could increase immune recognition of cancer cells through induction of the immune stimulatory NKG2D-ligands. Here we show that VSV infection leads to a robust induction of MICA mRNA expression, however the subsequent surface expression is potently hindered. Thus, VSV lines up with human cytomegalovirus (HCMV) and adenovirus, which actively subvert the immune system by negatively affecting NKG2D-ligand surface expression. VSV infection caused an active suppression of NKG2D-ligand surface expression, affecting both endogenous and histone deacetylase (HDAC)-inhibitor induced MICA, MICB and ULBP-2 expression. The classical immune escape mechanism of VSV (i.e., the M protein blockade of nucleocytoplasmic mRNA transport) was not involved, as the VSV mutant strain, VSVΔM51, which possess a defective M protein, prevented MICA surface expression similarly to wild-type VSV. The VSV mediated down modulation of NKG2D-ligand expression did not involve apoptosis. Constitutive expression of MICA bypassed the escape mechanism, suggesting that VSV affect NKG2D-ligand expression at an early post-transcriptional level. Our results show that VSV possess an escape mechanism, which could affect the immune recognition of VSV infected cancer cells. This may also have implications for immune recognition of cancer cells after combined treatment with VSV and chemotherapeutic drugs