254 research outputs found
Immune- and nonimmune-compartment-specific interferon responses are critical determinants of herpes simplex virus-induced generalized infections and acute liver failure
The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN-αβγR-/- mice are exquisitely susceptible to liver infection following corneal infection with HSV-1. In this study, we used bone marrow chimeras of IFN-αβγR-/- (AG129) and wild-type (WT; 129SvEv) mice to probe the underlying IFN-dependent mechanisms that control HSV-1 pathogenesis. After infection, WT mice with either IFN-αβγR-/- or WT marrow exhibited comparable survival, while IFN-αβγR-/- mice with WT marrow had a significant survival advantage over their counterparts with IFN-αβγR-/- marrow. Furthermore, using bioluminescent imaging to maximize data acquisition, we showed that the transfer of IFN-competent hematopoietic cells controlled HSV-1 replication and damage in the livers of IFN-αβγR-/- mice. Consistent with this, the inability of IFN-αβγR-/- immune cells to control liver infection in IFN-αβγR-/- mice manifested as profoundly elevated aspartate transaminase (AST) and alanine transaminase (ALT) levels, indicative of severe liver damage. In contrast, IFN-αβγR-/-mice receiving WT marrow exhibited only modest elevations of AST and ALT levels. These studies indicate that IFN responsiveness of the immune system is a major determinant of viral tropism and damage during visceral HSV infections
Corneal Replication Is an Interferon Response-Independent Bottleneck for Virulence of Herpes Simplex Virus 1 in the Absence of Virion Host Shutoff
Herpes simplex viruses lacking the virion host shutoff function (Δvhs) are avirulent and hypersensitive to type I and type II interferon (IFN). In this study, we demonstrate that even in the absence of IFN responses in AG129 (IFN-αβγR−/−) mice, Δvhs remains highly attenuated via corneal infection but is fully virulent via intracranial infection. The data demonstrate that the interferon-independent inherent replication defect of Δvhs has a significant impact upon peripheral replication and neuroinvasion
Optical implementation of a unitarily correctable code
Noise poses a challenge for any real-world implementation in quantum
information science. The theory of quantum error correction deals with this
problem via methods to encode and recover quantum information in a way that is
resilient against that noise. Unitarily correctable codes are an error
correction technique wherein a single unitary recovery operation is applied
without the need for an ancilla Hilbert space. Here, we present the first
optical implementation of a non-trivial unitarily correctable code for a noisy
quantum channel with no decoherence-free subspaces or noiseless subsystems. We
show that recovery of our initial states is achieved with high fidelity
(>=0.97), quantitatively proving the efficacy of this unitarily correctable
code.Comment: 6 pages, 3 figure
Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues
In a randomized, double-blind, Phase III study, we compared pasireotide long-acting
release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing
carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid
tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg)
or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on
frequency of bowel movements and flushing episodes. Objective tumor response was a secondary
outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse
events were recorded. At the time of a planned interim analysis, the data monitoring committee
recommended halting the study because of a low predictive probability of showing superiority
of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45
octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27–1.97; P=0.53).
Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds
ratio, 1.96; 95% CI, 0.89–4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 – not
reached) with pasireotide versus 6.8 months (5.6 – not reached) with octreotide (hazard ratio,
0.46; 95% CI, 0.20–0.98; P=0.045). The most frequent drug-related adverse events (pasireotide
vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea
(9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available
somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide
LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher
tumor control rate at month 6, although it was statistically not significant, and was associated
with a longer PFS than octreotide LAR
Bioluminescent Imaging Reveals Divergent Viral Pathogenesis in Two Strains of Stat1-Deficient Mice, and in αßγ Interferon Receptor-Deficient Mice
Pivotal components of the IFN response to virus infection include the IFN receptors (IFNR), and the downstream factor signal transducer and activator of transcription 1 (Stat1). Mice deficient for Stat1 and IFNR (Stat1−/− and IFNαßγR−/− mice) lack responsiveness to IFN and exhibit high sensitivity to various pathogens. Here we examined herpes simplex virus type 1 (HSV-1) pathogenesis in Stat1−/− mice and in IFNαßγR−/− mice following corneal infection and bioluminescent imaging. Two divergent and paradoxical patterns of infection were observed. Mice with an N-terminal deletion in Stat1 (129Stat1−/− (N-term)) had transient infection of the liver and spleen, but succumbed to encephalitis by day 10 post-infection. In stark contrast, infection of IFNαßγR−/− mice was rapidly fatal, with associated viremia and fulminant infection of the liver and spleen, with infected infiltrating cells being primarily of the monocyte/macrophage lineage. To resolve the surprising difference between Stat1−/− and IFNαßγR−/− mice, we infected an additional Stat1−/− strain deleted in the DNA-binding domain (129Stat1−/− (DBD)). These 129Stat1−/− (DBD) mice recapitulated the lethal pattern of liver and spleen infection seen following infection of IFNαßγR−/− mice. This lethal pattern was also observed when 129Stat1−/− (N-term) mice were infected and treated with a Type I IFN-blocking antibody, and immune cells derived from 129Stat1−/− (N-term) mice were shown to be responsive to Type I IFN. These data therefore show significant differences in viral pathogenesis between two commonly-used Stat1−/− mouse strains. The data are consistent with the hypothesis that Stat1−/− (N-term) mice have residual Type I IFN receptor-dependent IFN responses. Complete loss of IFN signaling pathways allows viremia and rapid viral spread with a fatal infection of the liver. This study underscores the importance of careful comparisons between knockout mouse strains in viral pathogenesis, and may also be relevant to the causation of HSV hepatitis in humans, a rare but frequently fatal infection
COMPILATION AND MANAGEMENT OF ORP GLASS FORMULATION DATABASE, VSL-12R2470-1 REV 0
The present report describes the first steps in the development of a glass property-composition database for WTP LAW and HL W glasses that includes all of the data that were used in the development of the WTP baseline models and all of the data collected subsequently as part of WTP enhancement studies perfonned for ORP. The data were reviewed to identifY some of the more significant gaps in the composition space that will need to be filled to support waste processing at Hanford. The WTP baseline models have been evaluated against the new data in terms of range of validity and prediction perfonnance
Repeated Radionuclide therapy in metastatic paraganglioma leading to the highest reported cumulative activity of 131I-MIBG
131I-MIBG therapy for neuroendocrine tumours may be dose limited. The common range of applied cumulative activities is 10-40 GBq. We report the uneventful cumulative administration of 111 GBq (= 3 Ci) 131I-MIBG in a patient with metastatic paraganglioma. Ten courses of 131I-MIBG therapy were given within six years, accomplishing symptomatic, hormonal and tumour responses with no serious adverse effects. Chemotherapy with cisplatin/vinblastine/dacarbazine was the final treatment modality with temporary control of disease, but eventually the patient died of progression. The observed cumulative activity of 131I-MIBG represents the highest value reported to our knowledge, and even though 12.6 GBq of 90Y-DOTATOC were added intermediately, no associated relevant bone marrow, hepatic or other toxicity were observed. In an individual attempt to palliate metastatic disease high cumulative activity alone should not preclude the patient from repeat treatment
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