Commensal bacteria are important in intestinal homeostasis and appear to play a role in early tolerance to foreign antigens. The requirement for homeostatic balance between tolerance and immunity poses a unique regulatory challenge to mucosal immune systems. Dysregulation of this balance can contribute to the pathogenesis of numerous inflammatory conditions such as inflammatory bowel diseases. The primary response to these bacteria is triggered by pattern recognition receptors (PRR), which bind pathogen-associated molecular patterns (PAMP). PRR comprise Toll-like receptors (TLR), nucleotide-binding oligomerization domains, adhesion molecules and lectins. Probiotics are living commensal micro-organisms of the intestinal tract with clinically documented health effects in human subjects. They are known to affect the gastrointestinal tract and the associated immune system and to have numerous effects on intestinal function and immune responses, including immunotolerance. This last effect appears to be mediated via regulatory T-cell activation by intestinal dendritic cells and the low activation of T-helper 1 and 2 (Th1 and Th2) cell inflammatory responses. However, the precise mechanisms of probiotic activity remain poorly understood. The aim of the present work was to review the function of TLR in the development of immunotolerance and examine the specific role of probiotics in the regulation of tolerance to antigens.
High energy cosmic rays illuminate the Sun and produce an image that could be observed in up to five different channels: a cosmic-ray shadow (whose energy dependence has been studied by HAWC); a gamma-ray flux (observed at E ≤ 200 GeV by Fermi-LAT); a muon shadow (detected by ANTARES and IceCube); a neutron flux (undetected, as there are no hadronic calorimeters in space); a flux of high energy neutrinos. Since these signals are correlated, the ones already observed can be used to reduce the uncertainty in the still undetected ones. Here we define a simple setup that uses the Fermi-LAT and HAWC observations to imply very definite fluxes of neutrons and neutrinos from the solar disk. In particular, we provide a fit of the neutrino flux at 10 GeV–10 TeV that includes its dependence on the zenith angle and on the period of the solar cycle. This flux represents a neutrino floor in indirect dark matter searches. We show that in some benchmark models the current bounds on the dark matter–nucleon cross section push the solar signal below this neutrino floor.
Background
Telaprevir is used in the treatment of chronic hepatitis C (HCV).
Purpose
To find out at what point adverse reactions (ADRs) appear from the start of telaprevir treatment in order to prevent harm and improve management.
Materials and methods
Retrospective observational study. HCV genotype-1 patients were included who had completed telaprevir treatment in our Health Department.
Severity of ADRs detected was classified according to the SPC.
We measured:
Time to appearance of ADRs: time from the start of triple therapy until the appearance of ADRs including all grades.
Time to appearance of higher grade ADRs: time from start of treatment until the appearance of higher grade ADRs.
Time to need supportive treatment: time from start of treatment until the prescription of exogenous erythropoietin or colony stimulating factors.
Results
68 patients (76% male) were included with an average age of 52.3 ± 8.7 years old.
ADRs including all grades: thrombocytopenia (76.5%), anaemia (60.3%), neutropenia (55.9%), hyperuricaemia (52.9%), hyperbilirubinaemia (39.7%), lymphopenia (38.2%) and raised creatinine (4.4%).
29.4% of patients required exogenous erythropoietin and 1.5% granulocyte colony stimulating factors.
Time to appearance of ADRs: 33 days (13–80) for anaemia, 31 (7–82) neutropenia, 35 (11–76) lymphopenia, 27 (10–69) thrombocytopenia, 31 (14–82) hyperuricaemia, 43 (16–70) increased creatinine, and 32 (15–77) hyperbilirubinaemia.
Time to appearance of more severe ADRs: 56 days (27–82) for anaemia, 46 (7–82) neutropenia, 53 (17–82) lymphopenia, 30 (10–82) thrombocytopenia, 57 (16–82) hyperuricaemia, 66 (62–70) increased creatinine, and 36 (15–77) hyperbilirubinaemia.
Time to supportive treatment needed: 57 days (22–82) for erythropoietin, and 22 for colony stimulating factors.
Conclusions
The study shows an early appearance of thrombocytopenia and the highest grade of hyperbilirubinaemia. It took longer for the maximum degree of toxicity to appear in other ADRs. Time to erythropoietin treatment corresponded well with the appearance of more severe anaemia.
Knowing when ADRs are likely to appear can help us design early intervention strategies to improve patient safety.
No conflict of interest.
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