10 research outputs found
Mild Crigler–Najjar Syndrome with Progressive Liver Disease—A Multicenter Retrospective Cohort Study
Crigler–Najjar Syndrome (CNS) with residual activity of UDP-glucuronosyltransferase 1A1 (UGT1A1) and no need for daily phototherapy is called mild Crigler–Najjar Syndrome. Most of these patients need medical treatment for enzyme induction (phenobarbital) to lower blood levels of unconjugated bilirubin (UCB). Apart from this, no long-term problems have been described so far. The phenotype of patients with the homozygous pathogenic variant c.115C>G p.(His39Asp) in UGT1A1 is described as variable. Clinical observations of our patients led to the assumption that patients with variant c.115C>G have a mild CNS phenotype while having a high risk of developing progressive liver disease. For mild CNS disease, progressive liver disease has not been described so far. Therefore, we conducted a retrospective multicenter analysis of 14 patients with this particular variant, aiming for better characterization of this variant. We could confirm that patients with variant c.115C>G have a high risk of progressive liver disease (seven of fourteen), which increases with age despite having a very mild CNS phenotype. Earlier predictors and causes for an unfavorable disease course are not detectable, but close follow-up could identify patients with progressive liver disease at the beginning. In conclusion, these patients need close and specialized follow-up. Our study questions whether fibrosis in the CNS is really driven by high amounts of UCB or phototherapy
Time imaging reconstruction for the PANDA Barrel DIRC
The innovative Barrel DIRC (Detection of Internally Reflected Cherenkov
light) counter will provide hadronic particle identification (PID) in the
central region of the PANDA experiment at the new Facility for Antiproton and
Ion Research (FAIR), Darmstadt, Germany. This detector is designed to separate
charged pions and kaons with at least 3 standard deviations for momenta up to
3.5 GeV/c, covering the polar angle range of 22-140. An
array of microchannel plate photomultiplier tubes is used to detect the
location and arrival time of the Cherenkov photons with a position resolution
of 2 mm and time precision of about 100 ps. The time imaging reconstruction has
been developed to make optimum use of the observables and to determine the
performance of the detector. This reconstruction algorithm performs particle
identification by directly calculating the maximum likelihoods using
probability density functions based on detected photon propagation time in each
pixel, determined directly from the data, or analytically, or from detailed
simulations.Comment: International Workshop on Fast Cherenkov Detectors (DIRC2019
The PANDA DIRCs
The PANDA experiment at the FAIR facility adresses open questions in hadron
physics with antiproton beams in the momentum range of 1.5-15 GeV/c. The
antiprotons are stored and cooled in a High Energy Storage RING (HESR) with a
momentum spread down to Dp/p = 4*10^-5. A high luminosity of up to 2*10^32 cm-2
s-1 can be achieved. An excellent hadronic particle identification (PID) will
be provided by two Cherenkov detectors using the priciple of Detection of
Internally Reflected Cherenkov light (DIRC). In the forward direction from
polar angles of 5 degree to 22 degree, the Endcap Disc DIRC (EDD) separates
pions from kaons up to momenta of 4 GeV/c. Between 22 degree and 140 degree the
Barrel DIRC cleanly separates pions from kaons for momenta up to 3.5 GeV/c.
This article describes the design of the Barrel DIRC and of the Endcap Disc
DIRC and the validation of their designs in particle beams at the CERN PS.Comment: 10 pages, 8 figure
Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency
BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs = 194 mu mol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] mu mol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 mu mol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS
Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency
Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs <194 µmol/L: 49% versus sBAs ≥194 µmol/L: 15%; P=0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P=0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P=0.06) and post-SBD sBA concentrations <65μmol/L (P=0.05) tended to be associated with improved NLS. Conclusion: Less than half of FIC1 deficiency patients reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS
Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency
BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1
(ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1)
deficiency, or progressive familial intrahepatic cholestasis type 1. The
rarity of FIC1 deficiency has largely prevented a detailed analysis of
its natural history, effects of predicted protein truncating mutations
(PPTMs), and possible associations of serum bile acid (sBA)
concentrations and surgical biliary diversion (SBD) with long-term
outcome. We aimed to provide insights by using the largest genetically
defined cohort of patients with FIC1 deficiency to date.
APPROACH AND RESULTS: This multicenter, combined retrospective and
prospective study included 130 patients with compound heterozygous or
homozygous predicted pathogenic ATP8B1 variants. Patients were
categorized according to the number of PPTMs (i.e., splice site,
frameshift due to deletion or insertion, nonsense, duplication), FIC1-A
(n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two
PPTMs). Survival analysis showed an overall native liver survival (NLS)
of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and
FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P =
0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years:
65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were
negatively associated with NLS (NLS at age 10 years, sBAs < 194 mu
mol/L: 49% vs. sBAs >= 194 mu mol/L: 15%; P = 0.03). SBD decreased
sBAs (230 [125-282] to 74 [11-177] mu mol/L; P = 0.005). SBD (HR
0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65
mu mol/L (P = 0.05) tended to be associated with improved NLS.
CONCLUSIONS: Less than half of patients with FIC1 deficiency reach
adulthood with native liver. The number of PPTMs did not associate with
the natural history or prognosis of FIC1 deficiency. sBA concentrations
at initial presentation and after SBD provide limited prognostic
information on long-term NLS