We report on the experimental search for the bound state of an eta meson and He-3 nucleus performed using the WASA-at-COSY detector setup. In order to search for the eta-mesic nucleus decay, the pd ...-> (3)He2(gamma) and pd -> (3)He6 gamma channels have been analysed. These reactions manifest the direct decay of the ti meson bound in a He-3 nucleus. This non-mesonic decay channel has been considered for the first time. When taking into account only statistical errors, the obtained excitation functions reveal a slight indication for a possible bound state signal corresponding to a He-3-eta nucleus width Gamma above 20 MeV and binding energy B-s between 0 and 15 MeV. However, the determined cross sections are consistent with zero in the range of the systematic uncertainty. Therefore, as final result we estimate only the upper limit for the cross section of the eta-mesic He-3 nucleus formation followed by the eta meson decay which varies between 2 nb and 15 nb depending on possible bound state parameters.
We examined the impact of the Model for End‐Stage Liver Disease (MELD) organ allocation scheme on 44 patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) ...between February 2002 and January 2003, and compared the outcome with 58 patients listed in the 4 years before MELD implementation. Patients undergoing living‐donor liver transplantation were excluded. The Kaplan‐Meier probabilities for OLT at 3, 6, and up to 8.5 months were 22.5%, 64.0%, and 88.0%, respectively, under MELD versus 17.2%, 24.7%, and 35.8% at 3, 6 and 9 months, respectively, in the pre‐MELD group (P = .0006). In Cox regression analysis, non‐O blood group (hazard ratio 2.5; P = .047 versus blood group O) and 3 tumor nodules (hazard ratio 5.5; P = .005) were associated with a significantly higher probability for OLT under MELD. The probabilities of dropout were 5.6% at 6 and 8.5 months under MELD versus 7.2% and 37.8% at 6 and 12 months, respectively, in the pre‐MELD group (P = .74). The lack of a significant difference in dropout may be due to low dropout rates in the first 6 months in either group. No HCC was found in the explant in 1 patient from each group. In conclusion, the HCC‐adjusted MELD system significantly improved the probability of timely OLT, albeit a significant disadvantage for blood group O was evident. Compared with preliminary UNOS data, in which 90% of patients with HCC have received OLT within 3 months, our results reflect the wide regional variation in the impact of MELD. (Liver Transpl 2004;10:621–630)
Corresponding author's email: mgillesp@southalabama.edu Rationale: Emerging evidence shows that the majority of sequence variants determining complex human traits are localized in non-coding ...regulatory elements, but the reason why such regulatory regions are prone to mutation is unknown. Rather, the close spatial relationship between mutagenic base damage and newly acquired sequence variants points to the prospect that regulatory sequence variants are initiated by oxidant stress-associated transcriptional signaling and, most provocatively, that a substantial proportion of these variants are misclassified; many could be mutational artifacts caused by the presence of base damage in template DNA during PCR-based library preparation prior to DNA sequencing.
We report a case of sarcoidosis with severe cholestasis and cholangiographic features of sclerosing cholangitis that responded dramatically to corticosteroid therapy. Although an association between ...sarcoidosis and primary sclerosing cholangitis has been suggested by previous reports, features suggestive of primary sclerosing cholangitis, including inflammatory bowel disease, hepatic histology and serum neutrophil cytoplasmic antibodies, were absent in this case. Cholangiography may be useful in the evaluation of patients with cholestatic sarcoid liver disease, and intrahepatic biliary strictures should be included in the spectrum of hepatic involvement by sarcoidosis. A trial of corticosteroid therapy may be of benefit in patients with bile ductal involvement by sarcoidosis.
Background & Aims:
HCV-related cirrhosis is a leading risk factor for hepatocellular carcinoma (HCC). Surveillance might detect HCC at a treatable stage. We estimated the clinical and economic ...consequences of a common HCC surveillance strategy in patients with HCV-related cirrhosis in the context of alternative HCC treatment strategies.
Methods:
With a Markov model, we examined surveillance with serum α-fetoprotein and ultrasound every 6 months in patients with compensated HCV-related cirrhosis from age 45–70 years or death, and HCC treatment with resection, cadaveric liver transplantation (CLT), or living donor liver transplantation (LDLT).
Results:
Compared to natural history in the base case, surveillance with resection, listing for CLT, or LDLT increased life expectancy by 0.49, 2.58, and 3.81 quality-adjusted life-years (QALYs), respectively, all at costs less than $51,000/QALY gained. The consequences of surveillance were most sensitive to the outcomes and costs of HCC treatments but not surveillance test performance characteristics or cost. Prioritizing CLT for patients with HCC over those with decompensated cirrhosis resulted in greater overall life expectancy with minimal increase in cost.
Conclusions:
Surveillance for HCC in patients with compensated HCV-related cirrhosis might gain QALYs at acceptable costs. The impact of surveillance depends most on the outcomes and costs of HCC treatments, rather than surveillance test characteristics. By increasing organ availability for timely definitive treatment, LDLT might achieve the greatest gain in life expectancy at acceptable costs. Prioritizing CLT for HCC might increase the population-wide benefits of CLT.
Despite increasing understanding of the genetic control of cell growth and the identification of several involved chemical and infectious factors, the pathogenesis of clinical and experimental ...hepatocellular carcinoma remains unknown. Available evidence is consistent with the possibility that selected changes in the hepatocellular metabolism of long-chain fatty acids may contribute significantly to this, process. Specifically, studies of the peroxisome proliferators, a diverse group of xenobiotics that includes the fibrate class of hypolipidemic drugs, suggest that increased fatty acid oxidation by way of extramitochondrial pathways (i.e., omega-oxidation in the smooth endoplasmic reticulum and beta-oxidation in the peroxisomes) results in a corresponding increase in the generation of hydrogen peroxide and, thus, oxidative stress. This in turn leads to alterations in gene expression and in DNA itself. We also review evidence supporting a potentially decisive influence of particular aspects of hepatocellular fatty acid metabolism in determining the activity of the extramitochondrial pathways. Moreover, certain intermediates of extramitochondrial fatty acid oxidation (e.g., the long-chain dicarboxylic fatty acids) impair mitochondrial function and are implicated as modulators of gene expression through their interaction with the peroxisome proliferator-activated receptor. Finally, the occurrence of hepatic tumors in type I glycogen storage disease (glucose-6-phosphatase deficiency) may exemplify this general mechanism, which may also contribute to nonneoplastic liver injury and to tumorigenesis in other tissues.
The current policy for determining priority for organ allocation is based on the model for end stage liver disease (MELD). We hypothesize that severity of graft dysfunction assessed by either the ...MELD score or the Child‐Turcotte‐Pugh (CTP) score correlates with mortality after liver retransplantation (re‐OLT). To test this hypothesis, we analyzed the outcome of 40 consecutive patients who received re‐OLT more than 90 days after primary orthotopic liver transplantation (OLT). The Kaplan‐Meier 1‐year and 5‐year survival rates after re‐OLT were 69% and 62%, respectively. The area under the curve (AUC) values generated by the receiver operating characteristics (ROC) curves were 0.82 (CI 0.70‐0.94) and 0.68 (CI 0.49‐0.86), respectively (P = .11), for the CTP and MELD models in predicting 1‐year mortality after re‐OLT. The 1‐year and 5‐year survival rates for patients with CTP scores less than 10 were 100% versus 50% and 40%, respectively, for CTP scores of at least 10 (P = .0006). Patients with MELD scores less than or equal to 25 had 1‐year and 5‐year survival rates of 89% and 79%, respectively, versus 53% and 47%, respectively, for MELD scores greater than 25 (P = .038). Other mortality predictors include hepatic encephalopathy, intensive care unit (ICU) stay, recurrent hepatitis C virus (HCV) infection, and creatinine level of 2 mg/dL or higher. Analysis of an independent cohort of 49 patients showed a trend for a correlation between CTP and MELD scores with 1‐year mortality, with AUC of 0.59 and 0.57, in respective ROC curves. In conclusion, our results suggest that severity of graft failure based on CTP and MELD scores may be associated with worse outcome after re‐OLT and provide a cautionary note for the “sickest first” policy of organ allocation. (HEPATOLOGY 2004;39:230–238.)
An ex vivo photochemical treatment (PCT) process was developed to inactivate pathogens in fresh frozen plasma (PCT-FFP). A prospective, controlled, double-blinded, randomized study was conducted to ...evaluate the efficacy and safety of PCT-FFP compared with conventional FFP (C-FFP). Patients (n = 121) with acquired coagulopathy, largely due to liver disease, including hepatic transplantation, were transfused with either PCT-FFP or C-FFP for up to 7 days. Primary end points were changes in the prothrombin time (PT) and the partial thromboplastin time (PTT) in response to the first FFP transfusion. Secondary analyses compared changes in the PT and the PTT, factor VII levels, clinical hemostasis, blood component usage, and safety following FFP transfusions for up to 7 days. Following the first transfusion, correction in the PT and PTT adjusted for FFP dose and patient weight was not different. Changes in the PT were equivalent between treatment groups (P = .002 by noninferiority). Equivalence was not demonstrated for changes in the PTT. Following multiple transfusions, correction of the PT and the PTT was similar between groups. No differences were observed in use of blood components, clinical hemostasis, or safety. These results suggest PCT-FFP supported hemostasis in the treatment of acquired coagulopathy similarly to conventional FFP.
The cellular fatty acid-binding proteins (FABP) and cellular retinoid (retinol, retinoic acid)-binding proteins (CRtBP) are structurally and functionally-defined groups within an evolutionarily ...conserved gene family. CRtBP are expressed in both fully differentiated and developing tissues in a manner that supports a relationship to the action of retinoic acid in morphogenesis and cellular differentiation. The FABP are, by contrast, expressed only in fully differentiated tissues in a manner compatible with a major function in the metabolism of long-chain fatty acids (LCFA) for energy production or storage. The precise function(s) of FABP and CRtBP remain imperfectly understood, while subspecialization of function(s) within the two groups is suggested by the complex diversity in both of structurally distinct members that display striking tissue and temporal specificity of expression in addition to ligand specificity. Notwithstanding this considerable apparent functional diversity among the FABP and CRtBP, available evidence supports a dual set of generic functions for both protein groups in a) promoting cellular flux of poorly water-soluble ligands and their subsequent metabolic utilization or transformation, and b) sequestration of ligands in a manner that limits their association with alternative binding sites within the cell, of which members of the steroid hormone nuclear receptor superfamily (HNR) are a potentially important category. Theoretical as well as experimental models probing diffusional fluxes of LCFA in vitro and in living cells have provided support for a function for FABP in intracellular LCFA transport. Protein-bound ligand also appears to provide the substrate for metabolic transformation of retinoids bound to CRtBP, but convincing evidence is lacking for an analogous mechanism in the direct facilitation of fatty acid utilization by FABP. An emerging relationship between FABP and CRtBP function centers on their binding of, and induction by, ligands which activate or transform specific HNR-the retinoic acid receptors and the peroxisome proliferator activated receptor in the case of CRtBP and FABP, respectively. Evidence consistent with both a 'promotive' role (provision of ligands for HNR) and a 'protective' role (limiting availability of free ligand for HNR association) has been advanced for CRtBP. Available data supports a 'protective' function for cellular retinoic acid-binding proteins (CRABP) and liver FABP (L-FABP) and points to the existence of ligand-defined, lipid-binding-protein-HNR relationships in which CRABP serve to attenuate the induction of gene expression by retinoic acid, and in which L-FABP may modulate a cellular adaptive multigene response to increased LCFA flux or compromised LCFA utilization.
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