A Common Variant in CLDN14 is Associated with Primary Biliary Cirrhosis and Bone Mineral Density.

Primary biliary cirrhosis (PBC), a chronic autoimmune liver disease, has been associated with increased incidence of osteoporosis. Intriguingly, two PBC susceptibility loci identified through genome-wide association studies are also involved in bone mineral density (BMD). These observations led us to investigate the genetic variants shared between PBC and BMD. We evaluated 72 genome-wide significant BMD SNPs for association with PBC using two European GWAS data sets (n = 8392), with replication of significant findings in a Chinese cohort (685 cases, 1152 controls). Our analysis identified a novel variant in the intron of the CLDN14 gene (rs170183, Pfdr = 0.015) after multiple testing correction. The three associated variants were followed-up in the Chinese cohort; one SNP rs170183 demonstrated consistent evidence of association in diverse ethnic populations (Pcombined = 2.43 × 10(-5)). Notably, expression quantitative trait loci (eQTL) data revealed that rs170183 was correlated with a decline in CLDN14 expression in both lymphoblastoid cell lines and T cells (Padj = 0.003 and 0.016, respectively). In conclusion, our study identified a novel PBC susceptibility variant that has been shown to be strongly associated with BMD, highlighting the potential of pleiotropy to improve gene discovery

Management of Febrile Neutropenia - a German Prospective Hospital Cost Analysis in Lymphoproliferative Disorders, Non-Small Cell Lung Cancer, and Primary Breast Cancer

Background: Febrile neutropenia/leukopenia (FN/FL) is the most frequent dose-limiting toxicity of myelosuppressive chemotherapy, but German data on economic consequences are limited. Patients and Methods: A prospective, multicentre, longitudinal, observational study was carried out to evaluate the occurrence of FN/FL and its impact on health resource utilization and costs in non-small cell lung cancer (NSCLC), lymphoproliferative disorder (LPD), and primary breast cancer (PBC) patients. Costs are presented from a hospital perspective. Results: A total of 325 consecutive patients (47% LPD, 37% NSCLC, 16% PBC; 46% women; 38% age >= 65 years) with 68 FN/FL episodes were evaluated. FN/FL occurred in 22% of the LPD patients, 8% of the NSCLC patients, and 27% of the PBC patients. 55 FN/FL episodes were associated with at least 1 hospital stay (LPD n = 34, NSCLC n = 10, PBC n = 11). Mean (median) cost per FN/FL episode requiring hospital care amounted to (sic) 3,950 ((sic) 2,355) and varied between (sic) 4,808 ((sic) 3,056) for LPD, (sic) 3,627 ((sic) 2,255) for NSCLC, and (sic) 1,827 ((sic) 1,969) for PBC patients. 12 FN/FL episodes (LPD n = 9, NSCLC n = 3) accounted for 60% of the total expenses. Main cost drivers were hospitalization and drugs (60 and 19% of the total costs). Conclusions: FN/FL treatment has economic relevance for hospitals. Costs vary between tumour types, being significantly higher for LPD compared to PBC patients. The impact of clinical characteristics on asymmetrically distributed costs needs further evaluation

Liver transplantation in primary biliary cirrhosis: Risk assessment and 11-year follow-up

Background/Aims: Liver transplantation (LTx) is the only established treatment in patients with end-stage primary biliary cirrhosis (PBC). Although short-term survival after LTx in this group of patients is usually good, few data exist on the long-term survival. The optimal timing of transplantation is difficult. Thus, the aims of this study were to assess the long-term survival of patients with PBC after LTx and to identify potential predictive factors for a positive outcome. Methods: Survival of 28 patients with PBC who underwent LTx between 1985 and July 1999 in a single center was studied by Kaplan-Meier analysis and was compared to predicted survival without LTx using established prognostic models for PBC, the Mayo and European risk scores. Potential prognostic parameters obtained before LTx were tested for correlation to survival. Rates of bone fractures as markers of hepatic osteodystrophy were compared before and after LTx. Results: Median follow-up after LTx was 90 months with a maximum of 140 months. Actuarial survival of patients with PBC was 89% after 1, 5, and 10 years and was significantly better than estimated survival without LTx after 1-7 years as calculated by the Mayo and European risk scores. Of several parameters tested, only serum bilirubin and the prognostic scores, but no other liver function tests obtained immediately prior to transplantation were significantly correlated with survival after LTx. The duration of intensive care after LTx was not associated with any parameters obtained before LTx. Bone fractures were diagnosed in 43% of patients of whom the vast majority were osteopenic before LTx as determined by osteodensitometry. Conclusion: Longterm survival of a well-defined group of patients with PBC was excellent after LTx and was inversely correlated with preoperative serum bilirubin levels as well as Mayo and European risk scores. Copyright (C) 2000 S. Karger AG. Basel

Separation of Powers and Political Budget Cycles

From a theoretical viewpoint, political budget cycles (PBC) arise in equilibrium when rational voters are imperfectly informed about the incumbent's competency and the incumbent enjoys discretionary power over the budget. This paper focuses on the second condition, examining how executive discretion is affected by the budgetary process under separation of powers. We specifically model PBC in the composition of government spending. The main result is that effective checks and balances in the budgetary process curb PBC. The institutional features of the executive-legislature bargaining game, namely, the actual agenda-setting authority, the status quo location and the degree of legislative oversight and control of the implementation of the budgetary law, play critical roles for the existence and the size of PBC. These results are consistent with recent empirical findings, which show that PBC are more pronounced in developing countries, where there are also less effective checks and balances.Rational political budget cycles; budget composition; separation of powers; checks and balances; budgetary process.

Gene polymorphisms in primary biliary cirrhosis: association with the disease and hepatic osteopathy

Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis (PBC). Estrogen receptor-alpha gene (ER-�), vitamin-D-receptor gene (VDR) and IL-1-receptor-antagonist gene (IL-1RN) are all attractive candidates for osteoporosis susceptibility. Furthermore insulin-like growth factor-I (IGF-I) gene microsatellite repeat polymorphism was found to be associated with osteoporosis in some studies and collagen-I�1 (COLIA1) Sp1 s allele was associated with lower bone mineral density (BMD) in one study in PBC. IGF-I treatment restored osteopenia and reduced fibrogenesis in experimental cirrhosis. In this study we summarize our results on polymorphisms of the above genes and bone disease in Hungarian PBC patients. Patients and methods: 70 female patients with PBC were enrolled (age:57.6yrs, range:37-76yrs, each AMA-M2 positive, stage II-IV). 139 age-matched female subjects served as controls (age: 55.9 yrs, range:43-72 yrs). COLIA1 Sp1 and IGF-I microsatellite polymorphisms were determined by PCR in all patients and controls. VDR BsmI, IL-1RN variable-number tandem repeat (VNTR) and ER-� PvuII and XbaI polymorphisms were detected in 33 patients and controls. BMD was measured by dual energy x-ray absorptiometry (Lunar,Prodigy,USA) in lumbar spine (LS) and femoral neck (FN). Results: There was no difference in IGF-I microsatellite repeat polymorphism (192/192=34.2%, 194/192=28.6%, other=37.2%) and COLIA1 Sp1 polymorphism (SS=72.9%, Ss=22.8% and ss=4.3%) and IL-1 VNTR polymorphism between PBC patients and controls, however, the COLIA1 Sp1 s allele was significantly less frequent in patients with PBC (p=0.038). The genotype frequency of VDR BsmI (BB=57.5%, Bb=33.3%, bb=9.1%, p=0.01) and ER-a PvuII (PP=18.2%, Pp=75.6%, pp=6.2%, p=0.03) and XbaI (XX=9.1%, Xx=90.9%, xx=0%, p=0.0003) of the patients was different from that of the control group, with higher frequency of the BB, Pp and Xx genotypes in PBC. Osteoporosis (t score<-2.5) was detected in 22 patients (31.4%). Osteoporotic patients were elder and had longer disease history (p=0.01 for both). An association was found between the IGF-I genotypes and ODM data, the 192/192 genotype was associated with higher FN Z-score compared to other genotypes (p=0.036). Conclusions: In contrast to previous studies the COLIA1 Sp1 s allele was less frequent in patients with PBC, and its presence was not associated with BMD. We confirmed previous findings on higher frequency of VDR BsmI BB genotype in patients with PBC. The ER-α PvuII and XbaI Pp and Xx genotypes were more frequent in PBC patients, while IL-1RN VNTR and IGF-I microsatellite repeat polymorphism was not different. Since IGF-I polymorphism was associated to BMD, it may be hypothesized that not COLIA1 but IGF-I together with other genetic and environmental factors may be involved in the complex regulation of BMD in PBC

Saddle-Node Bifurcation to Jammed State for Quasi-One-Dimensional Counter Chemotactic Flow

The transition of a counter chemotactic particle flow from a free-flow state to a jammed state in a quasi-one-dimensional path is investigated. One of the characteristic features of such a flow is that the constituent particles spontaneously form a cluster that blocks the path, called a path-blocking cluster (PBC), and causes a jammed state when the particle density is greater than a threshold value. Near the threshold value, the PBC occasionally desolve itself to recover the free flow. In other words, the time evolution of the size of the PBC governs the flux of a counter chemotactic flow. In this paper, on the basis of numerical results of a stochastic cellular automata (SCA) model, we introduce a Langevin equation model for the size evolution of the PBC that reproduces the qualitative characteristics of the SCA model. The results suggest that the emergence of the jammed state in a quasi-one-dimensional counter flow is caused by a saddle-node bifurcation.Comment: 5pages, 8figure

Clinical characteristics of antimitochondrial antibody-positive patients at a safety net health care system in Arizona.

Background and aimsTo assess whether aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (AP) levels can predict the diagnosis of primary biliary cholangitis (PBC) or any other diagnoses and whether PBC occurs either simultaneously or independently of other liver diseases among antimitochondrial antibody (AMA)-positive patients.MethodsDemographic and clinical variables were assessed in 90 AMA-positive patients with and without liver biopsies. These patients were further categorised as having a diagnosis of PBC, overlap syndrome or 'not established with a diagnosis of PBC'. Receiver operating characteristic curves were constructed to determine the thresholds of liver enzymes that predict these three diagnoses.ResultsThe 48 patients with liver biopsies were more frequently female and had significantly higher AP levels compared with the non-liver biopsy group. Based on liver biopsy findings, 12, 12 and 22 patients were assigned a diagnosis of PBC, overlap syndrome with autoimmune hepatitis and PBC and 'not established diagnosis of PBC', respectively. Seven of 12 patients classified as PBC had AP level of ˂200 IU. AST, ALT and AP levels were significant predictors of a diagnosis of overlap syndrome compared with the rest of the patients; however, these tests were not discriminatory between diagnoses of PBC and 'not established with PBC'. Findings of fatty liver and bile duct injury on liver biopsies were not significantly associated with any liver test pattern.ConclusionsAs the liver test pattern did not correlate with the liver biopsy findings of PBC or other non-PBC diagnoses in AMA-positive patients at risk for other disease, a liver biopsy and/or non-invasive liver assessment along with serum liver tests should be interpreted to complete liver evaluation