Background: Wilson disease is an autosomal recessive disorder of copper metabolism and requires lifelong medical treatment. Therefore, the analysis of quality of life has gathered more attention. Aims of this study were to examine risk for depression and health-related quality of life in patients suffering from Wilson disease.Methods: Sixty-eight patients were included in this retrospective cross sectional study. The Personal Health Questionnaire-9 Depression Scale was used to assess depression. The Short Form-36 Health Survey questionnaire was used to assess health-related quality of life.Results: The Personal Health Questionnaire-9 indicated that 21% (14/68) of patients were at risk for major depressive disorders (scores > 10) and 35% (24/68) were at risk for mild depression (scores 5-9). Women had significantly lower life quality scores than men. Primary neurologic disease manifestation was associated with significantly lower total Short Form-36 and subdimension scores compared with primary hepatic or mixed presentation. Overall, patients with Wilson disease experienced higher quality of life than patients with other chronic liver diseases.Conclusions: As patients with Wilson disease have a high risk for depressive disorders, active assessment for depression is mandatory. Patients with primary neurological symptoms are at higher risk for reduction of life quality. (C) 2015 Elsevier Masson SAS. All rights reserved.

BACKGROUND & AIMS:Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. Alterations of copper metabolism have been associated with changes in coagulation factors. The aim of the present study was the analysis of coagulation factors in WD patients.METHODS:100 patients attending a tertiary WD outpatient clinic were analyzed in a prospective cross sectional cohort study. Out of peripheral venous blood samples coagulation factors were assessed including: full blood count, INR, partial thromboplastin time (PTT), clotting factors II, V, VII, VIII, IX, X, XI, XII, XIII, von Willebrand factor/-antigen, fibrinogen, antithrombin III, protein S, protein C, activated protein C (APC) resistance. Subgroup analyses of the blood tests were performed for sex, initial clinical presentation, WD treatment and liver function.RESULTS:Subgroup analysis by liver function showed decreased levels of factors II, V, VII and X. Subgroup analysis by gender or clinical course of the disease did not reveal significant coagulation changes. In patients treated with trientine significantly decreased levels of factors II, VII and antithrombin III and increased von Willebrand factor/-antigen levels were detected. Factor VIII levels were significantly reduced in patients receiving zinc.CONCLUSION:Although significant differences of some coagulation parameters in subgroup analysis were found, no clinically relevant alterations of the coagulation system in WD patients could be detected.

GOALS:To determine the prevalence and characteristics of lipomas in patients with Wilson disease.BACKGROUND:Wilson disease is an autosomal recessive disorder resulting in copper accumulation in the liver and the central nervous tissue. Subcutaneous lipomas were often noted by the authors during clinical examinations of patients with Wilson disease. This is the first study to analyze the prevalence and progression of lipoma development in patients with Wilson disease.STUDY:Eighty consecutive patients attending a tertiary care center were examined for the presence of subcutaneous lipomas.RESULTS:Subcutaneous lipomas could be detected during the examination of 21 (26%) of the 80 patients with Wilson disease. Multiple subcutaneous lipomas were present in 16 (76%) of the 21 affected patients. Lipomas were mainly found on the extremities and the trunk. Neither initial presentation nor decoppering treatment influenced the presence or course of lipomas in these patients.CONCLUSIONS:Subcutaneous lipoma formation is more common in patients with Wilson disease than in the general population. We suggest that the presence of lipomas contributes to the differential diagnosis of Wilson disease.

BACKGROUND:Wilson disease (WD) is an autosomal recessive copper storage disease resulting in hepatic and neurologic dysfunction. Liver transplantation is an effective treatment for fulminant cases for patients with chronic liver disease. Reports on the outcome of neuropsychiatric symptoms after orthotopic liver transplantation (OLT) are limited.AIM:To assess the course of neuropsychiatric and hepatic symptoms after liver transplantation for Wilson diseaseMETHODS:Nineteen patients with Wilson disease received liver transplantation and were followed prospectively from 2005 to 2010 for the development of hepatic, neurological and psychiatric symptoms.RESULTS:Eight patients (all female) were transplanted for acute liver failure and eleven patients for chronic liver failure. Patient survival rates one and five yr after transplantation were 78% and 65%, respectively. Of the surviving patients, hepatic symptom scores improved in all patients and neurological symptom scores improved in all but one patient after OLT compared to the time of initial diagnosis and compared to pre-OLT status. Psychiatric symptoms showed moderate improvements.CONCLUSION:Survival after OLT for Wilson disease with end-stage liver disease is excellent. Overall, neuropsychiatric symptoms improved after transplantation, substantiating arguments for widening of the indication for liver transplantation in symptomatic neurologic Wilson disease patients with stable liver function.

BACKGROUND & AIMS: Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease.METHODS: We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began).RESULTS: Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018).CONCLUSIONS: Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine.

BACKGROUND & AIMS:Wilson disease is a genetic disorder that affects copper storage, leading to liver failure and neurologic deterioration. Patients are treated with copper chelators and zinc salts, but it is not clear what approach is optimal because there have been few studies of large cohorts. We assessed long-term outcomes of different treatments.METHODS:Patients in tertiary care centers were retrospectively analyzed (n = 288; median follow-up time, 17.1 years) for adherence to therapy, survival, treatment failure, and adverse events from different treatment regimens (chelators, zinc, or a combination). Hepatic treatment failure was defined as an increase in activity of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase) >2-fold the upper limit of normal or >100% of baseline with an increase in urinary copper excretion.RESULTS:The median age at onset of Wilson disease was 17.5 years. Hepatic and neuropsychiatric symptoms occurred in 196 (68.1%) and 99 (34.4%) patients, respectively. Hepatic treatment failure occurred more often from zinc therapy (14/88 treatments) than from chelator therapy (4/313 treatments; P < .001). Actuarial survival, without transplantation, showed an advantage for chelating agents (P < .001 vs zinc). Changes in treatment resulted mostly from adverse events, but the frequency did not differ between groups. Patients who did not respond to zinc therapy showed hepatic improvement after reintroduction of a chelating agent.CONCLUSIONS:Treatments with chelating agents or zinc salt are effective in most patients with Wilson disease; chelating agents are better at preventing hepatic deterioration. It is important to identify patients who do not respond to zinc therapy and have increased activities of liver enzymes, indicating that a chelating agent should be added to the therapeutic regimen.

Logic synthesis of speed independent circuits based on STG decomposition is a promising approach to tackle complexity problems like state-space explosion. Unfortunately, decomposition can result in components that in isolation have irreducible CSC conflicts. Generalising earlier work, we show how to resolve such conflicts by introducing internal communication between the components. The new algorithms are successfully applied to some benchmarks, including very complex STGs arising in the context of control resynthesis.

STG-based logic synthesis of complex asynchronous circuits has to deal with state space explosion. To cope with it, a structural STG decomposition --based on transition contraction -- was first proposed by Chu and improved as well as proven correct by Vogler and Wollowski.We present an implementation of this improved version with significant further optimisations, e.g. achieving SI-implementability by internal communication.

For synthesising efficient asynchronous circuits one has to deal with the state space explosion problem. In order to alleviate this problem one can decompose the STG into smaller components. This paper deals with the decomposition method of Vogler and Wollowski and introduces several strategies for its efficient implementations. Furthermore, this approach is combined with another method to alleviate state space explosion, which is based on Petri net unfoldings. The developed algorithms are compared by means of benchmark examples, and the experimental results show significant improvement in terms of memory usage and runtime compared with other existing methods.

BACKGROUND:In Wilson disease, copper is not sufficiently excreted into bile due to the absence or malfunction of the Wilson protein copper ATPase in the excretory pathway of hepatocytes. Copper is found in sweat. It is unknown if the Wilson protein plays a role in copper excretion into sweat. It is the aim of this study to investigate Wilson protein expression in sweat glands and analysing its effects on copper excretion into sweat in controls and patients with Wilson disease.METHODS:Immunofluorescent analysis of the Wilson protein in skin samples from normal rat, LEC rat and human skin biopsies were performed. Pilocarpin-induced sweat gland stimulation by iontophoretic transfer adapted from the methods used for cystic fibrosis sweat test was used for sweat induction. Sweat volume, sweat copper concentration, serum ceruloplasmin and serum copper were analysed in 28 Wilson patients and 21 controls.RESULTS:The Wilson protein is expressed in human and rat sweat gland epithelia. Copper concentration in sweat is not significantly different between controls and Wilson patients. Wilson patients produce significantly smaller volumes of sweat compared to controls. Sweat production is partially reversible in Wilson patients under medical treatment for Wilson disease or after liver transplantationCONCLUSION:Wilson patients show a reduced sweat production with unaltered sweat copper concentration. The Wilson protein might play an important role in physiological sweat production.

Resynthesis of handshake specifications obtained e.g. from BALSA or TANGRAM with speed-independent logic synthesis from STGs is a promising approach. To deal with state-space explosion,we suggested STG decomposition; a problemis that decomposition can lead to irreducible CSC conflicts. Here, we present a new approach to solve such conflicts by introducing internal communication between the components. We give some first, very encouraging results for very large STGs concerning synthesis time and circuit area.

AIM:To analyze the metallochaperone antioxidant-1 (Atox1) gene sequence in Wilson disease patients. METHODS:Mutation analysis of the four exons of the Atox1 gene including the intron- exon boundaries was performed in 63 Wilson disease patients by direct sequencing. RESULTS:From 63 selected patients no mutations were identified after the entire coding region including the intron- exon boundaries of Atox1 were sequenced. One known polymorphism within the Atox1 gene (5'UTR -99 T>C) in 31 (49%) of the Wilson patients as well as one previously undescribed variation (5'UTR -68 C>T) in 2 of the Wilson patients could be detected. Statistical analyses revealed that the existence of a variation within the Atox1- gene showed a tendency towards an earlier onset of the disease. CONCLUSION:Based on the data of this study, no major role can be attributed to Atox1 in the pathophysiology or clinical variation of Wilson disease.

Signal Transition Graphs (STG) are a formalism for the description of asynchronous circuit behaviour. In this paper we propose (and justify) a formal semantics of non-deterministic STGs with dummies and OR-causality. For this, we introduce the concept of output-determinacy, which is a relaxation of determinism, and argue that it is reasonable and useful in the speed-independent context. We apply the developed theory to improve an STG decomposition algorithm used to tackle the state explosion problem during circuit synthesis, and present some experimental data for this improved algorithm and some benchmark examples.

For synthesising efficient asynchronous circuits one has to deal with the state space explosion problem. In this paper, we present a combined approach to alleviate it, based on using Petri net unfoldings and decomposition.

For synthesising efficient asynchronous circuits from STGs one has to deal with the state space explosion problem. For this purpose STG decomposition was introduced by Chu and improved by Vogler and Wollowski. Here, we present the tool DesiJ which is the implementation of STG decomposition and proposed by Vogler and several other optimisations.

AIM: To analyze our Wilson disease patient cohort (n = 106) for alterations in the gene coding for MURR1 .METHODS: Patients with an established diagnosis of Wilson disease but normal ceruloplasmin blood levels were chosen for our study (n = 14).Patients with two known disease-causing mutations in the ATP7B gene were not included.The three exons of the human MURR1 gene were sequenced after amplification of the genomic DNA by polymerase chain reaction.RESULTS: Our study did not reveal any mutations leading to an amino acid change in the MURR1 sequence of Wilson disease patients.A polymorphism at 472 bp of the coding sequence could be confirmed.CONCLUSION: The MURR1 gene plays no role in the pathogenesis of Wilson disease patients with normal serum ceruloplasmin levels.

When synthesising an asynchronous circuit from an STG, one often encounters the state explosion problem. In order to alleviate this problem one can decompose the STG into smaller components. This paper deals with the decomposition method of (W. Vogler et al., 2005), (W. Vogler et al., 2002) and introduces several strategies for efficient implementations, proves them correct and compares them by means of benchmark examples