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Summary 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.

Despite technological advances, detection of deamidation in large proteins remains a challenge and the use of orthogonal methods is needed for unequivocal assignment. By a combination of cation-exchange separation, papain digestion, and a panel of mass spectrometry techniques we identified asparagine deamidation in light chain complementarity determining region 1 (CDR1) of a humanized IgG1 monoclonal antibody. The reaction yields both Asp and isoAsp, which were assigned by Edman degradation and by isoAsp detection using protein isoaspartate methyltransferase. The deamidated antibody variants were less potent in antigen binding compared to the nondegraded antibody. Changes in near-UV CD spectra, susceptibility to papain cleavage in an adjacent CDR2 loop, and the tendency of the newly formed isoAsp to undergo isomerization suggest local perturbations in the structure of the isoAsp-containing antibody.

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.

The objective of this study is to test the hypotheses that bipolar disorders or depressive disorders, minority status, and the presence of pediatric inpatient psychiatric unit will be individual predictors of pediatric psychiatric inpatient admission, and to provide a model that will evaluate which individual and organizational characteristics predict pediatric psychiatric inpatient. For this purpose, a secondary analysis of the medical records of 1,520 pediatric patient visits between January 1, 2008 and June 30, 2008, was conducted using univariate and multivariate logistic regression. Independent predictors of pediatric psychiatric inpatient admission were presence of bipolar and depressive disorders, greater average daily census, and increasing operating margin. Minority status was a significant predictor of not being admitted, as was presence of an anxiety disorder, greater total margin and older age. The results indicate that both individual and organizational factors impact disposition outcomes in particular subsets of pediatric patients who present to emergency departments for psychiatric reasons.

The delivery of copper to specific sites within the cell is mediated by distinct intracellular carrier proteins termed copper chaperones. Previous studies in Saccharomyces cerevisiae suggested that the human copper chaperone HAH1 may play a role in copper trafficking to the secretory pathway of the cell. In this current study, HAH1 was detected in lysates from multiple human cell lines and tissues as a single-chain protein distributed throughout the cytoplasm and nucleus. Studies with a glutathione S -transferase-HAH1 fusion protein demonstrated direct protein–protein interaction between HAH1 and the Wilson disease protein, which required the cysteine copper ligands in the amino terminus of HAH1. Consistent with these in vitro observations, coimmunoprecipitation experiments revealed that HAH1 interacts with both the Wilson and Menkes proteins in vivo and that this interaction depends on available copper. When these studies were repeated utilizing three disease-associated mutations in the amino terminus of the Wilson protein, a marked diminution in HAH1 interaction was observed, suggesting that impaired copper delivery by HAH1 constitutes the molecular basis of Wilson disease in patients harboring these mutations. Taken together, these data provide a mechanism for the function of HAH1 as a copper chaperone in mammalian cells and demonstrate that this protein is essential for copper homeostasis.

Wilson’s disease is an inherited disorder of copper metabolism characterized by hepatic cirrhosis and neuronal degeneration. In this current study, a polyclonal antiserum specific for the Wilson’s disease ATPase was used to examine the hepatic expression of this protein. Immunoblot analysis of lysates from human and rat liver detected a single 165-kDa protein, which by immunofluorescence was present only in hepatocytes and localized predominantly to the trans-Golgi network and exclusively in this compartment under low hepatic copper concentrations. Although hepatic copper concentration had no effect on the steady-state levels of the Wilson’s disease protein, copper administration in vivo resulted in redistribution of this protein to a cytoplasmic vesicular compartment localized toward the hepatocyte canalicular membrane. The relative abundance of the Wilson’s disease protein in the liver was found to be greatest in the fetus before the onset of biliary copper excretion. Taken together, these studies reveal a novel posttranslational mechanism of copper homeostasis in vivo consistent with the proposed function of the Wilson’s disease protein in holoceruloplasmin biosynthesis and biliary copper excretion and of relevance to the broad clinical heterogeneity observed in this disease.

We report the case of a 52 year old male with diabetes mellitus and long standing evidence of hepatic iron excess. Initially considered to have haemochromatosis, this patient was reevaluated when hepatic iron stores were found to be unaffected by a prolonged course of weekly phlebotomy. The development of neurological disease prompted diagnostic consideration of aceruloplasminaemia, which we confirmed by demonstration of a novel frameshift mutation in the ceruloplasmin gene. Our inability to resolve the patient's iron overload by regular phlebotomy is consistent with recent animal studies indicating an essential role for ceruloplasmin in cellular iron efflux. Evaluation of this case underscores the clinical relevance of aceruloplasminaemia in the differential diagnosis of hepatic iron overload and provides insight into the pathogenetic mechanisms of hepatocellular iron storage and efflux. Keywords: aceruloplasminaemia; ceruloplasmin; diabetes; haemochromatosis; iron

Wilson disease is a human disorder of copper metabolism resulting in toxic copper accumulation. Patients present with a high clinical variability, even when sharing identical mutations. MURR1, the gene causing canine copper toxicosis in Bedlington terriers, maps to chromosome 2 in humans, a region different to the Wilson gene locus. MURR1 might influence human copper metabolism and the clinical presentation of Wilson disease patients. This study analyzed MURR1 gene sequence in Wilson disease patients and MURR1 gene transcription in selected patients. Mutation analysis of three exons of the MURR1 gene including the intron-exon boundaries was performed in 63 Wilson disease patients by direct sequencing. Of the 63 Wilson patients 19 (30%) had basepair changes in the MURR1 gene. Three intronic base pair changes, one new sequence variation and two known polymorphisms were detected, including the GAT/GAC heterozygous state at codon Asn 164 in 15 (24%) of the analyzed patients. This suggests that GAT/GAC heterozygous state at codon Asn 164 is associated with an earlier onset of disease.

In the course of the nation's evolution toward managed-care service delivery and financing models, state administration of Medicaid and other public-sector health care services has become increasingly complex. This article reviews and comments on key policy issues that state administrators face in the organization and financing of Medicaid-managed behavioral health care services. The author offers recommendations for states that are considering additional reforms.

Managed behavioral health care is widely perceived as a threat to traditional practice in mental health at the expense of quality care. Although such assertions by mental health providers may prove to be justified in certain circumstances, they should not serve to obscure the quite reasonable public health motives behind managed care and the favorable effect managed care organizations may ultimately have on clinical decision-making and practice. By compelling practitioners to more clearly articulate the basis for their clinical judgments and by increasingly requiring evidence to support such judgments, they discourage the application of ill-considered, sometimes inappropriate, and occasionally iatrogenic evaluation and treatment interventions. In the future, there is significant danger that developmental assessment and treatment procedures for young children will be inappropriately constrained and diminished. This is especially true if those who work with young children fail to use the tools available to them to make the case for the best of current practice, whether a clearly stated clinical rationale, a formal appeal, the advocacy of our health professions, or applied clinical services research. The practices of our health plans need to be understood by providers in the context of managed care values. Primitive systems should not be confused with corrupt systems. Although undoubtedly the latter exist, they do not necessarily predominate. Within a managed care context and with due respect to managed care assumptions, it is possible to bring utilization management and contemporary practices in developmental assessment into closer alignment, ultimately to the benefit of children who need them.

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.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 or100% of baseline with an increase in urinary copper excretion.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.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.

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.

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.

Despite early warnings of lead toxicity, until recently this metal was added to a variety of consumer and industrial products. Today, thousands of children in the United States, and probably tens of thousands more worldwide, are suffering the consequences of exposure to lead. The lead story looms as major public policy failure that will eventually cost billions of dollars to remedy. Little is known about the toxicological properties of the more than 70,000 chemicals in commerce. Consequently, it seems likely that other "leads" are finding their way into our food, water, and air. Inadequate testing of chemicals to which the public is exposed presents a serious public health risk, particularly to children whose nervous systems are still developing. The Federal government should expand toxicological testing programs for existing and new chemicals, requiring increased developmental toxicological, particularly neurotoxicological, testing of chemicals to which the public is significantly exposed. In keeping with the concept of full-cost pricing, the costs of these tests should be incurred by the manufacturer, not the government, and should be considered a routine cost of product development.

The test-retest reliability of the Multiple Sleep Latency Test (MSLT) was evaluated in 14 healthy normal subjects. Each slept a single night in the laboratory (8 h time in bed) and received the MSLT the following day (1000, 1200, 1400, and 1600 h) on two occasions separated by 4-14 months. Mean sleep latency (four tests) was highly reliable from MSLT to MSLT (r = 0.97, p less than 0.001). The test-retest reliability did not change as a function of the interval of time between tests or as a function of the level of sleepiness (range = 4-20 min) within the population. However, as the number of tests comprising the MSLT was reduced below three, the reliability was reduced such that only 50% or less of the variance could be predicted.

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 transplantation Conclusion Wilson patients show a reduced sweat production with unaltered sweat copper concentration. The Wilson protein might play an important role in physiological sweat production.