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1.
Wilson’s disease is an autosomal recessive disorder of copper accumulation in various organs, with most common clinical manifestations
such as hepatic, neurological, and renal dysfunctions. Serum copper and ceruloplasmin in Wilson’s disease were significantly
lower as compared to normals, controls, and relatives of Wilson’s disease patients, whereas marked hypercupriuria (145 ± 7
μg/24 h) was observed in Wilson’s children only. A good correlation (r = 0.92) was found between non-ceruloplasmin-bound copper and 24-h urinary copper excretion in Wilson’s disease patients.
Further, copper studies among the different phenotypes of Wilson’s disease revealed substantially low serum ceruloplasmin
and a marked hypercupriuria in Wilson’s disease children associated with renal tubular acidosis as compared to the patients
with either hepatological or neurological manifestations. Serum ceruloplasmin levels in 14 patients of Wilson’s disease were
between 14 and 20 mg/dL. These patients of Wilson’s disease were confirmed by measuring liver biopsy copper, which was about
nine times higher than normal hepatic copper content. During the family screening by copper studies, four asymptomatic siblings
were diagnosed for Wilson’s disease. These subjects were then started on D-penicillamine therapy because presymptomatic treatment
prevents progression of the disease complications. 相似文献
2.
Wilson's disease is a rare genetic disorder of copper metabolism. The difference in copper tissue accumulation is responsible for the various clinical manifestations of this disorder. If left untreated, Wilson's disease progresses to hepatic failure, severe neurological disability, and even death. Due to the complex clinical picture of Wilson's disease, its diagnosis relies on a high index of suspicion. In our paper, we present endocrine symptoms suggesting the presence of insulinoma and hyperprolactinemia as the initial clinical manifestation of Wilson's disease in a young female. Zinc acetate treatment resulted in the disappearance of hypoglycemia, galactorrhea, and menstrual abnormalities. 相似文献
3.
Daphne M. Y. Cheah Yolanda J. Deal Paul F. A. Wright Nicole E. Buck Chung Wo Chow Julian F. B. Mercer Katrina J. Allen 《Biometals》2007,20(5):751-757
Wilson’s disease carriers constitute 1% of the human population. It is unknown whether Wilson’s disease carriers are at increased
susceptibility to copper overload when exposed to chronically high levels of ingested copper. This study investigated the
effect of chronic excess copper in drinking water on the heterozygous form of the Wilson's disease mouse model – the toxic
milk (tx) mouse. Mice were provided with drinking water containing 300 mg/l copper for 4–7, 8–11, 12–15 or 16–20 months. At the completion
of the study liver, spleen, kidney and brain tissue were analyzed by atomic absorption spectroscopy to determine copper concentration.
Plasma ceruloplasmin oxidase activity and liver histology were also assessed. Chronic copper loading resulted in significantly
increased liver copper in both tx heterozygous and tx homozygous mice, while wild type mice were resistant to the effects of copper loading. Copper loading effects were greatest
in tx homozygous mice, with increased extrahepatic copper deposition in spleen and kidney – an effect absent in heterozygote and
wild type mice. Although liver histology in homozygous mice was markedly abnormal, no histological differences were noted
between heterozygous and wild type mice with copper loading. Tx heterozygous mice have a reduced ability to excrete excess copper, indicating that half of the normal liver Atp7b copper
transporter activity is insufficient to deal with large copper intakes. Our results suggest that Wilson’s disease carriers
in the human population may be at increased risk of copper loading if chronically exposed to elevated copper in food or drinking
water. 相似文献
4.
Determination of copper in human tissues and body fluids may be crucial in the diagnosis of Wilson’s disease. In this study
we evaluated urinary copper excretion and urine and blood concentration in 14 patients in whom Wilson’s disease was confirmed
(group A) and in 21 subjects in whom the disease was only suspected (group B). The following values (mean ± SD) were found:
24-h urine (μg Cu/24 h), 152 ± 135 (A) and 31.8 ± 10.9 (B); urine (μg Cu/ml), 0.091 ± 0.087 (A) and 0.028 ± 0.011 (B); and
blood (μg Cu/ml), 0.62 ± 0.25 (A) and 0.72 ± 0.09 (B). By comparison, urine copper concentration in the group of apparently
healthy subjects was 0.035 ± 0.010 (n = 50), and blood copper concentration in autopsy cases of nonpoisoned people was 0.85 ± 0.19 (n = 73). 相似文献
5.
Nakao K Suzuki Y Imaseki H Joshima H Tamanoi I Saito Y 《Biological trace element research》2004,98(1):27-43
Intestinal permeability has been suggested to be closely linked with the etiology or activity of Crohn’s disease. However,
current methods for measurement of intestinal permeability are too laborious for routine examination, as they require urine
collection and/or use of radioisotopes. The present study was performed to develop a more convenient and safer method for
assessing intestinal permeability using blood samples rather than urine. Rats with indomethacin-induced enteritis were orally
administered Rb, Mn, and Zn as tracers. Intestinal permeability was determined by assaying the levels of Rb, Mn, and Zn in
blood samples by particle-induced X-ray emission (PIXE). The distributions of Rb, Mn, and Zn in the small intestine after
administration were analyzed by micro-PIXE. The conventional PIXE analysis showed that the levels of Rb and Zn in the blood
in the enteritis group were correlated with the grade of enteritis. The micro-PIXE analysis showed that Rb, Mn, and Zn were
translocated into the wall of the proximal small intestine 5 min after administration, and this effect was more conspicuous
in the enteritis group than in controls. Analysis of blood or small intestine tissue samples using the PIXE allows determination
of both intestinal permeability and the route of permeation. 相似文献
6.
Electron paramagnetic resonance spectroscopy (EPR) has the potential to give much detail on the structure of the paramagnetic
transition ion coordination sites, principally of Cu2+, in a number of proteins associated with central nervous system diseases. Since these sites have been implicated in misfolding/mis-oligomerisation
events associated with neurotoxic molecular species and/or the catalysis of damaging redox reactions in neurodegeneration,
an understanding of their structure is important to the development of therapeutic agents. Nevertheless EPR, by its nature
an in vitro technique, has its limitations in the study of such complex biochemical systems involving self-associating proteins
that are sensitive to their chemical environment. These limitations are at the instrumental and theoretical level, which must
be understood and the EPR data interpreted in the light of other biophysical and biochemical studies if useful conclusions
are to be drawn.
Australian Society for Biophysics Special Issue: Metals and Membranes in Neuroscience, held in Melbourne on 11 July 2007. 相似文献
7.
Gaasch JA Geldenhuys WJ Lockman PR Allen DD Van der Schyf CJ 《Neurochemical research》2007,32(10):1686-1693
Recent studies suggest that iron enters cardiomyocytes via the L-type voltage-gated calcium channel (VGCC). The neuronal VGCC
may also provide iron entry. As with calcium, extraneous iron is associated with the pathology and progression of neurodegenerative
diseases such as Parkinson’s and Alzheimer’s disease. VGCCs, ubiquitously expressed, may be an important route of excessive
entry for both iron and calcium, contributing to cell toxicity or death. We evaluated the uptake of 45Ca2+ and 55Fe2+ into NGF-treated rat PC12, and murine N-2α cells. Iron not only competed with calcium for entry into these cells, but iron
uptake (similar to calcium uptake) was inhibited by nimodipine, a specific L-type VGCC blocker, and enhanced by FPL 64176,
an L-VGCC activator, in a dose-dependent manner. Taken together, these data suggest that voltage-gated calcium channels are
an alternate route for iron entry into neuronal cells under conditions that promote cellular iron overload toxicity.
Special issue dedicated to Dr. Moussa Youdim. 相似文献
8.
9.
Feda E. Ali Frances Separovic Colin J. Barrow Shenggen Yao Kevin J. Barnham 《International journal of peptide research and therapeutics》2006,12(2):153-164
The accumulation of senile plaques composed primarily of aggregated amyloid β-peptide (Aβ), is the major characteristic of Alzheimer’s disease. Many studies correlate plaque accumulation and the presence of metal ions, particularly copper and zinc. The metal binding sites of the amyloid Aβ peptide of Alzheimer’s disease are located in the N-terminal region of the full-length peptide. In this work, the interactions with metals of a model peptide comprising the first 16 amino acid residues of the amyloid Aβ peptide, Aβ(1–16), were studied. The effect of Cu2+ and Zn2+ binding to Aβ(1–16) on peptide structure and oligomerisation are reported. The results of ESI-MS, gel filtration chromatography and NMR spectroscopy demonstrated formation of oligomeric complexes of the peptide in the presence of the metal ions and revealed the stoichiometry of Cu2+ and Zn2+ binding to Aβ(1–16), with Cu2+ showing a higher affinity for binding the peptide than Zn2+. 相似文献
10.
Mitochondria and Neurodegeneration 总被引:2,自引:0,他引:2
Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration. 相似文献
11.
Wang Lin-ding 《中国病毒学》2007,22(3):248-255
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the primary etiological agent of Kaposi’s sarcoma, primary effusion lymphoma
and muticentric Castleman’s disease. In common with the other herpesviruses, KSHV exhibits both latent and lytic life cycles,
both of which are characterized by distinct gene expression profiles and programs. KSHV encodes proteins which play essential
roles in the inhibition of host adaptive and innate immunity, the inhibition of apoptosis, and the regulation of the cell
cycle. KSHV also encodes several proteins which have transforming and intrcellular signalling activity.
Foundation item: DAAD (Germany Academic Exchange Service) scholar. 相似文献
12.
The precise nature of the variation in cellular copper load against medium copper concentration is defined using a comprehensive logarithmically incremented series of medium copper concentrations ranging from low levels (4.8 p.p.b.) through normal to toxic levels (40 p.p.m.) in which fibroblasts were grown followed by determination of intracellular content. Menkes' fibroblasts showed an unexpected plateau region of stable intracellular copper content against a change in medium concentration of over 100-fold, albeit only when sufficient copper was present in the medium (0.08–8.0 p.p.m.). Thus, Menkes' cells are clearly capable of balancing uptake/efflux providing copper availability allows. Simultaneous analysis of cellular copper and zinc load at various medium copper concentrations shows an indistinguishable intracellular copper:zinc ratio between the two cell lines. The nature of non-labeled copper uptake by fibroblasts over a 40 min and 7 day period is reported. During the 40 min period copper uptake (20 p.p.m.) was essentially the same in both cell lines. However, copper absorbed was superimposed upon large pre-existing copper pools in the case of Menkes' cells only. Advantages of techniques determining non-labeled copper in copper uptake/efflux experiments are discussed in the light of these results. Fibroblast growth studies showed that, compared with normal cells, Menkes' cells are significantly (P < 0.01) more growth sensitive to extended exposure to low copper concentrations. Thus, Menkes' disease appears to be not only a result of copper maldistribution but also a direct result of an inability of Menkes' cells to function normally in low copper environments. 相似文献
13.
Federico Licastro Lizabeth Jane Davis Eugenio Mocchegiani Nicola Fabris 《Biological trace element research》1996,51(1):55-62
Plasma concentrations of a zinc carrier peptide, namely thymulin, were measured according to a bioassay in young donors, healthy
elderly, and patients with senile dementia of Alzheimer’s type (SDAT). Thymulin is a hormone released by thymic epithelial
cells and its biological activity on cells of immune system is dependent on the presence of one molecule of zinc bound to
the peptide. Plasma from different subjects were fractionated by gel filtration to yield protein-bound thymulin and free thymulin.
The biological activity of the peptide was then assessed in the two different fractions. The activity of protein-bound thymulin
was higher in young donors than in elderly of SDAT patients, being the lowest in SDAT. Addition of zinc ions to plasma fractions
increased the thymulin activity of samples from elderly and SDAT patients to levels observed in young donors. Thymulin activity
in free thymulin fractions was lower in the elderly than in the young and was practically undetectable in SDAT patients. The
addition of zinc ions normalized the activity of thymulin in these fractions from both the elderly and SDAT patients. These
findings confirm the presence of an altered zinc status in the elderly and suggest that an impaired zinc metabolism may be
present in SDAT patients. 相似文献
14.
The molecular determinants of Alzheimer''s (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca2+) and zinc (Zn2+). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-β dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca2+ and Zn2+ dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca2+ and Zn2+ rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca2+ and Zn2+ dyshomeostasis may offer a great opportunity for disease-modifying strategies. 相似文献
15.
G. Mielcarz A.N. Howard B. Mielcarz N.R. Williams J. Rajput-Williams S.V. Nigdigar D.L. Stone 《Journal of trace elements in medicine and biology》2001,15(1):31-35
To elucidate the relationship between leucocyte copper as a reliable, sensitive index of copper body status and extent of atherosclerosis in patients with Coronary Artery Disease (CAD) the present case-control study was carried out. 80 subjects were studied (23 females and 57 males), aged between 30-70, due to have a angiography. Individual angiograms were scored by combining the individual scores in all the major coronary arteries into one score of a scale 1.00 for patency to 0.00 for severe CAD. Serum and leucocyte copper and zinc were determined by GFAAS. No significant difference between patients with advanced CAD and relatively normal arteries were observed in the lipid profile and levels of plasma copper. Leucocyte copper had a significant link with the severity of atherosclerosis which was independent of sex. There was a linear relationship between the degree of decreasing leucocyte copper concentration and angiogram score. These findings give support to the hypothesis that marginal copper status, assessed by decreased leucocyte copper level, is associated with developing CAD. 相似文献
16.
Hee Y. Paik Hyojee Joung Joo Y. Lee Hong K. Lee Janet C. King Carl L. Keen 《Biological trace element research》1999,69(1):45-57
The present study focused on whether serum extracellular superoxide dimutase (EC-SOD) activity can be used as a functional
indicator of marginal zinc deficiency in humans. Subjects in this study were 444 healthy adults over 30 yr of age living a
normal rural life in Kyunggi province, Korea. The mean dietary zinc intake of subjects obtained from one 24-h recall was 6.41
± 4.35 mg and the average serum zinc concentration of the subjects was 11.06 ± 2.44 (μmol/L. Subjects were divided into three
groups by serum zinc concentrations: adequate (serum zinc >10.7 (μmol/L), low (serum zinc 9.0–10.7 μmol/L), and very low (serum
zinc <9.0 μmol/L) groups. A total of 50 subjects were selected from the three groups for analysis of EC-SOD activities. The
EC-SOD activity of subjects increased with increasing serum zinc concentrations, and the activities of the three groups were
significantly different as indicated by the Kruskal-Wallis test (p = 0.0239). Also, serum EC-SOD activities were significantly
correlated with serum zinc concentrations (r = 0.289,p = 0.04). Serum EC-SOD activities, however, were not significantly correlated to the dietary zinc intakes. In conclusion,
these results show that EC-SOD activities are decreased in subjects with low serum zinc concentrations and suggest that EC-SOD
activity may be a functional indicator of zinc nutritional status in humans. 相似文献
17.
Cristoph Renner Frank Hartmann M. Pfreundschuh 《Cancer immunology, immunotherapy : CII》1997,45(3-4):184-186
A group of 15 patients with refractory Hodgkin′s disease were treated in a phase I/II trial with the natural-killer (NK)-cell-activating
bispecific monoclonal antibody HRS-3/A9, which is directed against the Fcγ receptor III (CD16 antigen) and the Hodgkin’s associated
CD30 antigen. The antibody was given four times every 3 – 4 days, starting with 1 mg/m2. The treatment was well tolerated and the maximum tolerated dose was not reached at 64 mg/m2. Side-effects were rare and consisted of fever, pain in involved lymph nodes and a maculopapulous rash. Nine patients developed
human anti-(mouse immunoglobulin) antibodies. One complete and one partial remission (lasting 5 and 3 months, respectively),
three minor responses (1 to 11+ months), and one mixed response were achieved. There was no clear-cut dose side-effect or
dose/response correlation. NK cell activity increased in most of the patients treated with 4 mg/m2 or higher doses but lasted no longer than 6 weeks after therapy. Our results encourage further clinical trials with this novel
immunotherapeutic approach and emphasize the necessity to reduce the immunogenicity of the antibody to allow retreatment of
responding patients.
Accepted: 14 October 1997 相似文献
18.
Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene–environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, and prion diseases.) and discuss possible links of gene–environment interplay including, where implicated, mitochondrial genes. 相似文献
19.
The frequency of zinc deficiency, copper toxicity and low zinc/copper in children with autism spectrum disorders (ASDs) may indicate decrement in metallothionein system functioning. A retrospective review of plasma zinc, serum copper and zinc/copper was performed on data from 230 children with autistic disorder, pervasive developmental disorder-NOS and Asperger’s syndrome. The entire cohort’s mean zinc level was 77.2 μg dl?1, mean copper level was 131.5 μg dl?1, and mean Zn/Cu was 0.608, which was below the 0.7 cut-off of the lowest 2.5% of healthy children. The plasma zinc/serum copper ratio may be a biomarker of heavy metal, particularly mercury, toxicity in children with ASDs. 相似文献
20.
The abnormal assembly and deposition of specific proteins in the brain is the probable cause of most neurodegenerative disease
afflicting the elderly. These “cerebral proteopathies” include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s
disease (HD), prion diseases, and a variety of other disorders. Evidence is accumulating that the anomalous aggregation of
the proteins, and not a loss of protein function, is central to the pathogenesis of these diseases. Thus, therapeutic strategies
that reduce the production, accumulation, or polymerization of pathogenic proteins might be applicable to a wide range of
some of the most devastating diseases of old age. 相似文献