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1.  Serum copper and erythrocyte superoxide dismutase in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1982;41(5):458-462.
Serum copper and thiol levels an caeruloplasmin activity were determined and compared with measurements of articular index, erythrocyte sedimentation rate, and zinc and haemoglobin levels in patients with rheumatoid arthritis. Superoxide dismutase activity, thiol, zinc, and copper levels of haemolysate were measured and compared with each other and to the above parameters. In serum, caeruloplasmin activity increased and thiol levels decreased, whereas in the haemolysate superoxide dismutase activity decreased and thiol levels increased. It is suggested that the changes in copper levels and in the activities of process which may be copper-dependent between plasma and cytosol in patients with rheumatoid arthritis reflect a change in oxidative status of the blood which may have implications in the pathogenesis of the disease.
PMCID: PMC1001022  PMID: 7125714
2.  Plasma zinc and its relationship to clinical symptoms and drug treatment in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1980;39(4):329-332.
Total plasma zinc levels in patients with rheumatoid arthritis on different therapeutic treatments were determined in conjunction with total serum proteins, serum albumin and globulin, and articular index of joint tenderness, erythrocyte sedimentation rate, rheumatoid factor, serum copper, and serum iron. There were significantly lower zinc levels in patients with rheumatoid arthritis on nonsteroidal anti-inflammatory drugs than in patients on levamisole and penicillamine. Zinc levels correlated positively with serum albumin, and there was an inverse correlation between zinc levels and both ESR and globulin concentration in all rheumatoid patients. However, the correlation coefficient varied in the different treatment groups. The results of this study support the hypothesis that low plasma zinc level in rheumatoid arthritis is one of the nonspecific features of inflammation.
PMCID: PMC1000551  PMID: 7436558
3.  Wilson's disease: assessment of D-penicillamine treatment. 
Archives of Disease in Childhood  1985;60(7):652-655.
Serum copper and zinc concentrations and 24 hour urinary copper and zinc excretion were determined serially from the beginning of treatment with D-penicillamine in four children with Wilson's disease. The data show a progressive decrease in both serum copper and zinc concentrations in all. Urinary copper excretion gradually levelled off to approximately 50% of initial values, but zinc excretion increased. Urinary zinc:copper ratios therefore increased with the duration of treatment. Copper elimination was considered adequate as soon as challenge with a test dose of D-penicillamine did not result in an increase in copper excretion. Urinary zinc excretion was increased further by the test dose. Zinc depletion was suspected clinically in one patient on D-penicillamine maintenance treatment. Lowering the dose alleviated the symptoms, urinary zinc loss decreased from 64 to 34 mumol/24 hours, and copper excretion remained largely unchanged. Data obtained indicate that D-penicillamine alters the metabolism of both copper and zinc. The extent of this is not only dose dependent but is also related to the efficacy of copper elimination. Both copper and zinc concentrations must by monitored to assess the benefits of treatment and the risks of inducing manifest or subclinical zinc deficiency.
PMCID: PMC1777273  PMID: 4026361
4.  Evaluation of Serum Levels of Zinc, Copper, Iron, and Zinc/Copper Ratio in Cutaneous Leishmaniasis 
The purpose of this study was to evaluate the levels of zinc (Zn), copper (Cu), iron (Fe) and zinc/ copper ratio in the serum of patients with cutaneous leishmaniasis in Qom Province, center of Iran.
Serum levels of zinc and copper were determined by flame atomic absorption spectrophotometer and serum iron concentration was measured by using an Auto Analyzer. The study group consisted of 60 patients with cutaneous leishmaniasis and the control group of 100 healthy volunteers from the same area who were not exposed to cutaneous leishmaniasis.
There were no statistically significant differences in age and body mass index between the two groups. Serum Zn (P< 0.001) and Fe (P< 0.05) levels were lower in patients with cutaneous leishmaniasis than the control group. We also found serum Cu concentration (P< 0.05) in the patient group was significantly higher than that of the control group. However, zinc/ copper ratio (P< 0.001) was lower in patients with cutaneous leishmaniasis than in the control group.
Our data indicated that Zn/Cu ratio was significantly lower in patients with CL as compared to the controls. Earlier reports suggest that, this ratio imbalance could be a useful marker for immune dysfunction in leishmaniasis. There was also strong association of Zn, Cu and Fe with CL. It suggests the use of blood zinc, copper, iron concentration and the copper/zinc ratio (Zn/Cu), as a means for estimating the prognosis of CL.
PMCID: PMC3385530  PMID: 22808376
Cutaneous leishmaniasis; Zn; Cu; Fe; Zn/Cu ratio; Iran
5.  A Pilot Study on Zinc Levels in Patients with Rheumatoid Arthritis 
Biological Trace Element Research  2011;143(2):854-862.
The aim of the study was to evaluate zinc levels in three biological compartments (serum, erythrocytes and hair) in patients with rheumatoid arthritis (RA) as compared to healthy individuals. Zinc levels in serum, erythrocytes and hair (in 74 patients with RA and 30 healthy individuals) were assessed by atomic absorption spectroscopy. The mean hair zinc content was significantly lower in RA patients as compared to healthy individuals (p < 0.001). Moreover, a positive correlation was observed in the RA patient group between the erythrocyte zinc levels and the prednisone dose (rs = 0.48, p < 0.05), and a negative correlation was found in this population between the serum zinc levels and disease duration (rs = −0.42, p < 0.0006). In conclusion, it seems that hair may be a useful complementary study material for evaluating “zinc status” in rheumatoid arthritis patients.
PMCID: PMC3187853  PMID: 21279466
Rheumatoid arthritis; Zinc; Serum; Erythrocytes; Hair
6.  Serum thymulin in human zinc deficiency. 
Journal of Clinical Investigation  1988;82(4):1202-1210.
The activity of thymulin (a thymic hormone) is dependent on the presence of zinc in the molecule. We assayed serum thymulin activity in three models of mildly zinc-deficient (ZD) human subjects before and after zinc supplementation: (a) two human volunteers in whom a specific and mild zinc deficiency was induced by dietary means; (b) six mildly ZD adult sickle cell anemia (SCA) subjects; and (c) six mildly ZD adult non-SCA subjects. Their plasma zinc levels were normal and they showed no overt clinical manifestations of zinc deficiency. The diagnosis of mild zinc deficiency was based on the assay of zinc in lymphocytes, granulocytes, and platelets. Serum thymulin activity was decreased as a result of mild zinc deficiency and was corrected by in vivo and in vitro zinc supplementation, suggesting that this parameter was a sensitive indicator of zinc deficiency in humans. An increase in T101-, sIg-cells, decrease in T4+/T8+ ratio, and decreased IL 2 activity were observed in the experimental human model during the zinc depletion phase, all of which were corrected after repletion with zinc. Similar changes in lymphocyte subpopulation, correctable with zinc supplementation, were also observed in mildly ZD SCA subjects. Inasmuch as thymulin is known to induce intra- and extrathymic T cell differentiation, our studies provide a possible mechanism for the role of zinc on T cell functions.
PMCID: PMC442670  PMID: 3262625
7.  Zinc and Copper Status in Children with Beta-Thalassemia Major  
Iranian Journal of Pediatrics  2010;20(3):297-302.
There are some reports in which a condition of zinc deficiency and its associated outcomes with a change in concentration of serum copper among the thalassemic patients has been highlighted. The aim of this prospective study was to determine the serum zinc and copper levels in children with beta-thalassemia major.
In this cross sectional study all children under 12 years affected by beta thalassemia major (40 patients) were evaluated for serum zinc and copper levels in Qazvin thalassemia center (Qazvin, Iran) in 2007. Serum measurements for zinc and copper were performed by atomic absorption spectrophotometer.
The mean concentrations of serum zinc and copper levels were 67.35±20.38 and 152.42±24.17 µg/dl respectively. Twenty-six (65%) of thalassemic patients had zinc concentration under 70 µg/dl (hypozincemia). None of the thalassemic children had copper deficiency. No significant correlation between serum zinc level with age, weight, height, body mass index, duration of blood transfusion, desferrioxamine dose and ferritin level was observed in thalassemic patients (P=0.3).
This study revealed that hypozincemia is common in thalassemic patients, but in contrast, there is no copper deficiency. Further evaluation in this regard is recommended.
PMCID: PMC3446035  PMID: 23056720
Beta-thalassemia; Zinc; Copper; Children
8.  Thrombocytosis of active rheumatoid disease. 
Annals of the Rheumatic Diseases  1983;42(5):545-549.
Two cross-sectional and one longitudinal study of patients with rheumatoid arthritis showed that platelet number correlated with both clinical and laboratory parameters of disease activity, including erythrocyte sedimentation rate, zeta sedimentation ratio, viscosity of plasma and blood, white cell count, liver enzymes, rheumatoid factor, and several acute-phase proteins. There was also an inverse relationship between platelet number and the haemoglobin and serum albumin levels. III Indium-labelled platelet survival was reduced in 4 patients with active rheumatoid arthritis despite a raised platelet count, with labelled platelets being localised to inflamed joints in the 2 patients studied. Platelet aggregation was normal. We suggest that the raised platelet count of active rheumatoid arthritis may be a useful index of disease activity and may represent a bone marrow stress (syndrome) response to shortened platelet survival, with platelet sequestration occurring in areas of synovial inflammation.
PMCID: PMC1001293  PMID: 6605121
9.  Relationship between Painful Crisis and Serum Zinc Level in Children with Sickle Cell Anaemia 
Anemia  2010;2011:698586.
Sickle cell anaemia (SCA) is associated with zinc deficiency; zinc supplementation may ameliorate some of its clinical manifestations including the relief of painful crisis. Subjects and Methods. Serum zinc levels were determined in 71 children with SCA and painful crisis and in equal numbers in steady state. Seventy-one children with AA genotype acted as controls. Qualitative assessment of zinc content of 24-hour dietary recall and the last meal consumed before blood was drawn was taken. Serum zinc was determined using atomic absorption spectrophotometer. Haemoglobin concentration and packed cell volume (PCV) were determined using standard methods. Results. The mean serum zinc concentration in the study was less than international reference range. The controls had significantly higher serum zinc concentrations than the SCA group (42.7 ± 13.6 versus 32.3 ± 14.0 μg/dL, P < .000); this difference was due to the significantly lower values of serum zinc in SCA with painful crisis compared with the remaining two groups F = 30.9, P<.000. There was a positive correlation between serum zinc and haemoglobin concentration only in the control group (r = 0.4; P = .001). Conclusion. The serum zinc levels in this study were low. Painful crisis in SCA may exert greater demand for zinc utilization in children with SCA thereby resulting in lower serum levels.
PMCID: PMC3065914  PMID: 21490764
10.  Serum copper: a marker of disease activity in rheumatoid arthritis. 
Journal of Clinical Pathology  1983;36(1):14-17.
Serum copper concentrations were measured in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), osteoarthritis (OA), and in healthy controls. Median serum copper concentrations were raised significantly in RA and AS, but not in OA. Serum copper in RA correlated significantly with a number of disease activity markers--for example erythrocyte sedimentation rate (ESR), C-reactive protein, haemoglobin concentration, morning stiffness, and grip strength. It also correlated well with the overall disease activity as assessed by a composite index. Raised serum copper was associated with severe RA as manifested by the presence of immunoglobulin M rheumatoid factor, extra-articular features, weak grip and highly active disease. High serum copper might be related to the development of the pathological lesions observed in RA and not just be a secondary response.
PMCID: PMC498097  PMID: 6822675
11.  The Relationship Between Serum Lipid Profile and Selected Trace Elements for Adult Men in Mosul City 
Oman Medical Journal  2012;27(4):300-303.
To evaluate the correlations of the serum concentrations of copper, zinc, and manganese with lipid profile parameters of adult men in Mosul City, Iraq.
The study included 51 apparently healthy adult men as a control group aged 34-62 years (group 1), and 31 hyperlipidemic patients aged 37-60 years (group 2). Trace elements copper, zinc and manganese were determined using atomic absorption spectrometry. Concentrations of total cholesterol, triglyceride and high density lipoprotein cholesterol were determined using enzymatic method. Indirect serum concentration of low-density lipoprotein cholesterol were calculated via the Friedewald formula. Data were evaluated as mean and standard deviation by analysis of variance (ANOVA) and t-test.
The results indicated that there is a significant lower level of serum zinc in hyperlipidemic patients compared with the control group, while copper and manganese showed no significant differences between the two groups. A significant negative correlation was found between serum zinc and total cholesterol, low-density lipoprotein cholesterol, triglyceride and low/high-density lipoprotein cholesterol ratio; while a significant positive correlation was found between serum zinc and high density lipoprotein cholesterol. In addition, a significant positive correlation between copper and triglyceride existed in the patient group, while the control group showed no such correlation.
Hyperlipidemia may possibly be related to a decrease in the level of serum zinc in hyperlipidemic adult men. The data also supports the concept that zinc supplementation might be useful in improving metabolic complications in subjects with hyperlipidemia.
PMCID: PMC3464753  PMID: 23071882
Lipid profile; Trace elements; Hyperlipidemic patient
12.  Oral zinc sulphate for Wilson's disease. 
Archives of Disease in Childhood  1985;60(7):656-659.
After initial promotion of copper excretion with D-penicillamine, the effect of oral zinc sulphate (3 X 150 mg/day, loading dose; 3 X 100 mg/day, maintenance dose) in two children with clinically stable Wilson's disease was evaluated after completion of three years' treatment. The course, judged by clinical, biochemical, and histological parameters was satisfactory in both. The urinary copper concentration reverted to less than 1.26 mumol/24 hours; and the serum copper concentration decreased further during zinc sulphate treatment. In one child the rise in 24 hour urinary copper excretion observed after a challenge dose of D-penicillamine (+/- 20 mg/kg) remained constant throughout the period of observation while the liver copper content fell from 1460 micrograms/g dry weight to 890 micrograms/g dry weight. In the other patient, however, the liver copper content as well as the 24 hour urinary copper excretion increased after D-penicillamine challenge during the third year of treatment. We conclude that zinc sulphate is a low toxic and well tolerated alternative for D-penicillamine. The dosage depends, however, on individual factors not yet well understood, and we recommend restriction of its use to patients who do not tolerate D-penicillamine well. We suggest monitoring of treatment with yearly D-penicillamine challenge and a liver biopsy if liver function deteriorates.
PMCID: PMC1777290  PMID: 4026362
13.  Evaluation and comparison of zinc absorption level from 2-Alkyle 3-Hydroxy pyranon-zinc complexes and zinc sulfate in rat in vivo 
Although zinc sulfate has been used to improve disorders originated from zinc deficiency, its low compliance is due to gastrointestinal complications; therefore, other zinc compounds have been suggested as replacers for zinc deficient people. The objective of this study was to evaluate and compare the absorption of ethyl and methyl zinc-maltol with that of zinc sulfate to substitute zinc sulfate with those complexes.
Materials and Methods:
After five weeks of being fed by zinc deficient food, zinc deficient rats were divided into four groups randomly receiving medicinal solutions of zinc sulfate, zinc ethyl maltol and zinc methyl maltol using feeding tube method for two weeks while the control was received distilled water. Serum zinc concentration and ALP (Alkaline Phosphatase) and LDH (Lactate Dehydrogenase) activity of rats were determined before and after the study. Statistical analyses were performed using SPSS 11.5. The study was conducted from 2008 to 2010.
Serum zinc concentration and enzyme activity in all groups receiving drug solution increased. The most and least increase were in zinc sulfate and zinc methyl maltol groups, respectively. The difference between zinc methyl maltol and zinc sulfate group was significant (P < 0.05); however, this difference was not significant in the case of zinc ethyl maltol.
Zinc ethyl maltol can be a suitable and preferable substitute for zinc sulfate.
PMCID: PMC3814584  PMID: 24223392
Alkaline phosphatase; Lactate dehydrogenase; zinc ethyl maltol; zinc intestinal absorption; zinc methyl maltol; zinc sulfate
14.  Serum antioxidant micromineral (Cu, Zn, Fe) status of drug dependent subjects: Influence of illicit drugs and lifestyle 
Use of illicit drugs induces multiple nutrient deficiencies. Drug habit, sexual practice and socioeconomic factors influence the nutrient profile of drug dependent subjects. The literature on this issue is still insufficient. This study has tested the hypothesis that illicit drug use and lifestyle impair mineral status. To test this hypothesis, 253 men multiple drug users of age 18–45 years were recruited to investigate their serum copper, zinc and iron levels. Influence of illicit drugs and their lifestyle on the mineral levels was also examined. The study subjects were drug dependent who had shared needles and had sexual activity with multiple partners. Serum concentrations of the minerals were estimated by atomic absorption flame spectrometry.
Results showed a significant increase in serum copper and zinc concentrations, and decrease in iron level in drug dependent subjects. The increase of copper level was found to be much higher than that of zinc. Period of drug abuse had made a significant positive influence on the copper and iron levels, but it was apparently reversed for zinc concentration. Multiple sexual partnerships had significant influence on zinc status. There also were significant relationships observed between body mass index (BMI) as well as certain socioeconomic factors, and mineral status of drug dependent subjects and non-drug dependent controls. A series of multiple linear regression analysis predicted mineral values for education, age and BMI. The group (drug dependent subject = 1, non-drug dependent control = 2) had a significant influence on these parameters. However, after controlling these factors, it was shown that illicit drug use significantly contributed to influence the serum mineral levels.
Illicit drug use impairs serum mineral value causing an increase in copper and zinc and a decrease in iron. Lifestyle and nutritional status of drug dependent subjects influence serum mineral concentrations.
PMCID: PMC1872021  PMID: 17417973
15.  The Effect of Five-Year Zinc Supplementation on Serum Zinc, Serum Cholesterol and Hematocrit in Persons Randomly Assigned to Treatment Group in the Age-Related Eye Disease Study: AREDS Report No. 71 
The Journal of nutrition  2002;132(4):697-702.
The effects of long-term supplementation with pharmacologic doses of zinc oxide on serum levels of zinc, lipids and hematocrit have not been studied systematically to date. Eleven Clinical Centers enrolled 4757 participants from 1992 to 1998 as part of the Age-Related Eye Disease Study (AREDS). Of these, 3640 participants, aged 55–80 y, who had early-to-late age-related macular degeneration (AMD) were randomly assigned to daily supplementation with or without 80 mg of zinc as zinc oxide plus 2 mg of copper as cupric oxide to study the effects of zinc supplementation on the progression to late AMD. This paper reports on the effect of a 5-y supplementation with zinc oxide and cupric oxide on serum zinc, copper, lipids, and hematocrit for 717 participants from three clinical centers. At the 5-y exam, the median increase in serum zinc levels for participants assigned to zinc formulations was 17% compared with a 2% increase for participants not assigned to zinc (P < 0.001). The differential effect on serum zinc was observed at 1 y and remained fairly constant over the 5-y period. After 5 y, no significant differences in changes in serum hematocrit, copper or lipids were found between participants assigned to formulations containing zinc and copper, and those assigned to formulations without zinc and copper. Estimates from a modified Block Food-Frequency Questionnaire suggest the AREDS population at baseline had a zinc intake from diet similar to that of the general population.
PMCID: PMC1464086  PMID: 11925463
AREDS; zinc oxide; cupric oxide; serum cholesterol; randomized trial; humans
16.  Zinc and its importance for human health: An integrative review 
Since its first discovery in an Iranian male in 1961, zinc deficiency in humans is now known to be an important malnutrition problem world-wide. It is more prevalent in areas of high cereal and low animal food consumption. The diet may not necessarily be low in zinc, but its bio-availability plays a major role in its absorption. Phytic acid is the main known inhibitor of zinc. Compared to adults, infants, children, adolescents, pregnant, and lactating women have increased requirements for zinc and thus, are at increased risk of zinc depletion. Zinc deficiency during growth periods results in growth failure. Epidermal, gastrointestinal, central nervous, immune, skeletal, and reproductive systems are the organs most affected clinically by zinc deficiency. Clinical diagnosis of marginal Zn deficiency in humans remains problematic. So far, blood plasma/serum zinc concentration, dietary intake, and stunting prevalence are the best known indicators of zinc deficiency. Four main intervention strategies for combating zinc deficiency include dietary modification/diversification, supplementation, fortification, and bio-fortification. The choice of each method depends on the availability of resources, technical feasibility, target group, and social acceptance. In this paper, we provide a review on zinc biochemical and physiological functions, metabolism including, absorption, excretion, and homeostasis, zinc bio-availability (inhibitors and enhancers), human requirement, groups at high-risk, consequences and causes of zinc deficiency, evaluation of zinc status, and prevention strategies of zinc deficiency.
PMCID: PMC3724376  PMID: 23914218
Zinc absorption; zinc bio-availability; zinc deficiency; zinc intervention; zinc nutrition; zinc requirement
17.  Randomized Controlled Clinical Trial of Zinc Supplementation to Prevent Immunological Failure in HIV-Positive Adults1,2 
Adequate zinc is critical for immune function; however, zinc deficiency occurs in >50% of HIV-infected adults. We examined the safety and efficacy of long-term zinc supplementation on HIV disease progression.
A prospective randomized controlled clinical trial was conducted with 231 HIV+ adults with low plasma zinc levels (<0.75 μg/ml), randomly assigned into zinc (12 mg of elemental zinc for women and 15 mg for men) or placebo, for 18 months. The primary endpoint was immunological failure. HIV-viral load and CD4+ cell count were determined every 6 months. Questionnaires, pill-counts, plasma zinc and C-reactive protein (hsCRP) were used to monitor adherence with study supplements and ART. Intent-to-treat analysis utilized multiple-event analysis, treating CD4+ cell count <200 cells/mm3 as recurrent immunological failure event. Cox proportional-hazard models and the general-linear model were used to analyze morbidity and mortality data.
Zinc supplementation for 18 months reduced four-fold the likelihood of immunological failure, controlling for age, gender, lack of food, baseline CD4+ cell count, viral load, and antiretroviral therapy (RR=0.24[95%CI:0.10,0.56],p<0.002). Viral load indicated poor control with ART but was not affected by zinc supplementation. Zinc supplementation also reduced the rate of diarrhea by more than half (OR=0.4[95%CI:0.183-0.981],p=0.019) compared to placebo. There was no significant difference in mortality between the two groups.
This study demonstrated that long-term (18-month) zinc supplementation at nutritional levels delayed immunological failure and decreased diarrhea over time. This evidence supports the use of zinc supplementation as an adjunct therapy in HIV+ adult cohorts with poor viral control.
This study demonstrated that long-term (18-month) zinc supplementation at nutritional levels delayed immunological failure and decreased diarrhea over time. This evidence supports the use of zinc supplementation as an adjunct therapy in HIV+ adult cohorts with poor viral control.
PMCID: PMC2874106  PMID: 20455705
zinc supplementation; immunological failure; diarrhea; HIV disease progression
18.  Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran 
The combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemic patients. The main objective of this study is to determine the prevalence of prominent thalassemia complications.
Two hundred twenty patients entered the study. Physicians collected demographic and anthropometric data and the history of therapies as well as menstrual histories. Patients have been examined to determine their pubertal status. Serum levels of 25(OH) D, calcium, phosphate, iPTH were measured. Thyroid function was assessed by T3, T4 and TSH. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry. Bone mineral density (BMD) measurements at lumbar and femoral regions have been done using dual x-ray absorptiometry. The dietary calcium, zinc and copper intakes were estimated by food-frequency questionnaires.
Short stature was seen in 39.3% of our patients. Hypogonadism was seen in 22.9% of boys and 12.2% of girls. Hypoparathyroidism and primary hypothyroidism was present in 7.6% and 7.7% of the patients. About 13 % of patients had more than one endocrine complication with mean serum ferritin of 1678 ± 955 micrograms/lit. Prevalence of lumbar osteoporosis and osteopenia were 50.7% and 39.4%. Femoral osteoporosis and osteopenia were present in 10.8% and 36.9% of the patients. Lumbar BMD abnormalities were associated with duration of chelation therapy. Low serum zinc and copper was observed in 79.6% and 68% of the study population respectively. Serum zinc showed significant association with lumbar but not femoral BMD. In 37.2% of patients serum levels of 25(OH) D below 23 nmol/l were detected.
High prevalence of complications among our thalassemics signifies the importance of more detailed studies along with therapeutic interventions.
PMCID: PMC194672  PMID: 12914670
19.  Glutamate-Mediated Primary Somatosensory Cortex Excitability Correlated with Circulating Copper and Ceruloplasmin 
Objective. To verify whether markers of metal homeostasis are related to a magnetoencephalographic index representative of glutamate-mediated excitability of the primary somatosensory cortex. The index is identified as the source strength of the earliest component (M20) of the somatosensory magnetic fields (SEFs) evoked by right median nerve stimulation at wrist. Method. Thirty healthy right-handed subjects (51 ± 22 years) were enrolled in the study. A source reconstruction algorithm was applied to assess the amount of synchronously activated neurons subtending the M20 and the following SEF component (M30), which is generated by two independent contributions of gabaergic and glutamatergic transmission. Serum copper, ceruloplasmin, iron, transferrin, transferrin saturation, and zinc levels were measured. Results. Total copper and ceruloplasmin negatively correlated with the M20 source strength. Conclusion. This pilot study suggests that higher level of body copper reserve, as marked by ceruloplasmin variations, parallels lower cortical glutamatergic responsiveness.
PMCID: PMC3227495  PMID: 22145081
20.  High-dose intravenous methylprednisolone in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1982;41(5):444-446.
Fourteen patients with severe rheumatoid arthritis (RA) were given 27 courses of methylprednisolone intravenously, each of 3 infusions of 1 g on alternate days. After 7 days there was marked improvement in clinical state and most laboratory tests; levels of ESR and 4 serum acute-phase proteins, C3, C, IgG, and IgA, fell significantly. Serum IgM and rheumatoid factor titre were unchanged. 125I C1q binding fell in all instances where it was initially raised. Clinical remission lasted a mean of 10 weeks. Serum C-reactive protein (CRP) fell to less than 30 mg/l after all courses except one within 7 days and rose above this figure after a mean of 7 weeks. The ESR fell below 30 mm/h within seven days in 17 courses and remained below this value for a mean of 7 weeks. Three patients had clinical remissions, with serum CRP less than 30 mg/l and ESR less than 30 mm/h, lasting more than 42 weeks.
PMCID: PMC1001018  PMID: 7125712
21.  Zinc and Copper Concentrations in Human Milk and Infant Formulas 
Iranian Journal of Pediatrics  2010;20(1):53-57.
Available accurate data on the concentrations of copper (Cu) and zinc (Zn) in human milk throughout lactation and infant formulas is important both for formulating nutritional requirements for substances and to provide a base line for the understanding the physiology of their secretion. The objective of this study was to analyze the concentrations of zinc and copper in infant formulas and human milk during prolonged lactation. Levels of these metals were examined in relation to selected parameters such as age, weight, height, education and occupation of mothers.
Thirty mothers referred to the selected clinics in Tehran entered the study. Human milk samples were collected at 2 months postpartum. Zinc and copper concentrations were determined by atomic absorption spectrophotometer.
The mean values of Zn and Cu in human milk were 2.95±0.77mg/L and 0.36±0.11 mg/L. The mean values of Zn and Cu in infant formulas were 3.98±0.25 mg/L and 0.53±0.17mg/L.
No significant relationship was found between levels of trace elements in human milk and evaluated parameters such as age, weight, height, education and occupation of mothers. The concentrations of zinc and copper in breast milk were lower than those reported in the literature.
PMCID: PMC3446000  PMID: 23056682
Human milk; Infant formula; Zinc; Copper; Breast milk; Nutritional requirements
22.  A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation 
PLoS Medicine  2010;7(9):e1000341.
A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation.
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.
Methods and Findings
We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1–50.0) for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Please see later in the article for the Editors' Summary
Editors' Summary
C-reactive protein (CRP) is a serum marker for inflammation or infection and acts by binding to a chemical (phosphocholine) found on the surface of dead or dying cells (and some types of bacteria) in order to activate the immune system (via the complement system). Fat cells release factors that stimulate the liver to produce CRP, and serum levels greater than 10 mg/l are generally considered indicative of an infectious or inflammatory process. After an inflammatory stimulus, serum CRP levels may exceed 500 times baseline, so CRP is used in all medical specialities to help diagnose inflammation and infection. Although patients with chronic inflammatory diseases, such as rheumatoid arthritis, have raised levels of CRP, levels of CRP are still highly variable. Some studies have suggested that there may be genetic variations of CRP (CRP variants) that determine the magnitude of the acute-phase CRP response, a finding that has important clinical implications: CRP thresholds are used as a diagnostic component of formal clinical algorithms and play an important role in a clinician's decision-making process when diagnosing inflammatory disease and choosing treatment options. Therefore, it is possible that false reassurance could be given to a patient with disease, or optimal treatment withheld, because some patients are genetically predisposed to have only a modest increase in acute-phase CRP.
Why Was This Study Done?
Although some studies have looked at the CRP gene variant response, few, if any, studies have examined the CRP gene variant response in the context of chronic inflammation, such as in rheumatoid arthritis. Therefore, this study aimed to determine whether CRP gene variants could also influence CRP serum levels in rheumatoid arthritis.
What Did the Researchers Do and Find?
The authors studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients): one patient set used a cohort of 281 patients in the UK, and the other patient set (used for replication) consisted of 414 patients from New Zealand and Australia. A genetic technique (a tagSNP approach) was used to capture common variations at the CRP locus (haplotype association analysis) at both the population and the individual level. The relationship between genotype and serum CRP was explored by linear modeling. The researchers found that common genetic variants at the CRP locus were associated with acute-phase serum CRP in both patient sets translating into an approximate 3.5-fold change in expected serum CRP between carriers of two common CRP variants. For example, when ESR = 50 mm/h the expected CRP serum level for one common CRP variant was 43.1 mg/l and for another CRP variant was 14.2 mg/l.
What Do These Findings Mean?
The findings of this study raise questions about the interpretation of acute-phase serum CRP, as they suggest that there is a significant association between CRP variants and acute-phase serum CRP concentrations in a group of patients with rheumatoid arthritis, including those with chronic active inflammation. The size of the genetic effect may be large enough to have a clinically relevant impact on the assessment of inflammatory disease activity, which in turn may influence therapeutic decision making. Failure to take into account the potential for genetic effects may result in the inappropriate reassurance or undertreatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events, so these findings impact on the use of such algorithms. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Additional Information
Please access these Web sites via the online version of this summary at
Lab Test Online provides information on CRP
The Wellcome Trust provides a glossary of genetic terms
Learn.Genetics provides access to the Genetic Science Learning Center, which is part of the human genome project
PMCID: PMC2943443  PMID: 20877716
23.  A Family Knockout of All Four Drosophila Metallothioneins Reveals a Central Role in Copper Homeostasis and Detoxification†  
Molecular and Cellular Biology  2006;26(6):2286-2296.
Metallothioneins are ubiquitous, small, cysteine-rich proteins with the ability to bind heavy metals. In spite of their biochemical characterization, their in vivo function remains elusive. Here, we report the generation of a metallothionein gene family knockout in Drosophila melanogaster by targeted disruption of all four genes (MtnA to -D). These flies are viable if raised in standard laboratory food. During development, however, they are highly sensitive to copper, cadmium, and (to a lesser extent) zinc load. Metallothionein expression is particularly important for male viability; while copper load during development affects males and females equally, adult males lacking metallothioneins display a severely reduced life span, possibly due to copper-mediated oxidative stress. Using various reporter gene constructs, we find that different metallothioneins are expressed with virtually the same tissue specificity in larvae, notably in the intestinal tract at sites of metal accumulation, including the midgut's “copper cells.” The same expression pattern is observed with a synthetic minipromoter consisting only of four tandem metal response elements. From these and other experiments, we conclude that tissue specificity of metallothionein expression is a consequence, rather than a cause, of metal distribution in the organism. The bright orange luminescence of copper accumulated in copper cells of the midgut is severely reduced in the metallothionein gene family knockout, as well as in mutants of metal-responsive transcription factor 1 (MTF-1), the main regulator of metallothionein expression. This indicates that an in vivo metallothionein-copper complex forms the basis of this luminescence. Strikingly, metallothionein mutants show an increased, MTF-1-dependent induction of metallothionein promoters in response to copper, cadmium, silver, zinc, and mercury. We conclude that free metal, but not metallothionein-bound metal, triggers the activation of MTF-1 and that metallothioneins regulate their own expression by a negative feedback loop.
PMCID: PMC1430275  PMID: 16508004
24.  Serum Copper, Zinc and Copper/Zinc Ratio and their Relationship to Age and Growth Status in Yemeni Adolescent Girls 
As no previous study has evaluated copper and zinc status in adolescent Yemeni girls, the purpose of this study was to measure their serum levels of zinc and copper and to examine the relationship between the serum levels of these two trace minerals with age, and anthropometric parameters.
The study was conducted in April 2007 in Alwehda district in the municipality of Sana’a, Yemen. One hundred and fourteen adolescent girls were selected using systematic stratified sampling from a representative school which was randomly selected. Anthropometric indices were measured and blood samples were collected for biochemical analysis.
The mean ±SD for copper, zinc, and copper/zinc ratio for the entire cohort were 17.47±3.31 μmol/L, 12.24±1.04 μmol/L, and 1.44±0.31, respectively. The prevalence of hypocuprimea was 4.4% and hypercuprimea was 2.6%. The levels of zinc were marginal in 96.5% of the girls and the prevalence of hypozincimea was 3.5%. The levels of copper were significantly higher (p = 0.007) and the levels of zinc were significantly lower (p = 0.003) in the 10–12 yrs girls than in other age groups. Height showed significant negative correlation with the levels of copper (p = 0.01) and significant positive correlation with the levels of zinc (p = 0.008).
The results revealed that the Yemeni girls had marginal serum zinc levels, and 10–12 yrs girls had significantly lower zinc levels than other age groups. This provides a warning of consequent negative health effects since the physiological requirements for zinc are high in adolescence.
PMCID: PMC3074839  PMID: 21748074
Copper; Zinc; Copper/zinc ratio; Growth; Adolescent girls; Yemen
25.  Wilson disease: Histopathological correlations with treatment on follow-up liver biopsies 
AIM: To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease (WD) patients.
METHODS: We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent multiple follow-up liver biopsies. Demographic, clinical and laboratory data were gathered and all patients underwent an initial biopsy and at least one repeat biopsy.
RESULTS: Time to repeat biopsy ranged from 2 to 12 years. Six patients (non-progressors) showed stable hepatic histology or improvement. In one case, we observed improvement of fibrosis from stage 2 to 0. Six patients (progressors) had worsening of fibrosis. There was no significant correlation between the histological findings and serum aminotransferases or copper metabolism parameters. The hepatic copper concentration reached normal levels in only two patients: one from the non-progressors and one from the progressors group. The estimated rate of progression of hepatic fibrosis in the entire group was 0 units per year in the time frame between the first and the second liver biopsy (4 years), and 0.25 between the second and the third (3 years). In the progressors group, the rate of progression of liver fibrosis was estimated at 0.11 fibrosis units per year between the first and second biopsy and, 0.6 fibrosis units between the second and third biopsy.
CONCLUSION: The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered.
PMCID: PMC2846254  PMID: 20333789
Wilson disease; Copper; Liver biopsy; Histopathology

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