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1.  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.
Background
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.
Conclusions
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 http://dx.doi.org/10.1371/journal.pmed.1000341
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
doi:10.1371/journal.pmed.1000341
PMCID: PMC2943443  PMID: 20877716
2.  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
3.  Serum antioxidant micromineral (Cu, Zn, Fe) status of drug dependent subjects: Influence of illicit drugs and lifestyle 
Background
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
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.
Conclusion
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.
doi:10.1186/1747-597X-2-12
PMCID: PMC1872021  PMID: 17417973
4.  Associations between Serum C-reactive Protein and Serum Zinc, Ferritin, and Copper in Guatemalan School Children 
Biological trace element research  2012;148(2):154-160.
Inflammation affects trace nutrient concentrations, but research on copper and particularly in children is limited. We assessed associations between serum C-reactive protein (CRP) and zinc, iron, copper, and other biomarkers (alkaline phosphatase, hemoglobin, and albumin), in 634 healthy 6- to 11-year-old Guatemalan schoolchildren. CRP was measured by a standardized, high-sensitive method. For significant associations with CRP, we stratified nutrient concentrations across categories of CRP and compared concentrations above and below several CRP cutoff points (0.5, 1, 3, 5, and 10 mg/L), and then adjusted values using correction factors (ratios of geometric means of the nutrients in the low and high groups). Prevalence of serum zinc (<65 μg/dL0, ferritin (<15 μg/L), and copper (<90 μg/dL) deficiency were 21%, 2.1%, and 23.8%, respectively. Median (25th and 75th percentiles) CRP was 0.56 (0.26 and 1.54) mg/L. CRP concentration was positively associated with ferritin and copper concentrations (r=0.23 and 0.29, respectively; P<0.0001) but not with zinc and other bio-markers (P>0.05). Regardless of CRP cutoffs, high (> cutoff) vs. low (≤ cutoff) CRP levels had higher ferritin and copper concentrations and lower prevalence of copper deficiency of <90 μg/dL (P<0.05). Adjustment for inflammation had the greatest influence on recalculated prevalence for the CRP 0.5 mg/L cutoff. The low ferritin prevalence hardly changed (from 2.1% to 2.5%) while the low copper prevalence changed appreciably (from 23.8% to 31.2%). In conclusion, CRP was positively associated with ferritin and copper but not with zinc concentrations. Adjustment for inflammation had little effect on low ferritin prevalence, low to begin with, and a large impact on low copper prevalence. High-sensitive CRP methods and the use of very low CRP cutoffs may be more accurate than traditional CRP methods in the adjustment of serum copper concentrations for inflammation in healthy school children.
doi:10.1007/s12011-012-9358-0
PMCID: PMC3734531  PMID: 22354676
Inflammation; C-reactive protein; School children; Ferritin; Zinc; Copper
5.  Copper deficiency myelopathy 
Journal of Neurology  2010;257(6):869-881.
Acquired copper deficiency has been recognised as a rare cause of anaemia and neutropenia for over half a century. Copper deficiency myelopathy (CDM) was only described within the last decade, and represents a treatable cause of non-compressive myelopathy which closely mimics subacute combined degeneration due to vitamin B12 deficiency. Here, 55 case reports from the literature are reviewed regarding their demographics, aetiology, haematological and biochemical parameters, spinal imaging, treatment and outcome. The pathophysiology of disorders of copper metabolism is discussed. CDM most frequently presented in the fifth and sixth decades and was more common in women (F:M = 3.6:1). Risk factors included previous upper gastrointestinal surgery, zinc overload and malabsorption syndromes, all of which impair copper absorption in the upper gastrointestinal tract. No aetiology was established in 20% of cases. High zinc levels were detected in some cases not considered to have primary zinc overload, and in this situation the contribution of zinc to the copper deficiency state remained unclear. Cytopenias were found in 78%, particularly anaemia, and a myelodysplastic syndrome may have been falsely diagnosed in the past. Spinal MRI was abnormal in 47% and usually showed high T2 signal in the posterior cervical and thoracic cord. In a clinically compatible case, CDM may be suggested by the presence of one or more risk factors and/or cytopenias. Low serum copper and caeruloplasmin levels confirmed the diagnosis and, in contrast to Wilson’s disease, urinary copper levels were typically low. Treatment comprised copper supplementation and modification of any risk factors, and led to haematological normalisation and neurological improvement or stabilisation. Since any neurological recovery was partial and case numbers of CDM will continue to rise with the growing use of bariatric gastrointestinal surgery, clinical vigilance will remain the key to minimising neurological sequelae. Recommendations for treatment and prevention are made.
doi:10.1007/s00415-010-5511-x
PMCID: PMC3691478  PMID: 20232210
Anaemia; Copper deficiency; Spinal cord disease; Subacute combined degeneration; Vitamin B12 deficiency
6.  Significance of plasma copper and caeruloplasmin concentrations in rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1975;34(2):162-165.
To understand the role of copper in initiating protein alterations in rheumatoid arthritis (RA) as reported previously, concentrations of copper anc caeruloplasmin were determined in RA patients. The mean copper concentration of the RA population examined was 24.8 mumol/l (157.5 mug/100 ml), and the mean caeruloplasmin concentration in this RA population was 45.52 mg/100 ml. These values are not different from those reported by previous workers. However, when the RA population was divided into three groups according to sex and oestrogen therapy it was found that caeruloplasmin and copper concentrations in the group of female RA patients on oestrogens was significantly different from other groups (P less than 0.001). A highly significant (P less than 0.01) positive correlation was obtained between copper and caeruloplasmin concentrations (r = 0.91). Concentrations of copper and caeruloplasmin failed to explain the low sulphydryl content of plasma which was observed to be independent of these two parameters. Increased alpha2-globulin concentration, which was refractory to chrysotherapy but 'finger-printed' with a pure preparation of caeruloplasmin in electrophoresis, along with the absence of Kayser-Fleischer rings, supports the contention that copper is not present in a free ionic state in RA patients. This study shows that only a concurrent oestrogen therapy raises copper and caeruloplasmin concentration significantly in a female RA population. Past investigators appear to have overlooked this fact, and it could be that a disproportionate sex distribution (more female rheumatoid arthritics) could cause misleading results in RA studies. The role of oestrogens, copper, and caeruloplasmin in causing exacerbation of RA symptoms is discussed.
PMCID: PMC1006365  PMID: 49178
7.  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
8.  Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart 
Previous studies have shown that cardiac-specific overexpression of metallothionein (MT) inhibits progression of dietary copper restriction-induced cardiac hypertrophy. Because copper and zinc are critically involved in myocardial response to dietary copper restriction, the present study was undertaken to understand the effect of MT on the status of copper and zinc in the heart and the subsequent response to dietary copper restriction. Dams of cardiac-specific MT-transgenic (MT-TG) mouse pups and wild-type (WT) littermates were fed copper-adequate or copper-deficient diet starting on the fourth day post delivery and the weanling mice were continued on the same diet until they were sacrificed. Zinc and copper concentrations were significantly elevated in MT-TG mouse heart, but the extent of zinc elevation was much more than copper. Dietary copper restriction significantly decreased copper concentrations to the same extent in both MT-TG and WT mouse hearts, and decreased zinc concentrations along with a decrease in MT concentrations in the MT-TG mouse heart. Copper deficiency-induced heart hypertrophy was significantly inhibited, but copper deficiency-induced suppression of serum ceruloplasmin or hepatic Cu,Zn-SOD activities were not inhibited in the MT-TG mice. These results suggest that elevation in zinc but not copper in the heart may be involved in the MT inhibition of copper deficiency-induced cardiac hypertrophy.
doi:10.1016/j.jnutbio.2006.10.009
PMCID: PMC2572149  PMID: 17707633
copper; zinc; heart hypertrophy; metallothionein; transgenic mice
9.  Evaluation of Serum Levels of Zinc, Copper, Iron, and Zinc/Copper Ratio in Cutaneous Leishmaniasis 
Background:
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.
Methods:
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.
Result:
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.
Conclusion:
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
10.  Activity of Metal-Responsive Transcription Factor 1 by Toxic Heavy Metals and H2O2 In Vitro Is Modulated by Metallothionein 
Molecular and Cellular Biology  2003;23(23):8471-8485.
Metallothioneins are small, cysteine-rich proteins that avidly bind heavy metals such as zinc, copper, and cadmium to reduce their concentration to a physiological or nontoxic level. Metallothionein gene transcription is induced by several stimuli, notably heavy metal load and oxidative stress. Transcriptional induction of metallothionein genes is mediated by the metal-responsive transcription factor 1 (MTF-1), an essential zinc finger protein that binds to specific DNA motifs termed metal-response elements. In cell-free DNA binding reactions with nuclear extracts, MTF-1 requires elevated zinc concentrations for efficient DNA binding but paradoxically is inactivated by other in vivo inducers such as cadmium, copper, and hydrogen peroxide. Here we have developed a cell-free, MTF-1-dependent transcription system which accurately reproduces the activation of metallothionein gene promoters not only by zinc but also by these other inducers. We found that while transcriptional induction by zinc can be achieved by elevated zinc concentration alone, induction by cadmium, copper, or H2O2 additionally requires the presence of zinc-saturated metallothionein. This is explained by the preferential binding of cadmium or copper to metallothionein or its oxidation by H2O2; the concomitant release of zinc in turn leads to the activation of transcription factor MTF-1. Conversely, thionein, the metal-free form of metallothionein, inhibits activation of MTF-1. The release of zinc from cellular components, including metallothioneins, and the sequestration of zinc by newly produced apometallothionein might be a basic mechanism to regulate MTF-1 activity upon cellular stress.
doi:10.1128/MCB.23.23.8471-8485.2003
PMCID: PMC262672  PMID: 14612393
11.  Adjusting copper concentrations for caeruloplasmin levels in routine clinical practice 
Journal of Clinical Pathology  2006;59(8):867-869.
Background
An investigation on copper metabolism usually includes the measurement of serum levels of copper and caeruloplasmin. Using these levels, some laboratories derive levels of non‐caeruloplasmin‐bound copper (NCC); however, a considerable number of patients may show negative values, which is not physiologically possible.
Aim
To derive an equation for adjusted copper in a manner similar to that widely accepted for adjusted calcium.
Methods
A linear regression equation for the relationship between caeruloplasmin and copper was used: [copper] (μmol/l) = 0.052×[caeruloplasmin] (mg/l). An equation for copper adjusted for caeruloplasmin was derived using this equation and the reference interval of 10–25 μmol/l for copper.
Results
The derived equation was [adjusted copper] (μmol/l) = [total copper] (μmol/l)+0.052×[caeruloplasmin] (mg/l)+17.5 (μmol/l). The adjusted copper concentrations on the 2.5th and 97.5th centiles were 12.7 and 21.5 μmol/l, respectively, with the population having a gaussian distribution. The relationship between NCC and the adjusted copper concentrations is linear and independent of caeruloplasmin concentration.
Conclusion
Calculation of copper adjusted for caeruloplasmin uses the same variables as those for NCC. Accordingly, the problems that are caused by the lack of specificity of caeruloplasmin immunoassays are the same as those identified for NCC. This calculation, however, overcomes the negative values that are found in a considerable minority of patients with NCC, as well as age and sex differences in the caeruloplasmin reference interval. As the concept is already familiar to non‐laboratory healthcare professionals in the form of calcium adjusted for albumin, this method is potentially less confusing than that for NCC.
doi:10.1136/jcp.2005.034876
PMCID: PMC1860450  PMID: 16644878
12.  Effect of Supplementation with Zinc and Other Micronutrients on Malaria in Tanzanian Children: A Randomised Trial 
PLoS Medicine  2011;8(11):e1001125.
Hans Verhoef and colleagues report findings from a randomized trial conducted among Tanzanian children at high risk for malaria. Children in the trial received either daily oral supplementation with either zinc alone, multi-nutrients without zinc, multi-nutrients with zinc, or placebo. The investigators did not find evidence from this study that zinc or multi-nutrients protected against malaria episodes.
Background
It is uncertain to what extent oral supplementation with zinc can reduce episodes of malaria in endemic areas. Protection may depend on other nutrients. We measured the effect of supplementation with zinc and other nutrients on malaria rates.
Methods and Findings
In a 2×2 factorial trial, 612 rural Tanzanian children aged 6–60 months in an area with intense malaria transmission and with height-for-age z-score≤−1.5 SD were randomized to receive daily oral supplementation with either zinc alone (10 mg), multi-nutrients without zinc, multi-nutrients with zinc, or placebo. Intervention group was indicated by colour code, but neither participants, researchers, nor field staff knew who received what intervention. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. The primary outcome, an episode of malaria, was assessed among children reported sick at a primary care clinic, and pre-defined as current Plasmodium infection with an inflammatory response, shown by axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L. Nutritional indicators were assessed at baseline and at 251 days (median; 95% reference range: 191–296 days). In the primary intention-to-treat analysis, we adjusted for pre-specified baseline factors, using Cox regression models that accounted for multiple episodes per child. 592 children completed the study. The primary analysis included 1,572 malaria episodes during 526 child-years of observation (median follow-up: 331 days). Malaria incidence in groups receiving zinc, multi-nutrients without zinc, multi-nutrients with zinc and placebo was 2.89/child-year, 2.95/child-year, 3.26/child-year, and 2.87/child-year, respectively. There was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Neither zinc nor multi-nutrients influenced malaria rates (marginal analysis; adjusted HR, 95% CI: 1.04, 0.93–1.18 and 1.10, 0.97–1.24 respectively). The prevalence of zinc deficiency (plasma zinc concentration <9.9 µmol/L) was high at baseline (67% overall; 60% in those without inflammation) and strongly reduced by zinc supplementation.
Conclusions
We found no evidence from this trial that zinc supplementation protected against malaria.
Trial Registration
ClinicalTrials.gov NCT00623857
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a serious global public-health problem. Half of the world's population is at risk of this parasitic disease, which kills a million people (mainly children living in sub-Saharan Africa) every year. Malaria is transmitted to people through the bites of infected night-flying mosquitoes. Soon after entering the human body, the parasite begins to replicate in red blood cells, bursting out every 2–3 days and infecting more red blood cells. The presence of the parasite in the blood stream (parasitemia) causes malaria's characteristic recurring fever and can cause life-threatening organ damage and anemia (insufficient quantity of red blood cells). Malaria transmission can be reduced by using insecticide sprays to control the mosquitoes that spread the parasite and by avoiding mosquito bites by sleeping under insecticide-treated bed nets. Effective treatment with antimalarial drugs can also reduce malaria transmission.
Why Was This Study Done?
One reason why malaria kills so many children in Africa is poverty. Many children in Africa are malnourished, and malnutrition—in particular, insufficient micronutrients in the diet—impairs the immune system, which increases the frequency and severity of many childhood diseases. Micronutrients are vitamins and minerals that everyone needs in small quantities for good health. Zinc is one of the micronutrients that helps to maintain a healthy immune system, but zinc deficiency is very common among African children. Zinc supplementation has been shown to reduce the burden of diarrhea in developing countries, so might it also reduce the burden of malaria? Unfortunately, the existing evidence is confusing—some trials show that zinc supplementation protects against malaria but others show no evidence of protection. One possibility for these conflicting results could be that zinc supplementation alone is not sufficient—supplementation with other micronutrients might be needed for zinc to have an effect. In this randomized trial (a study that compares the effects of different interventions in groups that initially are similar in all characteristics except for intervention), the researchers investigate the effect of supplementation with zinc alone and in combination with other micronutrients on the rate of uncomplicated (mild) malaria among children living in Tanzania.
What Did the Researchers Do and Find?
The researchers enrolled 612 children aged 6–60 months who were living in a rural area of Tanzania with intense malaria transmission and randomly assigned them to receive daily oral supplements containing zinc alone, multi-nutrients (including iron) without zinc, multi-nutrients with zinc, or a placebo (no micronutrients). Nutritional indicators (including zinc concentrations in blood plasma) were assessed at baseline and 6–10 months after starting the intervention. During the study period, there were 1,572 malaria episodes. The incidence of malaria in all four intervention groups was very similar (about three episodes per child-year), and there was no evidence that multi-nutrients influenced the effect of zinc (or vice versa). Moreover, none of the supplements had any effect on malaria rates when compared to the placebo, even though the occurrence of zinc deficiency was strongly reduced by zinc supplementation. In a secondary analysis in which they analyzed their data by iron status at baseline, the researchers found that multi-nutrient supplementation increased the overall number of malaria episodes in children with iron deficiency by 41%, whereas multi-nutrient supplementation had no effect on the number of malaria episodes among children who were iron-replete at baseline.
What Do These Findings Mean?
In this study, the researchers found no evidence that zinc supplementation protected against malaria among young children living in Tanzania when given alone or in combination with other multi-nutrients. However, the researchers did find some evidence that multi-nutrient supplementation may increase the risk of malaria in children with iron deficiency. Because this finding came out of a secondary analysis of the data, it needs to be confirmed in a trial specifically designed to assess the effect of multi-nutrient supplements on malaria risk in iron-deficient children. Nevertheless, it is a potentially worrying result because, on the basis of evidence from a single study, the World Health Organization currently recommends that regular iron supplements be given to iron-deficient children in settings where there is adequate access to anti-malarial treatment. This recommendation should be reconsidered, suggest the researchers, and the safety of multi-nutrient mixes that contain iron and that are dispensed in countries affected by malaria should also be carefully evaluated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001125.
Information is available from the World Health Organization on malaria (in several languages), on micronutrients, and on zinc deficiency; the 2010 World Malaria Report provides details of the current global malaria situation
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa
The Malaria Centre at the UK London School of Hygiene & Tropical Medicine develops tools, techniques, and knowledge about malaria, and has a strong emphasis on teaching, training, and translating research outcomes into practice
The Micronutrient Initiative, the Global Alliance for Improved Nutrition, and the Flour Fortification Initiative are not-for-profit organizations dedicated to ensuring that people in developing countries get the minerals and vitamins they need to survive and thrive
The International Zinc Nutrition Consultative Group (iZiNCG) is a non-profit organization that aims to promote and assist efforts to reduce zinc deficiency worldwide, through advocacy efforts, education, and technical assistance
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1001125
PMCID: PMC3222646  PMID: 22131908
13.  Effects of B-lymphocyte dysfunction on the serum copper, selenium and zinc levels of rheumatoid arthritis patients 
Pakistan Journal of Medical Sciences  2014;30(5):1064-1067.
Objective: To study the effects of B-lymphocyte dysfunction on the serum copper, selenium and zinc levels of rheumatoid arthritis (RA) patients, and to provide evidence for clinical practice.
Methods: Sixty RA patients enrolled in our hospital from August 2009 to August 2013 were selected as the observation group. Another 60 healthy subjects who received physical examinations in our hospital were selected as the control group. Their B-lymphocyte stimulator (BlyS) levels and CD19+CD25+ lymphocyte percentages were determined. The levels of trace elements were measured, and correlation analysis was performed.
Results: The BlyS levels of the observation group and the control group were (0.39±0.21) ng/ml and (0.13±0.04) ng/ml respectively, which were significantly different (P<0.05). The percentages of CD25+, CD19+ and CD19+CD25+ lymphocytes in the observation group were significantly higher than those in the control group (P<0.05). The serum copper, selenium and zinc levels of the observation group were significantly lower than those of the control group (P<0.05). Pearson's correlation analysis showed that the BlyS level was correlated with the levels of copper, selenium and zinc respectively (r=-0.541, -0.370, -0.430, P<0.05).
Conclusion: Rheumatoid Arthritis may be induced by BlyS-mediated B-lymphocyte dysplasia and dysfunction, accompanied by decreased expressions of copper, selenium and zinc.
doi:10.12669/pjms.305.5214
PMCID: PMC4163233  PMID: 25225527
B-lymphocyte; Rheumatoid arthritis; Dysfunction; Trace element
14.  The Relationship Between Serum Lipid Profile and Selected Trace Elements for Adult Men in Mosul City 
Oman Medical Journal  2012;27(4):300-303.
Objectives
To evaluate the correlations of the serum concentrations of copper, zinc, and manganese with lipid profile parameters of adult men in Mosul City, Iraq.
Methods
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.
Results
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.
Conclusion
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.
doi:10.5001/omj.2012.74
PMCID: PMC3464753  PMID: 23071882
Lipid profile; Trace elements; Hyperlipidemic patient
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.  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
17.  Copper deficit as a potential pathogenic factor of reduced bone mineral density and severe tooth wear 
Osteoporosis International  2013;25(2):447-454.
Summary
The study evaluated if men and women with severe tooth wear were at increased risk of general bone loss. Enamel biopsies obtained from 50 subjects aged 47.5 ± 5 years showed decreased copper content, which was associated with reduced spine bone mineral density, suggesting deficits of this trace element contributing to bone demineralization, enamel attrition, and deteriorated quality of mineralized tissues.
Introduction
The objective of this cross-sectional study was to assess associations between enamel trace minerals and bone mineral density (BMD) in severe tooth wear. We hypothesized that similar factors contributed to both the excessive abrasion of dental enamel and reduced BMD in subjects with tooth wear.
Methods
Fifty patients aged 47.5 ± 5 years with severe tooth wear and 20 age-, sex-, and body mass index (BMI)-matched healthy volunteers with normal dental status were studied regarding dietary intakes of trace elements, serum and salivary copper (Cu), zinc (Zn), and calcium (Ca) concentrations, and serum PTH, osteocalcin, and hydroxyvitamin D levels. Tooth wear was determined using clinical examination based on standard protocol according to Smith and Knight. In all subjects, acid biopsies of the maxillary central incisors were carried out to assess mineral composition of the enamel. Atomic absorption spectroscopy with an air/acetylene flame was used to measure Ca and Zn, and graphite furnace atomic absorption spectroscopy was used to analyze Cu content. BMD was examined using dual energy X-ray absorptiometry.
Results
Tooth wear patients had reduced lumbar spine, but not femoral, BMD relative to controls (p < 0.001). No differences were found in enamel Ca concentration and Zn content was slightly higher in tooth wear patients than in controls whereas Cu content was significantly decreased in the patients: 19.59 ± 16.4 vs 36.86 ± 26.1 μg/l (p = 0.01) despite similar levels of Cu in serum and saliva. The differences were independent of serum 25-OH-D, osteocalcin concentrations or PTH either.
Conclusion
Severe tooth wear is associated with reduced spinal BMD. Enamel in adult individuals with severe tooth wear is low in copper content. Therefore, further work is needed to determine whether copper plays a role in bone pathophysiology in these patients.
doi:10.1007/s00198-013-2410-x
PMCID: PMC3906556  PMID: 23797848
Bone mineral density; Copper deficit; Dental status; Enamel attrition; Enamel composition; Microelements
18.  HIV-1 transgene expression in rats induces differential expression of tumor necrosis factor alpha and zinc transporters in the liver and the lung 
Background
Highly effective antiviral treatment can suppress HIV-1 infection, but the chronic effects of HIV-1-related viral proteins, including gp120 and Tat, on organs such as the lungs can be damaging. HIV-1 transgenic rodent models are useful for studying the systemic effects of these proteins independently of viral infection. We have previously shown that HIV-1 transgene expression (and therefore, HIV-1-related protein expression) in rats decreases alveolar macrophage zinc levels and phagocytic capacity by unknown mechanisms. We hypothesized that HIV-1 transgene expression induces chronic inflammation and zinc sequestration within the liver and thereby decreases zinc bioavailability in the lung. We examined the expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), the zinc storage protein, metallothionein (MT1), and the zinc exporter, ZNT1 in the livers and the lungs of wild type and HIV-1 transgenic rats ± dietary zinc supplementation. In addition, we measured zinc levels, the zinc importing protein ZIP1, and the phagocytic capacity in the alveolar macrophages.
Results
HIV-1 transgene expression increased the liver-specific expression of TNFα, suggesting a chronic inflammatory response within the liver in response to HIV-1-related protein expression. In parallel, HIV-1 transgene expression significantly increased MT1 and ZNT1 expression in the liver as compared to the lung, a pattern that is consistent with zinc sequestration in the liver as occurs during systemic inflammation. Further, HIV-1 transgene expression decreased intracellular zinc levels and increased expression of ZIP1 in the alveolar macrophages, a pattern consistent with zinc deficiency, and decreased their bacterial phagocytic capacity. Interestingly, dietary zinc supplementation in HIV-1 transgenic rats decreased gene expression of TNFα, MT1, and ZNT1 in the liver while simultaneously increasing their expression in the lung. In parallel, zinc supplementation increased alveolar macrophage intracellular zinc levels and bacterial phagocytic capacity in HIV-1 transgenic rats.
Conclusion
Taken together, these findings suggest that chronic HIV-1-related protein expression causes liver inflammation and zinc sequestration, which in turn limits zinc bioavailability in the lung and thereby impairs alveolar macrophage phagocytic function. Importantly, dietary zinc supplementation decreases liver inflammation and zinc sequestration and restores alveolar macrophage phagocytic function in HIV-1 transgenic rats, a result with potential clinical implications for improving lung health in HIV-1-infected individuals.
doi:10.1186/1742-6405-8-36
PMCID: PMC3204218  PMID: 21978457
pulmonary; alveolar macrophages; AIDS; rodent; inflammation; micronutrients
19.  Effects of Dietary Zinc Manipulation on Growth Performance, Zinc Status and Immune Response during Giardia lamblia Infection: A Study in CD-1 Mice 
Nutrients  2013;5(9):3447-3460.
Associations between Giardia lamblia infection and low serum concentrations of zinc have been reported in young children. Interestingly, relatively few studies have examined the effects of different dietary zinc levels on the parasite-infected host. The aims of this study were to compare the growth performance and zinc status in response to varying levels of dietary zinc and to measure the antibody-mediated response of mice during G. lamblia infection. Male CD-1 mice were fed using 1 of 4 experimental diets: adequate-zinc (ZnA), low-zinc (ZnL), high-zinc (ZnH) and supplemented-zinc (ZnS) diet containing 30, 10, 223 and 1383 mg Zn/kg respectively. After a 10 days feeding period, mice were inoculated orally with 5 × 106 G. lamblia trophozoites and were maintained on the assigned diet during the course of infection (30 days). Giardia-free mice fed ZnL diets were able to attain normal growth and antibody-mediated response. Giardia-infected mice fed ZnL and ZnA diets presented a significant growth retardation compared to non-infected controls. Zinc supplementation avoided this weight loss during G. lamblia infection and up-regulated the host’s humoral immune response by improving the production of specific antibodies. Clinical outcomes of zinc supplementation during giardiasis included significant weight gain, higher anti-G. lamblia IgG antibodies and improved serum zinc levels despite the ongoing infection. A maximum growth rate and antibody-mediated response were attained in mice fed ZnH diet. No further increases in body weight, zinc status and humoral immune capacity were noted by feeding higher zinc levels (ZnS) than the ZnH diet. These findings probably reflect biological effect of zinc that could be of public health importance in endemic areas of infection.
doi:10.3390/nu5093447
PMCID: PMC3798913  PMID: 24002196
zinc; Giardia lamblia; giardiasis; micronutrients; immune response; IgG; mice
20.  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
21.  Serum Copper, Zinc and Copper/Zinc Ratio and their Relationship to Age and Growth Status in Yemeni Adolescent Girls 
Objectives:
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.
Methods:
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.
Results:
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).
Conclusion:
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
22.  Studies of plasma zinc, copper, caeruloplasmin, and growth hormone 
Journal of Clinical Pathology  1979;32(4):325-333.
The levels of plasma zinc, copper, caeruloplasmin, and growth hormone were determined in a group of normal people and in four groups of patients who were suffering from carcinoma of the bronchus, other forms of malignancy, chest illnesses, and diseases other than chest illness or malignancy. The plasma zinc was higher, and the plasma copper lower, in people without malignancy below the age of 30 years than they were in other age groups.
It was confirmed that about 66% of patients with carcinoma of the bronchus had plasma zinc levels less than 11·5 μmol/l but low levels were also found in 23% of other cases of malignancy and in 9% of the other patients. In carcinoma of the bronchus the low plasma zinc was found to be associated with epidermoid and anaplastic tumours and was to some extent related to the duration of the disease.
In carcinoma of the bronchus the plasma copper was found to be higher than in all other groups, and values higher than 26·5 μmol/l were considered to support a diagnosis of carcinoma of the bronchus. There was, however, no relationship between the increase in the plasma copper and the decrease in the plasma zinc.
Raised caeruloplasmin levels above 420 mg/l were found in 65% of cases of carcinoma of the bronchus, and these high levels were usually associated with raised plasma copper. Growth hormone was normal in all groups except six patients with carcinoma of the bronchus with secondary carcinoma of the liver, in whom it was raised. Surgical operations lowered plasma zinc and raised growth hormone but did not affect plasma copper.
A plasma zinc below 11·5 μmol/l is helpful in the diagnosis of carcinoma of the bronchus, but by itself it is not sufficiently specific to be considered diagnostic or to form a reliable screening test. A raised plasma copper and a raised plasma caeruloplasmin were useful supportive findings.
PMCID: PMC1145668  PMID: 447867
23.  Relationship between Paratuberculosis and the microelements Copper, Zinc, Iron, Selenium and Molybdenum in Beef Cattle 
Brazilian Journal of Microbiology  2013;44(1):153-160.
To study the deficiency of minerals and its relationship with Paratuberculosis, blood, serum, and fecal samples were obtained from 75 adult bovines without clinical symptoms of the disease and from two bovines with clinical symptoms of the disease, from two beef herds with a previous history of Paratuberculosis in the Province of Buenos Aires, Argentina. Serum samples were processed by ELISA and feces were cultured in Herrolds medium. Copper, zinc and iron in serum were quantified by spectrophotometry and selenium was measured by the activity of glutathione peroxidase. We also determined copper, zinc, iron and molybdenum concentrations in pastures and the concentration of sulfate in water. Mycobacterium avium subsp paratuberculosis (Map) was isolated from 17.3% of fecal samples of asymptomatic animals and from the fecal samples from the two animals with clinical symptoms. All the Map-positive animals were also ELISA-positive or suspect, and among them, 84.6% presented low or marginal values of selenium and 69.2% presented low or marginal values of copper. The two animals with clinical symptoms, and isolation of Map from feces and organs were selenium-deficient and had the lowest activity of glutathione peroxidase of all the animals from both herds. All the animals negative to Map in feces and negative to ELISA had normal values of Se, while 13.8% of animals with positive ELISA or suspect and culture negative presented low levels of Se. Half of the animals that were negative both for ELISA and culture in feces were deficient in copper but none of them presented low values of selenium. The content of molybdenum and iron in pasture was high, 2.5 ppm and 1.13 ppm in one herd and 2.5 ppm and 2.02 ppm in the other, respectively, whereas the copper:molybdenum ratio was 1.5 and 5.2, respectively. These results do not confirm an interaction between imbalances of the micronutrients and clinical Paratuberculosis, but show evidence of the relationship between selenium deficiencies in animals with Map infection and ELISA positive results.
doi:10.1590/S1517-83822013005000034
PMCID: PMC3804192  PMID: 24159298
Paratuberculosis; micronutrients; selenium; molybdenum; copper
24.  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.
doi:10.1128/MCB.26.6.2286-2296.2006
PMCID: PMC1430275  PMID: 16508004
25.  Analysis of Serum Zinc and Copper Concentrations in Hair Loss 
Annals of Dermatology  2013;25(4):405-409.
Background
It is well known that some trace elements such as zinc and copper play a significant role in many forms of hair loss. However, the effect of zinc and copper in the pathogenesis of hair loss is still unknown.
Objective
The purpose of this study is to evaluate the zinc and copper status in each of four types of hair loss.
Methods
A study was carried out with 30 health controls and 312 patients who were diagnosed with alopecia areata (AA), male pattern hair loss, female pattern hair loss and telogen effluvium (TE) (2008 to 2011; Hallym University Kangdong Sacred Heart Hospital). Zinc and copper serum concentrations were evaluated between controls and each of four types of hair loss patients.
Results
In all of the hair loss patients, the mean serum zinc was 84.33±22.88, significantly lower than the control group (97.94±21.05 µg/dl) (p=0.002), whereas the serum copper was 96.44±22.62, which was not significantly different (p=0.975). The analysis of each group showed that all groups of hair loss had statistically lower zinc concentration, but not copper concentrations. However, the ratio of the patients with serum zinc concentration lower than 70 µg/dl was significantly high in only the AA group (odds ratio, OR 4.02; confidence interval, CI 1.13 to 14.31) and the TE group (OR 1.12; CI 1.12 to 17.68).
Conclusion
The data led to the hypothesis of zinc metabolism disturbances playing a key role in hair loss, especially AA and TE, whereas the effect of copper on hair growth and shedding cycles still needs more study.
doi:10.5021/ad.2013.25.4.405
PMCID: PMC3870206  PMID: 24371385
Alopecia; Copper; Zinc

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