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Abstracts

Zinc: 91 Research Abstracts

Acne

1. Endotoxin-induced changes in copper and zinc metabolism in the Syrian hamster.

Etzel KR, Swerdel MR, Swerdel JN, Cousins RJ

J Nutr 1982 Dec;112(12):2363-73

The temporal response of zinc and copper metabolism to endotoxin administration was examined in Syrian hamsters over a 144-hour period. Serum copper was significantly elevated at 12, 24 and 72 hours after endotoxin, whereas serum zinc was reduced 4-48 hours after treatment. A brief elevation (8 hours) in liver copper concentration and a sustained (72 hours) increase in liver zinc concentration were also observed. The amount of zinc associated with liver metallothionein (MT) progressively increased with time, to a plateau by 24 hours and persisted at the elevated level until 72 hours after endotoxin treatment. In vitro translation of poly (A)+ RNA from liver polyribosomes showed that following endotoxin treatment MTmRNA activity was maximally elevated 6 hours after endotoxin administration and remained elevated 24 and 48 hours thereafter. Slab gel electrophoresis of serum proteins indicated changes in a stainable protein comigrating with purified ceruloplasmin after endotoxin administration. Pooled gingival tissue from endotoxin-treated hamsters demonstrated a consistently elevated copper content 12-144 hours after treatment. Endotoxin isolated from Bacteroides melaninogenicus was more effective in elevating gingival and serum copper and gingival zinc than Escherichia coli endotoxin. It was concluded that endotoxin administration elicits responses that result in enhanced metaollthionein mRNA activity. In addition, Cu and Zn concentrations in serum, liver and gingival tissue are influenced by different endotoxins to different degrees.

2. [Current aspects about the role of zinc in nutrition]. [Article in French]

Favier A Groupe de recherche sur les pathologies oxydatives, Universite de Grenoble, La Tronche.

Rev Prat 1993 Jan 15;43(2):146-51

The role played by zinc in biology is now better known, and numerous biochemical mechanisms, such as immunity or actions on several hormones and more than 200 enzymes, have proved to be zinc-dependent. Thus, many functions are disturbed when this trace metal is deficient, including, for example, taste and appetite, cell multiplication, growth, pregnancy, fertility, defence against bacteria and brain functions. Zinc intake has been found to be unexcessive and indeed, at the limit of sufficiency in the French population. Groups at risk, such as neonates, growing children, pregnant women and elderly people, should have a higher zinc intake provided by dietary measures or supplementation. Zinc supplementation has been shown to exert a beneficial effect in randomized studies concerning children's growth, acne, old people's immunity or low female fertility. Such supplementation must be balanced and given in moderate doses since zinc interacts with other foodstuffs, and an excess of zinc can be as bad as its deficiency in our nutrition.

3. Effects of oral zinc and vitamin A in acne.

Michaelsson G, Juhlin L, Vahlquist A

Arch Dermatol 1977 Jan;113(1):31-6

The effects of oral zinc sulfate (corresponding to 135 mg of zinc daily) alone and in combination with vitamin A (300,000 international units) daily on acne lesions have been compared with those of vitamin A alone and of a placebo. The number of comedones, papules, pustules, and infiltrates were counted at each visit. After four weeks, there was a significant decrease in the number of papules, pustules, and infiltrates in the zinc-treated groups. The effect of zinc plus vitamin A was not better than zinc alone. After 12 weeks of treatment, the mean acne score had decreased from 100% to 15%. The mechanism for the effect of zinc therapy in acne, to our knowledge, is not presently known.

4. Serum zinc and retinol-binding protein in acne.

Michaelsson G, Vahlquist A, Juhlin L

Br J Dermatol 1977 Mar;96(3):283-6

The serum levels of zinc and retinol-binding protein (RBP) have been determined in 173 patients with acne and compared with those of a control group. The RBP is a specific transport protein and its level in plasma reflects the amount of vitamin A available to the tissues. Patients with severe acne were found to have lower levels of RBP than either patients with mild acne or healthy subjects of the same age. In the case of males with severe acne, the mean serum zinc level was significantly lower than that of the control group. No such difference was observed for girls. The observed condition of low levels of zinc and vitamin A in the serum of patients with severe acne may provide a rationale for the clinically good effect of oral zinc treatment.

5. A double-blind study of the effect of zinc and oxytetracycline in acne vulgaris.

Michaelsson G, Juhlin L, Ljunghall K

Br J Dermatol 1977 Nov;97(5):561-6

With a double-blind technique, the effects of oral zinc and tetracyclines were compared in 37 patients with moderate and severe acne. No difference in effect between the treatments was seen and no side-effects were noted in any group. After 12 weeks of treatment, the average decrease in the acne score was about 70% in both groups.

6. A double-blind controlled evaluation of the sebosuppressive activity of topical erythromycin-zinc complex.

Pierard-Franchimont C, Goffin V, Visser JN, Jacoby H, Pierard GE Department of Dermatopathology, University of Liege, Belgium.

Eur J Clin Pharmacol 1995;49(1-2):57-60

In a double-blind randomised study, 14 volunteers applied 4% erythromycin plus 1.2% zinc (Zineryt lotion) and 4% erythromycin lotions, each on half of the forehead twice daily for 3 months. The sebum output was evaluated at 3-week intervals using the photometric and the lipid-sensitive film methods. Evaluations of casual level (CL) and sebum excretion rate (SER) were made with a Sebumeter, and total area of lipid spots (TAS) was measured on Sebutapes. Compared to baseline values, the formulation of the erythromycin-zinc complex induced significant reductions in SER after 6 and 9 weeks, and in CL and TAS at 3, 6, 9 and 12 weeks. The mean reduction in TAS was over 20% for four successive 1-h samplings on completion of the study. Significant reductions in CL, SER and TAS were observed for the erythromycin-zinc formulation compared to the control lotion at 6 and 9 weeks, and also at 3 weeks for SER and TAS, and at 12 weeks for CL and TAS. This study indicates that sebum output is significantly reduced by the erythromycin-zinc complex. This reduction is theoretically beneficial for the acneic patient.

7. Zinc sulfate in acne vulgaris.

Weimar VM, Puhl SC, Smith WH, tenBroeke JE

Arch Dermatol 1978 Dec;114(12):1776-8

The effects of orally administered zinc sulfate in 52 patients with mild to moderate acne vulgaris were compared to those of a placebo capsule. The numbers of comedones, papules, pustules, infiltrates, and cysts were counted at each visit over a 12-week period. Forty patients completed the study. Zinc appeared to have a somewhat beneficial effect on pustules but not on comedones, papules, infiltrates, or cysts. Fourteen patients (50%) in the zinc group had side effects of nausea, vomiting, or diarrhea. Six patients (21%) in the zinc group could not tolerate the nausea and withdrew from the study.

8. Inhibition of erythromycin-resistant propionibacteria on the skin of acne patients by topical erythromycin with and without zinc.

Bojar RA, Eady EA, Jones CE, Cunliffe WJ, Holland KT Department of Microbiology, University of Leeds, U.K.

Br J Dermatol 1994 Mar;130(3):329-36

Propionibacteria resistant to high concentrations of erythromycin [minimal inhibitory concentration (MIC) > or = 0.5 mg/ml] are now commonly isolated from the skin of antibiotic-treated acne patients. This double-blind study was carried out to assess the ability of 4% w/v erythromycin with and without 1.2% w/v zinc acetate to reduce the numbers of erythromycin-resistant propionibacteria in vivo, and also to monitor the acquisition of resistant strains de novo during therapy. Under laboratory conditions, erythromycin-resistant propionibacteria were shown to be as sensitive to zinc acetate as fully sensitive strains. In vivo, the erythromycin/zinc complex and erythromycin alone produced highly significant reductions in total propionibacteria (P < 0.001) and in the number of erythromycin-resistant strains (P < 0.001 at 8 weeks). After 12 weeks, resistant propionibacteria were reacquired, or acquired de novo, by three patients treated with erythromycin alone and four patients treated with the erythromycin/zinc complex. In contrast, changes in numbers of Micrococcaceae were slight and, after 12 weeks, erythromycin-resistant strains were predominant in both treatment groups. In vitro MIC determinations suggested that this finding might be explained by the exceptionally high degree of erythromycin resistance displayed by some staphylococcal strains (MIC > 4 mg/ml) and by the relative insensitivity of all staphylococcal strains to zinc acetate. Erythromycin with and without zinc was clinically effective, and both preparations produced significant reductions in acne grade, and inflamed and non-inflamed lesion counts (P < 0.001).

9. Endotoxin-induced changes in copper and zinc metabolism in the Syrian hamster.

Etzel KR, Swerdel MR, Swerdel JN, Cousins RJ

J Nutr 1982 Dec;112(12):2363-73

The temporal response of zinc and copper metabolism to endotoxin administration was examined in Syrian hamsters over a 144-hour period. Serum copper was significantly elevated at 12, 24 and 72 hours after endotoxin, whereas serum zinc was reduced 4-48 hours after treatment. A brief elevation (8 hours) in liver copper concentration and a sustained (72 hours) increase in liver zinc concentration were also observed. The amount of zinc associated with liver metallothionein (MT) progressively increased with time, to a plateau by 24 hours and persisted at the elevated level until 72 hours after endotoxin treatment. In vitro translation of poly (A)+ RNA from liver polyribosomes showed that following endotoxin treatment MTmRNA activity was maximally elevated 6 hours after endotoxin administration and remained elevated 24 and 48 hours thereafter. Slab gel electrophoresis of serum proteins indicated changes in a stainable protein comigrating with purified ceruloplasmin after endotoxin administration. Pooled gingival tissue from endotoxin-treated hamsters demonstrated a consistently elevated copper content 12-144 hours after treatment. Endotoxin isolated from Bacteroides melaninogenicus was more effective in elevating gingival and serum copper and gingival zinc than Escherichia coli endotoxin. It was concluded that endotoxin administration elicits responses that result in enhanced metaollthionein mRNA activity. In addition, Cu and Zn concentrations in serum, liver and gingival tissue are influenced by different endotoxins to different degrees.

10. [Current aspects about the role of zinc in nutrition]. [Article in French]

Favier A Groupe de recherche sur les pathologies oxydatives, Universite de Grenoble, La Tronche.

Rev Prat 1993 Jan 15;43(2):146-51

The role played by zinc in biology is now better known, and numerous biochemical mechanisms, such as immunity or actions on several hormones and more than 200 enzymes, have proved to be zinc-dependent. Thus, many functions are disturbed when this trace metal is deficient, including, for example, taste and appetite, cell multiplication, growth, pregnancy, fertility, defence against bacteria and brain functions. Zinc intake has been found to be unexcessive and indeed, at the limit of sufficiency in the French population. Groups at risk, such as neonates, growing children, pregnant women and elderly people, should have a higher zinc intake provided by dietary measures or supplementation. Zinc supplementation has been shown to exert a beneficial effect in randomized studies concerning children's growth, acne, old people's immunity or low female fertility. Such supplementation must be balanced and given in moderate doses since zinc interacts with other foodstuffs, and an excess of zinc can be as bad as its deficiency in our nutrition.

11. Effects of oral zinc and vitamin A in acne.

Michaelsson G, Juhlin L, Vahlquist A

Arch Dermatol 1977 Jan;113(1):31-6

The effects of oral zinc sulfate (corresponding to 135 mg of zinc daily) alone and in combination with vitamin A (300,000 international units) daily on acne lesions have been compared with those of vitamin A alone and of a placebo. The number of comedones, papules, pustules, and infiltrates were counted at each visit. After four weeks, there was a significant decrease in the number of papules, pustules, and infiltrates in the zinc-treated groups. The effect of zinc plus vitamin A was not better than zinc alone. After 12 weeks of treatment, the mean acne score had decreased from 100% to 15%. The mechanism for the effect of zinc therapy in acne, to our knowledge, is not presently known.

12. Serum zinc and retinol-binding protein in acne.

Michaelsson G, Vahlquist A, Juhlin L

Br J Dermatol 1977 Mar;96(3):283-6

The serum levels of zinc and retinol-binding protein (RBP) have been determined in 173 patients with acne and compared with those of a control group. The RBP is a specific transport protein and its level in plasma reflects the amount of vitamin A available to the tissues. Patients with severe acne were found to have lower levels of RBP than either patients with mild acne or healthy subjects of the same age. In the case of males with severe acne, the mean serum zinc level was significantly lower than that of the control group. No such difference was observed for girls. The observed condition of low levels of zinc and vitamin A in the serum of patients with severe acne may provide a rationale for the clinically good effect of oral zinc treatment.

13. A double-blind controlled evaluation of the sebosuppressive activity of topical erythromycin-zinc complex.

Pierard-Franchimont C, Goffin V, Visser JN, Jacoby H, Pierard GE Department of Dermatopathology, University of Liege, Belgium.

Eur J Clin Pharmacol 1995;49(1-2):57-60

In a double-blind randomised study, 14 volunteers applied 4% erythromycin plus 1.2% zinc (Zineryt lotion) and 4% erythromycin lotions, each on half of the forehead twice daily for 3 months. The sebum output was evaluated at 3-week intervals using the photometric and the lipid-sensitive film methods. Evaluations of casual level (CL) and sebum excretion rate (SER) were made with a Sebumeter, and total area of lipid spots (TAS) was measured on Sebutapes. Compared to baseline values, the formulation of the erythromycin-zinc complex induced significant reductions in SER after 6 and 9 weeks, and in CL and TAS at 3, 6, 9 and 12 weeks. The mean reduction in TAS was over 20% for four successive 1-h samplings on completion of the study. Significant reductions in CL, SER and TAS were observed for the erythromycin-zinc formulation compared to the control lotion at 6 and 9 weeks, and also at 3 weeks for SER and TAS, and at 12 weeks for CL and TAS. This study indicates that sebum output is significantly reduced by the erythromycin-zinc complex. This reduction is theoretically beneficial for the acneic patient.

ADD – ADHD

14. Does zinc moderate essential fatty acid and amphetamine treatment of attention-deficit/hyperactivity disorder?

Arnold LE, Pinkham SM, Votolato N. Department of Psychiatry, Ohio State University, Columbus, USA. Arnold.6@osu.edu

J Child Adolesc Psychopharmacol 2000 SUMMMER;10(2):111-7

Zinc is an important co-factor for metabolism relevant to neurotransmitters, fatty acids, prostaglandins, and melatonin, and indirectly affects dopamine metabolism, believed intimately involved in attention-deficit/hyperactivity disorder (ADHD). To explore the relationship of zinc nutrition to essential fatty acid supplement and stimulant effects in treatment of ADHD, we re-analyzed data from an 18-subject double-blind, placebo-controlled crossover treatment comparison of d-amphetamine and Efamol (evening primrose oil, rich in gamma-linolenic acid). Subjects were categorized as zinc-adequate (n = 5), borderline zinc (n = 5), and zinc-deficient (n = 8) by hair, red cell, and urine zinc levels; for each category, placebo-active difference means were calculated on teachers' ratings. Placebo-controlled d-amphetamine response appeared linear with zinc nutrition, but the relationship of Efamol response to zinc appeared U-shaped; Efamol benefit was evident only with borderline zinc. Placebo-controlled effect size (Cohen's d) for both treatments ranged up to 1.5 for borderline zinc and dropped to 0.3-0.7 with mild zinc deficiency. If upheld by prospective research, this post-hoc exploration suggests that zinc nutrition may be important for treatment of ADHD even by pharmacotherapy, and if Efamol benefits ADHD, it likely does so by improving or compensating for borderline zinc nutrition.

CARDIOVASCULAR DISEASE

15. Emerging concepts of neurohumoral modulation in the treatment of congestive heart failure.

Mulder P, Thuillez Ch. INSERM E9920, IFRMP No. 23, Rouen University Medical School, France. paul.mulder@univ-rouen.fr

Arch Mal Coeur Vaiss. 2002 Sep;95(9):821-6.

The angiotensin converting enzyme (ACE), endothelin (ET) converting enzyme (ECE) and neutral endopeptidase (NEP) are all zinc-metallopeptidases expressed in almost all the organs, such as heart, vessels and kidneys. While ACE and ECE are respectively involved in the transformation of angiotensin I and Big-ET into angiotensin II and ET-1 respectively, which possess vasoconstrictor and mitogenic properties, NEP is involved in the degradation of atrial natriuric factor (ANF), which possesses vasorelaxant, diuretic/natriuretic and antihypertrophic properties. These three systems are activated in heart failure and modulate the progression of heart failure. This article will discuss preliminary date concerning simultaneous inhibition of ACE, ECE and/or NEP and their therapeutic potential interest in the treatment of heart failure.

16. Magnesium and zinc status in survivors of sudden unexplained death syndrome in northeast Thailand.

Pansin P, Wathanavaha A, Tosukhowong P, Sriboonlue P, Tungsanga K, Dissayabutr T, Tosukhowong T, Sitprija V. Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Southeast Asian J Trop Med Public Health. 2002 Mar;33(1):172-9.

Sudden Unexplained Death Syndrome (SUDS) is a major health problem in rural residents of Northeast Thailand. The cause of death in SUDS is suspected to be cardiovascular abnormalities. As magnesium (Mg) and zinc (Zn) deficiency contribute significantly to several cardiovascular diseases, we investigated the Mg- and Zn-status of patients with sudden respiratory distress and cardiac arrest who had survived resuscitation attempts or a near-SUDS episode (N-SUDS). The following subjects were enrolled: 12 N-SUDS inhabitants of rural Northeast Thailand (rural group 1, R1), 13 rural villagers with no past history of N-SUDS (rural group 2, R2), 15 urban Northeasterners (urban group 1, U1); 13 Bangkokians (urban group 2, U2). All subjects were free of structural heart disease. Magnesium and zinc were assessed by atomic absorption spectrophotometry of samples of plasma, red blood cells (RBC), white blood cells (WBC), and 24-hour urine. The mean levels of magnesium in the RBC, WBC, and 24-hour urine of N-SUDS patients (R1) were significantly lower than those of the urban groups (U1 and U2), while the plasma levels did not show any differences. When comparing the Zn-status of R1 with that of the urban groups (U1 and U2), the plasma, RBC, and WBC levels were found to be significantly lower in R1 (except for the RBC-Zn of the U1 group), while the 24-hour urine levels was higher. Although the magnesium and zinc parameters were not significantly different between the rural groups R1 and R2, the prevalence of hypomagnesuria (<2.2 mmol/day), hypozincemia (<9.7 micromol/l), and hyperzincuria (>10.7 micromol/day) was higher in the R1 group. These findings suggest that the homeostasis of both magnesium and zinc is altered in N-SUDS patients. Similar alterations, to a lesser degree, were observed in those people living in the same rural environment (R2).

17. Analysis of ionic ratios in myocardial tissue and their relation to cardiac damage.

Torres MC, Osuna E, Perez-Carceles MD, Gomez-Zapata M, Luna A. Institute of Forensic Medicine of Murcia, Spain.

Am J Forensic Med Pathol. 2002 Jun;23(2):155-8.

The authors evaluated the usefulness of the postmortem biochemical analysis of ionic ratios in different parts of the heart and their relation to cardiac damage caused by chest trauma, as observed by anatomopathologic study. Fifty-nine 59 cases were studied, selected from routine necropsies, and samples were taken from different sites of cardiac tissue. The cause of death was trauma in 40 cases and nontraumatic causes in 19 cases. The object of this study was to analyze the levels of Na+, K+, Ca+2, Mg+2, and Zn+2 in different zones of the heart, and the relationship between intracellular and extracellular ion ratios and the different causes of death and any anatomopathologic alterations observed. The biochemical tests revealed a possible relation between the ionic values and cause of death. Alterations in cell membrane permeability and corresponding modification of the ionic ratios were produced earlier than histologic alterations, which need longer to establish themselves whether or not they follow a traumatic process.

18. Influence of zinc on cardiac and serum biochemical parameters in rabbits.

Bhaskar M, Madhuri E, Abdul Latheef SA, Subramanyam G. Department of Zoology, S.V. University Post Graduate Centre, Kavali, India.

Indian J Exp Biol. 2001 Nov;39(11):1170-2.

The pattern of lipid profiles and organic constituents of cardiac and serum tissues of rabbits were studied on treatment with cholesterol, zinc and zinc + cholesterol. Total carbohydrate and total protein levels were decreased with elevated lipid levels in cholesterol fed rabbits. However, the zinc and cholesterol + zinc fed rabbits showed decreased lipid fractions in cardiac and serum tissues leading to reduced atherosclerotic process in rabbits. These results suggest that the zinc is acting as a hypolipidaemic and anti atherogenic agent in experimental rabbits.

19. Diagnostic and therapeutic potential of the endothelin system in patients with chronic heart failure.

Krum H, Denver R, Tzanidis A, Martin P. Clinical Pharmacology Unit, Dept of Epidemiology & Preventive Medicine/Department of Medicine, Monash University/Alfred Hospital, Prahran, Victoria, Australia. henry.krum@med.monash.edu.au

Heart Fail Rev. 2001 Dec;6(4):341-52.

There is now considerable evidence to support a role for the endothelin (ET) system in the pathogenesis and progression of chronic heart failure (CHF). As such, the potential exists for this system to be useful in both diagnosis (by measurement of peptide levels in plasma and other body fluids) and treatment (by pharmacological blockade) of this condition.Plasma levels of endothelin-1 (ET-1) are elevated in CHF and the magnitude of elevation correlates with disease severity. ET-1 levels in plasma predict subsequent mortality in patients with CHF. ET-1 may also contribute to symptoms associated with CHF, such as exercise intolerance. In the diagnosis of CHF, plasma levels of ET-1 appear to be a less powerful discriminator between patients with mild disease and control subjects with normal ventricular function on multivariate analyses, compared to brain natriuretic peptide (BNP), or its N-terminal fragment. ET-1 concentrations are also elevated in the saliva of patients with CHF and may represent an alternative approach to assessment of the status of the ET system in these patients.Specific ET receptor antagonists (both mixed and ET(A)-selective) have been developed. Studies with these agents in animal models of CHF have demonstrated beneficial effects via both haemodynamic and non-haemodynamic pathways. A number of short-term clinical studies have been performed demonstrating improvements in haemodynamic parameters without neurohormonal activation. Long-term clinical studies with ET receptor antagonists are currently underway to definitively test the impact of blockade of this system on mortality and major cardiovascular endpoints. Endothelin converting enzyme (ECE) inhibitors represent an alternative strategy of ET blockade, and early data from animal models suggest these agents may be of clinical utility, either alone or, more likely, in combination with other zinc metallopeptidases.

20. Antioxidant status in cerebrovascular accident.

Kocaturk PA, Akbostanci MC, Isikay C, Ocal A, Tuncel D, Kavas GO, Mutluer N. Departments of Pathophysiology, Faculty of Medicine, Ankara University, Sihhiye, Turkey.

Biol Trace Elem Res. 2001 May;80(2):115-24.

Ischemia is associated with the pathological changes caused by the accumulation of reactive oxygen metabolites (ROM) in cerebrovascular accident (CVA). The aim of this study was to determine red cell copper/zinc-superoxide dismutase (Cu/Zn-SOD) and catalase activities and copper and zinc concentrations both in plasma and in red cells in CVA. Cu/Zn-SOD and catalase activities of 16 patients, with an average age of 64 yr, were measured spectrophotometrically; copper and zinc concentrations were determined by atomic absorption spectrophotometer. The results showed that Cu/Zn-SOD activity was increased markedly in patients compared to the young controls and reached a peak on the d 5 of the disease, whereas the catalase activity of the patients on d 3 and d 5 were in the normal range, but higher on d 10. The enzyme activities of the elderly group were generally increased compared to the young controls. Copper and zinc concentrations showed corresponding alterations. These findings suggested that the effects of oxidative stress in CVA might be reflected in red cell and plasma parameters.

21. Nutritional factors in the pathobiology of human essential hypertension.

Das UN. EFA Sciences LLC, Norwood, Massachusetts 02062, USA. undurti@hotmail.com

Nutrition. 2001 Apr;17(4):337-46.

Endothelial cells produce vasodilator and vasoconstrictor substances. Dietary factors such as sodium, potassium, calcium, magnesium, zinc, selenium, vitamins A, C, and E, and essential fatty acids and their products such as eicosanoids can influence blood pressure, cardio- and cerebrovascular diseases, and concentrations of blood lipids and atherosclerosis. There might be a close interaction between these dietary factors, sympathetic and parasympathetic nervous systems, the metabolism of essential fatty acids, nitric oxide, prostacyclin, and endothelium in human essential hypertension. A deficiency in any one factor, dietary or endogenous, or alterations in their interactions with each other, can lead to endothelial dysfunction and development of hypertension. Therefore, alterations in the metabolism of essential fatty acids might be a predisposing factor to the development of essential hypertension and insulin resistance.

22. Cardiovascular risk factors in relation to the serum concentrations of copper and zinc: epidemiological study on children and adolescents in the Spanish province of Navarra.

Elcarte Lopez T, Villa Elizaga I, Gost Garde JI, Elcarte Lopez R, Martin Perez A, Navascues Pujada J, Navarro Blasco I, Aparicio Madre MI. Primary Health Care Center, Pamplona, Navarra, Spain.

Acta Paediatr. 1997 Mar;86(3):248-53.

This investigation was carried out to show the possible association between groups of children with extreme values of copper and zinc concentrations and cardiovascular risk indicators. Serum copper and zinc concentrations were analysed in a group of 3887 children from Navarra, Spain (both sexes. aged 4-17 years). Hypertension, unfavourable serum lipid profile (total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, and cholesterol/HDL and LDL/HDL ratios), and degree of adiposity (weight, height, subcutaneous skinfolds, Quetelet's index and mean of subcutaneous skinfolds) were evaluated. Positive correlation was found between several lipid parameters and copper and zinc concentrations, i.e. degree of correlation related with age, except for copper/HDL and triglycerides/zinc ratios, where correlation remained negative at all points. Copper levels were correlated with adiposity parameters in an age-dependent fashion (Quetelet's index: r = 0.01 for ages 4-7 years to r = 0.10, p < 0.01 for ages 14-17 years; mean skinfold thickness: r = 0.05 for ages 4-7 years up to r = 0.18, p < 0.01 for ages 14-17 years). Most correlations between lipid parameters and copper and zinc are markedly amplified if adiposity parameters are taken into account. However, the only significant association was the established relation between high copper concentrations (> x + 2SD) and unfavourable serum lipid profile(LDL/HDL > 2.2).

23. Serum calcium, magnesium, copper and zinc and risk of cardiovascular death.

Reunanen A; Knekt P; Marniemi J; Maki J; Maatela J; Aromaa A National Public Health Institute, Helsinki, Finland.

Eur J Clin Nutr (England) Jul 1996, 50 (7) p431-7

OBJECTIVE: To study the association of serum calcium, magnesium, copper and zinc concentrations with cardiovascular mortality. DESIGN: A nested case-control study within a prospective population study. SUBJECTS AND METHODS: 230 men dying from cardiovascular diseases and 298 controls matched for age, place of residence, smoking and follow-up time. Mean follow-up time was 10 years. Serum calcium, magnesium, copper and zinc concentrations were determined from samples kept frozen at -20 degrees C. RESULTS: High serum copper and low serum zinc concentrations were significantly associated with an increased mortality from all cardiovascular diseases and from coronary heart disease in particular. The relative risk of coronary heart disease mortality between the highest and lowest tertiles of serum copper and zinc were 2.86 (P = 0.03) and 0.69 (P = 0.04), respectively. Adjustment for social class, serum cholesterol, body mass index, hypertension and known heart disease at baseline examination did not materially alter the results. No significant differences were observed in concentrations of serum calcium and magnesium between cases and controls. CONCLUSIONS: High serum copper and low serum zinc are associated with increased cardiovascular mortality whereas no association was found with serum calcium and magnesium and mortality risk.

COMMON COLD

24. Zinc lozenges reduce the duration of common cold symptoms.

ANON [No Authors Listed]

Nutr Rev (United States) Mar 1997, 55 (3) p82-5

A randomized, double-blind, placebo-controlled clinical trial has shown that treatment of the common cold with zinc gluconate lozenges resulted in a significant reduction in duration of symptoms of the cold. Patients received zinc-containing lozenges or placebo lozenges every 2 hours for the duration of cold symptoms. The median time to complete resolution of cold symptoms was 4.4 days in the zinc group compared with 7.6 days in the placebo group. The mechanism of action of zinc in treating the common cold remains unknown. (13 Refs.)

25. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study

Mossad SB; Macknin ML; Medendorp SV; Mason P Cleveland Clinic Foundation, Ohio, USA.

Ann Intern Med (United States) Jul 15 1996, 125 (2) p81-8, Comment in Ann Intern Med 1996 Jul 15;125(2):142-4

BACKGROUND. The common cold is one of the most frequent human illnesses and is responsible for substantial morbidity and economic loss. No consistently effective therapy for the common cold has been well documented, but evidence suggests that several possible mechanisms may make zinc an effective treatment. OBJECTIVE. To test the efficacy of zinc gluconate lozenges in reducing the duration of symptoms caused by the common cold. DESIGN. Randomized, double-blind, placebo-controlled study. SETTING. Outpatient department of a large tertiary care center. PATIENTS. 100 employees of the Cleveland Clinic who developed symptoms of the common cold within 24 hours before enrollment. INTERVENTION. Patients in the zinc group (n = 50) received lozenges (one lozenge every 2 hours while awake) containing 13.3 mg of zinc from zinc gluconate as long as they had cold symptoms. Patients in the placebo group (n = 50) received similarly administered lozenges that contained 5% calcium lactate pentahydrate instead of zinc gluconate. MAIN OUTCOME MEASURES. Subjective daily symptom scores for cough, headache, hoarseness, muscle ache, nasal drainage, nasal congestion, scratchy throat, sore throat, sneezing, and fever (assessed by oral temperature). RESULTS. The time to complete resolution of symptoms was significantly shorter in the zinc group than in the placebo group (median, 4.4 days compared with 7.6 days; P &lt; 0.001). The zinc group had significantly fewer days with coughing (median, 2.0 days compared with 4.5 days; P = 0.04), headache (2.0 days and 3.0 days; P = 0.02), hoarseness (2.0 days and 3.0 days; P = 0.02), nasal congestion (4.0 days and 6.0 days; P = 0.002), nasal drainage (4.0 days and 7.0 days; P &lt; 0.001), and sore throat (1.0 day and 3.0 days; P &lt; 0.001). The groups did not differ significantly in the resolution of fever, muscle ache, scratchy throat, or sneezing. More patients in the zinc group than in the placebo group had side effects (90% compared with 62%; P &lt; 0.001), nausea (20% compared with 4%; P = 0.02), and bad-taste reactions (80% compared with 30%; P &lt; 0.001), CONCLUSION. Zinc gluconate in the form and dosage studied significantly reduced the duration of symptoms of the common cold. The mechanism of action of this substance in treating the common cold remains unknown. Individual patients must decide whether the possible beneficial effects of zinc gluconate on cold symptoms outweigh the possible adverse effects.

DIABETES

26. Decreased serum magnesium and zinc levels: atherogenic implications in type-2 diabetes mellitus in Nigerians.

Anetor JI, Senjobi A, Ajose OA, Agbedana EO. Department of Chemical Pathology, College of Medicine, University College Hospital, Ibadan, Nigeria.

Nutr Health. 2002;16(4):291-300.

Serum magnesium, zinc and total cholesterol were evaluated in 40 Nigerian patients suffering from type-2 diabetes mellitus (21M, 19F) and 20 (14M, 6F) apparently normal non diabetic control subjects. The mean age of the diabetic patients was similar to that of controls (p > 0.05). The mean duration of the disease was (4.7 + 0.7 SEM) in these patients. Fasting blood glucose and total cholesterol were significantly higher in diabetics than in non diabetic control subjects (p > 0.001). The serum total cholesterol showed inter-group variation when the patients were classified into four different age groups. In contrast, the serum level of magnesium (Mg) and zinc (Zn) were significantly lower in diabetics than in controls (p > 0.001). There were no significant correlation between glucose and the minerals, Mg. and Zn. Serum total cholesterol showed a significant positive correlation with magnesium (r = 0.6: p > 0.001), while the correlation with zinc was not significant. In type-2 diabetic mellitus the concentration of both Mg and Zn levels were significantly reduced, probably suggesting lower antioxidant status in this condition. The implication is the greater susceptibility to LDL-cholesterol oxidation. The attendant risk of development of premature Coronary Heart Disease is discussed. Magnesium and zinc are nutritional minerals that play crucial roles in the regulation of carbohydrate and lipid metabolism.

27. Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice.

Ho E, Quan N, Tsai YH, Lai W, Bray TM. Department of Human Nutrition, The Ohio State University, Columbus 43210, USA.

Exp Biol Med (Maywood) 2001 Feb;226(2):103-11

Zinc status in patients with Type I diabetes is significantly lower than healthy controls. Whether zinc supplementation can prevent the onset of Type I diabetes is unknown. Recent studies have suggested that the generation of reactive oxygen species (ROS) is a cause of beta cell death leading to Type I diabetes. In addition, we found that activation of NFkappaB (a ROS-sensitive transcription factor that regulates immune responses) may be the key cellular process that bridges oxidative stress and the death of beta cells. Zinc is a known antioxidant in the immune system. Therefore, this study is designed to test whether an increase in dietary zinc can prevent the onset of Type I diabetes by blocking NFkappaB activation in the pancreas. The results show that high zinc intake significantly reduced the severity of Type I diabetes (based on hyperglycemia, insulin level, and islet morphology) in alloxan and streptozotocin-induced diabetic models. Zinc supplementation also inhibited NFkappaB activation and decreased the expression of inducible NO synthase, a downstream target gene of NFkappaB. It is concluded that zinc supplementation can significantly inhibit the development of Type I diabetes. The ability of zinc to modulate NFkappaB activation in the diabetogenic pathway may be the key mechanism for zinc's protective effect. Inhibition of the NFkappaB pathway may prove to be an important criterion for choosing nutritional strategies for Type I diabetes prevention.

28. Oral zinc therapy in diabetic neuropathy.

Gupta R, Garg VK, Mathur DK, Goyal RK. Dept. of Medicine, JLN Medical College and Associated Group of Hospital, Ajmer, Rajasthan-305 001.

J Assoc Physicians India. 1998 Nov;46(11):939-42.

The present double blind randomized study was conducted on 50 subjects; 20 age and sex matched healthy controls (Group--I); 15 patients of diabetes mellitus with neuropathy who received placebo for 6 weeks (Group--IIA); and 15 patients of diabetes mellitus with neuropathy who were given supplemental zinc sulphate (660 mg) for 6 weeks (Group--IIB). Serum zinc level, fasting blood sugar (FBS) and post prandial blood sugar (PPBS) levels and motor nerve conduction velocity (MNCV) were estimated on day 0 and after 6 weeks in all subjects. Serum zinc levels were significantly low (p < 0.001) in group IIA and IIB as compared to healthy controls (Group--I) at baseline. After 6 weeks the change in pre and post therapy values of FBS, PPBS and MNCV (median and common peroneal nerve) were highly significant (P = < 0.001) for group IIB alone with insignificant change (P = > 0.05) in group IIA. No improvement (P = > 0.05) in autonomic dysfunction was observed in either groups. Therefore, oral zinc supplementation helps in achieving better glycemic control and improvement in severity of peripheral neuropathy as assessed by MNCV.

29. [Low zinc levels in metabolic X syndrome (mzX) patients measured by hair zinc composition analysis] [Article in Polish]

Lukasiak J, Cajzer D, Dabrowska E, Falkiewicz B. Pracownia Analizy Instrumentalnej, Katedra Chemii Fizycznej AM w Gdansku.

Rocz Panstw Zakl Hig. 1998;49(2):241-4.

The hair zinc content in 16 patients with metabolic X syndrome (mzX) was measured by means of atomic absorption spectrometry method. The mean concentration (125.13 mg/kg) was lower than in the majority of other published studies. The differences among groups of patients with different sex or diseases (e.g. coronary heart disease, hypertension, type II diabetes mellitus) were not significant. It seems to be probably that deficiency of zinc plays a role in pathogenesis of mzX or that it is a consequence of mzX.

30. [Influence of insufficient zinc on immune functions in NIDDM patients] [Article in Chinese]

Wang P, Yang Z. Department of Endocrinology, Second Affiliated Hospital, Hunan Medical University, Changsha.

Hunan Yi Ke Da Xue Xue Bao. 1998;23(6):599-601.

The serum zinc level and immune functions were analyzed in 34 patients with NIDDM before and after the treatment with zinc gluconate supplement during conventional therapy (after the blood glucose level stabilization). The results showed that before treatment the level of serum zinc and red cell C3b receptor rosette(RBCK-C3b RR), T-lymphocyte subgroup CD3, CD4, and CD4/CD8 were decreased(P < 0.01), while CD8, red cell immune complex rosette(RBC-ICR) were increased. After treatment with zinc gluconate for 1 month the serum zinc level, RBC-C3b RR, RBC-ICR, CD3 and CD4/CD8 became normal, CD8 also approached to normal. All the above figures were significantly different before and after zinc therapy. The data showed that various degrees of lowering of serum zinc and abnormal immune functions were present during the conventional antidiabetic therapy. Thus, zinc supplement should be used as an important adjunctive therapy for NIDDM patients.

31. Hyperzincuria in individuals with insulin-dependent diabetes mellitus: concurrent zinc status and the effect of high-dose zinc supplementation.

Cunningham JJ, Fu A, Mearkle PL, Brown RG. Department of Nutrition, University of Massachusetts, Amherst, MA 01003-1420.

Metabolism 1994 Dec;43(12):1558-62

The urinary excretion of zinc in individuals with insulin-dependent diabetes mellitus (IDDM) is approximately doubled. In the absence of a compensatory mechanism, this hyperzincuria should induce a deficient or marginal Zn status. We examined parameters of Zn status in plasma and in blood cells with respect to urinary Zn losses and Zn supplementation. We measured Zn levels in the urine, plasma, and erythrocytes of 14 IDDM subjects and 15 nondiabetics who kept dietary records for 3 consecutive days. Subsequently, six IDDM subjects and seven nondiabetics were supplemented with 50 mg Zn daily for 28 days. We measured the above parameters, as well as mononuclear leukocyte Zn (MNL-Zn) and the plasma subfraction of albumin-bound Zn (alb-Zn). The total plasma Zn-binding capacity was also assessed. Plasma copper and erythrocyte Cu were monitored as indicators of potential Zn toxicity. Individuals with IDDM displayed the expected hyperzincuria, but had normal blood Zn parameters. Zincuria increased by a similar amount in both groups during supplementation, as did the MNL-Zn content. However, erythrocyte Zn (e-Zn) was refractory, so a trend toward lower e-Zn among IDDM subjects persisted during Zn supplementation. Hemoglobin A1c (HbA1c) increased markedly in the Zn-supplemented IDDM group. Despite their chronic hyperzincuria, individuals with IDDM appear not to be Zn-deficient. Large-dose Zn supplementation increases MNL-Zn and induces an undesirable elevation of HbA1c in all individuals. This is especially disconcerting for those with IDDM, and may reflect an exacerbation of a chronic "Zn diabetes." These data suggest a potential for toxicity from large-dose Zn supplementation.

32. Zinc and insulin sensitivity.

Faure P, Roussel A, Coudray C, Richard MJ, Halimi S, Favier A. Laboratoire de Biochimie C, Hopital A. Michallon, Grenoble, France.

Biol Trace Elem Res 1992 Jan-Mar;32:305-10

Many studies have shown that zinc deficiency could decrease the response to insulin. In genetically diabetic animals, a low zinc status has been observed contrary to induced diabetic animals. The zinc status of human patients depends on the type of diabetes and the age. Zinc supplementation seems to have beneficial effects on glucose homeostasis. However, the mechanism of insulin resistance secondary to zinc depletion is yet unclear. More studies are therefore necessary to document better zinc metabolism in diabetes mellitus, and the antioxidant activity of zinc on the insulin receptor and the glucose transporter.

33. The influence of zinc supplementation on glucose homeostasis in NIDDM.

Raz I, Karsai D, Katz M. Department of Medicine B, Hadassah University Hospital, Ein Karem, Israel.

Diabetes Res 1989 Jun;11(2):73-9

Decreased serum zinc levels and hyperzincuria occur in some non-insulin dependent diabetic subjects (NIDDM). Zinc deficiency was demonstrated in various tissues of animal models for NIDDM. Serum zinc and 24-hr urine zinc of subjects with NIDDM were compared with that of age- and sex-matched healthy volunteers. Zincuria was significantly increased in the diabetic group. Thirteen diabetic subjects with hyperzincuria and hypozincemia were supplemented with zinc sulfate 220 mg x 3/day for 7-8 weeks. At the end of the study, glucose disposal (evaluated by kg) decreased significantly from 0.562 +/- 0.03 to 0.414 +/- 0.05 (p less than 0.05) and fasting glucose and fructosamine were significantly increased from 177 +/- 10 mg/dl to 207 +/- 15 mg/dl (p less than 0.05) and from 2.7 +/- 0.2% to 3.2 +/- 0.28% (p less than 0.05), respectively. T-lymphocyte response to phytohemagglutinin was increased significantly. We conclude that zinc supplementation to NIDD patients with hypozincemia and hyperzincemia might aggravate their glucose intolerance. More accurate methods to assess zinc deficiency in NIDD patients is needed to justify the supplementation of zinc in these patients.

ELDERLY

34. Zinc and immunoresistance to infection in aging: new biological tools.

Mocchegiani E, Muzzioli M, Giacconi R. Immunology Centre, Research Department 'Nino Masera', Italian National Research Centres on Aging (I.N.R.C.A.), Via Birarelli 8, 60121, Ancona, Italy. e.mocchegiani@inrca.it

Trends Pharmacol Sci. 2000 Jun;21(6):205-8. Comment in: Trends Pharmacol Sci. 2001 Mar;22(3):112-3.

Infections can cause mortality when the immune system is damaged. The catalytic, structural (in zinc-finger proteins) and regulatory roles of zinc mean that this ion is involved in the maintenance of an effective immune response. Both zinc deficiency and impaired cell-mediated immunity combine during aging to result in increased susceptibility to infection. Dietary supplementation with the recommended daily allowance of zinc for between one and two months decreases the incidence of infection and increases the survival rate following infection in the elderly. This article reviews the biochemical pathways through which zinc might act to increase immunoresistance to infection in the elderly.

35. Zinc and copper intakes and their major food sources for older adults in the 1994-96 continuing survey of food intakes by individuals (CSFII).

Ma J, Betts NM. Department of Nutritional Science and Dietetics, University of Nebraska, Lincoln, NE 68583, USA.

J Nutr. 2000 Nov;130(11):2838-43. Full text article http://www.nutrition.org/cgi/content/full/130/11/2838

Zinc and copper are two trace minerals essential for important biochemical functions and necessary for maintaining health throughout life. Several national food surveys revealed marginally to moderately low contents of both nutrients in the typical American diet. Using data from the respondents >/= 60 y old in the 1994-96 Continuing Survey of Food Intakes by Individuals (CSFII), we examined average dietary intakes of zinc, copper and relevant dietary factors; primary dietary contributors of zinc and copper; and Zn:Cu ratios of the primary dietary contributors. Data were analyzed with the use of a chi(2) test, Student's t test and multivariate analysis of covariance with Bonferroni correction. The daily zinc intake was 12 +/- 6.4 mg for men and 8.0 +/- 4.0 mg for women (P < 0.05); the daily copper intake was 1.3 +/- 0.7 mg for men and 1.0 +/- 0.5 mg for women (P < 0.05). Foods such as beef, ground beef, legumes, poultry, ready-to-eat and hot cereals, and pork constituted the major sources of zinc. Copper consumption was contributed mainly by legumes, potato and potato products, nuts and seeds, and beef. The less-than-recommended intakes of zinc and copper by the elderly were likely associated with age, low income and less education. The intakes of zinc and copper could be improved by more frequent consumption of food sources rich in these minerals. An inherent limitation of this study was the use of the 24-h dietary recall method, which may underestimate usual dietary intakes. Nonetheless, this study affirms the need for assessment of zinc and copper nutriture in the elderly.

36. [Zinc: pathophysiological effects, deficiency status and effects of supplementation in elderly persons--an overview of the research] [Article in German]

Abbasi A, Shetty K. Medical College of Wisconsin, Milwaukee 53226, USA.

Z Gerontol Geriatr. 1999 Jul;32 Suppl 1:I75-9.

Zinc is an essential micronutrient. Several studies have shown that zinc deficiency is common in older people. Zinc has been extensively studied with regard to its role in wound healing, infections, immune system, cardiovascular disease, and several other medical conditions. Several investigators have published intervention studies using zinc supplements in older people with favorable outcomes. This paper will briefly review the pathophysiologic effects of zinc, nutritional deficiency, and effects of zinc supplementation in older people.

37. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network.

Girodon F, Galan P, Monget AL, Boutron-Ruault MC, Brunet-Lecomte P, Preziosi P, Arnaud J, Manuguerra JC, Herchberg S. Scientific and Technical Institute for Foods and Nutrition, Conservatiore National des Arts et Mettiers, Paris, France.

Arch Intern Med. 1999 Apr 12;159(7):748-54.

BACKGROUND: Antioxidant supplementation is thought to improve immunity and thereby reduce infectious morbidity. However, few large trials in elderly people have been conducted that include end points for clinical variables. OBJECTIVE: To determine the effects of long-term daily supplementation with trace elements (zinc sulfate and selenium sulfide) or vitamins (beta carotene, ascorbic acid, and vitamin E) on immunity and the incidence of infections in institutionalized elderly people. METHODS: This randomized, double-blind, placebo-controlled intervention study included 725 institutionalized elderly patients (>65 years) from 25 geriatric centers in France. Patients received an oral daily supplement of nutritional doses of trace elements (zinc and selenium sulfide) or vitamins (beta carotene, ascorbic acid, and vitamin E) or a placebo within a 2 x 2 factorial design for 2 years. MAIN OUTCOME MEASURES: Delayed-type hypersensitivity skin response, humoral response to influenza vaccine, and infectious morbidity and mortality. RESULTS: Correction of specific nutrient deficiencies was observed after 6 months of supplementation and was maintained for the first year, during which there was no effect of any treatment on delayed-type hypersensitivity skin response. Antibody titers after influenza vaccine were higher in groups that received trace elements alone or associated with vitamins, whereas the vitamin group had significantly lower antibody titers (P<.05). The number of patients without respiratory tract infections during the study was higher in groups that received trace elements (P = .06). Supplementation with neither trace elements nor vitamins significantly reduced the incidence of urogenital infections. Survival analysis for the 2 years did not show any differences between the 4 groups. CONCLUSIONS: Low-dose supplementation of zinc and selenium provides significant improvement in elderly patients by increasing the humoral response after vaccination and could have considerable public health importance by reducing morbidity from respiratory tract infections.

38. [Diagnosis of zinc deficiency] [Article in German]

Roth HP, Kirchgessner M. Institut fur Ernahrungsphysiologie, Technischen Universitat Munchen.

Z Gerontol Geriatr. 1999 Jul;32 Suppl 1:I55-63.

Though far more common, particularly in elderly people, than was previously assumed, marginal zinc deficiency does not lead to the classical manifestations of zinc deficiency and is therefore difficult to diagnose. There is therefore a need for sensitive parameters that can reliably demonstrate even marginal zinc deficiency, as suboptimal zinc status can seriously impair human health, performance, reproductive functions, and mental and physical development. The most important criteria for the diagnosis of zinc deficiency are critically discussed. The laboratory parameters currently considered to be the most useful indicators of marginal zinc deficiency are zinc-binding capacity and serum/plasma alkaline phosphatase activity before and after zinc supplementation (zinc tolerance test!). In order to obtain a reliable assessment of a patients zinc status, a number of different diagnostic parameters should always be measured.

39. Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial.

Girodon F, Lombard M, Galan P, Brunet-Lecomte P, Monget AL, Arnaud J, Preziosi P, Hercberg S. Institut Scientifique et Technique de la Nutrition et de l'Alimentation, Paris, France.

Ann Nutr Metab. 1997;41(2):98-107.

To determine the impact of a trace element and vitamin supplementation on infectious morbidity, a double-blind controlled trial was performed on 81 elderly subjects in a geriatric center during a 2-year period. Subjects were randomly assigned to one of four treatment groups, and received daily: placebo; trace elements/zinc 20 mg; selenium 100 micrograms); vitamins (vitamin C 120 mg; beta-carotene 6 mg; alpha-tocopherol 15 mg); or a combination of trace elements and vitamins at equal doses. (1) Before supplementation, low serum values in vitamin C, folate, zinc and selenium were observed in more than two thirds of the patients. (2) After 6 months of supplementation, a significant increase in vitamin and trace element serum levels was obtained in the corresponding treatment groups: a plateau was then observed for the whole study. (3) Subjects who received trace elements (zinc and selenium) alone or associated with vitamins had significantly less infectious events during the 2 years of supplementation. These results indicate that supplementation with low doses of vitamins and trace elements is able to rapidly correct corresponding deficiencies in the institutionalized elderly. Moreover, zinc and selenium reduced infectious events.

40. [Zinc status evaluation in an elderly institutionalized population] [Article in Spanish]

Meertens L, Solano L, Pena E. Unidad de Investigaciones en Nutricion, Facultad de Ciencias de la Salud, Universidad de Carabobo, Valencia, Venezuela.

Arch Latinoam Nutr. 1997 Dec;47(4):311-4.

Elderly people is at high nutritional risk for zinc, specially marginal deficit, which could contribute to complications of chronic diseases and undernutrition. The aim of study was to know the zinc status of 83 elderly people (older than 60), from both sexes, living in geriatric home. Zinc serum levels, alkaline phosphatase serum levels; albumin serum levels, energy, proteins and zinc dietary intake and gustative sensitivity were determined. Results expressed as mean +/- DS are the following: serum zinc: 90.89 +/- 19.0 micrograms/dl, alkaline phosphatase: 125.41 +/- 24.2 IU/L, albumin serum: 3.9 +/- 0.76 g/dl energy intake: 1643 +/- 309.9 Kcal/day, protein intake: 59.96 +/- 13.2 g/day, zinc intake 7.9 +/- 3.0 mg/day, only energy and zinc intake were deficient. 18.1% had zinc values under 70 micrograms/dl. There was 54% of positive responses to the taste acuity tests. This results qualify this group as at risk, specially for zinc nutritional.

41. Beneficial effects of oral zinc supplementation on the immune response of old people.

Duchateau J, Delepesse G, Vrijens R, Collet H

Am J Med 1981 May;70(5):1001-4

Zinc is known to have beneficial effects on the immune response. In an attempt to modify age-associated immune dysfunction, supplemental zinc was administered to 15 subjects over 70 years of age (220 mg zinc sulfate twice daily for a month). As compared to 15 controls, matched for age and sex, there was a significant improvement in the following immune parameters in the treated group: (1) number of circulating T lymphocytes; (2) delayed cutaneous hypersensitivity reactions to purified protein derivative, Candidin and streptokinase-streptodornase; (3) immunoglobulin G (IgG) antibody response to tetanus vaccine. Zinc treatment had no influence on the number of total circulating leukocytes or lymphocytes, or on the in vitro lymphocyte response to three mitogens: phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). The data suggest that the addition of zinc to the diet of old persons could be an effective and simple way to improve their immune function.

42. Effect of a two-year supplementation with low doses of antioxidant vitamins and/or minerals in elderly subjects on levels of nutrients and antioxidant defense parameters.

Girodon F, Blache D, Monget AL, Lombart M, Brunet-Lecompte P, Arnaud J, Richard MJ, Galan P Laboratoire de Biochimie des Lipoproteines, Universite de Bourgogne, Digon, France.

J Am Coll Nutr 1997 Aug;16(4):357-65

BACKGROUND: Eighty-one elderly hospitalized subjects (> 65 years) were recruited for a double-blind placebo-controlled study to examine low dose supplementation of antioxidant vitamins and minerals on biological and functional parameters of free radical metabolism. Subjects were randomly assigned to one of the four treatment groups, daily receiving for 2 years: placebo group; mineral group: 20 mg zinc, 100 micrograms selenium; vitamin group: 120 mg VITAMIN C (Vit C), 6 mg beta-carotene (beta CA), 15 mg vitamin E (Vit E); mineral and vitamin group: Zn 20 mg, Se 100 micrograms, Vit C 120 mg, beta CA 6 mg, Vit E 15 mg. RESULTS: Fifty-seven subjects completed the study. A large frequency of Vit C, Zn and Se deficiencies were observed at baseline. As early as 6 months of treatment, a significant increase in vitamin and mineral serum levels was observed in the corresponding groups. The increases ranged from 1.1-4.0 fold depending on the nutrient. Antioxidant defense, studied in vitro with a test using red blood cells in presence of 2,2'-azo-bis (2-amidinopropane) by hydrochloride, showed an increase of cell resistance in patients receiving vitamins (p = 0.002); it was positively correlated with serum Vit C (p < 0.0001), alpha-tocopherol/cholesterol (p = 0.06), beta CA (p = 0.0014), serum Cu and Se (p < 0.05). Moreover, red blood cell antioxidant defense was reduced in elderly compared with young control subjects (50% hemolysis time: 69 +/- 14 mn and 109 +/- 12 mn, respectively). Erythrocyte glutathione peroxidase activity was enhanced in groups receiving minerals, whereas no significant change was observed for other indicators of oxidative stress (erythrocyte superoxide dismutase activity, thiobarbituric acid-reactive substances, total glutathione, reduced and oxidized forms). DISCUSSION: Our results provide experimental evidence that a low dose supplementation with vitamins and minerals was able to normalize biological nutrient status as early as 6 months of treatment. In addition, our data indicate that antioxidant defense in elderly subjects was improved with low doses of Vit C, vit E and beta CA as studied by means of a functional test utilizing red blood cells challenged in vitro with free radicals.

43. In vitro modulation of keratinocyte wound healing integrins by zinc, copper and manganese.

Tenaud I, Sainte-Marie I, Jumbou O, Litoux P, Dreno B. Laboratory of Immuno-Dermatology, CHU Hotel-Dieu, Place A. Ricordeau, 44035 Nantes Cedex 01, France.

Br J Dermatol 1999 Jan;140(1):26-34

Although the trace elements zinc, copper and manganese are used in vivo for their healing properties, their mechanism of action is still only partially known. Some integrins expressed by basal layer keratinocytes play an essential part in healing, notably alpha2beta1, alpha3beta1, alpha6beta4 and alphaVbeta5, whose expression and distribution in epidermis are modified during the re-epithelialization phase. This study demonstrates how the expression of these integrins are modulated in vitro by trace elements. Integrin expression was studied in proliferating keratinocytes in monolayer cultures and in reconstituted skin that included a differentiation state. After 48 h incubation with zinc gluconate (0.9, 1.8 and 3.6 microg/mL), copper gluconate (1, 2 and 4 microg/mL), manganese gluconate (0.5, 1 and 2 microg/mL) and control medium, integrin expression was evaluated by FACScan and immunohistochemistry. Induction of alpha2, alpha3, alphaV and alpha6 was produced by zinc gluconate 1.8 microg/mL in monolayers, of alpha2, alpha6 and beta1 by copper gluconate 2 and 4 microg/mL and of all the integrins studied except alpha3 by manganese gluconate 1 microg/mL. Thus, alpha6 expression was induced by all three trace elements. The inductive effect of zinc was particularly notable on integrins affecting cellular mobility in the proliferation phase of wound healing (alpha3, alpha6, alphaV) and that of copper on integrins expressed by suprabasally differentiated keratinocytes during the final healing phase (alpha2, beta1 and alpha6), while manganese had a mixed effect.

44. Prevalence of magnesium and zinc deficiencies in nursing home residents in Germany.

Worwag M, Classen HG, Schumacher E. Department of Pharmacology and Toxicology of Nutrition, University of Hohenheim, Stuttgart, Germany.

Magnes Res. 1999 Sep;12(3):181-9.

In a multicentric study with 345 seniors over 70 years old we investigated magnesium and zinc levels in serum together with the prevalence of their typical symptoms of deficiency in nursing home residents (NHR) and non-nursing home residents (nNHR). In addition calcium, sodium and potassium levels in serum were determined as well as creatinine and albumin. Considering all seniors 33 per cent exhibited hypomagnesemia and 19 per cent hypozincemia. Zinc levels of female and male NHR were significantly lower than levels of nNHR. Hypomagnesemia was significantly associated with calf cramps and with diabetes mellitus. Hypozincemia was significantly associated with impaired wound healing.

Hearing

45. [The serum zinc level in patients with tinnitus and the effect of zinc treatment] [Article in Japanese] Ochi K, Ohashi T, Kinoshita H, Akagi M, Kikuchi H, Mitsui M, Kaneko T, Kato I. Department of Otorhinolaryngology, St. Marianna University School of Medicine, Kyoto-fu.

Nippon Jibiinkoka Gakkai Kaiho 1997 Sep;100(9):915-9

We measured the serum zinc level in patients with tinnitus and evaluated the effectiveness of zinc in the treatment of tinnitus. Blood zinc levels were measured in 121 patients with tinnitus. All patients were examined between 1995 and 1997 at the outpatient clinic of otorhinolaryngology St. Marianna University Toyoko Hospital. Forty-seven patients who had received any drug such as a calcium channel blocker and others or had been affected by any diseases were excluded and therefore 74 patients consisting of 46 females (62%) and 28 males (38%) were investigated. Twenty two healthy volunteers served as a control group. The mean age and standard deviations for the tinnitus group and the control group were 47.8 +/- 17.1 and 31.4 +/- 8.2 years, respectively. There was a significant decrease (p < 0.0001) in serum zinc levels in patients with tinnitus compared with the control group. Because there was a significant difference (p < 0.0001) in age distribution between tinnitus and control groups, patients were selected by their age in order to neglect the effect of aging. In this situation, a significant difference (p < 0.01) was noted between the tinnitus group and control group. Low blood zinc level was defined by using the mean and standard deviation for the control group (mean-1 S.D.). We treated patients with low blood zinc levels. A total dose of 34-68 mg of Zn++ was administered daily for over 2 weeks. The degree of tinnitus was expressed on a numeric scale from 0 to 10 before and after treatment. Blood zinc levels were significantly elevated (p < 0.05) after treatment. We found a significant decrease (p < 0.01) in the numeric scale. These findings suggest that zinc is useful in at least some patients suffering from tinnitus. It is possible to classify patients with tinnitus by measuring serum zinc level and this leads to improvement of the overall treatment effect.

46. Chemical anatomy of excitatory endings in the dorsal cochlear nucleus of the rat: differential synaptic distribution of aspartate aminotransferase, glutamate, and vesicular zinc.

Rubio ME, Juiz JM. Instituto de Neurociencias, Universidad Miguel Hernandez, Alicante, Spain. lrubio@pop.nidcd.nih.gov

J Comp Neurol 1998 Sep 28;399(3):341-58

In order to identify cytochemical traits relevant to understanding excitatory neurotransmission in brainstem auditory nuclei, we have analyzed in the dorsal cochlear nucleus the synaptic distribution of aspartate aminotransferase, glutamate, and vesicular zinc, three molecules probably involved in different steps of excitatory glutamatergic signaling. High levels of glutamate immunolabeling were found in three classes of synaptic endings in the dorsal cochlear nucleus, as determined by quantitation of immunogold labeling. The first type included auditory nerve endings, the second were granule cell endings in the molecular layer, and the third very large endings, better described as "mossy." This finding points to a neurotransmitter role for glutamate in at least three synaptic populations in the dorsal cochlear nucleus. The same three types of endings enriched in glutamate immunoreactivity also contained histochemically detectable levels of aspartate aminotransferase activity, suggesting that this enzyme may be involved in the synaptic handling of glutamate in excitatory endings in the dorsal cochlear nucleus. There was also extrasynaptic localization of the enzyme. Zinc ions were localized exclusively in granule cell endings, as determined by a Danscher-selenite method, suggesting that this ion is involved in the operation of granule cell synapses in the dorsal cochlear nucleus.

47. The role of zinc in the treatment of tinnitus.

Arda HN, Tuncel U, Akdogan O, Ozluoglu LN. Department of Ear, Nose, Throat, Head and Neck Surgery, Ankara Numune Research and Education Hospital, Turkey. nedard@yahoo.com

Otol Neurotol. 2003 Jan;24(1):86-9.

OBJECTIVE: This study was designed to investigate the role of zinc administration in treatment of tinnitus.

STUDY DESIGN: Randomized, prospective, placebo-controlled study.

SETTING: Patients with tinnitus were admitted to the ear, nose, and throat clinic of the authors' hospital.

PATIENTS: Patients with tinnitus with no know pathologic conditions of the ear, nose, and throat; the mean age of 28 patients receiving zinc was 51.2 years, and that of 13 patients given placebo was 55 years.

INTERVENTION: Blood zinc levels were measured. Frequency was detected by audiometry, and loudness of tinnitus was screened by tinnitus match test. A questionnaire that scored tinnitus subjectively between 0 and 7 was given to patients before zinc treatment. After 2 months of treatment (zinc 50 mg daily to zinc group, placebo pill containing starch to placebo group), all of the tests were performed again. There was no difference in age, sex, duration of tinnitus, and affected ears between the patients treated with zinc and those treated with placebo. Blood zinc levels were lower than normal in 31% of patients before treatment.

MAIN OUTCOME MEASURES: A decrease in tinnitus loudness by at least 10 dB was accepted as clinically favorable progress. A decrease of more than 1 point in subjective tinnitus scoring was accepted as valid.

RESULTS: Clinically favorable progress was detected in 46.4% of patients given zinc. Although this decrease was not statistically significant, the severity of subjective tinnitus decreased in 82% of the patients receiving zinc. The mean of subjective tinnitus decreased from 5.25 +/- 1.08 to 2.82 +/- 1.81 (< 0.001). However, the decrease in severity of the tinnitus was not significant in patients receiving placebo.

CONCLUSION: It can be concluded that patients with tinnitus may have low blood zinc levels (31%) and clinical and subjective improvement can be achieved by oral zinc medication. However, it remains to be seen whether the longer duration of treatment has more significant results.

48. The role of zinc in management of tinnitus.

Yetiser S, Tosun F, Satar B, Arslanhan M, Akcam T, Ozkaptan Y. Department of ORL and HNS, Gulhane Medical School, Etlik, 06018 Ankara, Turkey. syetiser@yahoo.com

Auris Nasus Larynx. 2002 Oct;29(4):329-33.

OBJECTIVE: Several therapeutic modalities have been tried in patients with tinnitus. These trials have given rise to unsatisfactory results in most of the patients since the etiology and pathophysiology of tinnitus is unclear. Significant correlation between tinnitus and decreased zinc level and also reduction in severity of tinnitus after zinc therapy has been reported in some clinical studies. The aim of this study is to find out the prevalence of hypozincemia in patients suffering from tinnitus of various origins (presbyacusis, acoustic trauma and ototoxicity) at young and elderly population and to investigate the effect of zinc therapy upon the severity of tinnitus.

METHODS: Forty consecutive patients with severe tinnitus were included in this study between April 1998 and May 2000. There were 32 men (80%) and eight women (20%) with an age ranging between 19 and 67 (mean 40.6 years). Eleven patients were over the age of 50. The zinc level was measured in non-diluted serum by flame atomic absorption spectrophotometry (normal values; 50-120 microg/dl) from fasting blood samples. All the patients were given zinc pills 220 mg each, once a day and 2 h before lunch for 2 months. The patients were required to fulfill a tinnitus scoring scale and a handicap questionnaire before and after treatment. The Wilcoxon rank sum test and McNemar test were used for the statistical analysis.

RESULTS: Six patients were hypozincemic and seven patients had decreased serum zinc levels. No significant change has been observed in frequency and severity of tinnitus measured by audiologic tests after zinc therapy. Twenty-three (57.5%) of these patients reported some relief of tinnitus in the tinnitus scoring scale but the rate of improvement was minor (P>0.05). Decrease in severity of tinnitus after zinc therapy in elder group was better than the younger ones.

CONCLUSION: Our study could not confirm the high incidence of hypozincemia in patients with tinnitus as reported previously. Zinc therapy for 8 weeks presented no promising effect on tinnitus in three groups of patients and the difference between the rate of improvement in severity of tinnitus after zinc intake in patients with normal and low serum zinc level was not significant. Zinc supplement provided relief of tinnitus in some of the elder people who apparently had dietary zinc deficiency.

49. Zinc: the neglected nutrient.

Shambaugh GE Jr. Shambaugh Hearing and Allergy, Hinsdale, IL 60521.

Am J Otol 1989 Mar;10(2):156-60

Zinc was first recognized as essential for animals at the University of Illinois School of Agriculture in 1916, when it was found that zinc-deficient baby pigs were runty, developed dermatitis on their legs, and were sterile. Zinc deficiency was first recognized in man by Dr. Ananda Prasad of Detroit 26 years ago when he measured serum and hair zinc levels in young male Egyptian dwarfs who had failed to mature and were small in stature. By simply adding zinc to their regular diet, they grew in height and became sexually mature. It is now recognized that dwarfism in males is frequent around the Mediterranean, where wheat is the staple of life and has been grown for 4,000 years on the same soil, thereby resulting in the depletion of zinc. Professor Robert Henkin first suggested that zinc deficiency might cause hearing-nerve impairment. Assay of the soft tissues of the cochlea and vestibule revealed a zinc level higher than that of any other part of the body. Previously, the eye was considered to have the highest level of zinc of any organ. To diagnose zinc deficiency clinically, we use serum zinc assays made at the Mayo Clinic Trace Element Laboratory. With zinc supplementation in patients who are marginally zinc deficient, there has been improvement in tinnitus and sensorineural hearing loss in about one-third of elderly adults. We believe zinc deficiency is one causation of presbycusis; by recognizing and correcting it, a progressive hearing loss can be arrested.

Hepatitis

50. Determination of hepatic zinc content in chronic liver disease due to hepatitis B virus.

Gur G; Bayraktar Y; Ozer D; Ozdogan M; Kayhan B Hacettepe University, Faculty of Medicine, Department of Internal Medicine, Ankara-Turkey.

Hepatogastroenterology (Greece) Mar-Apr 1998, 45 (20) p472-6

BACKGROUND/AIMS: Zinc is an essential, mostly intracellular, trace element which participates in many physiologic mechanisms. Some liver functions like urea formation require the presence of zinc; thus the determination of hepatic zinc content may contribute to the understanding of probable zinc-related clinical consequences of chronic liver disease. In this study, we aimed to determine the hepatic zinc concentrations in patients with chronic liver disease due to the Hepatitis B virus and to ascertain the relationship between the severity of liver disease and hepatic zinc content, if one in fact exists.

METHODOLOGY: A total of 99 HBsAg positive subjects were included in the study. We performed a liver biopsy on all subjects. Hepatic zinc concentrations were determined by atomic absorption spectrophotometry.

RESULTS: The liver biopsies were normal in 25 subjects. There were 33 chronic active hepatitis (CAH), 34 cirrhosis and 7 chronic persistent hepatitis (CPH) patients in the study group. In the control group, CAH, cirrhosis and CPH groups, the mean liver zinc concentrations were 3.83 +/- 1.86, 1.86 +/- 0.92, 1.14 +/- 0.68 and 3.74 +/- 1.81 mumol/g dry weight, respectively. Hepatic zinc in the CAH and cirrhosis groups were lower than that of the control group (p < 0.05). We also found that liver zinc in the cirrhosis group was lower than in the CAH group (p < 0.05).

CONCLUSION: According to these results, as the severity of liver damage increases, the hepatic zinc concentration decreases. Therefore, it can be suggested that zinc supplementation may improve hepatic encephalopathy by increasing the efficiency of the urea cycle.

51. Zinc supplementation improves glucose disposal in patients with cirrhosis.

Marchesini G; Bugianesi E; Ronchi M; Flamia R; Thomaseth K; Pacini G Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Universita di Bologna, Italy.

Metabolism (United States) Jul 1998, 47 (7) p792-8

Zinc deficiency is common in cirrhosis, and was proved to affect nitrogen metabolism. In experimental animals, zinc status may also affect glucose disposal, and acute zinc supplementation improves glucose tolerance in healthy subjects. This study was aimed at measuring the effects of long-term oral zinc supplements on glucose tolerance in cirrhosis . The time courses of glucose, insulin, and C-peptide in response to an intravenous (i.v.) glucose load were analyzed by the minimal-model technique before and after long-term oral zinc supplements (200 mg three times per day for 60 days) in 10 subjects with advanced cirrhosis and impaired glucose tolerance or diabetes. The test was performed using a simplified procedure, based on 20 blood samples collected within 4 hours from the glucose load. Normal values were obtained in 25 age-matched healthy subjects. Zinc levels were low to normal or reduced before treatment, and were normalized by oral zinc. Glucose disappearance improved by greater than 30% in response to treatment. There were no changes in pancreatic insulin secretion and systemic delivery, or in the hepatic extraction of insulin. Insulin sensitivity (SI), which was reduced by 80% before treatment, did not change. Glucose effectiveness (SG) was nearly halved in cirrhosis before treatment (0.013 [SD 0.007] min(-1) v. 0.028 [SD 0.009] in controls; P < .001), and increased to 0.017 (SD 0.009) after zinc (P < .05 v. baseline). The return to normal of plasma zinc levels after long-term zinc treatment in advanced cirrhosis improves glucose tolerance via an increase of the effects of glucose per se on glucose metabolism. Poor zinc status may contribute to the impaired glucose tolerance and diabetes of cirrhosis.

52. Effect of dietary zinc deficiency on alkaline phosphatase and nucleic acids in rats.

Okegbile EO, Odunuga O, Oyewo A. Department of Biochemistry, Ogun State University, Ago-Iwoye, Nigeria.

Afr J Med Med Sci. 1998 Sep-Dec;27(3-4):189-92

Weanling male albino rats were randomly alloted to zinc deficient fed (ZnDF) pair-fed (ZnPF) or ad libitum-fed (ZnAL) dietary treatments. The rats were fed diets with either low (5 micrograms/g) or adequate (100 micrograms/g) zinc for 28 days. Zinc deficiency significantly reduced growth rate by 60% and was associated with a significantly low feed intake when compared with ZnPF and ZnAL groups. DNA and RNA contents of the liver were used as indication of nitrogen metabolism. DNA content was similar for both ZnPF and ZnAL groups (1.90 and 2.20 mg/g wet weight, respectively), but significantly different from ZnDF (1.42 mg/g wet weight). Liver RNA values of ZnAL, ZnPF and ZnDF groups similarly varied (25.0, 20.2 and 14.8 mg/g wet weight, respectively). Liver, muscle, spleen, femur and serum zinc concentrations were lowest in rats fed ZnDF relative to adequate zinc levels. The levels of the alkaline phosphatase activity was highest in the serum and lowest in the brain (spleen value was greater than that of the liver). Alkaline phosphatase activity was similar in ZnAL and ZnPF groups, but significantly different from ZnDF. In conclusion, the constitutively expressed growth rate, DNA level, RNA level, organ/serum zinc contents and alkaline phosphatase activities were markedly affected by zinc deficiency in rats.

HIV

53. Zinc status in human immunodeficiency virus type 1 infection and illicit drug use.

Baum MK, Campa A, Lai S, Lai H, Page JB. Florida International University, College of Health and Urban Affairs, University Park, Rm. HLS 337, Miami, FL 33199, USA. baumm@fiu.edu

Clin Infect Dis. 2003;37 Suppl 2:S117-23.

Zinc deficiency is the most prevalent micronutrient abnormality seen in human immunodeficiency virus (HIV) infection. Low levels of plasma zinc predict a 3-fold increase in HIV-related mortality, whereas normalization has been associated with significantly slower disease progression and a decrease in the rate of opportunistic infections. Studies in Miami, Florida, indicated that HIV-positive users of illicit drugs are at risk for developing zinc deficiency, at least partially because of their poor dietary intake. Zinc deficiency characterized by low plasma zinc levels over time enhances HIV-associated disease progression, and low dietary zinc intake is an independent predictor of mortality in HIV-infected drug users. The amount of zinc supplementation in HIV infection appears to be critical, because deficiency, as well as excessive dietary intake of zinc, has been linked with declining CD4 cell counts and reduced survival. More research is needed to determine the optimal zinc supplementation level in HIV-infected patients, to prevent further burden on an already compromised immune system.

54. Modulatory effects of selenium and zinc on the immune system.

Ferencik M, Ebringer L. Institute of Immunology, Faculty of Medicine, Comenius University, Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.

Folia Microbiol (Praha). 2003;48(3):417-26.

Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, and both insufficient and excessive intakes can have negative consequences on the immune status and susceptibility to a variety of pathogens. We summarize the evidence for the importance of two micronutrients, selenium and zinc, and describe the mechanisms through which they affect the immune status and other physiological functions. As a constituent of selenoproteins, selenium is needed for the proper functioning of neutrophils, macrophages, NK cells, T lymphocytes and some other immune mechanisms. Elevated selenium intake may be associated with reduced cancer risk and may alleviate other pathological conditions including oxidative stress and inflammation. Selenium appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Selenium deficiency has been linked to adverse mood states and some findings suggest that selenium deficiency may be a risk factor in cardiovascular diseases. Zinc is required as a catalytic, structural and regulatory ion for enzymes, proteins and transcription factors, and is thus a key trace element in many homeostatic mechanisms of the body, including immune responses. Low zinc ion bioavailability results in limited immunoresistance to infection in aging. Physiological supplementation of zinc for 1-2 months restores immune responses, reduces the incidence of infections and prolongs survival. However, in every single individual zinc supplementation of food should be adjusted to the particular zinc status in views of the great variability in habitat conditions, health status and dietary requirements.

55. Nutrients and HIV: part two-vitamins A and E, zinc, B-vitamins, and magnesium.

Patrick L.

Altern Med Rev 2000 Feb;5(1):39-51

There is compelling evidence that micronutrient deficiencies can profoundly affect immunity; micronutrient deficiencies are widely seen in HIV, even in asymptomatic patients. Direct relationships have been found between deficiencies of specific nutrients, such as vitamins A and B12, and a decline in CD4 counts. Deficiencies appear to influence vertical transmission (vitamin A) and may affect progression to AIDS (vitamin A, B12, zinc). Correction of deficiencies has been shown to affect symptoms and disease manifestation (AIDS dementia complex and B12; diarrhea, weight loss, and zinc), and certain micronutrients have demonstrated a direct anti-viral effect in vitro (vitamin E and zinc). The previous article in this series focused on selenium and beta carotene deficiencies in HIV/AIDS. This literature review elucidates how deficiencies of the micronutrients zinc, magnesium, vitamins A, E, and specific B vitamins relate to HIV symptomology and progression, and clearly illustrates the need for nutritional supplementation in HIV disease.

56. Zinc serum level in human immunodeficiency virus-infected patients in relation to immunological status.

Wellinghausen N, Kern WV, Jochle W, Kern P. Section of Infectious Diseases and Clinical Immunology, Medical University of Ulm, Germany.

Biol Trace Elem Res 2000 Feb;73(2):139-49

In human immunodeficiency virus (HIV) infection, serum level of zinc, an important micronutrient for immune function, is frequently diminished. The aim of this study was to determine the zinc status in relation to immunological parameters and disease stage in 79 HIV-1 seropositive patients. The median serum level of zinc was within normal limits (12.5 micromol/L) but in 23% of patients, zinc deficiency was seen. Decreased serum zinc was associated with a low CD4 cell count, high viral load, and increased neopterin and IgA levels. According to current treatment recommendations, the majority of patients received antiretroviral triple therapy. Zinc levels in treated and untreated patients were comparable. Referring to disease stage (CDC classification, 1993), the mean zinc level was highest in stage C and lowest in stage A. In conclusion, even under antiretroviral triple therapy, zinc deficiency is still of great importance in HIV infection, and zinc substitution in zinc deficient individuals should be taken into account to optimize therapeutical success.

57. Zinc serum level in human immunodeficiency virus-infected patients in relation to immunological status.

Wellinghausen N, Kern WV, Jochle W, Kern P. Section of Infectious Diseases and Clinical Immunology, Medical University of Ulm, Germany.

Biol Trace Elem Res. 2000 Feb;73(2):139-49.

In human immunodeficiency virus (HIV) infection, serum level of zinc, an important micronutrient for immune function, is frequently diminished. The aim of this study was to determine the zinc status in relation to immunological parameters and disease stage in 79 HIV-1 seropositive patients. The median serum level of zinc was within normal limits (12.5 micromol/L) but in 23% of patients, zinc deficiency was seen. Decreased serum zinc was associated with a low CD4 cell count, high viral load, and increased neopterin and IgA levels. According to current treatment recommendations, the majority of patients received antiretroviral triple therapy. Zinc levels in treated and untreated patients were comparable. Referring to disease stage (CDC classification, 1993), the mean zinc level was highest in stage C and lowest in stage A. In conclusion, even under antiretroviral triple therapy, zinc deficiency is still of great importance in HIV infection, and zinc substitution in zinc deficient individuals should be taken into account to optimize therapeutical success.

Hypertension

58. Free radical disease prevention and nutrition.

Krajcovicova-Kudlackova M, Ursinyova M, Blazicek P, Spustova V, Ginter E, Hladikova V, Klvanova J. Institute of Preventive and Clinical Medicine, Bratislava, Slovakia. Kudlackova@upkm.sk

Bratisl Lek Listy. 2003;104(2):64-8.

An improved antioxidant status (overthreshold plasma values of essential antioxidants) minimizes the oxidative damage. The levels of antioxidant vitamins C and E, ,,antioxidant" trace elements selenium, zinc, copper and iron were measured in two groups of adults with different nutritional habits--alternative (vegetarians; n=110) and traditional (mixed diet, control, n=101). The prevalence of iron and zinc deficiencies was found in the alternative group (20% vs 11%--iron, 13% vs 9%--zinc) as a consequence of higher intake of plant trace element absorption inhibitors. As opposed to the latter, the control group had higher findings of iron and copper levels over the optimal range (18% vs 8%--iron, 11% vs 2%--copper). The subjects on mixed diet was showed a significant negative linear correlation between serum zinc and iron levels. This favourable relationship means a decrease in Fenton reaction by indirect zinc effect. Average plasma values of vitamin C, vitamin C/vitamin E, vitamin E/ cholesterol (LDL protection), vitamin E/triacylglycerols (polyunsaturated fatty acid protection) in vegetarians are over the threshold with high number of individual overthreshold values (94% vs 17%--vitamin C, 100% vs 58%--vitamin C/vitamin E, 89% vs 68%--vitamin E/cholesterol, 100% vs 64%--vitamin E/triacylglycerols). Homocysteine levels in vegetarians (36% atherogenic levels) correlate significantly inversely to vitamin C levels, the fact of which means a positive vitamin C effect in free radical remove also in hyperhomocysteinemia. Plant food is a rich source of antioxidants. A correct vegetarian nutrition or optimized mixed diets with regular and frequent consumption of protective food commodities may be an effective contribution to the age-related chronic degenerative disease prevention. (Tab. 2, Fig. 2, Ref. 31.).

59. Angiotensin-I-converting enzyme and its relatives.

Riordan JF. Center for Biochemical and Biophysical Sciences and Medicine, Harvard Medical School, One Kendall Square, Cambridge, MA 02139, USA. james_riordan@hms.harvard.edu

Genome Biol. 2003;4(8):225. Epub 2003 Jul 25.

SUMMARY: Angiotensin-I-converting enzyme (ACE) is a monomeric, membrane-bound, zinc- and chloride-dependent peptidyl dipeptidase that catalyzes the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a carboxy-terminal dipeptide. ACE has long been known to be a key part of the renin angiotensin system that regulates blood pressure, and ACE inhibitors are important for the treatment of hypertension. There are two forms of the enzyme in humans, the ubiquitous somatic ACE and the sperm-specific germinal ACE, both encoded by the same gene through transcription from alternative promoters. Somatic ACE has two tandem active sites with distinct catalytic properties, whereas germinal ACE, the function of which is largely unknown, has just a single active site. Recently, an ACE homolog, ACE2, has been identified in humans that differs from ACE in being a carboxypeptidase that preferentially removes carboxy-terminal hydrophobic or basic amino acids; it appears to be important in cardiac function. ACE homologs (also known as members of the M2 gluzincin family) have been found in a wide variety of species, even in those that neither have a cardiovascular system nor synthesize angiotensin. X-ray structures of a truncated, deglycosylated form of germinal ACE and a related enzyme from Drosophila have been reported, and these show that the active site is deep within a central cavity. Structure-based drug design targeting the individual active sites of somatic ACE may lead to a new generation of ACE inhibitors, with fewer side-effects than currently available inhibitors.

60. Studies of five microelement contents in human serum, hair, and fingernails correlated with aged hypertension and coronary heart disease.

Tang YR, Zhang SQ, Xiong Y, Zhao Y, Fu H, Zhang HP, Xiong KM. College of Chemistry and Molecular Science, College of Life Sciences, Wuhan University, 430072 Wuhan Hubei, China.

Biol Trace Elem Res. 2003 May;92(2):97-104.

Using atomic absorption spectrometry (AAS), five microelements in human serum, hair, and fingernails of aged hypertension, coronary heart disease (diseased group) and aged health control (healthy group) were detected. Results of the t-test are as follows: The iron, zinc, and cadmium contents and Zn/Cu (mol/mol) ratio of the diseased group were significantly higher than that of the healthy group in serum (p<0.01, p<0.05, p<0.01, and p<0.05, respectively); the chromium contents in the serum, hair, and fingernails (p<0.05, p<0.01, and p<0.05, respectively); the iron and zinc contents in the hair and fingernails (p<0.01, p<0.001, p<0.05, and p<0.01 respectively) and Zn/Cu ratio in the hair (p<0.01) of the diseased group were significantly lower than that of the healthy group.

61. Zn deficiency aggravates hypertension in spontaneously hypertensive rats: possible role of Cu/Zn-superoxide dismutase.

Sato M, Yanagisawa H, Nojima Y, Tamura J, Wada O. Department of Hygiene and Preventive Medicine, Faculty of Medicine, Saitama Medical School, Iruma-gun, Japan.

Clin Exp Hypertens. 2002 Jul;24(5):355-70.

Using spontaneously hypertensive rats (SHR) fed a standard or a Zn-deficient diet for 4 weeks, we examined whether Zn deficiency affects systemic blood pressure (BP) levels in a genetically hypertensive state through a fall in the activity of Cu/Zn-superoxide dismutase (SOD). SHR fed a Zn-deficient diet had a progressive increase in systolic BP during the dietary conditioning. Consequently, SHR fed a Zn-deficient diet exhibited significantly increased levels of systolic BP by 2 weeks after the start of dietary treatment when compared with SHR fed a standard diet. Similarly, levels of basal mean arterial pressure (MAP) observed at the end of dietary treatment were SHR fed a Zn-deficient diet > SHR fed a standard diet. Administration of the nitric oxide synthase (NOS) inhibitor, L-NAME, caused an increase in MAP levels in the two groups of rats, demonstrating the involvement of the vasodilator, nitric oxide (NO), in the regulation of systemic BP in a genetically hypertensive state. The expression of endothelial (e) NOS mRNA and protein in the thoracic aorta paralleled basal MAP levels in the two groups of rats, suggesting the counter-regulation of eNOS against the developed hypertensive state in SHR fed a Zn-deficient diet. On the other hand, administration of the superoxide scavenger, tempol (a SOD mimetic compound), led to a decrease in MAP levels in the two groups of rats, indicating the participation of the oxygen free radical, superoxide, in an increase in systemic BP in a genetically hypertensive state. As reported recently, the mechanism involved is due likely to a decrease in the action of the vasodilator, NO, based on the formation of peroxynitrite coming from the non-enzymatic reaction of superoxide and NO. In addition, tempol treatment completely restored MAP levels in SHR fed a Zn-deficient diet to levels comparable to those observed in SHR fed a standard diet, indicating that a further increase in systemic BP levels seen in SHR fed a Zn-deficient vs. a standard diet is presumably brought by a reduction in the action of the vasodilator, NO, resulting from an increase in the action of superoxide. The activity of the superoxide scavenger, Cu/Zn-SOD, in the thoracic aorta was significantly decreased in SHR fed a Zn-deficient diet relative to SHR fed a standard diet. It appears that a decrease in the activity of Cu/Zn-SOD observed in the thoracic aorta of SHR fed a Zn-deficient diet at least in part plays a role in an increase in the action of superoxide in this model. Thus, Zn deficiency may be a factor to develop genetic hypertension presumably through the oxidative stress caused by superoxide.

62. Increased absorption of zinc from alimentary tract in primary arterial hypertension.

Tubek S. Department of Internal Diseases, Regional Hospital, Strzelce Opolskie, Faculty of Physical Education and Physiotherapy, Institute of Technology, Opole, Poland. szpital.strzelce-op.pl

Biol Trace Elem Res. 2001 Oct;83(1):31-8.

Zinc absorption from the alimentary tract, as revealed by serum zinc concentration, was studied in a group of 10 patients (age 37.7+/-5.1 yr) with moderate and severe untreated primary arterial hypertension before and after a 30-d treatment with perindopril 4 mg/d. Blood pressure was 177.33+/-16.24/111.33+/-15.26 mm Hg before and 143.41+/-17.34/91.29+/-12.54 mm Hg after treatment (p < 0.05/p < 0.05). Nine persons (age 37+/-6.2 yr) with normal blood pressure (121.33+/-9.9/78+/-5.23 mm Hg) were the control group. Blood samples were taken from the ulnar vein at 8.00 AM (0 h), before taking zinc orally (one tablet of Zincas (zinc aspartate), containing 5 mg Zn2+) and at 1, 3, and 6 h after the dose. Serum zinc concentration in control and hypertensive group (before treatment) were initially 15.47+/-6.26 versus 15.99+/-5.65 (NS), 19.37+/-6.40 versus 20.83+/-4.48 (NS) after 1 h, 17.91+/-4.76 versus 31.32+/-10.49 (p < 0.003) after 3 h, and 15.32+/-5.47 versus 17.87+/-6.56 (NS) after 6 h. Maximal increase of Zn was 4.77+/-2.10 versus 17.53+/-4.13, respectively (p < 0.001). In the hypertensive group, serum Zn before and after perindopril treatment was initially 15.98+/-5.65 versus 14.81+/-3.11 (NS), 20.83+/-4.48 versus 18.17+/-2.50 (NS) after 1 h, 31.32+/-10.49 versus 22.94+/-5.80 (NS) after 3 h, 17.53+/-4.13 (p < 0.001) after 6 h. Maximal increase of Zn before treatment was 17.53+/-4.13 versus 9.17+/-4.67 (p < 0.017) after treatment. The following conclusions were reached: (1) In patients with primary arterial hypertension, an increased zinc absorption from alimentary tract was found; (2) A 30-d perindopril treatment 4 mg/d orally decreased zinc absorption in these patients.

63. Zinc and copper status and blood pressure.

Bergomi M, Rovesti S, Vinceti M, Vivoli R, Caselgrandi E, Vivoli G. Department of Biomedical Sciences, University of Modena, Italy.

J Trace Elem Med Biol. 1997 Nov;11(3):166-9. Comment in: J Trace Elem Med Biol. 1998 Mar;12(1):1.

In order to elucidate the relationships between Zn and Cu and blood pressure, the present case-control study was carried out. Zn and Cu status was evaluated in 60 subjects, pharmacologically untreated, affected by mild stable hypertension and in 60 normotensives matched for sex, age and smoking habits. Different markers of Zn and Cu status, including serum, erythrocyte and urine levels of the two trace elements and activities of some Zn- or Cu-dependent enzymes (alkaline phosphatase, lactic dehydrogenase, superoxide dismutase and lysyl oxidase) were evaluated. No significant difference between hypertensives and normotensives was observed in the mean levels of Zn and Cu as well as in Zn- or Cu-dependent enzymes, though higher levels of serum copper were associated with increased risk of hypertension. Interesting relationships between the biological parameters investigated were observed in the hypertensive subjects. Inverse correlations between blood pressures and serum Zn were observed. Furthermore, blood pressure was inversely related to lysyl oxidase activity. These findings give further support to the hypothesis that an imbalance of Zn and Cu bioavailability may be associated to hypertensive condition.

64. [Evaluation of selected parameters of zinc metabolism in patients with primary hypertension]

Peczkowska M; Kabat M; Janaszek-Sitkowska H; PuLawska M Kliniki Nadcisnienia Tetniczego Instytutu Kardiologii w Warszawie.

Pol Arch Med Wewn (Poland) Mar 1996, 95 (3) p198-204

The aim of the study was to investigate the role of zinc (Zn) in essential hypertension (EH).

PATIENTS AND METHODS: Material of the study consisted of 31 patients (12 female, 19 male) with mild and moderate EH and 20 healthy persons (NT) (7 female, 13 male). Erythrocyte (ZnE) and serum (ZnS) zinc as well as 24 hour urinary zinc excretion (ZuU) were assessed in both groups. Zn parameters were measured by atomic absorption spectrophotomery.

RESULTS: ZnS was lower and ZnE was higher in EH (p < 0.001) than in normotensives. ZnU did not differ between EH and NT. ZnE and ZnS negatively correlated with age in NT but not in EH, ZnU negatively correlated with age only in EH. BP positively correlated with ZnS in EH but not in NT. In both groups negative correlations were found between BP and ZnU.

CONCLUSIONS: 1. Zinc probably plays a role in pathogenesis of essential hypertension.

65. Zinc, cadmium, and hypertension in parturient women

Lazebnik N; Kuhnert BR; Kuhnert PM Department of Obstetrics and Gynecology, Cleveland Metropolitan General Hospital, OH 44109.

Am J Obstet Gynecol (United States) Aug 1989, 161 (2) p437-40

Zinc deficiency and cadmium toxicity have both been implicated in hypertension during pregnancy. The goals of this study were twofold: first, to assess the different zinc indices (plasma, red blood cell zinc, heat-labile alkaline phosphatase, and placental zinc) in normotensive and hypertensive parturients to determine whether they are altered in the different types of hypertension that occur during pregnancy; second, to assess whole-blood cadmium and placental cadmium with regard to hypertension and zinc status. Patients were diagnosed as having chronic hypertension or preeclamptic toxemia and were then further divided into groups on the basis of smoking status. Each patient was matched with a normal control subject based on age, parity, and smoking status. Forty-three hypertensive patients and their matched control subjects were studied. No differences were found in the various zinc indices between chronic hypertensive parturients and normal control subjects. However, in parturients with preeclamptic toxemia, the plasma zinc level was 19% lower than in control subjects (p less than 0.02); these patients had the lowest plasma zinc level of the three groups. Placental zinc was also 12% lower in patients with preeclamptic toxemia than in control subjects (p less than 0.04). Whole-blood cadmium and placental cadmium levels did not differ between control subjects or hypertensive patients. However, a significant positive correlation was found between whole-blood cadmium and plasma zinc levels in preeclamptic toxemia (r = 0.53; p less than 0.05). The results support a marginal zinc deficiency in parturients with preeclamptic toxemia but not in those with chronic hypertension. The role of cadmium in the cause of preeclamptic toxemia remains unclear.

Immune Enhancement

66. Zinc treatment prevents lipid peroxidation and increases glutathione availability in Wilson's disease.

Farinati F, Cardin R, D'inca R, Naccarato R, Sturniolo GC. Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy. J Lab Clin Med. 2003 Jun;141(6):372-7.

Oxidative and reductive mechanisms are important in Wilson's disease. In this study, we sought to evaluate tissue levels of glutathione and cysteine, an important detoxification system, and of malondialdehyde, a marker of lipoperoxidation, in patients with Wilson's disease receiving penicillamine or zinc treatment, in comparison with patients with chronic liver disease of different origin. Concentrations of cysteine, reduced/oxidized glutathione, malondialdehyde, zinc, and copper were determined (with the use of high-pressure liquid chromatography, fluorimetry and atomic-absorption spectrophotometry) in liver-biopsy specimens from 24 patients with Wilson's disease (18 treated with zinc, 6 with penicillamine), 34 patients with chronic viral hepatitis, and 10 patients with alcoholic liver disease. In patients with Wilson's disease, the concentration of reduced glutathione was lower than that in patients with viral hepatitis and as high as that in subjects with alcoholic liver damage. The cysteine level was significantly lower than those in the control groups, and the percentage of oxidized glutathione/total glutathione was higher than that in viral or alcoholic disease. Malondialdehyde levels were low, but when zinc- and penicillamine-treated patients were considered separately, only the former had low malondialdehyde levels. Zinc-treated patients had higher concentrations of reduced glutathione and a lower percentage of oxidized glutathione. In summary, patients with Wilson's disease have relevant glutathione depression, with low levels of reduced glutathione and cysteine and high concentrations of oxidized glutathione: This is prevented by zinc administration, which inhibits lipid peroxidation and increases glutathione availability.

67. Zinc-altered immune function.

Ibs KH, Rink L. Institute of Immunology, University Hospital, Technical University of Aachen, D-52074 Aachen, Germany.

J Nutr. 2003 May;133(5 Suppl 1):1452S-6S.

Zinc is known to be essential for all highly proliferating cells in the human body, especially the immune system. A variety of in vivo and in vitro effects of zinc on immune cells mainly depend on the zinc concentration. All kinds of immune cells show decreased function after zinc depletion. In monocytes, all functions are impaired, whereas in natural killer cells, cytotoxicity is decreased, and in neutrophil granulocytes, phagocytosis is reduced. The normal functions of T cells are impaired, but autoreactivity and alloreactivity are increased. B cells undergo apoptosis. Impaired immune functions due to zinc deficiency are shown to be reversed by an adequate zinc supplementation, which must be adapted to the actual requirements of the patient. High dosages of zinc evoke negative effects on immune cells and show alterations that are similar to those observed with zinc deficiency. Furthermore, when peripheral blood mononuclear cells are incubated with zinc in vitro, the release of cytokines such as interleukins (IL)-1 and -6, tumor necrosis factor-alpha, soluble IL-2R and interferon-gamma is induced. In a concentration of 100 micro mol/L, zinc suppresses natural killer cell killing and T-cell functions whereas monocytes are activated directly, and in a concentration of 500 micro mol/L, zinc evokes a direct chemotactic activation of neutrophil granulocytes. All of these effects are discussed in this short overview.

68. Metallothioneins/PARP-1/IL-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. Effect of zinc supply.

Mocchegiani E, Muzzioli M, Giacconi R, Cipriano C, Gasparini N, Franceschi C, Gaetti R, Cavalieri E, Suzuki H. Immunology Center (Section Nutrition, Immunity and Ageing), Research Department Italian National Research Centres on Ageing (INRCA), Via Birarelli 8, 60121, Ancona, Italy

Mech Ageing Dev. 2003 Apr;124(4):459-68.

Metallothioneins (MTs) play pivotal role in zinc-related cell homeostasis because of their high affinity for this trace element which is in turn relevant against oxidative stress and for the efficiency of the entire immune system, including natural killer (NK) cell activity. In order to accomplish this role, MTs sequester and/or dispense zinc during stress and inflammation to protect cells against reactive oxygen species. MTs gene expression is affected by IL-6 for a prompt immune response. Concomitantly, MTs release zinc for the activity of antioxidant zinc-dependent enzymes, including poly(ADP-ribose)polymerase-1(PARP-1), which is involved in base excision DNA-repair. This role of MTs is peculiar in young adult-age during transient stress and inflammation, but not in ageing because stress-like condition and inflammation are persistent. This may lead MTs to turn-off from role of protection in young age to deleterious one in ageing with subsequent appearance of age-related diseases (severe infections). The aim is to study the role played by MTs/IL-6/PARP-1 interplay on NK cell activity in elderly, in old infected patients (acute and remission phases by bronchopneumonia infection) and in health nonagenarian/centenarian subjects. MTmRNA is high in lymphocytes from elderly people coupled with high IL-6, low zinc ion bioavailability, decreased NK cell activity and impaired capacity of PARP-1 in base excision DNA-repair. The same trend in this altered physiological cascade during ageing also occurs in old infected patients (both acute and remission phases) with more marked immune damage, inflammatory condition and very impaired PARP-1 in base excision DNA-repair. By contrast, centenarian subjects display low MTmRNA, good zinc ion bioavailability, satisfactory NK cell activity and higher capacity of PARP-1 in base excision DNA-repair. These findings clearly demonstrate that the sequester of zinc by MTs in ageing is deleterious because leading to low zinc ion bioavailability with subsequent impairment of PARP-1 and NK cell activity and appearance of severe infections. Physiological zinc supply (12 mg Zn(++)/day) for 1 month in elderly and in old infected patients (remission phase) restores NK cells activity with values observed in health centenarians. Therefore, the zinc ion bioavailability by zinc-bound MTs homeostasis is pivotal to reach health longevity and successful ageing.

69. Zinc and immune function.

Dardenne M. CNRS UMR 8603, Universite Paris V, Hopital Necker, Paris, France. dardenne@necker.fr

Eur J Clin Nutr. 2002 Aug;56 Suppl 3:S20-3.

It is well recognized that zinc is an essential trace element, influencing growth and affecting the development and integrity of the immune system. Research has begun to clarify the molecular mechanisms underlying the action of zinc on the immune function. It is clear that this trace element has a broad impact on key immunity mediators, such as enzymes, thymic peptides and cytokines, explaining the paramount importance of zinc's status on the regulation of lymphoid cell activation, proliferation and apoptosis. Ongoing and future studies regarding the immunological status of zinc deficiency 'at risk' groups could lead to public health interventions with nutritional doses of zinc supplements to prevent alteration of the immune system and improve resistance to infections.

70. Zinc deficiency impairs immune responses against parasitic nematode infections at intestinal and systemic sites.

Scott ME, Koski KG. Institute of Parasitology, School of Dietetics and Human Nutrition, McGill University, Macdonald Campus, Ste-Anne de Bellevue, Quebec H9X 3V9, Canada.

J Nutr. 2000 May;130(5S Suppl):1412S-20S.

Research on the complex interactions among host nutritional status, parasitic infection and immune responsiveness has focused on the detrimental consequences of parasitic infections on host nutritional status and on mechanisms by which malnutrition impairs immunocompetence. Curiously, relatively few studies have examined the effects of malnutrition on the immune response in the parasite-infected host, and even fewer have considered the events occurring at the intestinal level, where absorption of nutrients occurs, intestinal parasites reside, and the gastrointestinal-associated lymphoid tissues play a role in directing both the local and the more systemic immune responses. Our work using a zinc-deficient nematode-infected mouse model reveals that parasites are better able to survive in the zinc-deficient hosts than in well-nourished hosts; that the production of interleukin-4 in the spleen of zinc-deficient mice is depressed, leading to depressed levels of IgE, IgG(1) and eosinophils; and that the function of T cells and antigen-presenting cells is impaired by zinc deficiency as well as by energy restriction. Given the paramount role of the gastrointestinal-associated lymphoid tissues in inducing and regulating immune responses to intestinal parasites and in orchestrating responses in the spleen and peripheral circulation, we conclude that zinc deficiency (in association with energy restriction) exerts profound effects on the gut mucosal immune system, leading to changes in systemically disseminated immune responses and, importantly, to prolonged parasite survival.

71. Zinc-altered immune function and cytokine production.

Rink L, Kirchner H. Institute of Immunology and Transfusion Medicine, University of Lubeck School of Medicine, Lubeck, Germany.

J Nutr. 2000 May;130(5S Suppl):1407S-11S.

Although the intriguing role of zinc as an essential trace element for immune function is well established, particular progress in determining the molecular principles of action of this ion was made recently. Leukocyte responsiveness is delicately regulated by zinc concentration. Zinc deficiency as well as supraphysiologic levels impair immune function. Furthermore, the activities of many immunostimulants frequently used in immunologic studies are influenced by zinc concentration. Therefore, our knowledge from in vitro studies is widely dependent on the zinc concentration, and when not in physiologic range, immunologic responses are artificially low. Decreased production of TH1 cytokines and interferon-alpha by leukocytes in the healthy elderly person is correlated with low zinc serum level. The defect in interferon-alpha production is reconstituted by the addition of physiologic amounts of zinc in vitro. Interestingly, zinc induces cytokine production by isolated leukocytes. Zinc induces monocytes to produce interleukin-1, interleukin-6 and tumor necrosis factor-alpha in peripheral blood mononuclear cells and separated monocytes. This effect is higher in serum-free medium. However, only in the presence of serum does zinc also induce T cells to produce lymphokines. This effect on T cells is mediated by cytokines produced by monocytes. Stimulation also requires cell-to-cell contact of monocytes and T cells. Information is presented to illustrate the concepts that the zinc concentration must be taken into account whenever in vitro studies are made or complex alterations of immune functions are observed in vivo.

72. Zinc status and immune system relationship: a review.

Salgueiro MJ, Zubillaga M, Lysionek A, Cremaschi G, Goldman CG, Caro R, De Paoli T, Hager A, Weill R, Boccio J. Radioisotope Laboratory, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina. Biol Trace Elem Res. 2000 Sep;76(3):193-205.

The essentiality of zinc for humans was first documented by Prasad in the 1960s. The main clinical manifestations associated with zinc deficiency are growth retardation, hypogonadism, diarrhea, and increased susceptibility to infectious diseases. Thus, in the past 25 yr, there was an increased interest of researchers in studying the role of zinc in human immunity. Although mechanistic research has been carried out using animal models, there are several studies in humans with similar results. This work is an attempt to review the information available in this field to understand the important role that zinc plays in the normal development and function of the immune system.

73. Effects of zinc deficiency on Th1 and Th2 cytokine shifts.

Prasad AS. Wayne State University, University Health Center, Detroit, MI 48201, USA. prasada@karmanos.org

J Infect Dis. 2000 Sep;182 Suppl 1:S62-8.

Nutritional deficiency of zinc is widespread throughout developing countries, and zinc-deficient persons have increased susceptibility to a variety of pathogens. Zinc deficiency in an experimental human model caused an imbalance between Th1 and Th2 functions. Production of interferon-gamma and interleukin (IL)-2 (products of Th1) were decreased, whereas production of IL-4, IL-6, and IL-10 (products of Th2) were not affected during zinc deficiency. Zinc deficiency decreased natural killer cell lytic activity and percentage of precursors of cytolytic T cells. In HuT-78, a Th0 cell line, zinc deficiency decreased gene expression of thymidine kinase, delayed cell cycle, and decreased cell growth. Gene expression of IL-2 and IL-2 receptors (both alpha and beta) and binding of NF-kappaB to DNA were decreased by zinc deficiency in HuT-78. Decreased production of IL-2 in zinc deficiency may be due to decreased activation of NF-kappaB and subsequent decreased gene expression of IL-2 and IL-2 receptors.

74. Zinc status in patients with alveolar echinococcosis is related to disease progression.

Wellinghausen N, Jochle W, Reuter S, Flegel WA, Grunert A, Kern P. Section of Infectious Diseases and Clinical Immunology, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany.

Parasite Immunol. 1999 May;21(5):237-41.

Zinc is an essential trace element for immune function that plays a role in immune response against parasites. To determine a possible relationship between zinc level and disease status in alveolar echinococcosis (AE), we investigated serum concentrations of zinc, immunoglobulin (Ig)E, IgG, and C-reactive protein (CRP) in 40 AE patients and 20 controls. Patients were classified into three groups: group A: patients after curative surgery, group B: patients with stabilized disease, group C: patients with progressive disease. Patients showed significantly higher levels of IgE and IgG than controls. Amounts of IgE and IgG were related to disease severity, achieving highest levels in group C and lowest in group A. Zinc levels were comparable in patients and controls. However, there was an obvious association between zinc concentration and disease severity. Zinc was far below the normal range in group C (median 9.2 micromol/l) and significantly diminished compared to group B and controls. An inverse pattern was seen for CRP. In conclusion, lowered zinc concentration in progressive cases may be caused by enhanced immune activation but consumption of zinc by the growing parasite may also play a role. Furthermore, decreased zinc levels may contribute to the observed immunosuppression in AE.

75. Zinc deficiency: changes in cytokine production and T-cell subpopulations in patients with head and neck cancer and in noncancer subjects.

Prasad AS; Beck FW; Grabowski SM; Kaplan J; Mathog RH Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI

Proc Assoc Am Physicians Jan 1997, 109 (1) p68-77

Cell-mediated immune dysfunctions and susceptibility to infections have been observed in zinc -deficient human subjects. In this study, we investigated the production of cytokines and characterized the T-cell subpopulations in three groups of mildly zinc -deficient subjects. These included head and neck cancer patients, healthy volunteers who were found to have a dietary deficiency of zinc, and healthy volunteers in whom we induced zinc deficiency experimentally by dietary means. We used cellular zinc criteria for the diagnosis of zinc deficiency. We assayed enzyme-linked immunosorbent assay the production of cytokines from phytohemagglutinin-stimulated peripheral blood mononuclear cells and assessed by flow cytometry the differences in T-cell subpopulations. Our studies showed that the cytokines produced by TH1 cells were particularly sensitive to zinc status, inasmuch as the production of interleukin-2 (IL-2) and interferon-gamma were decreased even though the deficiency of zinc was mild in our subjects. TH2 cytokines (IL-4, IL-5, and IL-6) were not affected by zinc deficiency. Natural killer cell lytic activity also was decreased in zinc -deficient subjects. Recruitment of naive T cells (CD4+CD45 RA+) and CD8+ CD73+ CD11b-, precursors of cytolytic T cells, were decreased in mildly zinc -deficient subjects. An imbalance between the functions of TH1 and TH2 cells and changes in T-cell subpopulations are most probably responsible for cell-mediated immune dysfunctions in zinc deficiency.

76. Serum thymic factor activity in deficiencies of calories, zinc, vitamin A and pyridoxine.

Chandra RK, Heresi G, Au B

Clin Exp Immunol 1980 Nov;42(2):332-5

Cell-mediated immunity is invariably impaired in protein-energy malnutrition. The effect of selected nutrient deficiencies on serum thymic factor activity was assessed in deprived rats and pair-fed controls. Deficits of calories, zinc or pyridoxine resulted in significant lowering of serum thymic factor activity whereas vitamin A deficiency did not have any effect. It is suggested that variants nutrients modulate different steps of cell-mediated immunity and that reduced thymic hormone activity may be the underlying mechanism of impaired immunity in some but not all nutritional deficiencies.

77. Zinc and immune function.

Dardenne M. CNRS UMR 8603, Universite Paris V, Hopital Necker, Paris, France. dardenne@necker.fr

Eur J Clin Nutr. 2002 Aug;56 Suppl 3:S20-3.

It is well recognized that zinc is an essential trace element, influencing growth and affecting the development and integrity of the immune system. Research has begun to clarify the molecular mechanisms underlying the action of zinc on the immune function. It is clear that this trace element has a broad impact on key immunity mediators, such as enzymes, thymic peptides and cytokines, explaining the paramount importance of zinc's status on the regulation of lymphoid cell activation, proliferation and apoptosis. Ongoing and future studies regarding the immunological status of zinc deficiency 'at risk' groups could lead to public health interventions with nutritional doses of zinc supplements to prevent alteration of the immune system and improve resistance to infections.

78. Preventive nutrition: disease-specific dietary interventions for older adults.

Johnson K; Kligman EW Dept. of Family and Community Medicine, University of Arizona College of Medicine, Tucson.

Geriatrics Nov 1992, 47 (11) p39-40, 45-9

Disease prevention through dietary management is a cost-effective approach to promoting healthy aging. Fats, cholesterol, soluble fiber, and the trace elements copper and chromium affect the morbidity and mortality of CHD. Decreasing sodium and increasing potassium intake improves control of hypertension. Calcium and magnesium may also have a role in controlling hypertension. The antioxidant vitamins A and beta-carotene, vitamin C, vitamin E, and the trace mineral selenium may protect against types of cancer. A decrease in simple carbohydrates and an increase in soluble dietary fiber may normalize moderately elevated blood glucose levels. Deficiencies of zinc or iron diminish immune function . Adequate levels of calcium and vitamin D can help prevent senile osteoporosis in both older men and women. (27 Refs.)

79. Effects of zinc deficiency on Th1 and Th2 cytokine shifts.

Prasad AS. Wayne State University, University Health Center, Detroit, MI 48201, USA. prasada@karmanos.org

J Infect Dis. 2000 Sep;182 Suppl 1:S62-8.

Nutritional deficiency of zinc is widespread throughout developing countries, and zinc-deficient persons have increased susceptibility to a variety of pathogens. Zinc deficiency in an experimental human model caused an imbalance between Th1 and Th2 functions. Production of interferon-gamma and interleukin (IL)-2 (products of Th1) were decreased, whereas production of IL-4, IL-6, and IL-10 (products of Th2) were not affected during zinc deficiency. Zinc deficiency decreased natural killer cell lytic activity and percentage of precursors of cytolytic T cells. In HuT-78, a Th0 cell line, zinc deficiency decreased gene expression of thymidine kinase, delayed cell cycle, and decreased cell growth. Gene expression of IL-2 and IL-2 receptors (both alpha and beta) and binding of NF-kappaB to DNA were decreased by zinc deficiency in HuT-78. Decreased production of IL-2 in zinc deficiency may be due to decreased activation of NF-kappaB and subsequent decreased gene expression of IL-2 and IL-2 receptors.

80. Zinc deficiency: changes in cytokine production and T-cell subpopulations in patients with head and neck cancer and in noncancer subjects.

Prasad AS; Beck FW; Grabowski SM; Kaplan J; Mathog RH Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI

Proc Assoc Am Physicians Jan 1997, 109 (1) p68-77

Cell-mediated immune dysfunctions and susceptibility to infections have been observed in zinc -deficient human subjects. In this study, we investigated the production of cytokines and characterized the T-cell subpopulations in three groups of mildly zinc -deficient subjects. These included head and neck cancer patients, healthy volunteers who were found to have a dietary deficiency of zinc, and healthy volunteers in whom we induced zinc deficiency experimentally by dietary means. We used cellular zinc criteria for the diagnosis of zinc deficiency. We assayed enzyme-linked immunosorbent assay the production of cytokines from phytohemagglutinin-stimulated peripheral blood mononuclear cells and assessed by flow cytometry the differences in T-cell subpopulations. Our studies showed that the cytokines produced by TH1 cells were particularly sensitive to zinc status, inasmuch as the production of interleukin-2 (IL-2) and interferon-gamma were decreased even though the deficiency of zinc was mild in our subjects. TH2 cytokines (IL-4, IL-5, and IL-6) were not affected by zinc deficiency. Natural killer cell lytic activity also was decreased in zinc -deficient subjects. Recruitment of naive T cells (CD4+CD45 RA+) and CD8+ CD73+ CD11b-, precursors of cytolytic T cells, were decreased in mildly zinc -deficient subjects. An imbalance between the functions of TH1 and TH2 cells and changes in T-cell subpopulations are most probably responsible for cell-mediated immune dysfunctions in zinc deficiency.

81. Zinc deficiency impairs immune responses against parasitic nematode infections at intestinal and systemic sites.

Scott ME, Koski KG. Institute of Parasitology, School of Dietetics and Human Nutrition, McGill University, Macdonald Campus, Ste-Anne de Bellevue, Quebec H9X 3V9, Canada.

J Nutr. 2000 May;130(5S Suppl):1412S-20S.

Research on the complex interactions among host nutritional status, parasitic infection and immune responsiveness has focused on the detrimental consequences of parasitic infections on host nutritional status and on mechanisms by which malnutrition impairs immunocompetence. Curiously, relatively few studies have examined the effects of malnutrition on the immune response in the parasite-infected host, and even fewer have considered the events occurring at the intestinal level, where absorption of nutrients occurs, intestinal parasites reside, and the gastrointestinal-associated lymphoid tissues play a role in directing both the local and the more systemic immune responses. Our work using a zinc-deficient nematode-infected mouse model reveals that parasites are better able to survive in the zinc-deficient hosts than in well-nourished hosts; that the production of interleukin-4 in the spleen of zinc-deficient mice is depressed, leading to depressed levels of IgE, IgG(1) and eosinophils; and that the function of T cells and antigen-presenting cells is impaired by zinc deficiency as well as by energy restriction. Given the paramount role of the gastrointestinal-associated lymphoid tissues in inducing and regulating immune responses to intestinal parasites and in orchestrating responses in the spleen and peripheral circulation, we conclude that zinc deficiency (in association with energy restriction) exerts profound effects on the gut mucosal immune system, leading to changes in systemically disseminated immune responses and, importantly, to prolonged parasite survival.

82. Zinc and immune function: the biological basis of altered resistance to infection.

Shankar AH; Prasad AS Department of International Health, The Johns Hopkins University School of Public Health, Baltimore, MD 21205, USA. ashankar@jhsph.edu

Am J Clin Nutr Aug 1998, 68 (2 Suppl) p447S-463S

Zinc is known to play a central role in the immune system, and zinc-deficient persons experience increased susceptibility to a variety of pathogens. The immunologic mechanisms whereby zinc modulates increased susceptibility to infection have been studied for several decades. It is clear that zinc affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. Zinc is crucial for normal development and function of cells mediating nonspecific immunity such as neutrophils and natural killer cells. Zinc deficiency also affects development of acquired immunity by preventing both the outgrowth and certain functions of T lymphocytes such as activation, Th1 cytokine production, and B lymphocyte help. Likewise, B lymphocyte development and antibody production, particularly immunoglobulin G, is compromised. The macrophage, a pivotal cell in many immunologic functions, is adversely affected by zinc deficiency, which can dysregulate intracellular killing, cytokine production, and phagocytosis. The effects of zinc on these key immunologic mediators is rooted in the myriad roles for zinc in basic cellular functions such as DNA replication, RNA transcription, cell division, and cell activation. Apoptosis is potentiated by zinc deficiency. Zinc also functions as an antioxidant and can stabilize membranes. This review explores these aspects of zinc biology of the immune system and attempts to provide a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation. (271Refs.) MACULAR

83. Risk factors for age-related macular degeneration: an update.

Hyman L, Neborsky R. Stony Brook University, Department of Preventive Medicine, Stony Brook, New York 11794-8036, USA. lhyman@notes.cc.sunysb.edu

Curr Opin Ophthalmol. 2002 Jun;13(3):171-5.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the United States and other western nations. Limited treatment is available, and there are no established means of prevention. The detection of modifiable risk factors is important to suggest preventive behaviors that can reduce disease occurrence or prevent the progression to the late stages of AMD. Results of recent studies suggest that the etiology and pathogenesis of AMD are a complex interaction of genetic and external factors. Although a number of factors seem promising, only age and cigarette smoking are confirmed as increasing AMD risk. Other factors that most likely play a significant role in AMD are nutritional factors, e.g., antioxidants, and hypertension or other underlying atherosclerotic disease processes. The results of the Age-Related Eye Disease Study suggest a moderate beneficial effect of antioxidant, vitamin, and zinc supplementation in reducing progression to severe AMD.

84. [Antioxidants and angiogenetic factor associated with age-related macular degeneration (exudative type)]

Ishihara N; Yuzawa M; Tamakoshi A Department of Ophthalmology, Nihon University School of Medicine, Tokyo, Japan.

Nippon Ganka Gakkai Zasshi (Japan) Mar 1997, 101 (3) p248-51

To confirm the hypothesis that antioxidants and angiogenetic factors may be associated with the development of age-related macular degeneration (exudative type), we compared serum levels of vitamins A, C, and E and carotinoid, zinc, selenium and b-FGF (basic-fibroblast growth factor) in 35 patients with age-related macular degeneration (exudative type) with the levels in 66 controls. The average serum zinc level was significantly lower in the patient group than in the control group. Serum vitamin E-alpha levels also tended to be lower. Most serum b-FGF levels were below the standard value in each group. Based on the above results, we conclude that subnormal levels of zinc and vitamin E may be associated with the development of age-related macular degeneration.

85. Nutrition in the elderly.

Morley JE, Mooradian AD, Silver AJ, Heber D, Alfin-Slater RB. Department of Medicine, University of California School of Medicine, Los Angeles.

Ann Intern Med. 1988 Dec 1;109(11):890-904.

Nutritional modulation is one approach to successful aging. In animals, dietary restriction increases life span. Alterations in the macronutrient and micronutrient constituent of the diet can modulate gene expression. Anorexia is common in elderly persons. The results of studies in animals suggest that aging is associated with a decrease in the opioid feeding drive and an increase in the satiating effect of cholecystokinin. Unrecognized depression is a common, treatable cause of anorexia and weight loss in elderly persons. Protein synthesis decreases in elderly persons; nevertheless, nitrogen balance can be maintained in patients with fairly low intakes of protein. Carbohydrate intolerance is common and may be modulated by nutritional intervention and physical activity. The role of cholesterol in the development of heart disease in very old persons is controversial. Homebound and institutionalized elderly persons often do not expose their skin to sunlight; because the skin of older persons has a decreased ability to form vitamin D, the vitamin D status in these persons is precarious and they are at risk for osteopenia. Vitamins are often abused by elderly persons. Drug administration alters the vitamin requirements of persons. Borderline zinc state has been associated with deteriorating immune function, especially in persons who have diabetes mellitus or who abuse alcohol. Zinc administration appears to protect against the deteriorating vision associated with age-related macular degeneration. Selenium deficiency seems to be associated with an increased prevalence of cancer.

OSTEOPOROSIS

86. Increased incidence of fractures in middle-aged and elderly men with low intakes of phosphorus and zinc.

Elmstahl S, Gullberg B, Janzon L, Johnell O, Elmstahl B. Department of Community Medicine, Lund University, Malmo, Sweden. solve.elmstahl@smi.mas.lu.se

Osteoporos Int. 1998;8(4):333-40.

The aim of the study was to determine dietary risk factors for fracture in men aged 46-68 years. Six thousand five hundred and seventy-six men were randomly invited using the Municipal Registry to a diet and health study. The diet was assessed using a combined 7-day menu book for hot meals, beverages and dietary supplements and a quantitative food frequency questionnaire for other foods. The fracture incidence was 103/10,000 person-years during a mean follow-up of 2.4 years. Zinc and phosphorus intake were associated with fracture risk and showed a threshold effect. The zinc intake in the lowest decentile, 10 mg daily, was associated with almost a doubled risk of fracture compared with the fourth and fifth quintiles (RR = 0.47; 95% confidence interval, 27-82) of zinc intake adjusted for energy, previous fractures, lifestyle factors and co-morbidity. Energy-adjusted phosphorus intake in the lowest quintile, mean level 1357 mg, was associated with an increased fracture risk compared with subjects in the second quintile. Smoking, martial status and physical activity were independently associated with fracture risk. Calcium, retinol and vitamin D showed no associations with fracture risk. We conclude that inadequate intakes of zinc and phosphorus are important risk factors for fracture.

PARKINSON’S DISEASE

87. Evidence of functional zinc deficiency in Parkinson's disease.

Forsleff L, Schauss AG, Bier ID, Stuart S. School of Community Health Service, Western Michigan University, Kalamazoo, USA.

J Altern Complement Med. 1999 Feb;5(1):57-64.

One of the primary areas of investigation in the pathophysiology of Parkinson's disease (PD) is the loss of the dopamine-producing cells in the melanized neurons of the substantia nigra, believed to be caused by oxidative stress resulting from excessive free radical activity. The cuprozinc enzyme, superoxide dismutase (SODCu2Zn2), catalyzes the dismutation of superoxide anions to hydrogen peroxide plus oxygen, and is normally found in high concentrations in the substantia nigra where it protects neurons by scavenging free radicals. Zinc supplementation has been shown to significantly increase SODCu2Zn2 in vitro. A novel oral zinc tally test (ZTT) used in the assessment of zinc status was administered to 100 PD patients and 25 controls. Patients with PD showed a significantly decreased zinc status as compared to controls (p < 0.001). Significance was also established for 3 self-reported health-related variables thought to be related to zinc status: vision problems, olfactory loss, and taste loss (p < 0.05). Relative risks for patients with PD for these variables were 1.51, 1.56, and 1.33, respectively. Zinc status as measured by the ZTT is negatively correlated with PD status. PD status is positively correlated with self-reported vision problems, and olfactory and taste loss. Further study of the role of zinc in the development and treatment of PD is warranted.

PROSTATE

88. Carcinogenicity of oral cadmium in the male Wistar (WF/NCr) rat: Effect of chronic dietary zinc deficiency Waalkes M.P.; Rehm S. Lab. of Comparative Carcinogenesis, NCI-FCRDC, Frederick, MD 21702-1201 USA Fundam. Aappl Toxicol. (USA), 1992, 19/4 (512-520) The effect of chronic dietary zinc deficiency on the carcinogenic potential of dietary cadmium was assessed in male Wistar (WF/NCr) rats. Groups (n = 28) of rats were fed diets adequate (60 ppm) or marginally deficient (7 ppm) in zinc and containing cadmium at various levels (0, 25, 50, 100, or 200 ppm). Lesions were assessed over the following 77 weeks. Zinc deficiency alone had no effect on survival, growth, or food consumption. Cadmium treatment did not reduce survival or food consumption and only at the highest doses of cadmium (100 and 200 ppm) was body weight reduced (maximum 17%). The incidence of prostatic proliferative lesions, both hyperplasias and adenomas, was increased over that seen in controls (1.8%) in both zinc-adequate (20%) and zinc-deficient rats (14%) fed 50 ppm cadmium. The overall incidence for prostatic lesions for all cadmium treatment groups was, however, much lower in zinc-deficient rats, possibly because of a marked increase in prostatic atrophy that was associated with reduced zinc intake. Cadmium treatment resulted in an elevated leukemia incidence (maximum 4.8-fold over control) in both zinc-adequate and zinc-deficient groups, although zinc deficiency reduced the potency of cadmium in this respect. Testicular tumors were significantly elevated only in rats receiving 200 ppm cadmium and diets adequate in zinc. Both zinc-deficient and zinc-adequate groups showed significant positive trends for development of testicular neoplasia with increasing cadmium dosage. Thus, oral cadmium exposure is clearly associated with tumors of the prostate, testes, and hematopoietic system in rats, while dietary zinc deficiency has complex, apparently inhibitory, effects on cadmium carcinogenesis by this route.

89. Zinc, vitamin A and prostatic cancer

Whelan P.; Walker B.E.; Kelleher J. Dep. Urol., St. James's Univ. Hosp., Leeds LS9 7TF United Kingdom

Br. J. Urol. (England), 1983, 55/5 (525-528)

The serum zinc, vitamin A, albumin, copper and retinoid-binding protein content was measured in 27 patients with benign prostatic hyperplasia and 19 patients with carcinoma of the prostate. A significantly lower (P = < 0.05) level of serum zinc was found in the cancer group as well as a significant zinc/vitamin A correlation (P = < 0.05). The possible significance of this in relation to the pathogenesis of carcinoma of the prostate is discussed.

SKIN AGING

90. Evidence supporting zinc as an important antioxidant for skin.

Rostan EF, DeBuys HV, Madey DL, Pinnell SR. Duke University, Durham, NC 27710, USA.

Int J Dermatol. 2002 Sep;41(9):606-11.

Antioxidants play a critical role in keeping skin healthy. The antioxidant benefits of vitamin C and E are well known, but the importance of the trace mineral, zinc, has been overlooked. This article reviews the evidence supporting zinc's antioxidant role in protecting against free radical-induced oxidative damage. Zinc protects against UV radiation, enhances wound healing, contributes to immune and neuropsychiatric functions, and decreases the relative risk of cancer and cardiovascular disease. All body tissues contain zinc; in skin, it is five to six times more concentrated in the epidermis than the dermis. Zinc is required for the normal growth, development and function of mammals. It is an essential element of more than 200 metalloenzymes, including the antioxidant enzyme, superoxide dismutase, and affects their conformity, stability, and activity. Zinc also is important for the proper functioning of the immune system, and for glandular, reproductive and cell health. Abundant evidence demonstrates the antioxidant role of zinc. Topical zinc, in the form of divalent zinc ions, has been reported to provide antioxidant photoprotection for skin. Two antioxidant mechanisms have been proposed for zinc: zinc ions may replace redox active molecules, such as iron and copper, at critical sites in cell membranes and proteins; alternatively, zinc ions may induce the synthesis of metallothionein, sulfhydryl-rich proteins that protect against free radicals. No matter how they work, topical zinc ions may provide an important and helpful antioxidant defense for skin.

Wound Healing

91. The role of zinc in wound healing.

Andrews M, Gallagher-Allred C. Geriatric and Long Term Care Services, Ross Products Division, Abbott Laboratories, Columbus, OH, USA.

Adv Wound Care 1999 Apr;12(3):137-8

Zinc deficiency has been associated with delayed wound healing. Because zinc deficiency may be common in the United States, foods rich in zinc, as well as all other essential nutrients, should be promoted in the diet of patients who are malnourished or at risk for malnutrition. Effects of exogenous zinc supplementation on intestinal epithelial repair in vitro. Cario E, Jung S, Harder D'Heureuse J, Schulte C, Sturm A, Wiedenmann B, Goebell H, Dignass AU. University of Essen, Essen, Germany; Charite Medical School-Campus Virchow, Berlin, Germany. Eur J Clin Invest 2000 May;30(5):419-28 BACKGROUND: Substitution of zinc modulates antioxidant capabilities within the intestinal mucosa and improves intestinal wound healing in zinc-deficient patients with inflammatory bowel diseases. The aim of this study was to characterize the modulating effects of zinc on intestinal epithelial cell function in vitro. MATERIALS AND METHODS: The effects of zinc on intestinal epithelial cell morphology were assessed by phase contrast and transmission electron microscopy using the non-transformed small intestinal epithelial cell line IEC-6. Zinc-induced apoptosis was assessed by DNA fragmentation analysis, lactate dehydrogluase (LDH) release and flow cytometry with propidium iodine staining. Furthermore, the effects of zinc on IEC-6 cell proliferation were assessed using a colorimetric thiazolyl blue (MTT) assay and on IEC-6 cell restitution using an in vitro wounding model. RESULTS: Physiological concentrations of zinc (25 microM) did not significantly alter the morphological appearance of IEC-6 cells. However, a 10-fold higher dose of zinc (250 microM) induced epithelial cell rounding, loss of adherence and apoptotic characteristics. While physiological zinc concentrations (< 100 microM) did not induce apoptosis, supraphysiological zinc concentrations (> 100 microM) caused apoptosis. Physiological concentrations of zinc (6.25-50 microM) had no significant effect on intestinal epithelial cell proliferation. In contrast, physiological concentrations of zinc (12.5-50 microM) significantly enhanced epithelial cell restitution through a transforming growth factor-beta (TGFbeta)-independent mechanism. Simultaneous addition of TGFbeta and zinc resulted in an additive stimulation of IEC-6 cell restitution. CONCLUSION: Zinc may promote intestinal epithelial wound healing by enhancement of epithelial cell restitution, the initial step of epithelial wound healing. Zinc supplementation may improve epithelial repair; however, excessive amounts