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ZINC



Table of Contents
image Effect of zinc supplementation in fracture healing
image A multicenter clinical trial. Zinc acexamate versus famotidine in the treatment of acute duodenal ulcer. Study Group of Zinc acexamate (new UP doses)
image Endogenous zinc concentrations in cysteamine-induced duodenal ulcers in the rat.
image Necrolytic migratory erythema and zinc deficiency
image Wound healing: The role of the mast cell as a zinc carrier
image Serum protein and zinc levels in patients with thoracic empyema
image Protection by zinc against UVA- and UVB-induced cellular and genomic damage in vivo and in vitro
image Prevention of the inhibitory effect of intraperitoneal 5-FU on intestinal anastomosis by zinc
image The management of lower-extremity ulcers with zinc-saline wet dressings versus normal saline wet dressings
image Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: Effects of an oral zinc supplementation
image Carcinogenicity of oral cadmium in the male Wistar (WF/NCr) rat: Effect of chronic dietary zinc deficiency
image Zinc, vitamin A and prostatic cancer
image The impact of zinc supplementation on Schistosoma mansoni reinfection rate and intensities: a randomized, controlled trial among rural Zimbabwean schoolchildren.
image Increased pancreatic metallothionein and glutathione levels: protecting against cerulein- and taurocholate-induced acute pancreatitis in rats.
image Zinc administration prevents wasting in stressed mice.
image Pathogenic mechanisms in familial amyotrophic lateral sclerosis due to mutation of Cu, Zn superoxide dismutase.
image Clinical evaluation of in-feed zinc bacitracin for the control of porcine intestinal adenomatosis in growing/fattening pigs.
image The role of metals in ischemia/reperfusion injury of the liver.
image Plasma copper, zinc and magnesium levels in patients with premenstrual tension syndrome
image The pineal and regulation of fibrosis: pinealectomy as a model of primary biliary cirrhosis: Roles of melatonin and prostaglandins in fibrosis and regulation of T lymphocytes
image Zinc, copper and magnesium concentration in serum and CSF of patients with neurological disorders
image Expression and regulation of brain metallothionein.
image Studies on the mechanism of early onset macular degeneration in c ynomolgus monkeys. II. Suppression of metallothionein synthesis in the retina in oxidative stress
image Association of zinc and antioxidant nutrients with age-related maculopathy.
image Oral zinc and the second eye in age-related macular degeneration.
image Zinc deficiency: Changes in cytokine production and T-cell subpopulations in patients with head and neck cancer and in noncancer subjects
image Immunotherapy of leprosy
image Immune and nutritional recovery of severely malnourished children
image Cellular and humoral immunity in rats after gestational zinc or magnesium deficiency
image Effects of short-term zinc supplementation on cellular immunity, respiratory symptoms, and growth of malnourished Equadorian children
image The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice.
image The pathogenesis of eclampsia: the 'magnesium ischaemia' hypothesis.
image Serum calcium, magnesium, copper and zinc and risk of cardiovascular death.
image [Evaluation of selected parameters of zinc metabolism in patients with primary hypertension]
image Antioxidant status and lipid peroxidation in patients infected with HIV
image Zinc in etiology of periodontal disease.
image ZINC AND SANGUINARIA
image Supplementation or loca1 application may reduce gingival exudate from inflammed and infected gums - which suggests improved tissue health. (Folate mouthwash appears to to be more effective than oral folate.)
image Evidence of a relationship between childhood-onset type I diabetes and low groundwater concentration of zinc
image Zinc lozenges reduce the duration of common cold symptoms
image The age-associated decline in immune function of healthy individuals is not related to changes in plasma concentrations of beta-carotene, retinol, alpha-tocopherol or zinc
image How does zinc modify the common cold? Clinical observations and implications regarding mechanisms of action
image Zinc for treating the common cold: review of all clinical trials since 1984.
image Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study [see comments]
image In vivo anti-influenza virus activity of a zinc finger peptide.
image Evaluation of zinc complexes on the replication of rhinovirus 2 in vitro.
image Zinc gluconate and the common cold: a controlled clinical study.
image Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges.
image Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study.
image Zinc in different tissues: Relation to age and local concentrations in cachexia, liver cirrhosis and long-term intensive care
image Effect of antioxidants on adriamycin-induced microsomal lipid peroxidation.
image The prevention and management of pressure ulcers
image Gastrointestinal infections in children
image Effect of topical zinc oxide on bacterial growth and inflammation in full-thickness skin wounds in normal and diabetic rats.
image Bronchial reactivity and dietary antioxidants
image Decreased Cu,Zn-SOD activity in asthmatic airway epithelium: Correction by inhaled corticosteroid in vivo
image Asthma but not smoking-related airflow limitation is associated with a high fat diet in men: Results from the population study 'Men born in 1914'
image Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, copper, and magnesium
image Trace elements in prognosis of myocardial infarction and sudden coronary death
image The biological significance of zinc
image [Deficiency of certain trace elements in children with hyperactivity]
image Antioxidant status of hypercholesterolemic patients treated with LDL apheresis
image The role of free radicals in disease
image Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide
image Alzheimers disease/alcohol dementia: Association with zinc deficiency and cerebral vitamin B12 deficiency
image Rationales for micronutrient supplementation in diabetes.

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Effect of zinc supplementation in fracture healing

INDIAN J. ORTHOP. (INDIA), 1980, 14/1 (62-71)

In the present experimental study, 36 rabbits were subjected to fracture of the of the fibula and were treated in 3 groups viz., Control group, Zinc sulphate supplemented group and Zinc sulphate vit. C. + Methandienone supplemented group. Each group consisted of 12 rabbits. After roentgenological, macroscopic and histological examination of healing of fractures of weekly intervals, it was concluded that the Zinc supplementation to an appreciable extent enhanced the process of bone healing which could be further hastened by addition of Vitamin C and Dianabol. No significant toxic or side effect of zinc supplementation was observed in any of the rabbits. A clinical trial of the same drugs was also conducted in patients with fractures of the shaft of the femur.



A multicenter clinical trial. Zinc acexamate versus famotidine in the treatment of acute duodenal ulcer. Study Group of Zinc acexamate (new UP doses)

Rev Esp Enferm Dig (SPAIN) Nov 1996, 88 (11) p757-62

A multicentric double-blind trial comparing 600 mg/d of Zinc Acexamate (ACZ) and 40 mg/d of Famotidine (FMT) in the short term treatment of acute duodenal ulcer included 199 patients, diagnosed by endoscopy. One-hundred and five patients received ACZ and 94 FMT, during four weeks. A clinical control took place at two weeks and a second clinical and endoscopic control at the end of the treatment (4 weeks). Complete cicatrization of the ulcer was observed in 56.5% of patients on ACZ and in 69.5% of patients of FMT (N.S.). A reduction of more than 50% of the ulcer diameter was recorded in 78.8% of the ACZ group and in 79.9% of the FMT group. Alcohol and smoking did not influence the results. Both treatments were equally effective in the disappearance of symptoms. The incidence of adverse reactions was very low in both groups (< 5%) and no patient dropped from the trial for this reason. In conclusion, a dosage of 600 mg/d of ACZ has ptors:



Endogenous zinc concentrations in cysteamine-induced duodenal ulcers in the rat.

Biometals (ENGLAND) Oct 1996, 9 (4) p371-5

Exogenously administered zinc compounds have been shown to possess anti-ulcer activity against a wide variety of ulcerogenic agents, both in laboratory animal models and in human peptic ulcer disease. However, a strong possibility exists that endogenous zinc may also play an important role during noxious events by various mechanisms. Therefore, the aim of this study was to focus on the changes of endogenous zinc serum and tissue concentrations in cysteamine-induced duodenal lesions. We used atomic absorption spectrophotometry to determine the tissue and serum concentrations of zinc in normal (control) rats and those with cysteamine-induced duodenal ulcers. The results obtained in this study indicated that the onset, development and spontaneous healing of ulcer lesions were associated with certain shifts in zinc serum and tissue concentrations. Prior to ulcer formation, a significant increase was noted in serum zinc values. With the onset of duodenal lesions, zinc serum concentrations significantly decreased, while there was a significant increase in duodenal tissue concentrations when compared to healthy control animals. Zinc tissue concentrations decreased and returned to starting values by the end of the first week of spontaneous healing. This decrease in zinc tissue concentration corresponded to the healing rate of the duodenal ulcers. Serum zinc concentrations also returned to starting values within the first week period. These observations indicate and confirm that zinc could play an important role in duodenal ulcer disease and represent a natural defense system in the body.



Necrolytic migratory erythema and zinc deficiency

British Journal of Dermatology (United Kingdom), 1997, 136/5 (783-785)

Necrolytic migratory erythema (NME) is an uncommon condition classically associated with high plasma levels of circulating glucagon and a glucagonoma. We report a patient with cirrhosis who showed clinical and histological features of NME. Investigation revealed normal glucagon levels without evidence of glc supplementation resulted in rapid and complete resolution of the eruption.



Wound healing: The role of the mast cell as a zinc carrier

Asian Journal of Surgery (Hongkong), 1997, 20/1 (42-46)

The role of mast cells in wound healing in a racial group of Proto Malay people living in Timor, Indonesia was studied. The relationship between fine scar formation after cleft lip reconstruction surgery, the growing evidence of micronutrient zinc deficiency in the region and an unusual number of mast cells distributed in the skin compared with a racial group of Deutero Malay people living in Malang, East Java, Indonesia was explored. It has been suggested that a possible role of mast cells, in a zinc deficient area, is that they accumulate zinc to compensate for the deficiency and to provide the necessary amount for better wound healing. Further investigations are still under way to give a more sound understanding of mast cells as zinc carriers.



Serum protein and zinc levels in patients with thoracic empyema

Biological Trace Element Research (USA), 1996, 54/2 (105-112)

The element Zn is the metal component or activator of many important enzymes. The tissue concentrations and activities of Zn metalloenzymes direct the rate of protein and nucleic acid syntheses, thereby influencing tissue growth and reparative processes. Most of the serum Zn is normally bound to circulating proteins. Low serum Zn concentrations might result from depletion of Zn-binding proteins. Serum protein and Zn concentrations have been reported to be depressed in patients with acute and chronic diseases. We compare the serum protein and Zn values of patients with thoracic empyema (n = 20) with those of a control group (n = 20). The values obtained in the empyema group were significantly lower than those in the control group before the study. Test group administered 220 mg zinc sulfate (ZnSO4. 7H2O) over 20 d and there was a significant increase in the values for serum protein and Zn after the oral administration of the zinc sulfate.



Protection by zinc against UVA- and UVB-induced cellular and genomic damage in vivo and in vitro

Biological Trace Element Research (USA), 1996, 53/1-3 (19-25)

For many years, zinc salts have been used both topically and orally to treat minor burns and abrasions as well as to enhance wound repair in man and animals. In this study we describe the protective effects of zinc against UV- induced genotoxicity in vitro and against sunburn cell formation in mouse skin in vivo. Cultured skin cells from neonatal mice showed a dramatic increase in the number of micronuclei as a result of UVA and UVB irradiation. Inclusion of zinc at 5 microg/mL in the medium significantly reduced the frequency of micronuclei and of micronucleated cells. In hairless mice, topical application of zinc chloride for 5 consecutive days or a single application 2 h prior to UV exposure reduced the number of sunburn cells in the epidermis as did application of zinc 1 h after exposure. Application 2 h after irradiation also tended to have a protective effect, although there was a large variation between animals. It is proposed that an influx of zinc can protect epidermal cells against some of the more delayed effects of UV-induced damage.



Prevention of the inhibitory effect of intraperitoneal 5-FU on intestinal anastomosis by zinc

Turkish Journal of Gastroenterology (Turkey), 1996, 7/1 (72-81)

Today adjuvant therapy using early postoperative intraperitoneal chemotherapy, is particularly appropriate treatment to prevent the local and regional recurrence in resectable colon cancers. Intraperitoneal 5-Fluorouracil (5-FU) is the most preferable agent for this purpose. The aim of this study is to determine the effect of Zn against the inhibitory effect of 5-FU on the healing of colonic anastomosis. In 5-FU treated group, average bursting pressure (p:0.048) and hydroxyproline levels were significantly decreased (p:0.015). In only Zn treated group, average bursting pressure was significantly increased (p:0.02) whereas hydroxyproline levels showed no correlation with the control group (p:0.560). In both 5-FU and Zn treated groups average bursting pressure had statistically significant correlation only with the 5-FU treated group (p:0.014). In this group hydroxyproline levels were increased as well (p:0.014). The histological observations showed that 5-FU impaired the healing of colonic anastomosis with the appearance of necrotic tissue at the anastomosis region. However the 5-FU and Zn groups appeared to be nearly completely epithelialized and also the number of fibroblasts were increased while necrotic ti much as in the 5-FU treated group. We conclude that Zn addition modulates healing of colonic anastomosis by counteracting the negative effect of 5-FU.



The management of lower-extremity ulcers with zinc-saline wet dressings versus normal saline wet dressings

Advances in Therapy (USA), 1996, 13/2 (88-94)

Zinc-saline wet dressings were compared to normal-saline wet dressings for the management of lower extremity ulcers in a pilot study of 28 elderly patients. Although both study groups were comparable at baseline, the data suggest that the use of zinc-saline wet dressings creates a wound environment that is associated with trends toward faster healing and enhanced rates of epithelialization, as well as significantly more efficient wound management than the normal-saline controls. These data are presented in light of the requirement for maintaining a moist, acidic environment within a wound in order to permit the best possible healing and remodeling.



Lipid peroxidation in insulin-dependent diabetic patients with early retina degenerative lesions: Effects of an oral zinc supplementation

European Journal of Clinical Nutrition (United Kingdom), 1995, 49/4 (282-288)

Design: Placebo for 3 months, followed by 30 mg/day zinc gluconate in identical capsules. Setting: Diabetic out patients clinic at the University Hospital, Grenoble. Subjects: Diabetic patients cared for type I diabetes mellitus. 22 patients began the study, 4 dropped out. 10 patients suffered of an early retinopathy, 8 patients had no retinopathy. Interventions: In this order: T0 biological measurements, 3 months placebo treatment, T1 biological measurements, 3 months zinc gluconate treatment, T2 biological measurements. Plasma Zn, Cu, Se, thiobarbituric acid reactants and antioxidant enzymes were measured (plasma and red glutathione peroxidase (Se-GPx), red cell superoxide dismutase (Cu-Zn-SOD)). Results: Lower plasma zinc level in the two groups. An increase in zinc level was observed and was more important in diabetic patients with no retinopathy (P = 0.05). The thiobarbituric acid reactants were above the reference values in all the patients, and were decreased at T2 (P < 0.05). Increase of GPx activity after zinc supplementation in patients with retinopathy. Conclusions: Zinc deficiency in insulin-dependent diabetic patients is corrected by a zinc supplementation. Moreover this supplementation decreases lipid peroxidation. The effects of zinc are different in diabetic patients with or without retinopathy. The increase in Se-GPx activity observed in patients with retinopathy could be linked to the protective effect of zinc on the protein itself.



Carcinogenicity of oral cadmium in the male Wistar (WF/NCr) rat: Effect of chronic dietary zinc deficiency

FUNDAM. APPL. 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.



Zinc, vitamin A and prostatic cancer

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.



The impact of zinc supplementation on Schistosoma mansoni reinfection rate and intensities: a randomized, controlled trial among rural Zimbabwean schoolchildren.

Friis H; Ndhlovu P; Mduluza T; Kaondera K; Sandstrom B; Michaelsen KF; Vennervald BJ; Christensen NO

Danish Bilharziasis Laboratory, Denmark.

Eur J Clin Nutr (ENGLAND) Jan 1997, 51 (1) p33-7

OBJECTIVES: To assess the effect of zinc supplementation on susceptibility to S. mansoni reinfections among schoolchildren. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING AND SUBJECTS: 313 rural Zimbabwean schoolchildren (144 boys and 169 girls), 11-17 y). INTERVENTIONS: Supplementation with zinc (or placebo on schooldays for 12 months. Due to drought, a food programme was in operation during the last eight months of the study. OUTCOME MEASURES: S. mansoni and S. haematobium reinfection rates and intensities. RESULTS: There was no difference in reinfection rates between the zinc and placebo groups (25 vs 29%, P = 0.46). However, the median intensity of S. mansoni reinfection, although low in both groups, was significantly lower in the zinc than in the placebo group (7 vs 13 eggs per gram of faeces, P = 0.048). No difference in either S. haematobium reinfection rates or intensities were seen. CONCLUSIONS: Zinc supplementation reduced the intensity of S. mansoni reinfections. Although the intensities of reinfection were very low, the finding probably reflects a biological effect of zinc that could be of public health importance in settings with higher transmission.



Increased pancreatic metallothionein and glutathione levels: protecting against cerulein- and taurocholate-induced acute pancreatitis in rats.

Wang ZH; Iguchi H; Ohshio G; Imamura T; Okada N; Tanaka T; Imamura M

First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.

Pancreas (UNITED STATES) Aug 1996, 13 (2) p173-83

Recent findings have suggested that oxygen-derived free radicals play an important role in the development and progression of acute pancreatitis. Therefore, the present study was designed to investigate whether metallothionein, a free radical scavenger, can protect against acute pancreatitis. Rats were injected intraperitoneally with zinc, followed by either an infusion of cerulein at 10 micrograms/kg for 4 h or a retrograde injection with 100 microliters/100 g body weight of 5% sodium taurocholate into the pancreaticobiliary duct, in order to induce acute pancreatitis. Zn administration significantly increased the levels of both metallothionein and reduced glutathione in the pancreas; the metallothionein levels reached a peak of 83-fold of normal levels after 24 h. The indications of acute pancreatitis, as well as the mortality, were improved by Zn treatment before the onset of acute pancreatitis. Immunohistochemical studies showed that metallothionein nd with strong staining around the periphery of the vacuoles in the group treated with both Zn and cerulein. These findings suggested that Zn increased both metallothionein and glutathione levels in the pancreas and exerted a beneficial effect against ceruleinor taurocholate-induced acute pancreatitis in rats.



Zinc administration prevents wasting in stressed mice.

Garcia Tamayo F; Terrazas Valdes LI; Malpica Lopez N

Departamento de Biologia, Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Mexico, D.F.

Arch Med Res (MEXICO) Autumn 1996, 27 (3) p319-25

Experimentally induced chronic stress can produce severe retardation on the physical development of young animals. Moreover, the chronic stress and its associated secondary malnutrition cause a variable depression on immunity, whose pathogenesis has been related to the excessive production of cytokines and glucocorticoids. When stressful stimuli are excessive, animals increment their anorexia and express a progressively installed wasting syndrome, associated with hypozincemia and susceptibility to infections with high mortality rate. In this work, chronically stressed mice were studied to observe the prophylactic effect of a zinc treatment on the evolution of both their malnutrition and their immune competence. Stress was induced in newborn Balb/c mice by intraperitoneal (IP) injections with heat-killed bacteria for 4 weeks. Following this inductive period, almost all the stressed mice showed a transient wasting syndrome characterized by anorexia, deficient gain of corporal weight, diarrhea, skin infection, reduced antibody response against antigens of red blood sheep cells, and a decreased proliferative response in their Con-A stimulated splenic lymphocytes. However, when the stressed mice received an additional IP treatment with zinc acetate, their clinical condition showed a significant improvement and their immunocompetence was similar to that exhhe control groups. The results suggest that zinc supplementation can ameliorate the effects of chronic stress on the growth, corporal weight, and immunocompetence of young mice.



Pathogenic mechanisms in familial amyotrophic lateral sclerosis due to mutation of Cu, Zn superoxide dismutase.

Gurney ME; Cutting FB; Zhai P; Andrus PK; Hall ED

Central Nervous System Diseases Research Unit, Upjohn Laboratories, Kalamazoo, MI 49001, USA.

Pathol Biol (Paris) (FRANCE) Jan 1996, 44 (1) p51-6

Oxidative mechanisms of damage have been implicated indirectly in the damage to brain tissue caused acutely by ischemia or chronically by neurodegenerative diseases. A direct link between pathogenesis and antioxidant enzyme systems has come from studies of a genetic form of amyotrophic lateral sclerosis (ALS). ALS causes the degeneration of motor neurons in cortex, brainstem and spinal cord with consequent progressive paralysis and death. The disease occurs in both sporadic and familial forms. Some 20% of kindreds in which ALS is inherited in an autosomal dominant fashion have mutations in the gene (SOD1) encoding Cu, Zn superoxide dismutase (SOD). Several SOD1 mutations have been shown by ourselves and others to cause motor neuron disease when expressed at high levels in transgenic mice, whereas transgenic mice expressing comparable amounts of wild-type human SOD do not show clinical disease. Thus, we have argued that motor neuron disease is caused by gain-of-function mutations in the human SOD1 gene. Our current experiments investigate the link between mutation of SOD1 and oxidative pathways of damage. (38 Refs.)



Clinical evaluation of in-feed zinc bacitracin for the control of porcine intestinal adenomatosis in growing/fattening pigs.

Kyriakis SC; Tsinas A; Lekkas S; Sarris K; Bourtzi-Hatzopoulou E

Clinic of Medicine, Faculty of Veterinary Medicine, University of Thessaloniki, Macedonia, Greece.

Vet Rec (ENGLAND) May 18 1996, 138 (20) p489-92

This field trial was designed to investigate whether the incorporation of zinc bacitracin into pig feed would prevent porcine intestinal adenomatosis. Two hundred-and-eighty-eight weaned pigs on a farm with a previous history of the disease were divided into 16 pens of 18 pi bacitracin were tested: from weaning up to 100 days of age, either 300 or 200 ppm zinc bacitracin were incorporated; from 100 to 125 days of age, either 200 or 100 ppm zinc bacitracin were added; and from 125 to 156 days of age (slaughter), either 100 or 50 ppm zinc bacitracin were added. The results were compared with a positive control group which received 60, 60 and 30 ppm salinomycin during the same periods, and with a negative control group which received no antibacterial and/or performance enhancer. The mortality, diarrhoea scores, average daily weight gains, average daily feed intakes and feed conversion ratios of the pigs were assessed. At slaughter, samples of ileum were taken from eight randomly selected pigs per group for bacteriological and histopathological examinations. The three treated groups all performed better than the control group, and the group receiving the high dose regimen of zinc bacitracin performed significantly better than the groups receiving the low dose of zinc bacitracin or salinomycin.



The role of metals in ischemia/reperfusion injury of the liver.

Arora AS; Gores GJ

Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.

Semin Liver Dis (UNITED STATES) Feb 1996, 16 (1) p31-8

Based on current information, we have described the role that metals play in potentiating and ameliorating liver I/R injury. To date, most of the data have focused on the deleterious effects of free iron in mediating I/R injury. Several therapeutic strategies have proven useful in animal models to counteract the effect of iron as a potentiator of I/R injury. These approaches have predominantly centered on the role of iron chelation using DFO and DFO conjugates. The data suggest that chelation of iron may prove useful in preventing I/R injury such as occurs in liver transplantation. Indeed, enough data are now available to initiate and support clinical trials (e.g., addition of DFO conjugates to explant storage solutions). The role of copper, however, is less well defined. Copper is important for the function of copper-zinc SOD. However, free copper may be as injurious as free iron. Further studies are needed to clarify the role of copper in I/R-induced hepatocellular necrosis. Selenium has a well-defined antioxidant role as part of GSH peroxidase (GSH antioxidant pathway). More recent data suggest that selenium may also act as an antioxidant through selenoprotein P, but the role of selenoprotein P in I/R injury remains to be defined. Finally, zinc appears to function as an antioxidant in less well-defined pathways. Further studies are needed to identify the fundamental mechanisms by which zinc may ameliorate oxidative damage during I/R injury. These data demonstrate that metals play a critical role in I/R injury of the liver and remain a fruitful area for investigation and development of therapeutic strategies. (65 Refs.)



Plasma copper, zinc and magnesium levels in patients with premenstrual tension syndrome

ACTA OBSTET. GYNECOL. SCAND. (Denmark), 1994, 73/6 (452-455)

We measured plasma Cu, Zn and Mg levels in 40 women suffering from premenstrual tension syndrome (PMTS) and in 20 control subjects by atomic absorption spectrophotometer. Mean plasma Cu, Zn and Mg levels, the Zn/Cu ratio were 80.2 plus or minus 6.00 microg/dl, 112.6 plus or minus 8.35 microg/dl, 0.70 plus or minus 0.18 mmol/l, and 1.40 plus or minus 0.10 in the PMTS group; and 77.0 plus or minus 4.50 microg/dl, 117.4 plus or minus 9.50 microg/dl, 0.87 plus or minus 0.10 mmol/l, and 1.51 plus or minus 0.05 in the control group respectively. The mean Mg level and the Zn/Cu ratio were significantly lower in PMTS patients than in the control group. Plasma Mg and Zn levels were diminished significantly during the luteal phase compared to the follicular phase in PMTS group. Mg deficiency may play a role in the etiology of PMTS.



The pineal and regulation of fibrosis: pinealectomy as a model of primary biliary cirrhosis: Roles of melatonin and prostaglandins in fibrosis and regulation of T lymphocytes

MED. HYPOTHESES (ENGLAND), 1979, 5/4 (403-414)

Pinealectomy leads to increased formation of fibrous tissue in the abdominal cavity, increased skin pigmentation and elevated cholesterol and alkaline phosphatase levels. It also leads to reduced formation and/or action of prostaglandin (PG) E1 and thromboxane (TX) A2. PGE1 plays an important role in enhancing function of T suppressor lymphocytes. In primary biliary cirrhosis there are increased skin pigmentation, hepatic fibrosis, elevated cholesterol and alkaline phosphatase levels, defective T lymphocytes and hyperactive B lymphocytes. Primary biliary cirrhosis may be a pineal deficiency disease. Serotonin is important in the pineal and the serotonin antagonist methysergide may cause retroperitoneal fibrosis by interfering with pineal function. These is a good deal of other evidence which suggests that melatonin PGE1 and TXA2 are important in the regulation of fibrosis in other situations such as 'collagen' diseases, lithium-induced fibrosis and cardiomyopathies. This suggests that enhancement of formation of PGE1 and of TXA2 may be of value in diseases associated with excess fibrosis and defective T suppressor cell function. PGE1 levels may be raised by zinc, penicillin, penicillamine and essential fatty acids. TXA2 levels may be raised by low dose colchicine. These new approaches to treatment may prove safer and more effective than existing ones. They may be of value in disorders such as cardiomyopathy, Hodgkin's disease and other lymphomas, multiple sclerosis, Crohn's disease, atopy and other diseases in which defective T cell function is suspected.



Zinc, copper and magnesium concentration in serum and CSF of patients with neurological disorders

ACTA NEUROL. SCAND. (Denmark), 1989, 79/5 (373-378)

Zinc (Zn), copper (Cu) and magnesium (Mg) concentrations in cerebrospinal fluid (CSF) and serum were determined with atomic absorption spectrophotometry in 74 patients suffering from various neurological diseases, and in 28 healthy controls. Increased CSF zinc levels were found in the group of peripheral nervous system diseases (P < 0.01) and in the cases of different neurological syndromes with increased CSF protein concentration (P < 0.001). Increased CSF and serum copper levels were found in the cases with increased CSF protein levels (P < 0.05). It is probable that damaged blood-brain-barrier (BBB) permits the passage of the trace elements Zn, Cu and of Mg into the subarachnoid space. Decreased serum Cu levels (P < 0.01) were found in the group of multiple sclerosis (MS). The findings are correlated to those of previous communications.



Expression and regulation of brain metallothionein.

Neurochem Int (ENGLAND) Jul 1995, 27 (1) p1-22

Many, but not all, zinc-containing neurons in the brain are a subclass of the glutamatergic neurons, and they are found predominantly in the telencephalon. These neurons store zinc in their presynaptic terminals and release it by a calcium-dependent mechanism. These "vesicular" pools of zinc are viewed as endogenous modulators of ligand- and voltage-gated ion channels. Metallothioneins (MTs) are low molecular weight zinc-binding proteins consisting of 25-30% cysteine, with no aromatic amino acids or disulfide bonds. The areas of the brain containing high contents of zinc such as the retina, the pineal gland, and the hippocampus synthesize unique isoforms of MT on a continuous basis. The four MT isoforms are thought to provide the neurons and glial elements with mechanisms to distribute, donate, and sequester zinc at presynaptic terminals; or buffer the excess zinc at synaptic junctions. In this cause, glutathione disulfide may participate in releasing zinc from MT. A similar nucleotide and amino acid sequence has made it difficult to obtain cDNA probes and antibodies capable of distinguishing indisputably among MT isoforms. MT-I and MT-II isoforms are found in the brain and in the peripheral tissues; MT-III isoform, possessing an additional seven amino acids, is expressed mostly in the brain and to a very minute extent in the intestine and pancreas; whereas MT-IV isoform is found in tissues containing stratified squamous epithelial cells. Since MTs are expressed in neurons that sequester zinc in their synaptic vesicles, the regulation of the expression of MT isoforms is extremely important in terms of maintaining the steady-state level of zinc and controlling redox potentials. The concentration of zinc has been shown to be altered in an extensive number of disorders of the central nervous system, including alcoholism. Alzheimer-type dementia, amyotrophic lateral sclerosis, Down's syndrome, epilepsy, Friedreich's ataxia, Guillaine-Barre syndrome, hepatic encephalopathy, multiple sclerosis, Parkinson's disease, Pick's disease, retinitis pigmentosa, retinal dystrophy, schizophrenia, and Wernicke-Korsakoff syndrome. The status of MT isoforms and other low molecular weight zinc-binding proteins in these conditions, diseases, disorders, or syndromes is being delineated at this time. Since several of these disorders, such as amyotrophic lateral sclerosis, are associated with oxidative stress, and since MT is able to prevent the formation of free radicals, it is believed that cytokine-induced induction of MT provides a long-lasting protection to avert oxidative damage.



Studies on the mechanism of early onset macular degeneration in c ynomolgus monkeys. II. Suppression of metallothionein synthesis in the retina in oxidative stress

Experimental Eye Research (United Kingdom), 1996, 62/4 (399-408)

Initial investigations done in this laboratory detected increased albumin and decreased glyceraldehyde 3-phosphate dehydrogenase concentrations in the retina of an animal model manifesting early onset macular degeneration. Both glyceraldehyde 3-phosphate dehydrogenase and albumin are markers of oxidative stress in cells. In this study, we used the same animal model to study further biochemical and physiological processes which may be involved in the pathogenesis of early onset macular degeneration in monkeys. We detected 60% lower catalase and glutathione peroxidase activities in the affected retinas suggesting lower antioxidant activities and oxidative stress. One of the consequences of oxidative stress is the production of metallothionein, a low molecular weight protein also induced by high concentrations of heavy metals such as zinc. Metallothionein was detected by RT-PCR in these monkey retinas. However initial quantitative PCR studies on this protein showed that the synthesis of metallothionein in affected retinas appears to be less than in normal controls. The affected retinas also showed a fourfold lower zinc concentration compared with the normal controls. No significant difference, however, could be detected in the zinc concentrations in plasma samples. Since induction of metallothionein synthesis is mediated by transcription factors which require heavy metals such as zinc for binding to specific sites in the DNA, the lowered zinc concentration may, thus, correlate with the lowered metallothionein expression. And since metallothionein is suggested to function as a free radical scavenger, the lowered metallothionein synthesis may consequently contribute to increased peroxidation reactions in the affected retinas. It appears therefore, that oxidative stress and the decreased metallothionein synthesis may be involved in the pathogenesis of early onset macular degeneration in this animal model.



Association of zinc and antioxidant nutrients with age-related maculopathy.

Arch Ophthalmol (UNITED STATES) Aug 1996, 114 (8) p991-7

OBJECTIVE: To quantify relationships between dietary intake of zinc and antioxidant nutrients and early and late age-related maculopathy (ARM). DESIGN: A retrospective longitudinal cohort design using data pertaining to diets in the past (1978-1980), which were assessed retrospectively using a food frequency questionnaire. SETTING: Beaver Dam, Wis. PATIENTS: A 50% random sample of free-living Beaver Dam Eye Study participants, 43 to 86 years of age (N = 1968). MAIN OUTCOME MEASURE: The presence of early and late ARM determined from fundus photography. RESULTS: People in the highest vs lowest quintiles for intake of zinc from foods had lower risk for early ARM (odds ratio = 0.6, 95% confidence interval, 0.4-1.0, P for trend < .05). This relationship appeared to be stronger for some types of early ARM (increased retinal pigment) than for others. Zinc intake was unrelated to late ARM. However, small numbers (n = 30) of people with this condition limit the ability to draw conclusions about this later stage. Levels of carotenoids were unrelated to early or late ARM. Odds for early ARM were lower in people in the highest vs lowest quintiles for the intake of vitamins C or E. However, these associations were not statistically significant. CONCLUSIONS: The data are weakly supportive of a protective effect of zinc on the development of some forms of early ARM. Prospective studies are needed to further evaluate the potential influence of these and other nutritional factors on different types and stages of age-related macular degeneration.



Oral zinc and the second eye in age-related macular degeneration.

Invest Ophthalmol Vis Sci (UNITED STATES) Jun 1996, 37 (7) p1225-35

PURPOSE. To investigate the short-term effect of oral zinc substitution on the development of age-related macular degeneration in the second eye of patients with an exudative form of the disease in the first eye. METHODS. A 2-year, double-masked, randomized, placebo-controlled study including 112 white patients with age-related macular degeneration and exudative lesions (choroidal neovascularization, pigment epithelial detachment, or both) in one eye and a visual acuity of better than 20/40 and macular degeneration without any exudative lesion in the second eye was performed. Patients received either 200 mg of oral zinc sulfate or placebo once daily for 24 months. The main outcome parameters were visual acuity, contrast sensitivity, color discrimination, and retinal grating acuity, as well as serum levels of zinc and copper, red blood cell count, hemoglobin, and morphologic changes detected by grading of monochrome fundus photographs and fluorescein angiograms. RESULTS. In the treatment group, the mean zinc serum level increased significantly (P < 0.0001) from 79 +/- 10 micrograms/dl to 108 +/- 26 micrograms/dl compared to no change (82 +/- 16 micrograms/dl to 85 +/- 10 micrograms/dl) in the placebo group. Serum levels of copper, hemoglobin, and red blood cell count did not change significantly in either group. A choroidal neovascular membrane (CNV) was detected in 14 patients during the treatment period (nine in the treatment group, five in the placebo group). Seven additional patients (three in the treatment group, four in the placebo group) experienced visual loss caused by CNV, and in two patients (one in each group), serous pigment epithelial detachment developed without angiographic evidence of CNV after the end of treatment, during a mean additional follow-up time of 20.8 +/- 8.2 months. In eyes in which exudative lesions did not develop, there was no significant change in any of the functional parameters during the 24-month treatment period, but there was a significant increase in the nonexudative alterations (drusen size, drusen confluence, hyperpigmentation, and focal degeneration of the retinal pigment epithelium) in both groups. CONCLUSIONS. Oral zinc substitution has no short-term effect on the course of age-related macular degeneration in patients who have an exudative form of the disease in one eye.



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

Proceedings of the Association of American Physicians (USA), 1997, 109/1 (68-77) 50X

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.



Immunotherapy of leprosy

Indian Journal of Leprosy (India), 1996, 68/4 (349-361)

Immunotherapy aims to modify the defective cell-mediated immune response in a section of leprosy cases. This presentation reviews the various immunomodulators developed/investigated for this purpose. Among the various mycobacterial agents, BCG, BCG + M. leprae, Mycobacterium w, ICRC bacillus and M. vaccae have been tried in leprosy patients and varying degrees of beneficial effects on bacterial killing and clearance have been observed. Studies carried out at CJIL, Agra and elsewhere suggest an important role for these mycobacteria as immunotherapeutic agents. Other mycobacteria - M. habana, M. phlei, M. gordonae - have also been reported to be promising experimentally. In addition, various drugs such as levamisole, zinc and RACA 854 have been observed to have immunomodulatory role in leprosy cases. Other promising immunomodulators include transfer factor, interferon gamma, interleukin 2 and acetoacetylated M. leprae. The progress achieved shows that immunotherapy may be considered as adjunct to chemotherapy to enhance bacterial killing as well as bacterial clearance and thus may be recommended to shorten the treatment period, especially in bacilliferous leprosy cases.



Immune and nutritional recovery of severely malnourished children

Cahiers Sante (France), 1996, 6/4 (201-208)

In developing countries, more than 123 million children die each year from the combined effects of malnutrition and infection. Malnourished children have impaired cellular immunity and are particularly sensitive to opportunistic infections. However, immune recovery has rarely been investigated during nutritional rehabilitation. Indeed, mortality remains high during renutrition, and relapses are frequent. We established a center in Cochabamba, Bolivia, specifically to save these children by treating both clinical and nutritional problems and restoring immune function. The CRIN (center for immuno-nutritional recovery) admits children with severe malnutrition from the Cochabamba suburban area. They are from low income families, in crowded living conditions with poor sanitation and are weaned early. Nutritional diagnosis was based on weight-for-height, arm to head circumference ratio and clinical examination for edema, loss of subcutaneous tissue and diminished muscle mass. The children were examined daily and first treated for respiratory and intestinal infections. Sociological and psychological aspects were also included in our holistic approach to treating severe malnutrition. Children received a four-stage diet lasting 2 months. During the initial phase (1 week) they were given an oil-sugar-mild based diet, with half lactose concentration, seven times a day. This supplied 1.5 to 2.5 g of protein and 120 to 150 kcal/kg of body weight, according to the PEM pattern. Protein and energy intake was then slowly increased during the transition phase (1 week). During the next, 'calorific-protein bombing' phase (6 weeks) 5 g of protein and 200 kcal/kg of body weight were given daily, such that there was sufficient energy for protein accumulation. During the last, discharge phase (1 week), the protein and energy contents were slowly decreased. Weight, height, arm and head circumferences, and triceps skin-fold thickness were measured weekly by standardized methods. Thymus size was assessed weekly by mediastinal ultrasound scanning with a portable scanner (ALOKA SSD-210 DXII, Tokyo) using a 5 MHz linear pediatric probe. Lymphocyte subpopulations in peripheral blood were investigated monthly using monoclonal antibodies. Compared to controls, the malnourished group had severe involution of the thymus, a significantly higher proportion of circulating immature T lymphocytes and a lower proportion of mature T lymphocytes. The two month longitudinal study showed that normal anthropometric values (90% NCHS weight for height) were recovered after one month of rehabilitation. However, immune recovery (thymic area of 350 mm2) required two months. This may explain the frequent relapses among malnourished children discharged after one month on the basis of 'apparent nutritional health'. Such children may remain immunodepressed, and should therefore be considered as high risk children. To test an immunostimulatory treatment, we designed a historical cohort study of malnourished children who received 2 mg of zinc per day. The children were matched for age, sex, anthropometric criteria and nutritional status with malnourished control children (treated previously without zinc). Anthropometric recovery was obtained in both groups in one month. Children receiving zinc attained immunological recovery within one month, whereas children not receiving zinc took two months. Thus zinc hastened immunological recovery concomitant with nutritional recovery such that the duration of hospitalization could be halved: after one month of this immuno-nutritional treatment, malnourished children appear to be sufficiently healthy to face their pathogenic home environment.



Cellular and humoral immunity in rats after gestational zinc or magnesium deficiency

Journal of Nutritional Biochemistry (USA), 1996, 7/6 (327-332)

The effects of gestational Mg or Zn deficiency on the humoral or cellular immunity of newborn rats were investigated. Mg deficiency was induced by feeding a diet containing 180 ppm Mg from day 0 to day 21 of gestation and Zn deficiency was induced by feeding a diet containing 1.5 ppm Zn from day 0 to day 19. Controls were fed a diet with 1,000 ppm Mg and 100 ppm Zn from day 0 to day 21. Thereafter, all maternal rats and newborns were fed diets with normal amounts of Mg or Zn. Three and six weeks after birth, T-cell subpopulations in blood and thymus and B-cells in blood of the newborns were detected by flow cytometry. Plasma contents of IgG, IgM, and IgA were determined by radial immunodiffusion. Mg deficiency reduced litter size and pup weight. Three weeks after birth, the total number of leukocytes and lymphocytes in blood was significantly decreased, due to a reduction of T-helper and cytotoxic T-cells. Activated T-cells and B-cells were unchanged. Six weeks after birth, T-cell subpopulations approached controls values, whereas IgG content in plasma was slightly reduced. Gestational Zn deficiency reduced litter size and induced malformations. Three and six weeks after birth, body weight, number of leukocytes, lymphocyte, and T-cell subpopulations were not significantly changed. Plasma IgM was decreased 3 weeks after birth in correlation to the number of B-cells, which represented only 4% of total lymphocytes. These effects were repaired by the sixth week. Plasma IgG was reduced at 6 weeks. No effects on T-cell subpopulations in isolated thymocytes were detected after gestational Mg or Zn deficiency.



Effects of short-term zinc supplementation on cellular immunity, respiratory symptoms, and growth of malnourished Equadorian children

European Journal of Clinical Nutrition (United Kingdom), 1996, 50/1 (42-46)

Objective: To assess the effect of zinc supplementation on respiratory tract disease, immunity and growth in malnourished children. Design: A randomized double-blind placebo-controlled trial. Setting: A day-care center in Quite, Ecuador. Subjects: Fifty children (12-59 months old) recruited by height-for-age and weight-for-age deficit. Interventions: Twenty-five children (supplemented, S group) received 10 mg/day of zinc as zinc sulfate, and 25 (nonsupplemented, NS group) received a placebo during 60 days. All were also observed during a 60-day postsupplementation period. Two children of the S group dropped out. Daily the clinical presence of cough, respiratory tract secretions, and fever, was recorded. On days 0, 60 and 120, the cutaneous delayed-type hypersensitivity (DTH) to multiple antigens, and anthropometric parameters were assessed. On days 0 and 60 serum zinc levels were also measured. Results: On day 60, DTH was significantly larger (20.8 plus or minus 7.1 vs 16.1 plus or minus 9.7 mm), and serum zinc levels were significantly higher (118.6 plus or minus 47.1 vs 83.1 plus or minus 24.5 microg/dl) in the S group than in the NS group (P < 0.05 for each). The incidence of fever (relative risk (RR): 0.30, c.i. = 0.08-0.95, P = 0.02), cough (RR): 0.52, c.i. = 0.32-0.84, P = 0.004) and upper respiratory tract secretions (RR):0.72, c.i. = 0.59-0.88, P = 0.001) was lower in the S group than in the NS group at day 60. At the end of the postsupplementation observation period (day 120), the incidence of fever and upper respiratory tract secretions was the same in both the S and NS groups. The incidence of cough was higher at day 120 in the S group than in the NS group (RR): 2.28, c.i. = 1.37-3.83, P = 0.001). Conclusions: This study supports a role for zinc in immunity, and immunity to respiratory infections, while pointing out the need for larger studies.



The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice.

J Neuroimmunol (NETHERLANDS) Sep 1994, 53 (2) p189-201

It has been demonstrated that melatonin, the main neuro-hormone of the pineal gland, affects thymic functions and the regulation of the immune system. In addition, experimental evidences indicate that melatonin can modulate zinc turnover. The knowledge that with advancing age both melatonin and zinc plasma levels decline, and that zinc supplementation in old mice is able to restore the reduced immunological functions, has prompted investigations on the effect of chronic melatonin treatment or pineal graft in old mice on the age-related decline of thymic endocrine activity, peripheral immune functions and zinc turnover. Both melatonin treatment in old mice and pineal graft into the thymus of old mice correct the reduced thymic endocrine activity and increase the weight of the thymus and its cellularity. A restoration of cortical thymic volume, as detected by the percentage of tissue in active proliferation, is also observed in old mice after both treatments. Thymocyte CD phenotype expression is also restored to young values. At peripheral level, recovery of peripheral blood lymphocyte number and of spleen cell subsets, with increased mitogen responsiveness also occurs. Melatonin treatment or pineal graft induce also a restoration of the altered zinc turnover in aged mice with an increment of the crude zinc balance from negative (-1.6 microgram/day/mouse) to positive value (+1.2 microgram/day/mouse), similar to that one of young mice (+1.4 microgram/day/mouse). The reduced zinc plasma level is restored to normal values. These findings support the idea that the effect of melatonin on thymic endocrine activity and peripheral immune functions may be mediated by the zinc pool.



The pathogenesis of eclampsia: the 'magnesium ischaemia' hypothesis.

Med Hypotheses (ENGLAND) Apr 1993, 40 (4) p250-6

'Magnesium ischaemia' is a term used to denote the functional impairment of the ATP-dependent sodium/potassium and calcium pumps in the cell membranes and within the cell itself. The production of ATP and the functioning of these pumps is magnesium-dependent and is critically sensitive to acidosis. Zinc and iron deficiencies may secondarily impair these pumps and thus contribute to 'magnesium ischaemia' (as does acidosis). This term is two-dimensional at its simplest; it refers to a functional magnesium deficiency, whether actual or induced. It is argued that chronic acidosis is the most common inducing factor. This simple hypothesis can begin to unify diverse pathophysiologies: some spontaneous abortions, aspects of Type II and gestational diabetes and the curious observation that heroin addicts become diabetic. It can also unify clinical thinking about pregnancy-induced hypertension, pre-eclampsia/eclampsia and acute fatty liver of pregnancy, as well as the coagulopathy of pregnancy. It makes important predictions about perinatal morbidity and suggests that early supplementation might prevent much pregnancy-induced disease.

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