Oral zinc augmentation with vitamins A and D increases plasma zinc concentration: implications for burden of disease.

A study evaluating zinc supplementation in patients with Alzheimer's disease yielded variable zinc plasma levels in spite of positive cognitive and physiological results. In an attempt to raise and sustain plasma zinc levels, a single patient was given 15 mg zinc/day with various combinations of vitamins. A sustained raise in plasma zinc concentration (and therefore its potential bioavailability) was obtained only when the zinc was augmented with both vitamins A and D (in RDA concentrations). In order to verify these results, a follow-up study was conducted in 70 volunteers. Seven groups of 10 healthy subjects received various combinations of zinc and the two vitamins A and D, namely: zinc, vitamin A, vitamin D, zinc plus vitamin A, zinc plus vitamin D, vitamins A and D, and zinc plus vitamins A and D. Plasma zinc levels were determined at baseline, 3 weeks and 6 weeks. Plasma zinc levels increased significantly (p < 0.02) from 11.82 (+/-2.60) to 13.32 (+/-3.04) mum/L only in the group receiving the combination of zinc and vitamins A and D. This novel method of increasing plasma zinc levels by the augmentation of vitamins A and D may have implications for the reduction of burden of disease.

The effect of stress on the antioxidative potential of serum: implications for Alzheimer's disease.

There is growing consensus in the literature that oxidation status is increased in Alzheimer's disease (AD), and that antioxidant supplementation as prevention or treatment strategy should be investigated further. In the present study the total antioxidant status (TAS) was found to be highly significantly lower in 22 AD patients (p < 0.0001) than in 22 age- and gender matched non-demented controls. The TAS was also lower than controls in 22 patients with vascular dementia, but not significantly. The increased oxidation status in AD was verified using the benzoate hydroxylation method. The origin of the enhanced oxidation status in AD has not been elucidated. To determine whether a causal effect between stress and oxidative status of serum can be demonstrated, a rat model was used with two different kinds of stressors, swim stress (exercise) and restraint stress (non-exercise stress). Following swim stress the maximum oxidative effect was observed at one hour post stress (p < 0.001). At 24 h the oxidative status had recovered significantly to below control values. Restraint stress, however, showed progressively increased oxidation which attained significance after 24 h (p < 0.005). It is postulated that stress may contribute to the higher oxidation status in AD patients.

Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis.

UNLABELLED: Some subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient study suggest that iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites for this process are iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine iron status, folate and homocysteine in MS subjects, and to evaluate the effect on MS symptoms if deficiencies were addressed. RESULTS: In relapsing-remitting MS subjects, serum iron concentration correlated significantly with age at diagnosis (r=0.49; p=0.008). In Caucasian female MS subjects, serum iron and ferritin concentrations were significantly lower than in matched controls. In a 6-month pilot study, 12 subjects taking a regimen of nutritional supplements designed to promote myelin regeneration, improved significantly neurologically as measured by the Kurzke EDSS (Total Score means 3.50 to 2.45, 29.9%; p=0.021). These were significantly improved (p=0.002) compared to 6 control group patients taking multivitamins (Kurzke Score increased by 13.9% from 4.83 to 5.50). Both groups had significantly reduced homocysteine concentrations at 6 months, suggesting that methylation is necessary but not sufficient for myelin regeneration.

A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease.

This 12-week, multinational study compared the tolerability and cognitive effects of donepezil (up to 10 mg once daily) and rivastigmine (up to 6 mg twice daily) in 111 patients with mild to moderate Alzheimer's disease. Both medications were administered open label according to recommended dosing regimens from the respective product labelling available during the conduct of the study. More patients in the donepezil group (89.3%) completed the study compared with the rivastigmine group (69.1%; p=0.009), and 10.7% of the donepezil group and 21.8% of the rivastigmine group discontinued due to adverse events (AEs); 87.5% of donepezil-treated patients and 47.3% of rivastigmine-treated patients remained on the maximum approved dose of each drug at the last study visit. Both groups showed comparable improvements on the ADAS-cog administered by raters blind to study medication at weeks 4 and 12. Thus, using the recommended dosing schedules, donepezil was better tolerated with fewer discontinuations due to AEs, and both agents improved cognition to a similar extent.

Serum concentrations of some metals and steroids in patients with chronic fatigue syndrome with reference to neurological and cognitive abnormalities.

Chronic fatigue syndrome is defined by the Atlanta Centers for Disease Control (Atlanta, GA, USA) as debilitating fatigue lasting for longer than 6 months. Symptoms include disturbances of cognition. Certain factors have in the past been shown to influence cognition, including metals such as aluminum, iron, and zinc; and steroids such as dehydroepiandrosterone. In the present study, concentrations of these factors were determined in the serum and plasma of patients and their age- and gender-matched healthy controls (10 women and 5 men in each group). In addition, copper, dehydroepiandrosterone sulphate, cortisol, cholesterol, hemoglobin, ferritin and transferrin concentrations, as well as transferrin genetic subtypes were determined in both groups. The results indicate that patients had significantly increased serum aluminum and decreased iron compared to controls. In the females, serum iron and dehydroepiandrosterone sulphate were significantly decreased and correlated. Total cholesterol was significantly increased, and significantly negatively correlated with dehydroepiandrosterone sulphate. There were no differences in zinc, copper, cortisol, hemoglobin, transferrin and ferritin concentrations, or in transferrin genetic subtypes.

Earlier age of onset of Alzheimer's disease in patients with both the transferrin C2 and apolipoprotein E-epsilon 4 alleles.

The etiology of Alzheimer's disease is now known to be multifactorial. The genetic factors transferrin C2 (TfC2) and apolipoprotein E epsilon 4 (ApoE-epsilon 4) have both been associated with Alzheimer's disease (AD). Transferrin is the carrier protein for iron in the blood, while ApoE is involved with the transport and redistribution of lipids. In the present study, the polymerase chain reaction (PCR) method was used to determine the frequency of both TfC2 and ApoE-epsilon 4 in 27 AD patients, 9 vascular dementia (VaD) patients, and 27 controls. Patients were diagnosed according to the criteria as set out in the 4th edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV). The frequency of the TfC2 allele for the AD patients was 24%, while for the VaD patients it was 12.5%, which was not significantly different from the controls at 13%. The frequency of ApoE-epsilon 4 for the AD patients was 44%, for the VaD patients 22%, and controls 17%. Of the 27 AD patients, 8 had both TfC2 and ApoE-epsilon 4. The age of onset of the disease in these 8 patients (51-67 years, mean 60.25) was significantly earlier (p < 0.02) than in the remaining AD patients (49-76 years, mean 66.9). None of the VaD patients had both the TfC2 and the ApoE-epsilon 4 alleles.

Glycosylation of transferrin in Alzheimer's disease and alcohol-induced dementia.

Transferrin is a glycosylated metal-binding serum protein. Carbohydrate-deficient transferrin (CDT) is a marker of recent and heavy alcohol intake. A genetic variant of transferrin, TfC2, occurs with increased frequency in patients with Alzheimer's disease (AD). Hence the question arose whether, in addition to an altered amino acid sequence, there could also be a difference in the glycosylation state of transferrin in patients with dementia. Serum samples of 37 AD and 13 Alcohol-induced dementia patients as well as 10 healthy controls were analyzed for abnormal Tf variants, using isoelectric focusing followed by blotting with anti-Tf antibodies. This allowed the direct visualization of glycosylation variants of transferrin, and assessment of any increase in underglycosylated forms (di-, mono- and asialo transferrin).

A new model for the pathophysiology of Alzheimer's disease. Aluminium toxicity is exacerbated by hydrogen peroxide and attenuated by an amyloid protein fragment and melatonin.

OBJECTIVES: Although Alzheimer's disease (AD) is the leading cause of dementia in developed countries, there is an as yet unexplained lower prevalence of the disease in parts of Africa. AD is characterised by a catastrophic loss of neurons; free radicals (oxidative toxins) have been implicated in the destruction of the cells through the process of lipid peroxidative damage of cell membranes. Previously aluminium (Al) and a fragment of beta amyloid (A beta 25-35) were shown to exacerbate free-radical damage, while melatonin reduced this effect. The aim of the present study was: (i) to investigate the conditions determining the toxicity of Al and A beta 25-35; and (ii) to assess whether melatonin could attenuate the damage done by both aluminium and the amyloid fragment, thus suggesting a pathway for the aetiology of AD. DESIGN: An in vitro model system was used in which free radicals were generated, causing lipid peroxidation of platelet membranes, thus simulating the disease process found in the brain. RESULTS: 1. Al and A beta 25-35 caused lipid peroxidation in the presence of the iron (II) ion (Pe2+), Al being more toxic than A beta 25-35. 2. A beta 25-35 attenuated the lipid peroxidation promoted by Al. 3. Hydrogen peroxide (H2O2) greatly exacerbated the toxicity of Al and A beta 25-35. 4. Melatonin prevented lipid peroxidation by Al and A beta 25-35 in the absence of H2O2, but only reduced the process when H2O2 was present. CONCLUSIONS: In the light of the results obtained from the present study, the following hypotheses are formulated. 1. In AD, excessive quantities of Al are taken up into the brain, where the Al exacerbates iron-induced lipid peroxidation in the lysosomes. 2. In response, the normal synthetic pathway of amyloid protein is altered to produce A beta fragments which attenuate the toxicity of Al. In the process of sequestering the Al and iron, immature plaques are formed in the brain. 3. Microglia are activated, in an attempt to destroy the plaques by secreting reactive oxygen species such as H2O2. At this point in the disease process, lipid peroxidation causes a catastrophic loss of brain cells. 4. Melatonin, together with other free radical scavengers in the brain, reduces the free-radical damage caused by Al and A beta, except in the latter stages of the disease process. Since melatonin is produced by the pineal gland only in the dark, the excess of electric light in developed countries may help explain why AD is more prevalent in these countries than in rural Africa.

Zinc and platelet membrane microviscosity in Alzheimer's disease. The in vivo effect of zinc on platelet membranes and cognition.

OBJECTIVES: To investigate the effects of oral zinc supplementation on: (i) plasma zinc concentrations; (ii) platelet membrane microviscosity in vivo; and (iii) cognitive function of Alzheimer's disease (AD) patients. DESIGN: An open-labelled pilot study. SETTING: University of Stellenbosch Medical School and Stikland Hospital. SUBJECTS: Six volunteer AD patients. OUTCOME MEASURES: Plasma zinc levels, platelet membrane microviscosity and cognition (MMSE and ADAS-cog tests). RESULTS: Oral zinc supplementation (30 mg/day) did not increase plasma zinc levels significantly, but significantly increased platelet membrane microviscosity (P = 0.02; 6 patients). Four patients, who underwent 12 months of evaluation, showed modest cognitive improvement on psychometric testing (Mini-Mental State Examination and the cognitive portion of the Alzheimer's Disease Assessment scale scores). CONCLUSIONS: While earlier literature promoted the use of zinc in AD patients, a recent study has contradicted this and implicated zinc in the aetiology of Alzheimer's disease. On the basis of the above results, it may be premature to single out zinc as a causal agent in AD.

Transferrin C2 and Alzheimer's disease: another piece of the puzzle found?

A significant increase in the occurrence of the transferrin C2 genetic subtype has been found in patients with Alzheimer's disease. This variant has previously been linked to diseases thought to be associated with free radical damage. We hypothesize that Alzheimer's disease is caused by free radical damage to membranes of endocytic vesicles due to defective binding of iron and aluminium by Tf C2. The aluminium binds to the membranes, creating pores, while the iron reacts with H2O2 and superoxide radicals produced by activated microglia (brain phagocytes), to produce hydroxyl radicals (oxidative toxins), which attack the fatty acids in the membranes through these pores. In order to treat the disease successfully, it would be necessary to alleviate the multiple deficiencies caused by these toxins by constantly providing the cells with antioxidants and other essential nutrients. In addition, a drug that would stimulate the regrowth of neurons is needed.

Lipid peroxidation and platelet membrane fluidity--implications for Alzheimer's disease?

In humans, the fluidity of cell membranes generally decreases with age. Unexpectedly, several laboratories have found increased fluidity of platelet membranes (mainly endoplasmic reticulum) in patients with Alzheimer's disease (AD) compared with controls. In the present study, free radical induced lipid peroxidation was found to increase the fluidity of platelet membranes. Hydroxyl radicals were generated in the presence of Fe2+ and EDTA at low concentrations of ascorbate. It is hypothesised that platelet membranes are unable to restore their microviscosity by incorporating cholesterol. There may be a link between the result obtained in this study, the recently discovered decreased cholesterol content of affected AD neuronal membranes, and the increased frequency of epsilon 4 apolipoprotein E (a cholesterol carrier) found in AD patients.

Increased frequency of the transferrin C2 subtype in Alzheimer's disease.

Several genetic variants of transferrin can be separated by polyacrylamide gel isoelectric focusing. Studies by other workers have revealed that the genetic type Tf C2 has an increased frequency in certain malfunctions which are associated with the formation of free radicals, suggesting that the iron binding of Tf C2 promotes the formation of hydroxyl radicals. In our study population of 20 patients with Alzheimer's disease, 13 had the C2 genetic subtype. Since the frequency of C2 in the South African population is 0.136 (14%), this represents a significant increase (p < 0.005) in the appearance of this genetic subtype.

South African psychiatrists' attitudes to the present implementation of the Abortion and Sterilisation Act of 1975.

In 1980 and 1990 reports were published in the SAMJ on the attitudes of South African gynaecologists to the present Abortion and Sterilisation Act of 1975. The proportion of respondents favouring abortion on demand in the first trimester rose from 32% to 40% over this period, while that of respondents requesting a review of the Act increased from 71% to 85%. The Society of Psychiatrists of South Africa decided to conduct a similar survey of its members using the same questionnaire with some additional questions on current psychiatric practice. Of the 50% of psychiatrists who responded, 78% were personally involved in the implementation of the Act. Some 51% of psychiatrists supported termination on request before the 12th week of pregnancy, an equal number felt that the role of psychiatrists in the implementation of the Act should be reduced, and 89% considered that the present Abortion and Sterilisation Act requires review. Thus, many psychiatrists and gynaecologists are seeking a revision of existing legislation on the medical termination of pregnancy.

Membrane fluidity of platelets and erythrocytes in patients with Alzheimer's disease and the effect of small amounts of aluminium on platelet and erythrocyte membranes.

The membrane fluidity of platelet and erythrocyte membranes in 10 Alzheimer's disease patients and 9 age-matched controls was studied. The platelet membranes of patients with Alzheimer's disease were found to be significantly more fluid than those of controls (p less than 0.02). However, erythrocyte membranes of Alzheimer patients were less fluid (more viscous) than those of controls (p less than 0.05). On further investigation of platelet and erythrocyte membranes obtained from healthy volunteers, the fluidity was found to change with increasing aluminium concentrations. When aluminium ammonium sulphate (0.01-10 microM) was added to membrane suspensions, the fluidity of platelet membranes was increased, whereas the fluidity of erythrocyte membranes was decreased (i.e. the microviscosity was increased).