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Vitamin B12 absorption in some neurological and neuroendocrine disorders.

An assessment of vitamin B(12) absorption in neurological patients has been made by both serum and urine counting of (57)Co cyanocobalamin during the conventional Schilling test. Although patients with pernicious anaemia, some with subacute combined degeneration of the cord, have been studied, emphasis in the discussion is placed on the significantly increased excretion of the radioactive vitamin in a group of patients with pituitary insufficiency. Results are also given for epileptic patients who have developed folate deficiency (as assessed by serum folate levels) coincidental with anticonvulsant therapy, as well as for some patients who have had neurological symptoms or signs following partial gastrectomy operations.

Adult↗

Effect of folic acid by mouth on cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid concentration.

Administration of 30 mg folic acid by mouth caused a significant fall in cerebrospinal fluid homovanillic acid concentration in 11 subjects. There was no significant change of 5-hydroxyindoleacetic acid concentration. The fall was less marked in five patients on anticonvulsant medication and failed to reach statistical significance. Neither homovanillic acid nor 5-hydroxyindoleacetic acid concentrations changed significantly when 15 mg folic acid was given in divided dosage for one, two, and four weeks. The effect appeared to be related to the height of serum-folate levels reached and to be independent of cerebrospinal fluid-folate levels, which did not change significantly. Possible mechanisms and their potential therapeutic application are discussed.

Administration, Oral↗

The role of the polymorphic genes apolipoprotein E and methylene- tetrahydrofolate reductase in the development of dementia of the Alzheimer type.

The gene for apolipoprotein E (APOE) is polymorphic, and its variant APOE4 is a major risk factor for the development of Alzheimer-type dementia (AD). Another risk factor for AD appears to be negative cobalamin balance, which is very common in elderly people. Cobalamin and folate are interdependent and essential components of the one-carbon metabolism. Another important component is methylenetetrahydrofolate reductase (MTHFR), the gene for which is also polymorphic. Thermolabile MTHFR (tMTHFR), a gene variant that reduces the activity of its enzyme, is common in the general population. In the present study, 75% of 140 AD patients had at least one APOE4 allele. The numbers of APOE4 and tMTHFR alleles correlated significantly with the serum folate levels, however, in opposite directions. The significance of this was augmented by an inverse correlation between APOE4 and tMTHFR. Thus, not only MTHFR but also APOE appears to be related to the one-carbon metabolism, suggesting that APOE4 and insufficient one-carbon metabolism may be synergistic risk factors for AD.

Aged↗

Conversion of mild cognitive impairment to dementia: predictive role of mild cognitive impairment subtypes and vascular risk factors.

Mild cognitive impairment (MCI) is regarded as a precursor to dementia, but not all patients with MCI develop dementia. We followed up 165 elderly outpatients with MCI for a mean of 3 years. The aims were (1) to investigate the risk of conversion to dementia for different MCI subtypes diagnosed according to standardized criteria (amnestic; impairment of memory plus other cognitive domains; nonamnestic); (2) to assess whether the risk of conversion was affected by several established and emerging vascular risk factors. Forty-eight subjects (29%) converted to dementia, and the risk of conversion was doubled for amnestic MCI with respect to the other subtypes. Independently of MCI subtype, risk of conversion was associated with atrial fibrillation and low serum folate levels. Our results show that current diagnostic criteria for MCI define heterogeneous populations, but some potentially treatable vascular risk factors may be of help in predicting conversion to dementia.

Aged↗

Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients.

BACKGROUND: Dialysis patients have higher cardiovascular events rate than patients with normal renal function. Hyperhomocysteinemia, a risk factor for cardiovascular disease, is frequently detected in dialysis patients. Vitamin B supplementation lowers hyperhomocysteinemia, but it is unknown whether it reduces cardiovascular events rate. We planned a long-term study to analyze the effects of homocysteine-lowering vitamin B therapy on cardiovascular disease in hemodialysis patients. METHODS: We performed a single center open prospective trial. Patients, just on folate therapy at enrolment, were left out from randomization and maintained folate therapy according to study's protocol (group A). Patients, untreated with folic acid at recruitment, were randomly assigned to other 2 groups: patients submitted to folate supplementation according to study's protocol (group B), and untreated ones (group C). We instructed patients to take 5 mg oral daily folic acid or 5 mg every other day whether serum folate levels were up the normal high limit. We measured homocysteine, folate and vitamin B12 plasma levels at baseline and every 4 months. We chose the appearance of fatal and nonfatal cardiovascular events as end-points. RESULTS: We analyzed data of 114 patients for a median follow-up time of 871 days. Stepwise regression analysis demonstrated that baseline homocysteine levels were related to folate (coefficient: -1.02; F: 64.5), creatinine (coefficient: 0.98; F: 11.3), and C reactive protein (coefficient: -0.64; F: 4.3). Patients ended the study for the following reasons: cardiovascular morbidity (n = 44), death (n = 25), renal transplant (n = 9), moved away (n = 4). Cardiovascular events occurred in 58 of 114 patients (51%), in 26 of 63 (41%) treated patients (both group A and group B) and in 32 of 51 (63%; chi2 = 6.0; p = 0.05) untreated patients (group C). Kaplan-Meier survival analysis showed that cardiovascular events were less frequent in treated patients with low homocysteine levels (chi2 24.1; p < 0.0001). Cox regression analysis showed that cardiovascular events were explained by homocysteine, dialysis vintage, past cardiovascular accidents, and age. We noticed not only lower homocysteine levels, but also higher protein catabolic rate values in events-free patients as compared with patients with nonfatal cardiovascular events. After having divided patients into 4 subgroups according to high and low, split at median, Hcy and protein catabolic rate values, we observed in Kaplan-Meier survival curves for cardiovascular events by these subgroups that patients with low Hcy and high protein catabolic rate values showed a significant lower hazard rate than patients with high Hcy and low protein catabolic rate levels (chi2 = 21.7; p < 0.0001). CONCLUSIONS: This trial shows for the first time that homocysteine-lowering folate therapy decreases cardiovascular events in dialysis patients. It is necessary to perform large prospective studies to confirm our results.

Aged↗

Kinetics of the normal folate enterohepatic cycle.

Detailed studies were undertaken to better define the role of the liver and the folate enterohepatic cycle in folate homeostasis. Three isotopes of folate were employed in a rat model to study several parameters: (a) intestinal transport; (b) variation in hepatic uptake after different routes of administration; (c) hepatic reduction, methylation, and polyglutamate formation; (d) biliary excretion; (e) transport of folate to tissue and its return to liver for re-entry into the enterohepatic cycle. Folate absorption was not affected by the type of folate administered, but subsequent liver accumulation was greater when PteGlu(1) was given rather than CH(3)H(4)PteGlu(1). After liver uptake, CH(3)H(4)PteGlu(1) is rapidly and quantitatively excreted into bile, whereas nonmethylated folates are either methylated and transported into bile or incorporated into a hepatic polyglutamate pool. Bile folate is then reabsorbed for distribution to both tissue and liver, completing the enterohepatic cycle. The importance of this cycle was demonstrated by long-term bile drainage and by transport studies with two isotopes of CH(3)H(4)PteGlu(1). With bile drainage, serum folate levels fell to 30-40% of normal within 6 h, a much more dramatic drop than that seen with folate-free diets alone. Studies with labeled CH(3)H(4)PteGlu(1) demonstrated that about one-third was taken up by tissue, demethylated, and returned to liver for remethylation and recirculation through the bile and gut. This establishes the enterohepatic cycle as a major factor in folate homeostasis and, for the first time, demonstrates a transport pathway between tissue and liver for nonmethylated folate.

Animals↗

Metabolic studies of a family with massive formiminoglutamic aciduria.

We have described two siblings who excrete massive amounts (up to 3.89 mmol/24 hr) of N-formiminoglutamic acid (FIGLU) in their urine. This unusual compound was isolated from urine, purified, and firmly identified as FIGLU by combined gas chromatography-mass spectrometry. The patients presumably have a deficiency in activity of the hepatic enzyme, glutamate formiminotransferase, which carries out the fourth sequential step in the main pathway of histidine degradation. Unlike children reported previously with this disorder, our patients had normal serum folate levels, had no hematologic abnormalities, and were not mentally retarded. Very small amounts of FIGLU were present in the plasma of one of the patients, but FIGLU was not detectable in the cerebrospinal fluid of either patient. Administration of pharmacologic doses of folic or folinic acid produced a decrease in excretion of FIGLU in urine. Histidine loading caused a small and comparable urinary excretion of FIGLU in the children's parents and in control adult subjects.

Amino Acid Metabolism, Inborn Errors↗

Serum folate and chronic fatigue syndrome.

We assayed serum folate levels of 60 patients with chronic fatigue syndrome (CFS) and found that 50% had values below 3.0 micrograms/l. Some patients with CFS are deficient in folic acid.

Adolescent↗

Folate Status Following Gastric Bypass Surgery (The Great Folate Mystery).

Several previous investigators have reported an incidence of folic acid deficiency following gastric bypass surgery of up to 38%. Failure to encounter any folic acid deficiencies in our postoperative patients led us to discontinue follow-up folate studies for several years. However, due to repeated references to this deficiency in the literature, we re-instituted folate studies as part of the routine follow-up of our patients. Preoperative serum folate levels were obtained in 1,067 patients and preexisting deficiencies found in 63, an incidence of 6%. Of the 588 folate levels determined 1 to 10 years following gastric bypass, only six were less than 3.0 ng/di, an incidence of 1%. All patients were instructed preoperatively and postoperatively to take multivitamin/mineral supplements after gastric restrictive surgery, and were continually educated on their importance. In a bariatric surgery practice in which patients are instructed, reminded, encouraged and even badgered into taking postoperative vitamin/mineral supplements, folate deficiency should be a rarity. In such circumstances, folate deficiency may well act as a sensitive marker of non-compliance.

Journal Article↗

Intestinal absorption and biliary secretion of 5MTHF: effect of ethanol.

The aim of this work was to study intestinal absorption, using the whole intestine in vivo with 5-methyltetrahydrofolate (5MTHF), and the subsequent appearance of this compound in the bile, in control and in ethanol-fed rats. The ethanol-fed rats drank ethanol (5 to 30% vol/vol) in tap water for 5 wk. A consumption of 30% was maintained in this group for 20 additional weeks. The two groups of rats were cannulated at the beginning and at the end of the intestine. Three solutions containing 0.5, 1.0, and 2.5 microM of cold 5MTHF and 14C-methyltetrahydrofolic acid (0.01 microCi/mL) in each were perfused throughout the intestine at a flow rate of 4.5 mL/min. The absorption of folate was calculated from the difference between concentrations at the beginning and at the end of the perfusion. A decrease in 5MTHF uptake was observed at the concentration of 1.0 microM (p<0.05): however, folate absorption was not significantly modified at 0.5 and 2.5 microM in the perfusate. Serum folate levels were significantly lower in the ethanol-fed rat group. This fact could be due to a lower intake of folate in the diet and/or to the effect of alcohol on the intestinal absorption. The bile duct was isolated and cannulated with a polyethylene cathether. No significant differences were noted in the biliary folates between the control and the ethanol-fed rats.

Animals↗

[Folic acid intake of women in childbearing age].

An optimal maternal folate status reduces the risk of neural tube defects in the offspring. In the German National Health Interview and Examination Survey, red cell folate and serum folate levels have been measured in 1,266 women aged between 18 and 40 years. Applying the dietary assessment software DISHES 98 made it possible to estimate the individual folate intake. A high proportion of the participants showed sub-optimal red cell folate levels as well as folate intakes below the recommendations.

Adolescent↗

[Presentation of a case of hematological malignancy in reversed C.P.C].

We report a 68-year old male who was admitted to our hospital with the chief complaint of fatigue. Laboratory examinations revealed: 1) macrocytic anemia; 2) leukopenia; 3) reticulocytosis; 4) reduction in serum folate level; and 5) erythroid hyperplasia in bone marrow. One year later, the patient was admitted again to our hospital. At that time, laboratory data showed: 1) leukocytosis; 2) appearance of blast cells in peripheral blood; 3) normocytic anemia; 4) thrombocytopenia; and 5) predominant proliferation of blast cell(91%) in bone marrow. Blasts showed prominent nucleoli, markedly basophilic cytoplasma with vacuolation and some blebs on cell surface. The cells were negative for peroxidase stain but positive for PAS stain. We describe the evaluation of hematological laboratory data and the diagnosis in this patient.

Aged↗

Total folate binding capacity of normal human plasma, and variations in uremia, cirrhosis, and pregnancy.

The current study presents evidence that all human serum contains a class of high-affinity folate binders (KA=2.8 X10(10 liters/mole), which migrate as a single peak on gel filtration. Failure of previous studies to detect this characteristic in all but a minority of subjects is attributable to its variable, often total, saturation. Direct measurement of the total folate binding capacity (TFBC) has been made possible by dissociation of endogenous folate-binder complexes at acid pH, removal of free folate by coated charcoal, and radiofolate tagging. This procedure does not appear to significantly denature the binders, which release and rebind similar quantities of 3H-PGA. In 20 normal subjects, TFBC ranged from 100 to 325 pg/ml (mean+/-SE = 174+/-16), and was always at least 33% saturated. In three clinical conditions, all associated with elevated unsaturated folate binding capacity, three different patterns emerged when TFBC was also measured. Uremic subjects had significantly elevated mean TFBC with normal saturation. In cirrhotic subjects, mean TFBC approximated normal, but saturation was significantly decreased. In pregnancy, two groups were seen: one with increased TFBC and the other with a normal TFBC, some of whom had decreased saturation. Lactobacillus casei serum folate level was about 30 times greater than the TFBC; there was no correlation between the two measurements.

Adsorption↗

[Manifest and latent folic acid deficiency in the aged (author's transl)].

The serum folate level of 100 aged persons (after 70) was decreased (less than 4 ng/ml) in 41% of the cases (manifest deficiency of folic acid). In the group of aged persons having normal folate values, in 41% of the cases the clearance method proved a latent folic acid deficiency, being the 15 minute value after 15 gamma/kg folic acid i.v., less than 25 ng/ml.

Adult↗

[Treatable dementia syndromes].

Dementia--a syndrome of acquired intellectual deterioration--is an etiologically non-specific condition which is permanent, progressive, or reversible. In the evaluation of demented patients, a careful exposure history will determine the possible role of drugs, metals, or toxins. The physical examination may reveal focal deficits in cases of intracranial mass lesions and spasticity or ataxia of the lower limbs if hydrocephalus is present. Coexistance of dementia and peripheral neuropathy usually indicates a toxic or metabolic disorder. Asterixis, myoclonus, and postural tremor are common in toxic-metabolic dementias, while resting tremor, choreoathetosis, and rigidity occur in progressive extrapyramidal disorders. EEG is focally abnormal in cases of cerebral mass lesions and exhibits generalized slowing in toxic-metabolic encephalopathies. CT will aid in the identification of hydrocephalus, subdural hematomas, and intracranial mass lesions. A thorough laboratory evaluation including complete blood count, erythrocyte sedimentation rate, electrolytes, blood urea nitrogen and blood sugar, liver and thyroid tests, calcium and phosphorus levels, B12 and folate levels, serum copper and ceruloplasmin, VDRL, chest X-ray, electrocardiogram, and lumbar puncture may demonstrate treatable disorders that are adversely affecting intellectual function. Elderly individuals are particularly susceptible to the effects of toxic or metabolic disorders, and a mild dementia might be exaggerated by relatively minor fluctuations in metabolic status. Treatable causes of dementia should be considered in all demented patients.

Aged↗

Oral candidiasis--its pleomorphic clinical manifestations, diagnosis and treatment.

Up to 60% of the population carry Candida albicans as part of the oral flora without having evidence of candidiasis. The pleomorphic clinical manifestations of oral candidiasis viz. thrush, denture stomatitis, angular cheilitis, median rhomboid glossitis, speckled leukoplakia, and chronic mucocutaneous candidiasis and its variants are briefly discussed. Current diagnostic techniques of oral candidiasis (OC) are reviewed. A simple and quick method of helping the clinician in the diagnosis of OC by taking a direct smear of the lesion is emphasized. OC is a 'disease of the diseased'. As a routine a full blood picture, serum iron and serum folate levels should be looked at. Several predisposing causes of OC need to be investigated. An up-date on the treatment of OC with nystatin, amphotericin B lozenges, clotrimazole and miconazole is made.

Candidiasis, Oral↗